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Find video protocols related to scientific articles indexed in Pubmed.
Therapy with boceprevir or telaprevir in HIV/hepatitis C virus co-infected patients to treat recurrence of hepatitis C virus infection after liver transplantation.
AIDS
PUBLISHED: 11-12-2014
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Severe hepatitis C virus (HCV) recurrence affects post-transplant survival in HIV/HCV co-infected patients. This article describes the results of triple anti-HCV therapy with boceprevir or telaprevir in seven HIV/HCV co-infected patients following liver transplantation.
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Intrafamilial variability of ZRS-Associated syndrome: Characterisation of a mosaic ZRS mutation by pyrosequencing.
Clin. Genet.
PUBLISHED: 08-05-2014
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During limb development, the spatio-temporal expression of sonic hedgehog (SHH) is driven by the Zone of polarising activity Regulatory Sequence (ZRS), located 1 megabase upstream from SHH. Gain-of-function mutations of this enhancer, which cause ectopic expression of SHH, are known to be responsible for congenital limb malformations with variable expressivity, ranging from preaxial polydactyly or triphalangeal thumbs to polysyndactyly, which may also be associated with mesomelic deficiency. In this report, we describe a patient affected with mirror-image polydactyly of the four extremities and bilateral tibial deficiency. The proband's father had isolated preaxial polydactyly type II (PPD2). Using Sanger sequencing, a ZRS point mutation (NC_000007.14?g.156584153A>G, UCSC, Build hg.19) was only identified in the patient. However, pyrosequencing analysis enabled the detection of a 10% somatic mosaic in the blood and saliva from the father. To our knowledge, this is the first description of a ZRS mosaic mutation. This report highlights the complexity of genotype-phenotype correlation in ZRS-associated syndromes and the importance of detecting somatic mosaicism for accurate genetic counselling.
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The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation.
Nat. Genet.
PUBLISHED: 06-17-2014
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Centrioles are microtubule-based, barrel-shaped structures that initiate the assembly of centrosomes and cilia. How centriole length is precisely set remains elusive. The microcephaly protein CPAP (also known as MCPH6) promotes procentriole growth, whereas the oral-facial-digital (OFD) syndrome protein OFD1 represses centriole elongation. Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene. Concordant with the clinical overlap, C2CD3 colocalizes with OFD1 at the distal end of centrioles, and C2CD3 physically associates with OFD1. However, whereas OFD1 deletion leads to centriole hyperelongation, loss of C2CD3 results in short centrioles without subdistal and distal appendages. Because C2CD3 overexpression triggers centriole hyperelongation and OFD1 antagonizes this activity, we propose that C2CD3 directly promotes centriole elongation and that OFD1 acts as a negative regulator of C2CD3. Our results identify regulation of centriole length as an emerging pathogenic mechanism in ciliopathies.
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Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
Eur. J. Hum. Genet.
PUBLISHED: 05-29-2014
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6q16 deletions have been described in patients with a Prader-Willi-like (PWS-like) phenotype. Recent studies have shown that certain rare single-minded 1 (SIM1) loss-of-function variants were associated with a high intra-familial risk for obesity with or without features of PWS-like syndrome. Although SIM1 seems to have a key role in the phenotype of patients carrying 6q16 deletions, some data support a contribution of other genes, such as GRIK2, to explain associated behavioural problems. We describe 15 new patients in whom de novo 6q16 deletions were characterised by comparative genomic hybridisation or single-nucleotide polymorphism (SNP) array analysis, including the first patient with fetopathological data. This fetus showed dysmorphic facial features, cerebellar and cerebral migration defects with neuronal heterotopias, and fusion of brain nuclei. The size of the deletion in the 14 living patients ranged from 1.73 to 7.84?Mb, and the fetus had the largest deletion (14?Mb). Genotype-phenotype correlations confirmed the major role for SIM1 haploinsufficiency in obesity and the PWS-like phenotype. Nevertheless, only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency. This study in the largest series reported to date confirms that the PWS-like phenotype is strongly linked to 6q16.2q16.3 deletions and varies considerably in its clinical expression. The possible involvement of other genes in the 6q16.2q16.3-deletion phenotype is discussed.European Journal of Human Genetics advance online publication, 5 November 2014; doi:10.1038/ejhg.2014.230.
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Brief Report: Involvement of TNFRSF11A molecular defects in autoinflammatory disorders.
PUBLISHED: 05-22-2014
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Autoinflammatory disorders are caused by a primary dysfunction of the innate immune system. Among these disorders are hereditary recurrent fevers, which are characterized by recurrent episodes of fever and inflammatory manifestations affecting multiple tissues. Hereditary recurrent fevers often lack objective diagnostic criteria, thereby hampering the identification of disease-causing genes. This study was undertaken to identify a gene responsible for hereditary recurrent fevers.
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Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity.
Genet. Med.
PUBLISHED: 05-13-2014
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Purpose:Submicroscopic deletions of chromosome band 2p25.3 are associated with intellectual disability and/or central obesity. Although MYT1L is believed to be a critical gene responsible for intellectual disability, so far no unequivocal data have confirmed this hypothesis.Methods:In this study we evaluated a cohort of 22 patients (15 sporadic patients and two families) with a 2p25.3 aberration to further refine the clinical phenotype and to delineate the role of MYT1L in intellectual disability and obesity. In addition, myt1l spatiotemporal expression in zebrafish embryos was analyzed by quantitative polymerase chain reaction and whole-mount in situ hybridization.Results:Complete MYT1L deletion, intragenic deletion, or duplication was observed in all sporadic patients, in addition to two patients with a de novo point mutation in MYT1L. The familial cases comprise a 6-Mb deletion in a father and his three children and a 5' MYT1L overlapping duplication in a father and his two children. Expression analysis in zebrafish embryos shows specific myt1l expression in the developing brain.Conclusion:Our data strongly strengthen the hypothesis that MYT1L is the causal gene for the observed syndromal intellectual disability. Moreover, because 17 patients present with obesity/overweight, haploinsufficiency of MYT1L might predispose to weight problems with childhood onset.Genet Med advance online publication 18 September 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.124.
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Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma.
Eur. J. Hum. Genet.
PUBLISHED: 05-06-2014
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SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor gene involved in the tumorigenesis of a spectrum of solid cancers. Heterozygous SASH1 variants are known to cause autosomal-dominant dyschromatosis. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous Moroccan family with two affected siblings presenting an unclassified phenotype associating an abnormal pigmentation pattern (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), alopecia, palmoplantar keratoderma, ungueal dystrophy and recurrent spinocellular carcinoma. We identified a homozygous variant in SASH1 (c.1849G>A; p.Glu617Lys) in both affected individuals. Wound-healing assay showed that the patient's fibroblasts were better able than control fibroblasts to migrate. Following the identification of SASH1 heterozygous variants in dyschromatosis, we used reverse phenotyping to show that autosomal-recessive variants of this gene could be responsible for an overlapping but more complex phenotype that affected skin appendages. SASH1 should be added to the list of genes responsible for autosomal-dominant and -recessive genodermatosis, with no phenotype in heterozygous patients in the recessive form, and to the list of genes responsible for a predisposition to skin cancer.European Journal of Human Genetics advance online publication, 15 October 2014; doi:10.1038/ejhg.2014.213.
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Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
PLoS Genet.
PUBLISHED: 05-01-2014
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The Hedgehog (Hh) family of secreted proteins act as morphogens to control embryonic patterning and development in a variety of organ systems. Post-translational covalent attachment of cholesterol and palmitate to Hh proteins are critical for multimerization and long range signaling potency. However, the biological impact of lipid modifications on Hh ligand distribution and signal reception in humans remains unclear. In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (HHAT) gene. This mutation occurred in the conserved membrane bound O-acyltransferase (MBOAT) domain and experimentally disrupted the ability of HHAT to palmitoylate Hh proteins such as DHH and SHH. Consistent with the patient phenotype, HHAT was found to be expressed in the somatic cells of both XX and XY gonads at the time of sex determination, and Hhat loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans. In the developing testis, HHAT is not required for Sertoli cell commitment but plays a role in proper testis cord formation and the differentiation of fetal Leydig cells. Altogether, these results shed new light on the mechanisms of action of Hh proteins. Furthermore, they provide the first clinical evidence of the essential role played by lipid modification of Hh proteins in human testicular organogenesis and embryonic development.
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Mutations in SLC13A5 cause autosomal-recessive epileptic encephalopathy with seizure onset in the first days of life.
Am. J. Hum. Genet.
PUBLISHED: 04-09-2014
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Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy.
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Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.
Eur. J. Hum. Genet.
PUBLISHED: 04-05-2014
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Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode ?- and ?-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancer-predisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity.European Journal of Human Genetics advance online publication, 23 July 2014; doi:10.1038/ejhg.2014.95.
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Delineation of the 3p14.1p13 microdeletion associated with syndromic distal limb contractures.
Am. J. Med. Genet. A
PUBLISHED: 04-01-2014
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Distal limb contractures (DLC) represent a heterogeneous clinical and genetic condition. Overall, 20-25% of the DLC are caused by mutations in genes encoding the muscle contractile apparatus. Large interstitial deletions of the 3p have already been diagnosed by standard chromosomal analysis, but not associated with a specific phenotype. We report on four patients with syndromic DLC presenting with a de novo 3p14.1p13 microdeletion. The clinical features associated multiple contractures, feeding problems, developmental delay, and intellectual disability. Facial dysmorphism was constant with low-set posteriorly rotated ears and blepharophimosis. Review of previously reported cases with a precise mapping of the deletions, documented a 250?kb smallest region of overlap (SRO) necessary for DLC. This region contained one gene, EIF4E3, the first three exons of the FOXP1 gene, and an intronic enhancer of FOXP1 named hs1149. Sanger sequencing and locus quantification of hs1149, EIF4E3, and FOXP1 in a cohort of 11 French patients affected by DLC appeared normal. In conclusion, we delineate a new microdeletion syndrome involving the 3p14.1p13 locus and associated with DLC and severe developmental delay. © 2014 Wiley Periodicals, Inc.
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New candidate loci identified by array-CGH in a cohort of 100 children presenting with syndromic obesity.
Am. J. Med. Genet. A
PUBLISHED: 03-31-2014
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Syndromic obesity is defined by the association of obesity with one or more feature(s) including developmental delay, dysmorphic traits, and/or congenital malformations. Over 25 syndromic forms of obesity have been identified. However, most cases remain of unknown etiology. The aim of this study was to identify new candidate loci associated with syndromic obesity to find new candidate genes and to better understand molecular mechanisms involved in this pathology. We performed oligonucleotide microarray-based comparative genomic hybridization in a cohort of 100 children presenting with syndromic obesity of unknown etiology, after exhaustive clinical, biological, and molecular studies. Chromosomal copy number variations were detected in 42% of the children in our cohort, with 23% of patients with potentially pathogenic copy number variants. Our results support that chromosomal rearrangements are frequently associated with syndromic obesity with a variety of contributory genes having relevance to either obesity or developmental delay. A list of inherited or apparently de novo duplications and deletions including their enclosed genes and not previously linked to syndromic obesity was established. Proteins encoded by several of these genes are involved in lipid metabolism (ACOXL, MSMO1, MVD, and PDZK1) linked with nervous system function (BDH1 and LINGO2), neutral lipid storage (PLIN2), energy homeostasis and metabolic processes (CDH13, CNTNAP2, CPPED1, NDUFA4, PTGS2, and SOCS6).
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Further delineation of eye manifestations in homozygous 15q13.3 microdeletions including TRPM1: a differential diagnosis of ceroid lipofuscinosis.
Am. J. Med. Genet. A
PUBLISHED: 03-25-2014
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The 15q13.3 heterozygous microdeletion is a fairly common microdeletion syndrome with marked clinical variability and incomplete penetrance. The average size of the deletion, which comprises six genes including CHRNA7, is 1.5 Mb. CHRNA7 has been identified as the gene responsible for the neurological phenotype in this microdeletion syndrome. Only seven patients with a homozygous microdeletion that includes at least CHRNA7, and is inherited from both parents have been described in the literature. The aim of this study was to further describe the distinctive eye manifestations from the analysis in the three French patients diagnosed with the classical 1.5 Mb homozygous microdeletion. Patients' ages ranged from 30 months to 9 years, and included one sib pair. They all displayed a remarkably severe identifiable clinical phenotype that included congenital blindness and convulsive encephalopathy with inconstant abnormal movements. The ophthalmological examination revealed a lack of eye tracking, optic nerve pallor, an immature response with increased latencies with no response to the checkerboard stimulations at the visual evoked potential examination, and a distinctive retina dystrophy with a negative electroretinogram in which the "b" wave was smaller than the "a" wave after a dark adapted pupil and bright flash in all patients. Clear genotype-phenotype correlations emerged, showing that this eye phenotype was secondary to homozygous deletion of TRPM1, the gene responsible for autosomal recessive congenital stationary night blindness. The main differential diagnosis is ceroid lipofuscinosis.
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De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome.
Nat. Genet.
PUBLISHED: 03-12-2014
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Activating mutations in genes encoding phosphatidylinositol 3-kinase (PI3K)-AKT pathway components cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH, OMIM 603387). Here we report that individuals with MPPH lacking upstream PI3K-AKT pathway mutations carry de novo mutations in CCND2 (encoding cyclin D2) that are clustered around a residue that can be phosphorylated by glycogen synthase kinase 3? (GSK-3?). Mutant CCND2 was resistant to proteasomal degradation in vitro compared to wild-type CCND2. The PI3K-AKT pathway modulates GSK-3? activity, and cells from individuals with PIK3CA, PIK3R2 or AKT3 mutations showed similar CCND2 accumulation. CCND2 was expressed at higher levels in brains of mouse embryos expressing activated AKT3. In utero electroporation of mutant CCND2 into embryonic mouse brains produced more proliferating transfected progenitors and a smaller fraction of progenitors exiting the cell cycle compared to cells electroporated with wild-type CCND2. These observations suggest that cyclin D2 stabilization, caused by CCND2 mutation or PI3K-AKT activation, is a unifying mechanism in PI3K-AKT-related megalencephaly syndromes.
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Blepharophimosis, short humeri, developmental delay and hirschsprung disease: expanding the phenotypic spectrum of MED12 mutations.
Am. J. Med. Genet. A
PUBLISHED: 02-23-2014
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We report on two male sibs, a fetus and a newborn, with short humeri and dysmorphic facial features including blepharophimosis. The newborn also had Hirschsprung disease. Goldberg-Shprintzen syndrome and the Say-Barber-Biesecker-Young-Simpson type of Ohdo syndrome were suspected but direct sequencing of KBP and KAT6B failed to identify a mutation. Finally, direct sequencing of MED12, the gene mutated in Opitz-Kaveggia syndrome, Lujan-Fryns syndrome and X-linked Ohdo syndrome identified in the two sibs the missense mutation c.3443G>A (p.Arg1148His) inherited from the mother. This report further expands the phenotypic spectrum of MED12 mutations.
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Cetuximab increases concentrations of irinotecan and of its active metabolite SN-38 in plasma and tumour of human colorectal carcinoma-bearing mice.
Fundam Clin Pharmacol
PUBLISHED: 02-17-2014
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In a previous study, we showed that cetuximab, a monoclonal antibody directed towards epidermal growth factor receptor, could inhibit P-glycoprotein (P-gp), an efflux protein of ATP-binding cassette family, and lead to an increased P-gp substrate intracellular concentration. Cetuximab is given with irinotecan to patients with metastasis colorectal cancer who did not respond to irinotecan-based therapy. The mechanism of this successful clinical reversion remains unknown. As irinotecan is a P-gp substrate, we tested here whether cetuximab could modify irinotecan concentration in mice. Therefore, concentrations of irinotecan and of its active metabolite SN-38 were measured by HPLC in plasma and tumour of mice bearing a human colorectal carcinoma xenograft when irinotecan is given orally alone or after a pretreatment with cetuximab. Pharmacokinetic analysis showed no significant modification of irinotecan concentrations but a significant increase (1.7-fold) in SN-38 AUCs in plasma and in tumour after a pretreatment with cetuximab. Those results suggest that cetuximab influence irinotecan distribution into tissues probably due to inhibition of P-gp. As SN-38 is 200-fold more potent than irinotecan, cetuximab could reverse irinotecan resistance by an effect on its active metabolite. Inhibiting SN-38 efflux by P-gp drug transporters in biliary system and tumour can lead to pharmacokinetic modification and a higher anticancer efficacy.
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New insights into genotype-phenotype correlation for GLI3 mutations.
Eur. J. Hum. Genet.
PUBLISHED: 01-20-2014
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The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype-phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype-phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.European Journal of Human Genetics advance online publication, 16 April 2014; doi:10.1038/ejhg.2014.62.
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The Revised Ghent Nosology; Reclassifying Isolated Ectopia Lentis.
Clin. Genet.
PUBLISHED: 01-17-2014
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Inherited ectopia lentis (EL) is most commonly caused by Marfan syndrome (MFS), a multisystemic disorder caused by mutations in FBN1. Historically the diagnosis for patients with EL who have no systemic features of MFS is isolated ectopia lentis (IEL). However, the Ghent nosology for MFS was updated in 2010 and made some important alterations. In particular, patients with EL and a FBN1 mutation are now categorically diagnosed with MFS, if their mutation has previously been described with aortic dilation/dissection. This carries significant systemic implications, as many patients previously diagnosed with IEL are now reclassified. We provide a review of all published cases of IEL caused by FBN1 mutations over the last twenty years to assess what impact the new Ghent nosology has on these. Indeed, 57/123 probands (46.3%) are now classified as MFS according to the revised Ghent nosology and 37/96 mutations (38.5%) reported to cause isolated EL have also been found in patients with aortic dilation/dissection. These findings suggest that EL caused by mutations in FBN1 is actually part of a spectrum of fibrillinopathies with MFS, and the term "isolated ectopia lentis" should be avoided in such cases.
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Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.
Nat. Genet.
PUBLISHED: 01-01-2014
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The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.
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Cohen syndrome is associated with major glycosylation defects.
Hum. Mol. Genet.
PUBLISHED: 12-13-2013
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Cohen syndrome (CS) is a rare autosomal recessive disorder with multisytemic clinical features due to mutations in the VPS13B gene, which has recently been described encoding a mandatory membrane protein involved in Golgi integrity. As the Golgi complex is the place where glycosylation of newly synthesized proteins occurs, we hypothesized that VPS13B deficiency, responsible of Golgi apparatus disturbance, could lead to glycosylation defects and/or mysfunction of this organelle, and thus be a cause of the main clinical manifestations of CS. The glycosylation status of CS serum proteins showed a very unusual pattern of glycosylation characterized by a significant accumulation of agalactosylated fucosylated structures as well as asialylated fucosylated structures demonstrating a major defect of glycan maturation in CS. However, CS transferrin and ?1-AT profiles, two liver derived proteins, were normal. We also showed that ICAM-1 and LAMP-2, two highly glycosylated cellular proteins, presented an altered migration profile on SDS-polyacrylamide gels in peripheral blood mononuclear cells (PBMCs) from CS patients. RNA interference against VPS13B confirmed these glycosylation defects. Experiments with Brefeldin A demonstrated that intracellular retrograde cell trafficking was normal in CS fibroblasts. Furthermore, early endosomes were almost absent in these cells and lysosomes were abnormally enlarged, suggesting a crucial role of VPS13B in endosomal-lysosomal trafficking. Our work provides evidence that CS is associated to a tissue-specific major defect of glycosylation and endosomal-lysosomal trafficking defect, suggesting that this could be a new key element to decipher the mechanisms of CS physiopathology.
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Neuropsychological and neuroimaging phenotype induced by a CAMTA1 mutation.
Brain Dev.
PUBLISHED: 09-26-2013
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Background/Aims: CAMTA1 mutations have recently been reported in families with intellectual disability and/or non-progressive congenital ataxias. The objective of this study was to describe the neuropsychological and neuroimaging phenotype of CAMTA1 mutation. Methods: We performed neuropsychological examinations, MRI and FDG-PET imaging in three patients with autosomal dominant mild intellectual disabilities and ataxia induced by a CAMTA1 intragenic deletion at 1p36.31p36.23. Results: Neuropsychological tests showed similar findings in two patients, with low information processing speed, slow memory consolidation, phonological disorders, working memory deficits, but mainly preserved executive function. Bilateral parietal and medial temporal abnormalities were found on brain MRI. Diffuse parieto-occipital and local left temporo-parietal decrease of FDG uptake was observed on PET images. Conclusion: These results suggest that CAMTA1 mutation may induce an unusual neuropsychological profile and parieto-temporal developmental abnormalities. We recommend screening for CAMTA1 mutations in patients with autosomal dominant mild intellectual disability presenting with similar a phenotype.
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Successful anti-hepatitis C virus therapy with telaprevir in an HIV/hepatitis C virus co-infected patient with a severe recurrence of hepatitis C virus infection on the liver graft.
AIDS
PUBLISHED: 08-14-2013
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We report, for the first time, the outcome of anti-hepatitis C virus (HCV) triple therapy with telaprevir in an HIV/HCV co-infected transplanted patient. After liver transplantation, the patient experienced a severe HCV recurrence with fibrosing cholestatic hepatitis, and anti-HCV therapy with pegylated interferon alpha 2a, ribavirin and telaprevir was initiated. A sustained virological response was achieved after 48 weeks of anti-HCV therapy. Drug-drug interactions between antiretroviral therapy, immunosuppressive agents and anti-HCV therapy could be managed.
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Mutations in FAM111B Cause Hereditary Fibrosing Poikiloderma with Tendon Contracture, Myopathy, and Pulmonary Fibrosis.
Am. J. Hum. Genet.
PUBLISHED: 07-31-2013
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Congenital poikiloderma is characterized by a combination of mottled pigmentation, telangiectasia, and epidermal atrophy in the first few months of life. We have previously described a South African European-descent family affected by a rare autosomal-dominant form of hereditary fibrosing poikiloderma accompanied by tendon contracture, myopathy, and pulmonary fibrosis. Here, we report the identification of causative mutations in FAM111B by whole-exome sequencing. In total, three FAM111B missense mutations were identified in five kindreds of different ethnic backgrounds. The mutation segregated with the disease in one large pedigree, and mutations were de novo in two other pedigrees. All three mutations were absent from public databases and were not observed on Sanger sequencing of 388 ethnically matched control subjects. The three single-nucleotide mutations code for amino acid changes that are clustered within a putative trypsin-like cysteine/serine peptidase domain of FAM111B. These findings provide evidence of the involvement of FAM111B in congenital poikiloderma and multisystem fibrosis.
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C5orf42 is the major gene responsible for OFD syndrome type VI.
Hum. Genet.
PUBLISHED: 07-23-2013
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Oral-facial-digital syndrome type VI (OFD VI) is a recessive ciliopathy defined by two diagnostic criteria: molar tooth sign (MTS) and one or more of the following: (1) tongue hamartoma (s) and/or additional frenula and/or upper lip notch; (2) mesoaxial polydactyly of one or more hands or feet; (3) hypothalamic hamartoma. Because of the MTS, OFD VI belongs to the "Joubert syndrome related disorders". Its genetic aetiology remains largely unknown although mutations in the TMEM216 gene, responsible for Joubert (JBS2) and Meckel-Gruber (MKS2) syndromes, have been reported in two OFD VI patients. To explore the molecular cause(s) of OFD VI syndrome, we used an exome sequencing strategy in six unrelated families followed by Sanger sequencing. We identified a total of 14 novel mutations in the C5orf42 gene in 9/11 families with positive OFD VI diagnostic criteria including a severe fetal case with microphthalmia, cerebellar hypoplasia, corpus callosum agenesis, polydactyly and skeletal dysplasia. C5orf42 mutations have already been reported in Joubert syndrome confirming that OFD VI and JBS are allelic disorders, thus enhancing our knowledge of the complex, highly heterogeneous nature of ciliopathies.
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Finger creases lend a hand in Kabuki syndrome.
Eur J Med Genet
PUBLISHED: 05-21-2013
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Kabuki syndrome (KS) is a rare syndrome associating malformations with intellectual deficiency and numerous visceral, orthopedic, endocrinological, immune and autoimmune complications. The early establishment of a diagnostic of KS leads to better care of the patients and therefore prevents complications such as perception deafness, severe complications of auto-immune diseases or obesity. However, the diagnosis of KS remains difficult because based on the appreciation of facial features combined with other highly variable features. We describe a novel sign, namely the attenuation and/or congenital absence of the IPD crease of the third and fourth fingers associated with limitation of flexion of the corresponding joints, which seems to be specific of KS and could help the clinician to diagnose KS.
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20 ans après: a second mutation in MAOA identified by targeted high-throughput sequencing in a family with altered behavior and cognition.
Eur. J. Hum. Genet.
PUBLISHED: 05-13-2013
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Intellectual disability (ID) is characterized by an extraordinary genetic heterogeneity, with >250 genes that have been implicated in monogenic forms of ID. Because this complexity precluded systematic testing for mutations and because clinical features are often non-specific, for some of these genes only few cases or families have been unambiguously documented. It is the case of the X-linked gene encoding monoamine oxidase A (MAOA), for which only one nonsense mutation has been identified in Brunner syndrome, characterized in a single family by mild non-dysmorphic ID and impulsive, violent and aggressive behaviors. We have performed targeted high-throughput sequencing of 220 genes, including MAOA, in patients with undiagnosed ID. We identified a c.797_798delinsTT (p.C266F) missense mutation in MAOA in a boy with autism spectrum disorder, attention deficit and autoaggressive behavior. Two maternal uncles carry the mutation and have severe ID, with a history of maltreatment in early childhood. This novel missense mutation decreases MAOA enzymatic activity, leading to abnormal levels of urinary monoamines. The identification of this new point mutation confirms, for the first time since 1993, the monogenic implication of the MAOA gene in ID of various degrees, autism and behavioral disturbances. The variable expressivity of the mutation observed in male patients of this family may involve gene-environment interactions, and the identification of a perturbation in monoamine metabolism should be taken into account when prescribing psychoactive drugs in such patients.European Journal of Human Genetics advance online publication, 30 October 2013; doi:10.1038/ejhg.2013.243.
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Congenital neutropenia with retinopathy, a new phenotype without intellectual deficiency or obesity secondary to VPS13B mutations.
Am. J. Med. Genet. A
PUBLISHED: 05-07-2013
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Over one hundred VPS13B mutations are reported in Cohen syndrome (CS). Most cases exhibit a homogeneous phenotype that includes intellectual deficiency (ID), microcephaly, facial dysmorphism, slender extremities, truncal obesity, progressive chorioretinal dystrophy, and neutropenia. We report on a patient carrying two VPS13B splicing mutations with an atypical phenotype that included microcephaly, retinopathy, and congenital neutropenia, but neither obesity nor ID. RNA analysis of the IVS34+2T_+3AinsT mutation did not reveal any abnormal splice fragments but mRNA quantification showed a significant decrease in VPS13B expression. RNA sequencing analysis up- and downstream from the IVS57+2T>C mutation showed abnormal splice isoforms. In contrast to patients with typical CS, who express only abnormal VPS13B mRNA and truncated protein, a dose effect of residual normal VPS13B protein possibly explains the incomplete phenotype in the patient. This observation emphasizes that VPS13B analysis should be performed in cases of congenital neutropenia associated with retinopathy, even in the absence of ID, therefore extending the VPS13B phenotype spectrum. © 2013 Wiley Periodicals, Inc.
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The identification of MAFB mutations in eight patients with multicentric carpo-tarsal osteolysis supports genetic homogeneity but clinical variability.
Am. J. Med. Genet. A
PUBLISHED: 04-29-2013
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Multicentric carpo-tarsal osteolysis (MCTO) with or without nephropathy is a rare osteolysis disorder beginning in early childhood and involving mainly carpal and tarsal bones. Renal disease appears later in life in the majority of cases and evolves quickly to end stage renal failure. Autosomal dominant (AD) inheritance has been demonstrated, with a high frequency of sporadic cases. Recently, mutations in a highly conserved region of the MAFB gene (v-maf musculoaponeurotic fibrosarcoma oncogene ortholog B) have been identified in MCTO patients by exome sequencing. MafB, known as a regulator of various developmental processes, is essential for osteoclastogenesis and renal development. We report here the molecular screening of MAFB in eight MCTO patients from six families. We identified MAFB mutations in all, including three novel missense mutations clustering within the hot spot mutation region. Among the eight patients, six only presented renal disease. Our report confirms the genetic homogeneity of MCTO and provides data underlying the clinical variability of this disorder. © 2013 Wiley Periodicals, Inc.
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Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene.
Eur. J. Hum. Genet.
PUBLISHED: 04-22-2013
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Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846delCT, p.Asn615Lysfs*6) and a missense mutation (c.7802A>G, p.Tyr2601Cys). The diagnosis of FA was confirmed by the chromosomal analysis of lymphocytes. Reverse transcriptase (RT)-PCR analysis revealed that the c.7802A>G BRCA2 variation was in fact a splicing mutation that creates an aberrant splicing donor site and results partly into an aberrant transcript encoding a truncated protein (p.Tyr2601Trpfs*46). The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A>G in the patients harbouring the biallelic FANCD1/BRCA2 mutations. Although this report is based in a single family, it suggests that CRCs may be part of the tumour spectrum associated with FANCD1/BRCA2 biallelic mutations and that the presence of such mutations should be considered in families with CRCs, even in the absence of cardinal features of FA.European Journal of Human Genetics advance online publication, 4 December 2013; doi:10.1038/ejhg.2013.278.
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Expanding the clinical phenotype of patients with a ZDHHC9 mutation.
Am. J. Med. Genet. A
PUBLISHED: 04-19-2013
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In 2007, 250 families with X-linked intellectual disability (XLID) were screened for mutations in genes on the X-chromosome, and in 4 of these families, mutations in the ZDHHC9 gene were identified. The ID was either isolated or associated with a marfanoid habitus. ZDHHC9 encodes a palmitoyl transferase that catalyzes the posttranslational modification of NRAS and HRAS. Since this first description, no additional patient with a ZDHHC9 mutation has been reported in the literature. Here, we describe a large family in which we identified a novel pathogenic ZDHHC9 nonsense mutation (p.Arg298*) by parallel sequencing of all X-chromosome exons. The mutation cosegregated with the clinical phenotype in this family. An 18-year-old patient and his 40-year-old maternal uncle were evaluated. Clinical examination showed normal growth parameters, lingual fasciculation, limited extension of the elbows and metacarpophalangeal joints, and acrocyanosis. There was neither facial dysmorphism nor marfanoid habitus. Brain MRI detected a dysplastic corpus callosum. Neuropsychological testing showed mild intellectual disability. They both displayed generalized anxiety disorder, and the younger patient also suffered from significant behavior impairment that required attention or treatment. Speech evaluation detected satisfactory spoken language since both were able to provide information and to understand conversations of everyday life. Occupational therapy examination showed impaired visual-spatial and visual-motor performance with poor drawing/graphic skills. These manifestations are not specific enough to guide ZDHHC9 screening in patients with ID, and emphasize the value of next generation sequencing for making a molecular diagnosis and genetic counseling in families with XLID. © 2013 Wiley Periodicals, Inc.
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Phenotypic spectrum of Simpson-Golabi-Behmel syndrome in a series of 42 cases with a mutation in GPC3 and review of the literature.
Am J Med Genet C Semin Med Genet
PUBLISHED: 04-18-2013
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Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked multiple congenital abnormality/intellectual disability syndrome characterized by pre- and post-natal overgrowth, distinctive craniofacial features, macrocephaly, variable congenital malformations, organomegaly, increased risk of tumor and mild/moderate intellectual deficiency. In 1996, Glypican 3 (GPC3) was identified as the major gene causing SGBS but the mutation detection rate was only 28-70%, suggesting either genetic heterogeneity or that some patients could have alternative diagnoses. This was particularly suggested by some reports of atypical cases with more severe prognoses. In the family reported by Golabi and Rosen, a duplication of GPC4 was recently identified, suggesting that GPC4 could be the second gene for SGBS but no point mutations within GPC4 have yet been reported. In the genetics laboratory in Tours Hospital, GPC3 molecular testing over more than a decade has detected pathogenic mutations in only 8.7% of individuals with SGBS. In addition, GPC4 mutations have not been identified thus raising the question of frequent misdiagnosis. In order to better delineate the phenotypic spectrum of SGBS caused by GPC3 mutations, and to try to define specific clinical criteria for GPC3 molecular testing, we reviewed the clinical features of all male cases with a GPC3 mutation identified in the two molecular laboratories providing this test in France (Tours and Paris). We present here the results of the analysis of 42 patients belonging to 31 families and including five fetuses and three deceased neonates.
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PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.
Am. J. Hum. Genet.
PUBLISHED: 03-25-2013
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Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85?, p55?, and p50? regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts.
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Delineation of a new chromosome 20q11.2 duplication syndrome including the ASXL1 gene.
Am. J. Med. Genet. A
PUBLISHED: 03-09-2013
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We report on three males with de novo overlapping 7.5, 9.8, and 10 Mb duplication of chromosome 20q11.2. Together with another patient previously published in the literature with overlapping 20q11 microduplication, we show that such patients display common clinical features including metopic ridging/trigonocephaly, developmental delay, epicanthal folds, and short hands. The duplication comprised the ASXL1 gene, in which de novo heterozygous nonsense or truncating mutations have recently been reported in patients with Borhing-Opitz syndrome. Because of craniofacial features in common with Borhing-Opitz syndrome, in particular metopic ridging/trigonocephaly, we suggest that duplication of ASXL1 contributes to the phenotype. These observations suggest a novel microduplication syndrome, and reporting of additional patients with molecular characterization will allow more detailed genotype-phenotype correlations.
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Detailed clinical, genetic and neuroimaging characterization of OFD VI syndrome.
Eur J Med Genet
PUBLISHED: 03-03-2013
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Oral-facial-digital syndrome type VI (OFD VI) is characterized by the association of malformations of the face, oral cavity and extremities, distinguished from the 12 other OFD syndromes by cerebellar and metacarpal abnormalities. Cerebellar malformations in OFD VI have been described as a molar tooth sign (MTS), thus, including OFD VI among the "Joubert syndrome related disorders" (JSRD). OFD VI diagnostic criteria have recently been suggested: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of hands or feet; 3) hypothalamic hamartoma. In order to further delineate this rare entity, we present the neurological and radiological data of 6 additional OFD VI patients. All patients presented oral malformations, facial dysmorphism and distal abnormalities including frequent polydactyly (66%), as well as neurological symptoms with moderate to severe mental retardation. Contrary to historically reported patients, mesoaxial polydactyly did not appear to be a predominant clinical feature in OFD VI. Sequencing analyzes of the 14 genes implicated in JSRD up to 2011 revealed only an OFD1 frameshift mutation in one female OFD VI patient, strengthening the link between these two oral-facial-digital syndromes and JSRD.
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An improved method to extract DNA from 1 ml of uncultured amniotic fluid from patients at less than 16 weeks gestation.
PLoS ONE
PUBLISHED: 02-20-2013
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The aim of this study was to develop an improved technique for DNA extraction from 1 ml of uncultured AF from patients with a gestational age less than 16 weeks and to allow the use of array-CGH without DNA amplification. The DNA extraction protocol was tested in a series of 90 samples including 41 of uncultured AF at less than 16 weeks of gestation. Statistical analyses were performed using linear regression. To evaluate the sensitivity and the specificity of array-CGH on 1 ml of uncultured AF, five samples with an abnormal karyotype (three with aneuploidy, two with structural abnormalities) and five with a normal karyotype were studied. This protocol was reproducible and we were able to show a great improvement with higher yield of DNA obtained from all patients, including those with a gestational age less than 16 weeks (p?=?0.003). All chromosomal abnormalities were detected and characterized by array-CGH and normal samples showed normal profiles. This new DNA extraction protocol associated with array-CGH analysis could be used in prenatal testing even when gestational age is less than 16 weeks, especially in cases with abnormal ultrasound findings.
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Mutations in WNT10A are frequently involved in oligodontia associated with minor signs of ectodermal dysplasia.
Am. J. Med. Genet. A
PUBLISHED: 02-07-2013
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Ectodermal dysplasias (ED) are a clinically and genetically heterogeneous group of hereditary disorders that have in common abnormal development of ectodermal derivatives. Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of eccrine sweat glands, hair, and teeth. The X-linked form of the disease, caused by mutations in the EDA gene, represents the majority of patients with the hypohidrotic form. Autosomal dominant and autosomal recessive forms are occasionally seen, and result from mutations in at least three genes (WNT10A, EDAR, or more rarely EDARADD). We have screened for mutations in EDAR (commonly involved in the hypohidrotic form) and WNT10A (involved in a wide spectrum of ED and in isolated hypodontia) in a cohort of 36 patients referred for EDA molecular screening, which failed to identify any mutation. We identified eight EDAR mutations in five patients (two with homozygous mutations, one with compound heterozygous mutations, and two with heterozygous mutation), four of which were novel variants. We identified 28 WNT10A mutations in 16 patients (5 with homozygous mutations, 7 with compound heterozygous mutations, and 4 with heterozygous mutations), seven of which were novel variants. Our study allows a more precise definition of the phenotypic spectrum associated with EDAR and WNT10A mutations and underlines the importance of the implication of WNT10A among patients with ED.
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Craniosynostosis, anal anomalies, and porokeratosis (CDAGS syndrome): Case report and literature review.
Eur J Med Genet
PUBLISHED: 02-04-2013
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CDAGS syndrome is an autosomal recessive syndrome characterized by craniosynostosis, large open fontanelles, hearing loss, anal anomalies, genitourinary malformations and porokeratosis. To our knowledge, only four families from different geographic regions and ethnic backgrounds have been reported until now and no molecular defect has been identified. Here we report two sisters presenting with craniosynostosis, microcephaly, short downslanting palpebral fissures, sparse hair, eyelashes, and eyebrows and porokeratosis that appeared at the age of one month. The youngest sister had an imperforate anus with rectoperineal fistula. Array-CGH did not reveal any pathological CNV. Molecular analysis of the c16orf57, RECQL4 and MCM5 genes was normal.
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Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.
Stig E Bojesen, Karen A Pooley, Sharon E Johnatty, Jonathan Beesley, Kyriaki Michailidou, Jonathan P Tyrer, Stacey L Edwards, Hilda A Pickett, Howard C Shen, Chanel E Smart, Kristine M Hillman, Phuong L Mai, Kate Lawrenson, Michael D Stutz, Yi Lu, Rod Karevan, Nicholas Woods, Rebecca L Johnston, Juliet D French, Xiaoqing Chen, Maren Weischer, Sune F Nielsen, Melanie J Maranian, Maya Ghoussaini, Shahana Ahmed, Caroline Baynes, Manjeet K Bolla, Qin Wang, Joe Dennis, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, Sue Healey, Michael Lush, Daniel C Tessier, Daniel Vincent, Françis Bacot, , Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Harvey A Risch, Anna González-Neira, Mary Anne Rossing, Guillermo Pita, Jennifer A Doherty, Nuria Alvarez, Melissa C Larson, Brooke L Fridley, Nils Schoof, Jenny Chang-Claude, Mine S Cicek, Julian Peto, Kimberly R Kalli, Annegien Broeks, Sebastian M Armasu, Marjanka K Schmidt, Linde M Braaf, Boris Winterhoff, Heli Nevanlinna, Gottfried E Konecny, Diether Lambrechts, Lisa Rogmann, Pascal Guénel, Attila Teoman, Roger L Milne, Joaquín J García, Angela Cox, Vijayalakshmi Shridhar, Barbara Burwinkel, Frederik Marme, Rebecca Hein, Elinor J Sawyer, Christopher A Haiman, Shan Wang-Gohrke, Irene L Andrulis, Kirsten B Moysich, John L Hopper, Kunle Odunsi, Annika Lindblom, Graham G Giles, Hermann Brenner, Jacques Simard, Galina Lurie, Peter A Fasching, Michael E Carney, Paolo Radice, Lynne R Wilkens, Anthony Swerdlow, Marc T Goodman, Hiltrud Brauch, Montserrat Garcia-Closas, Peter Hillemanns, Robert Winqvist, Matthias Dürst, Peter Devilee, Ingo Runnebaum, Anna Jakubowska, Jan Lubiński, Arto Mannermaa, Ralf Bützow, Natalia V Bogdanova, Thilo Dörk, Liisa M Pelttari, Wei Zheng, Arto Leminen, Hoda Anton-Culver, Clareann H Bunker, Vessela Kristensen, Roberta B Ness, Kenneth Muir, Robert Edwards, Alfons Meindl, Florian Heitz, Keitaro Matsuo, Andreas du Bois, Anna H Wu, Philipp Harter, Soo-Hwang Teo, Ira Schwaab, Xiao-Ou Shu, William Blot, Satoyo Hosono, Daehee Kang, Toru Nakanishi, Mikael Hartman, Yasushi Yatabe, Ute Hamann, Beth Y Karlan, Suleeporn Sangrajrang, Susanne Krüger Kjaer, Valerie Gaborieau, Allan Jensen, Diana Eccles, Estrid Høgdall, Chen-Yang Shen, Judith Brown, Yin Ling Woo, Mitul Shah, Mat Adenan Noor Azmi, Robert Luben, Siti Zawiah Omar, Kamila Czene, Robert A Vierkant, Børge G Nordestgaard, Henrik Flyger, Celine Vachon, Janet E Olson, Xianshu Wang, Douglas A Levine, Anja Rudolph, Rachel Palmieri Weber, Dieter Flesch-Janys, Edwin Iversen, Stefan Nickels, Joellen M Schildkraut, Isabel dos Santos Silva, Daniel W Cramer, Lorna Gibson, Kathryn L Terry, Olivia Fletcher, Allison F Vitonis, C Ellen van der Schoot, Elizabeth M Poole, Frans B L Hogervorst, Shelley S Tworoger, Jianjun Liu, Elisa V Bandera, Jingmei Li, Sara H Olson, Keith Humphreys, Irene Orlow, Carl Blomqvist, Lorna Rodriguez-Rodriguez, Kristiina Aittomäki, Helga B Salvesen, Taru A Muranen, Elisabeth Wik, Barbara Brouwers, Camilla Krakstad, Els Wauters, Mari K Halle, Hans Wildiers, Lambertus A Kiemeney, Claire Mulot, Katja K Aben, Pierre Laurent-Puig, Anne Mvan Altena, Thérèse Truong, Leon F A G Massuger, Javier Benitez, Tanja Pejovic, Jose Ignacio Arias Perez, Maureen Hoatlin, M Pilar Zamora, Linda S Cook, Sabapathy P Balasubramanian, Linda E Kelemen, Andreas Schneeweiss, Nhu D Le, Christof Sohn, Angela Brooks-Wilson, Ian Tomlinson, Michael J Kerin, Nicola Miller, Cezary Cybulski, Brian E Henderson, Janusz Menkiszak, Fredrick Schumacher, Nicolas Wentzensen, Loic Le Marchand, Hannah P Yang, Anna Marie Mulligan, Gord Glendon, Svend Aage Engelholm, Julia A Knight, Claus K Høgdall, Carmel Apicella, Martin Gore, Helen Tsimiklis, Honglin Song, Melissa C Southey, Agnes Jager, Ans M Wvan den Ouweland, Robert Brown, John W M Martens, James M Flanagan, Mieke Kriege, James Paul, Sara Margolin, Nadeem Siddiqui, Gianluca Severi, Alice S Whittemore, Laura Baglietto, Valerie McGuire, Christa Stegmaier, Weiva Sieh, Heiko Muller, Volker Arndt, France Labrèche, Yu-Tang Gao, Mark S Goldberg, Gong Yang, Martine Dumont, John R McLaughlin, Arndt Hartmann, Arif B Ekici, Matthias W Beckmann, Catherine M Phelan, Michael P Lux, Jenny Permuth-Wey, Bernard Peissel, Thomas A Sellers, Filomena Ficarazzi, Monica Barile, Argyrios Ziogas, Alan Ashworth, Aleksandra Gentry-Maharaj, Michael Jones, Susan J Ramus, Nick Orr, Usha Menon, Celeste L Pearce, Thomas Brüning, Malcolm C Pike, Yon-Dschun Ko, Jolanta Lissowska, Jonine Figueroa, Jolanta Kupryjanczyk, Stephen J Chanock, Agnieszka Dansonka-Mieszkowska, Arja Jukkola-Vuorinen, Iwona K Rzepecka, Katri Pylkäs, Mariusz Bidzinski, Saila Kauppila, Antoinette Hollestelle, Caroline Seynaeve, Rob A E M Tollenaar, Katarzyna Durda, Katarzyna Jaworska, Jaana M Hartikainen, Veli-Matti Kosma, Vesa Kataja, Natalia N Antonenkova, Jirong Long, Martha Shrubsole, Sandra Deming-Halverson, Artitaya Lophatananon, Pornthep Siriwanarangsan, Sarah Stewart-Brown, Nina Ditsch, Peter Lichtner, Rita K Schmutzler, Hidemi Ito, Hiroji Iwata, Kazuo Tajima, Chiu-Chen Tseng, Daniel O Stram, David Van Den Berg, Cheng Har Yip, M Kamran Ikram, Yew-Ching Teh, Hui Cai, Wei Lu, Lisa B Signorello, Qiuyin Cai, Dong-Young Noh, Keun-Young Yoo, Hui Miao, Philip Tsau-Choong Iau, Yik Ying Teo, James McKay, Charles Shapiro, Foluso Ademuyiwa, George Fountzilas, Chia-Ni Hsiung, Jyh-Cherng Yu, Ming-Feng Hou, Catherine S Healey, Craig Luccarini, Susan Peock, Dominique Stoppa-Lyonnet, Paolo Peterlongo, Timothy R Rebbeck, Marion Piedmonte, Christian F Singer, Eitan Friedman, Mads Thomassen, Kenneth Offit, Thomas V O Hansen, Susan L Neuhausen, Csilla I Szabo, Ignacio Blanco, Judy Garber, Steven A Narod, Jeffrey N Weitzel, Marco Montagna, Edith Olah, Andrew K Godwin, Drakoulis Yannoukakos, David E Goldgar, Trinidad Caldés, Evgeny N Imyanitov, Laima Tihomirova, Banu K Arun, Ian Campbell, Arjen R Mensenkamp, Christi J van Asperen, Kees E P van Roozendaal, Hanne Meijers-Heijboer, J Margriet Collée, Jan C Oosterwijk, Maartje J Hooning, Matti A Rookus, Rob B van der Luijt, Theo A Mvan Os, D Gareth Evans, Debra Frost, Elena Fineberg, Julian Barwell, Lisa Walker, M John Kennedy, Radka Platte, Rosemarie Davidson, Steve D Ellis, Trevor Cole, Brigitte Bressac-de Paillerets, Bruno Buecher, Francesca Damiola, Laurence Faivre, Marc Frénay, Olga M Sinilnikova, Olivier Caron, Sophie Giraud, Sylvie Mazoyer, Valérie Bonadona, Virginie Caux-Moncoutier, Aleksandra Toloczko-Grabarek, Jacek Gronwald, Tomasz Byrski, Amanda B Spurdle, Bernardo Bonanni, Daniela Zaffaroni, Giuseppe Giannini, Loris Bernard, Riccardo Dolcetti, Siranoush Manoukian, Norbert Arnold, Christoph Engel, Helmut Deissler, Kerstin Rhiem, Dieter Niederacher, Hansjoerg Plendl, Christian Sutter, Barbara Wappenschmidt, Ake Borg, Beatrice Melin, Johanna Rantala, Maria Soller, Katherine L Nathanson, Susan M Domchek, Gustavo C Rodriguez, Ritu Salani, Daphne Gschwantler Kaulich, Muy-Kheng Tea, Shani Shimon Paluch, Yael Laitman, Anne-Bine Skytte, Torben A Kruse, Uffe Birk Jensen, Mark Robson, Anne-Marie Gerdes, Bent Ejlertsen, Lenka Foretova, Sharon A Savage, Jenny Lester, Penny Soucy, Karoline B Kuchenbaecker, Curtis Olswold, Julie M Cunningham, Susan Slager, Vernon S Pankratz, Ed Dicks, Sunil R Lakhani, Fergus J Couch, Per Hall, Alvaro N A Monteiro, Simon A Gayther, Paul D P Pharoah, Roger R Reddel, Ellen L Goode, Mark H Greene, Douglas F Easton, Andrew Berchuck, Antonis C Antoniou, Georgia Chenevix-Trench, Alison M Dunning.
Nat. Genet.
PUBLISHED: 01-31-2013
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TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ?480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
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Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe detude des Tumeurs Endocrines (GTE) cohort study.
Hum. Mol. Genet.
PUBLISHED: 01-31-2013
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Multiple endocrine neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Although genotype-phenotype studies have so far failed to identify any statistical correlations, some families harbor recurrent tumor patterns. The function of MENIN is unclear, but has been described through the discovery of its interacting partners. Mutations in the interacting domains of MENIN functional partners have been shown to directly alter its regulation abilities. We report on a cohort of MEN1 patients from the Groupe détude des Tumeurs Endocrines. Patients with a molecular diagnosis and a clinical follow-up, totaling 262 families and 806 patients, were included. Associations between mutation type, location or interacting factors of the MENIN protein and death as well as the occurrence of MEN1-related tumors were tested using a frailty Cox model to adjust for potential heterogeneity across families. Accounting for the heterogeneity across families, the overall risk of death was significantly higher when mutations affected the JunD interacting domain (adjusted HR = 1.88: 95%-CI = 1.15-3.07). Patients had a higher risk of death from cancers of the MEN1 spectrum (HR = 2.34; 95%-CI = 1.23-4.43). This genotype-phenotype correlation study confirmed the lack of direct genotype-phenotype correlations. However, patients with mutations affecting the JunD interacting domain had a higher risk of death secondary to a MEN1 tumor and should thus be considered for surgical indications, genetic counseling and follow-up.
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Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase.
Am. J. Hum. Genet.
PUBLISHED: 01-29-2013
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Yunis-Varón syndrome (YVS) is an autosomal-recessive disorder with cleidocranial dysplasia, digital anomalies, and severe neurological involvement. Enlarged vacuoles are found in neurons, muscle, and cartilage. By whole-exome sequencing, we identified frameshift and missense mutations of FIG4 in affected individuals from three unrelated families. FIG4 encodes a phosphoinositide phosphatase required for regulation of PI(3,5)P(2) levels, and thus endosomal trafficking and autophagy. In a functional assay, both missense substitutions failed to correct the vacuolar phenotype of Fig4-null mouse fibroblasts. Homozygous Fig4-null mice exhibit features of YVS, including neurodegeneration and enlarged vacuoles in neurons. We demonstrate that Fig4-null mice also have small skeletons with reduced trabecular bone volume and cortical thickness and that cultured osteoblasts accumulate large vacuoles. Our findings demonstrate that homozygosity or compound heterozygosity for null mutations of FIG4 is responsible for YVS, the most severe known human phenotype caused by defective phosphoinositide metabolism. In contrast, in Charcot-Marie-Tooth disease type 4J (also caused by FIG4 mutations), one of the FIG4 alleles is hypomorphic and disease is limited to the peripheral nervous system. This genotype-phenotype correlation demonstrates that absence of FIG4 activity leads to central nervous system dysfunction and extensive skeletal anomalies. Our results describe a role for PI(3,5)P(2) signaling in skeletal development and maintenance.
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Genetic and clinical specificity of 26 symptomatic carriers for dystrophinopathies at pediatric age.
Eur. J. Hum. Genet.
PUBLISHED: 01-09-2013
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The molecular basis underlying the clinical variability in symptomatic Duchenne muscular dystrophy (DMD) carriers are still to be precised. We report 26 cases of early symptomatic DMD carriers followed in the French neuromuscular network. Clinical presentation, muscular histological analysis and type of gene mutation, as well as X-chromosome inactivation (XCI) patterns using DNA extracted from peripheral blood or muscle are detailed. The initial symptoms were significant weakness (88%) or exercise intolerance (27%). Clinical severity varied from a Duchenne-like progression to a very mild Becker-like phenotype. Cardiac dysfunction was present in 19% of the cases. Cognitive impairment was worthy of notice, as 27% of the carriers are concerned. The muscular analysis was always contributive, revealing muscular dystrophy (83%), mosaic in immunostaining (81%) and dystrophin abnormalities in western blot analysis (84%). In all, 73% had exonic deletions or duplications and 27% had point mutations. XCI pattern was biased in 62% of the cases. In conclusion, we report the largest series of manifesting DMD carriers at pediatric age and show that exercise intolerance and cognitive impairment may reveal symptomatic DMD carriers. The complete histological and immunohistological study of the muscle is the key of the diagnosis leading to the dystrophin gene analysis. Our study shows also that cognitive impairment in symptomatic DMD carriers is associated with mutations in the distal part of the DMD gene. XCI study does not fully explain the mechanisms as well as the wide spectrum of clinical phenotype, though a clear correlation between the severity of the phenotype and inactivation bias was observed.
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Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases.
Hum. Mutat.
PUBLISHED: 12-20-2011
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Hypohidrotic and anhidrotic ectodermal dysplasia (HED/EDA) is a rare genodermatosis characterized by abnormal development of sweat glands, teeth, and hair. Three disease-causing genes have been hitherto identified, namely, (1) EDA1 accounting for X-linked forms, (2) EDAR, and (3) EDARADD, causing both autosomal dominant and recessive forms. Recently, WNT10A gene was identified as responsible for various autosomal recessive forms of ectodermal dysplasias, including onycho-odonto-dermal dysplasia (OODD) and Schöpf-Schulz-Passarge syndrome. We systematically studied EDA1, EDAR, EDARADD, and WNT10A genes in a large cohort of 65 unrelated patients, of which 61 presented with HED/EDA. A total of 50 mutations (including 32 novel mutations) accounted for 60/65 cases in our series. These four genes accounted for 92% (56/61 patients) of HED/EDA cases: (1) the EDA1 gene was the most common disease-causing gene (58% of cases), (2)WNT10A and EDAR were each responsible for 16% of cases. Moreover, a novel disease locus for dominant HED/EDA mapped to chromosome 14q12-q13.1. Although no clinical differences between patients carrying EDA1, EDAR, or EDARADD mutations could be identified, patients harboring WNT10A mutations displayed distinctive clinical features (marked dental phenotype, no facial dysmorphism), helping to decide which gene should be first investigated in HED/EDA.
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Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.
J. Med. Genet.
PUBLISHED: 11-02-2011
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The early gonad is bipotential and can differentiate into either a testis or an ovary. In XY embryos, the SRY gene triggers testicular differentiation and subsequent male development via its action on a single gene, SOX9. The supporting cell lineage of the bipotential gonad will differentiate as testicular Sertoli cells if SOX9 is expressed and conversely will differentiate as ovarian granulosa cells when SOX9 expression is switched off.
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Molecular study of the perforin gene in familial hematological malignancies.
Hered Cancer Clin Pract
PUBLISHED: 09-21-2011
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Perforin gene (PRF1) mutations have been identified in some patients diagnosed with the familial form of hemophagocytic lymphohistiocytosis (HLH) and in patients with lymphoma. The aim of the present study was to determine whether patients with a familial aggregation of hematological malignancies harbor germline perforin gene mutations. For this purpose, 81 unrelated families from Tunisia and France with aggregated hematological malignancies were investigated. The variants detected in the PRF1 coding region amounted to 3.7% (3/81). Two of the three variants identified were previously described: the p.Ala91Val pathogenic mutation and the p.Asn252Ser polymorphism. A new p.Ala 211Val missense substitution was identified in two related Tunisian patients. In order to assess the pathogenicity of this new variation, bioinformatic tools were used to predict its effects on the perforin protein structure and at the mRNA level. The segregation of the mutant allele was studied in the family of interest and a control population was screened. The fact that this variant was not found to occur in 200 control chromosomes suggests that it may be pathogenic. However, overexpression of mutated PRF1 in rat basophilic leukemia cells did not affect the lytic function of perforin differently from the wild type protein.
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Exploring the potential role of disease-causing mutation in a gene desert: duplication of noncoding elements 5 of GRIA3 is associated with GRIA3 silencing and X-linked intellectual disability.
Hum. Mutat.
PUBLISHED: 06-14-2011
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GRIA3 encodes glutamate receptor ionotropic AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) subunit 3 and has been previously involved in X-linked intellectual disability (ID). We report on a male proband with ID and epilepsy associated with a duplication mapping within a gene desert, 874-kb upstream of the GRIA3 gene. This 970-kb duplication is maternally inherited. The probands mother has a skewed X chromosome-inactivation pattern in agreement with her normal cognitive function. Quantitative polymerase chain reaction analysis indicates absence of GRIA3 mRNA in the proband lymphocytes relative to a wild-type control. Centromeric to the duplicated region, comparative genomic analysis showed a 2268-bp evolutionarily conserved region that could be a critical transcription factor binding-site for GRIA3 expression. The repositioning of distant-acting sequences, rather a missense/nonsense mutation, is considered to be causative for GRIA3-linked ID. This study illustrates the importance of high-resolution array-Comparative Genomic Hybridization analysis in exploring the potential role of disease-causing mutation in functional noncoding sequences.
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Systematic search for neutropenia should be part of the first screening in patients with poikiloderma.
Eur J Med Genet
PUBLISHED: 05-27-2011
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Poikiloderma occurs in a number of hereditary syndromes, the best known of which is Rothmund-Thomson syndrome (RTS). Differential diagnoses include Dyskeratosis Congenita (DC) with high genetic heterogeneity and Clericuzio-type Poikiloderma with Neutropenia (CPN) due to mutations in the C16orf57 gene. Mutations in the RECQL4 gene are only observed in two thirds of RTS patients. In this study, 10 patients referred for syndromic poikiloderma and negative for RECQL4 sequencing analysis were investigated for C16orf57 mutations. Two C16orf57 heterozygous nonsense mutations (p.W81X and p.Y89X) were identified in a 5-year-old female child presenting with generalized poikiloderma, dental dysplasia, gingivitis, nail dystrophy, palmoplantar keratoderma and pachyonychia of the great toenails. Previously undetected and silent neutropenia was evidenced after C16orf57 molecular analysis. Neutropenia was absent in the C16orf57-negative patients. This report confirms that neutrophil count should be performed in all patients with poikiloderma to target the C16orf57 gene sequencing analysis, prior to RECQL4 analysis.
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Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers.
Antonis C Antoniou, Christiana Kartsonaki, Olga M Sinilnikova, Penny Soucy, Lesley McGuffog, Sue Healey, Andrew Lee, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Elisa Cattaneo, Monica Barile, Valeria Pensotti, Barbara Pasini, Riccardo Dolcetti, Giuseppe Giannini, Anna Laura Putignano, Liliana Varesco, Paolo Radice, Phuong L Mai, Mark H Greene, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, Mads Thomassen, Anne-Marie Gerdes, Torben A Kruse, Uffe Birk Jensen, Dorthe G Crüger, Maria A Caligo, Yael Laitman, Roni Milgrom, Bella Kaufman, Shani Paluch-Shimon, Eitan Friedman, Niklas Loman, Katja Harbst, Annika Lindblom, Brita Arver, Hans Ehrencrona, Beatrice Melin, , Katherine L Nathanson, Susan M Domchek, Timothy Rebbeck, Ania Jakubowska, Jan Lubiński, Jacek Gronwald, Tomasz Huzarski, Tomasz Byrski, Cezary Cybulski, Bohdan Górski, Ana Osorio, Teresa Ramón Y Cajal, Florentia Fostira, Raquel Andrés, Javier Benitez, Ute Hamann, Frans B Hogervorst, Matti A Rookus, Maartje J Hooning, Marcel R Nelen, Rob B van der Luijt, Theo A M van Os, Christi J van Asperen, Peter Devilee, Hanne E J Meijers-Heijboer, Encarna B Gomez Garcia, Susan Peock, Margaret Cook, Debra Frost, Radka Platte, Jean Leyland, D Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Julian Adlard, Rosemarie Davidson, Diana Eccles, Kai-Ren Ong, Jackie Cook, Fiona Douglas, Joan Paterson, M John Kennedy, Zosia Miedzybrodzka, Andrew Godwin, Dominique Stoppa-Lyonnet, Bruno Buecher, Muriel Belotti, Carole Tirapo, Sylvie Mazoyer, Laure Barjhoux, Christine Lasset, Dominique Leroux, Laurence Faivre, Myriam Bronner, Fabienne Prieur, Catherine Noguès, Etienne Rouleau, Pascal Pujol, Isabelle Coupier, Marc Frénay, John L Hopper, Mary B Daly, Mary B Terry, Esther M John, Saundra S Buys, Yosuf Yassin, Alexander Miron, David Goldgar, Christian F Singer, Muy-Kheng Tea, Georg Pfeiler, Anne Catharina Dressler, Thomas V O Hansen, Lars Jønson, Bent Ejlertsen, Rosa Bjork Barkardottir, Tomas Kirchhoff, Kenneth Offit, Marion Piedmonte, Gustavo Rodriguez, Laurie Small, John Boggess, Stephanie Blank, Jack Basil, Masoud Azodi, Amanda Ewart Toland, Marco Montagna, Silvia Tognazzo, Simona Agata, Evgeny Imyanitov, Ramunas Janavicius, Conxi Lazaro, Ignacio Blanco, Paul D P Pharoah, Lara Sucheston, Beth Y Karlan, Christine S Walsh, Edith Olah, Aniko Bozsik, Soo-Hwang Teo, Joyce L Seldon, Mary S Beattie, Elizabeth J van Rensburg, Michelle D Sluiter, Orland Díez, Rita K Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Ina Ruehl, Raymonda Varon-Mateeva, Karin Kast, Helmut Deissler, Dieter Niederacher, Norbert Arnold, Dorothea Gadzicki, Ines Schönbuchner, Trinidad Caldés, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomäki, Martine Dumont, Jocelyne Chiquette, Marc Tischkowitz, Xiaoqing Chen, Jonathan Beesley, Amanda B Spurdle, Susan L Neuhausen, Yuan Chun Ding, Zachary Fredericksen, Xianshu Wang, Vernon S Pankratz, Fergus Couch, Jacques Simard, Douglas F Easton, Georgia Chenevix-Trench.
Hum. Mol. Genet.
PUBLISHED: 05-18-2011
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Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
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Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy.
Eur J Med Genet
PUBLISHED: 05-09-2011
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Dilated Cardiomyopathy (DCM) is one of the leading causes of heart failure with high morbidity and mortality. More than 30 genes have been reported to cause DCM. To provide new insights into the pathophysiology of dilated cardiomyopathy, a mutational screening on 4 DCM-causing genes (MYH7, TNNT2, TNNI3 and LMNA) was performed in a cohort of 105 unrelated DCM (64 familial cases and 41 sporadic cases) using a High Resolution Melting (HRM)/sequencing strategy. Screening of a highly conserved arginine/serine (RS)-rich region in exon 9 of RBM20 was also performed. Nineteen different mutations were identified in 20 index patients (19%), including 10 novels. These included 8 LMNA variants in 9 (8.6%) probands, 5 TNNT2 variants in 5 probands (4.8%), 4 MYH7 variants in 3 probands (3.8%), 1 TNNI3 variant in 1 proband (0.9%), and 1 RBM20 variant in 1 proband (0.9%). One proband was double-heterozygous. LMNA mutations represent the most prevalent genetic DCM cause. Most patients carrying LMNA mutations exhibit conduction system defects and/or cardiac arrhythmias. Our study also showed than prevalence of mutations affecting TNNI3 or the (RS)-rich region of RBM20 is lower than 1%. The discovery of novel DCM mutations is crucial for clinical management of patients and their families because pre-symptomatic diagnosis is possible and precocious intervention could prevent or ameliorate the prognosis.
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Prognosis factors in probands with an FBN1 mutation diagnosed before the age of 1 year.
Pediatr. Res.
PUBLISHED: 05-07-2011
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Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder. Diagnostic criteria of neonatal MFS (nMFS), the most severe form, are still debated. The aim of our study was to search for clinical and molecular prognostic factors that could be associated with length of survival. Probands ascertained via the framework of the Universal Marfan database-FBN1, diagnosed before the age of 1 y and presenting with cardiovascular features (aortic root dilatation or valvular insufficiency) were included in this study. Clinical and molecular data were correlated to survival. Among the 60 individuals, 38 had died, 82% died before the age of 1 y, mostly because of congestive heart failure. Three probands reached adulthood. Valvular insufficiencies and diaphragmatic hernia were predictive of shorter life expectancy. Two FBN1 mutations were found outside of the exon 24-32 region (in exons 4 and 21). Mutations in exons 25-26 were overrepresented and were associated with shorter survival (p = 0.03). We report the largest genotyped series of probands with MFS diagnosed before 1 y of life. In this population, factors significantly associated with shorter survival are presence of valvular insufficiencies or diaphragmatic hernia in addition to a mutation in exons 25 or 26.
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Variation in breast cancer risk with mutation position, smoking, alcohol, and chest X-ray history, in the French National BRCA1/2 carrier cohort (GENEPSO).
Breast Cancer Res. Treat.
PUBLISHED: 04-21-2011
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Germline mutations in BRCA1/2 confer a high risk of breast cancer (BC), but the magnitude of this risk varies according to various factors. Although controversial, there are data to support the hypothesis of allelic-risk heterogeneity. We assessed variation in BC risk according to the location of mutations recorded in the French study GENEPSO. Since the women in this study were selected from high-risk families, oversampling of affected women was eliminated by using a weighted Cox-regression model. Women were censored at the date of diagnosis when affected by any cancer, or the date of interview when unaffected. A total of 990 women were selected for the analysis: 379 were classified as affected, 611 as unaffected. For BRCA1, there was some evidence of a central region where the risk of BC is lower (codons 374-1161) (HR = 0.59, P = 0.04). For BRCA2, there was a strong evidence for a region at decreased risk (codons 957-1827) (HR = 0.35, P = 0.005) and for one at increased risk (codons 2546-2968) (HR = 3.56, P = 0.01). Moreover, we found an important association between radiation exposure from chest X-rays and BC risk (HR = 4.29, P < 10(-3)) and a positive association between smoking more than 21 pack-years and BC risk (HR = 2.09, P = 0.04). No significant variation in BC risk associated with chest X-ray exposure, smoking, and alcohol consumption was found according to the location of the mutation in BRCA1 and BRCA2. Our findings are consistent with those suggesting that the risk of BC is lower in the central regions of BRCA1/2. A new high-risk region in BRCA2 is described. Taking into account environmental and lifestyle modifiers, the location of mutations might be important in the clinical management of BRCA mutation carriers.
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Germline deletion of the miR-17?92 cluster causes skeletal and growth defects in humans.
Nat. Genet.
PUBLISHED: 04-12-2011
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MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17?92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17?92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17?92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17?92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.
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Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.
J. Med. Genet.
PUBLISHED: 03-12-2011
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Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder predisposing humans to cutaneous and uterine leiomyomas; in 20% of affected families, type 2 papillary renal cell cancers (PRCCII) also occur with aggressive course and poor prognosis. HLRCC results from heterozygous germline mutations in the tumour suppressor fumarate hydratase (FH) gene.
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Functional analysis reveals splicing mutations of the CASQ2 gene in patients with CPVT: implication for genetic counselling and clinical management.
Hum. Mutat.
PUBLISHED: 03-10-2011
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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and severe arrhythmogenic disorder. Although usually transmitted in a recessive form, few cases of dominant mutations have been reported. Thirteen mutations in the CASQ2 gene have been reported so far in association with CPVT. We performed molecular analysis of the CASQ2 gene in 43 probands with CPVT and identified eight mutations in five patients. Six mutations were novel: one was a single nucleotide deletion, three affected consensus splice sites, and two had unknown consequences: the c.939 + 5G>C and the synonymous c.381C>T variations. We demonstrated that these two variations affected CASQ2 splicing using a splicing minigene assay. These data increased significantly the number of CASQ2 mutations described in association with CPVT, revealed the high prevalence of splicing and truncating mutations in this gene and brought new insight regarding the dominant inheritance of the disease. Moreover, our report of the first splicing abnormalities in CASQ2 caused by intronic mutation or synonymous change underlines the absolute necessity to perform extensive molecular analysis for genetic diagnosis and counseling of CPVT.
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17q21.31 microdeletion in a patient with pituitary stalk interruption syndrome.
Eur J Med Genet
PUBLISHED: 03-02-2011
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We report the case of a 26-month-old boy with mental retardation, facial dysmorphism, childhood feeding difficulties, short stature, bilateral cryptorchidism, micropenis, and heart defect. Endocrinal evaluation revealed complete growth hormone deficiency (GHD) and gonadotropic deficiency, and pituitary magnetic resonance imaging showed partial pituitary stalk interruption syndrome (PSIS). A de novo 493 kb microdeletion on chromosome 17q21.31 was identified using array comparative genomic hybridization (array-CGH) analysis. This is the first report of PSIS in the phenotypical spectrum of 17q21.31 microdeletion syndrome, although other midline abnormalities have previously been described. Our report suggests that GHD should be investigated in patients with 17q21.31 microdeletion syndrome and short stature, defined by a body height below - 2 standard deviation scores (SDS) for age and sex. This finding also opens new avenues of research on the etiopathogenesis of PSIS, for which the genetic mechanisms remain unknown.
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Significance of isolated hepatic veno-occlusive disease/sinusoidal obstruction syndrome after liver transplantation.
Liver Transpl.
PUBLISHED: 02-26-2011
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After liver transplantation (LT), hepatic veno-occlusive disease (VOD), which is also known as sinusoidal obstruction syndrome (SOS), has been reported initially in relation to azathioprine use and subsequently in relation to acute rejection (AR). Isolated veno-occlusive disease (iVOD)/SOS raises some questions about its significance and especially its treatment. From the post-LT biopsy samples of 1364 patients (2000-2008), 31 patients with index biopsy samples showing VOD/SOS (2.3%) were identified. After a review of the index biopsy samples and previous biopsy samples, those patients not exposed to azathioprine therapy were subdivided into 2 groups according to the absence or presence of AR. Fifteen of the 31 patients had no previous evidence of AR, whereas 16 experienced episodes of AR (before or concurrently with VOD). The 2 groups were similar in terms of demographic and clinical data and the range of histological centrilobular changes. AR episodes were characterized by an endothelial predilection. iVOD/SOS occurred later than acute rejection-related veno-occlusive disease (AR-VOD)/SOS (mean times of 65 and 4.4 months, respectively, P = 0.0098). There was a tendency for iVOD/SOS to progress less frequently to chronic rejection in comparison with AR-VOD/SOS (3/15 versus 9/15, P = 0.06). The histological resolution of iVOD/SOS was significantly more frequent in patients who benefited from increased immunosuppression in comparison with those who did not (5/7 versus 2/8, P = 0.05). When the groups were considered together, the same result was obtained (14/18 versus 4/12, P = 0.024). In conclusion, despite a constant overall prevalence of VOD/SOS, the proportion of iVOD/SOS has increased. The histological resolution of iVOD/SOS after increase in immunosuppression suggests an immune-mediated origin. Better optimization of immunosuppression may be a curative treatment.
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Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus.
Sébastien Jacquemont, Alexandre Reymond, Flore Zufferey, Louise Harewood, Robin G Walters, Zoltan Kutalik, Danielle Martinet, Yiping Shen, Armand Valsesia, Noam D Beckmann, Gudmar Thorleifsson, Marco Belfiore, Sonia Bouquillon, Dominique Campion, Nicole de Leeuw, Bert B A de Vries, Tonu Esko, Bridget A Fernandez, Fernando Fernandez-Aranda, José Manuel Fernández-Real, Mònica Gratacòs, Audrey Guilmatre, Juliane Hoyer, Marjo-Riitta Järvelin, R Frank Kooy, Ants Kurg, Cédric Le Caignec, Katrin Männik, Orah S Platt, Damien Sanlaville, Mieke M van Haelst, Sergi Villatoro Gomez, Faida Walha, Bai-Lin Wu, Yongguo Yu, Azzedine Aboura, Marie-Claude Addor, Yves Alembik, Stylianos E Antonarakis, Benoit Arveiler, Magalie Barth, Nathalie Bednarek, Frédérique Béna, Sven Bergmann, Mylène Beri, Laura Bernardini, Bettina Blaumeiser, Dominique Bonneau, Armand Bottani, Odile Boute, Han G Brunner, Dorothée Cailley, Patrick Callier, Jean Chiesa, Jacqueline Chrast, Lachlan Coin, Charles Coutton, Jean-Marie Cuisset, Jean-Christophe Cuvellier, Albert David, Bénédicte de Freminville, Bruno Delobel, Marie-Ange Delrue, Bénédicte Demeer, Dominique Descamps, Gérard Didelot, Klaus Dieterich, Vittoria Disciglio, Martine Doco-Fenzy, Séverine Drunat, Bénédicte Duban-Bedu, Christèle Dubourg, Julia S El-Sayed Moustafa, Paul Elliott, Brigitte H W Faas, Laurence Faivre, Anne Faudet, Florence Fellmann, Alessandra Ferrarini, Richard Fisher, Elisabeth Flori, Lukas Forer, Dominique Gaillard, Marion Gérard, Christian Gieger, Stefania Gimelli, Giorgio Gimelli, Hans J Grabe, Agnès Guichet, Olivier Guillin, Anna-Liisa Hartikainen, Delphine Heron, Loyse Hippolyte, Muriel Holder, Georg Homuth, Bertrand Isidor, Sylvie Jaillard, Zdenek Jaros, Susana Jiménez-Murcia, Géraldine Joly Helas, Philippe Jonveaux, Satu Kaksonen, Boris Keren, Anita Kloss-Brandstätter, Nine V A M Knoers, David A Koolen, Peter M Kroisel, Florian Kronenberg, Audrey Labalme, Emilie Landais, Elisabetta Lapi, Valérie Layet, Solenn Legallic, Bruno Leheup, Barbara Leube, Suzanne Lewis, Josette Lucas, Kay D MacDermot, Páll Magnússon, Christian Marshall, Michèle Mathieu-Dramard, Mark I McCarthy, Thomas Meitinger, Maria Antonietta Mencarelli, Giuseppe Merla, Alexandre Moerman, Vincent Mooser, Fanny Morice-Picard, Mafalda Mucciolo, Matthias Nauck, Ndeye Coumba Ndiaye, Ann Nordgren, Laurent Pasquier, Florence Petit, Rolph Pfundt, Ghislaine Plessis, Evica Rajcan-Separovic, Gian Paolo Ramelli, Anita Rauch, Roberto Ravazzolo, André Reis, Alessandra Renieri, Cristóbal Richart, Janina S Ried, Claudine Rieubland, Wendy Roberts, Katharina M Roetzer, Caroline Rooryck, Massimiliano Rossi, Evald Saemundsen, Véronique Satre, Claudia Schurmann, Engilbert Sigurdsson, Dimitri J Stavropoulos, Hreinn Stefansson, Carola Tengström, Unnur Thorsteinsdottir, Francisco J Tinahones, Renaud Touraine, Louis Vallée, Ellen van Binsbergen, Nathalie Van der Aa, Catherine Vincent-Delorme, Sophie Visvikis-Siest, Peter Vollenweider, Henry Völzke, Anneke T Vulto-van Silfhout, Gérard Waeber, Carina Wallgren-Pettersson, Robert M Witwicki, Simon Zwolinksi, Joris Andrieux, Xavier Estivill, James F Gusella, Omar Gústafsson, Andres Metspalu, Stephen W Scherer, Kari Stefansson, Alexandra I F Blakemore, Jacques S Beckmann, Philippe Froguel.
Nature
PUBLISHED: 02-09-2011
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Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ??18.5?kg?per?m(2) in adults and ??-2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ?600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.
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New insights into the pathogenesis of Beckwith-Wiedemann and Silver-Russell syndromes: contribution of small copy number variations to 11p15 imprinting defects.
Hum. Mutat.
PUBLISHED: 02-09-2011
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The imprinted 11p15 region is organized in two domains, each of them under the control of its own imprinting control region (ICR1 for the IGF2/H19 domain and ICR2 for the KCNQ1OT1/CDKN1C domain). Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS) and the Silver-Russell (SRS) syndromes. Various 11p15 genetic and epigenetic defects have been demonstrated in BWS and SRS. Among them, isolated DNA methylation defects account for approximately 60% of patients. To investigate whether cryptic copy number variations (CNVs) involving only part of one of the two imprinted domains account for 11p15 isolated DNA methylation defects, we designed a single nucleotide polymorphism array covering the whole 11p15 imprinted region and genotyped 185 SRS or BWS cases with loss or gain of DNA methylation at either ICR1 or ICR2. We describe herein novel small gain and loss CNVs in six BWS or SRS patients, including maternally inherited cis-duplications involving only part of one of the two imprinted domains. We also show that ICR2 deletions do not account for BWS with ICR2 loss of methylation and that uniparental isodisomy involving only one of the two imprinted domains is not a mechanism for SRS or BWS.
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Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis.
Nat. Genet.
PUBLISHED: 02-04-2011
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Hajdu-Cheney syndrome is a rare autosomal dominant skeletal disorder with facial anomalies, osteoporosis and acro-osteolysis. We sequenced the exomes of six unrelated individuals with this syndrome and identified heterozygous nonsense and frameshift mutations in NOTCH2 in five of them. All mutations cluster to the last coding exon of the gene, suggesting that the mutant mRNA products escape nonsense-mediated decay and that the resulting truncated NOTCH2 proteins act in a gain-of-function manner.
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A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.
Corine Bertolotto, Fabienne Lesueur, Sandy Giuliano, Thomas Strub, Mahaut de Lichy, Karine Bille, Philippe Dessen, Benoit d'Hayer, Hamida Mohamdi, Audrey Remenieras, Eve Maubec, Arnaud de la Fouchardiere, Vincent Molinie, Pierre Vabres, Stéphane Dalle, Nicolas Poulalhon, Tanguy Martin-Denavit, Luc Thomas, Pascale Andry-Benzaquen, Nicolas Dupin, Françoise Boitier, Annick Rossi, Jean-Luc Perrot, Bruno Labeille, Caroline Robert, Bernard Escudier, Olivier Caron, Laurence Brugières, Simon Saule, Betty Gardie, Sophie Gad, Stéphane Richard, Jérôme Couturier, Bin Tean Teh, Paola Ghiorzo, Lorenza Pastorino, Susana Puig, Celia Badenas, Hakan Olsson, Christian Ingvar, Etienne Rouleau, Rosette Lidereau, Philippe Bahadoran, Philippe Vielh, Eve Corda, Hélène Blanché, Diana Zelenika, Pilar Galán, , François Aubin, Bertrand Bachollet, Céline Becuwe, Pascaline Berthet, Yves Jean Bignon, Valérie Bonadona, Jean-Louis Bonafe, Marie-Noëlle Bonnet-Dupeyron, Frédéric Cambazard, Jacqueline Chevrant-Breton, Isabelle Coupier, Sophie Dalac, Liliane Demange, Michel D'Incan, Catherine Dugast, Laurence Faivre, Lynda Vincent-Fétita, Marion Gauthier-Villars, Brigitte Gilbert, Florent Grange, Jean-Jacques Grob, Philippe Humbert, Nicolas Janin, Pascal Joly, Delphine Kerob, Christine Lasset, Dominique Leroux, Julien Levang, Jean-Marc Limacher, Cristina Livideanu, Michel Longy, Alain Lortholary, Dominique Stoppa-Lyonnet, Sandrine Mansard, Ludovic Mansuy, Karine Marrou, Christine Mateus, Christine Maugard, Nicolas Meyer, Catherine Noguès, Pierre Souteyrand, Laurence Venat-Bouvet, Hélène Zattara, Valérie Chaudru, Gilbert M Lenoir, Mark Lathrop, Irwin Davidson, Marie-Françoise Avril, Florence Demenais, Robert Ballotti, Brigitte Bressac-de Paillerets.
Nature
PUBLISHED: 02-01-2011
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So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes; risk factors associated with RCC include smoking, obesity and hypertension. A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers. The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene; it also stimulates the transcription of hypoxia inducible factor (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes. We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (?KXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K-occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.
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Dissection of the MYCN locus in Feingold syndrome and isolated oesophageal atresia.
Eur. J. Hum. Genet.
PUBLISHED: 01-12-2011
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Feingold syndrome (FS) is a syndromic microcephaly entity for which MYCN is the major disease-causing gene. We studied the expression pattern of MYCN at different stages of human embryonic development and collected a series of 17 FS and 12 isolated oesophageal atresia (IOA) cases. An MYCN gene deletion/mutation was identified in 47% of FS cases exclusively. We hypothesized that mutations or deletions of highly conserved non-coding elements (HCNEs) at the MYCN locus could lead to its misregulation and thereby to FS and/or IOA. We subsequently sequenced five HCNEs at the MYCN locus and designed a high-density tiling path comparative genomic hybridization array of 3.3 Mb at the MYCN locus. We found no mutations or deletions in this region, supporting the hypothesis of genetic heterogeneity in FS.
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ARX polyalanine expansions are highly implicated in familial cases of mental retardation with infantile epilepsy and/or hand dystonia.
Am. J. Med. Genet. A
PUBLISHED: 01-05-2011
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Mutations in the ARX gene cause both nonsyndromic and several forms of syndromic mental retardation (MR). Two polyalanine (polyA) expansions of ARX are recurrent mutations. The most common one, the c.428_451dup, is associated with a wide spectrum of phenotypes, ranging from the most severe West syndrome to Partington syndrome (MR and hand dystonia), and even nonsyndromic X-linked mental retardation (NS-XLMR). Studies of patients not selected for specific clinical signs showed that the c.428_451dup is relatively frequent in families harboring X-linked MR (7.5%), but less common in familial cases compatible with X-linked NR (1%), and very rare in sporadic cases (0.1%). The c.333_334ins(GCG)7 expansion is less frequent and mainly associated with West syndrome. We screened for both ARX polyA expansions in 98 unrelated patients selected for the presence of NR associated with different types of epilepsy and/or with hand dystonia. We also studied two families with an initial diagnosis of NS-XLMR, one of which was identified as showing linkage to the ARX locus. The c.428_451dup was identified in three patients and the c.333_334ins(GCG)7 in one; all of the patients were from families with two affected brothers. We also found the c.428_451dup in the family linked to ARX, and clinical re-evaluation showed subtle, previously undetected signs. Our study illustrates that ARX polyA expansions are primarily associated with syndromic MR and shows a higher yield (18% in our cohort) when these mutations are screened in familial cases of MR with epilepsy and/or dystonia.
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Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers.
Susan J Ramus, Christiana Kartsonaki, Simon A Gayther, Paul D P Pharoah, Olga M Sinilnikova, Jonathan Beesley, Xiaoqing Chen, Lesley McGuffog, Sue Healey, Fergus J Couch, Xianshu Wang, Zachary Fredericksen, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Gaia Roversi, Monica Barile, Alessandra Viel, Anna Allavena, Laura Ottini, Laura Papi, Viviana Gismondi, Fabio Capra, Paolo Radice, Mark H Greene, Phuong L Mai, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, , Mads Thomassen, Anne-Marie Gerdes, Torben A Kruse, Dorthe Crüger, Uffe Birk Jensen, Maria Adelaide Caligo, Hakan Olsson, Ulf Kristoffersson, Annika Lindblom, Brita Arver, Per Karlsson, Marie Stenmark Askmalm, Ake Borg, Susan L Neuhausen, Yuan Chun Ding, Katherine L Nathanson, Susan M Domchek, Anna Jakubowska, Jan Lubiński, Tomasz Huzarski, Tomasz Byrski, Jacek Gronwald, Bohdan Górski, Cezary Cybulski, Tadeusz Dębniak, Ana Osorio, Mercedes Durán, Maria-Isabel Tejada, Javier Benitez, Ute Hamann, Matti A Rookus, Senno Verhoef, Madeleine A Tilanus-Linthorst, Maaike P Vreeswijk, Danielle Bodmer, Margreet G E M Ausems, Theo A van Os, Christi J Asperen, Marinus J Blok, Hanne E J Meijers-Heijboer, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Alison M Dunning, D Gareth Evans, Ros Eeles, Gabriella Pichert, Trevor Cole, Shirley Hodgson, Carole Brewer, Patrick J Morrison, Mary Porteous, M John Kennedy, Mark T Rogers, Lucy E Side, Alan Donaldson, Helen Gregory, Andrew Godwin, Dominique Stoppa-Lyonnet, Virginie Moncoutier, Laurent Castera, Sylvie Mazoyer, Laure Barjhoux, Valérie Bonadona, Dominique Leroux, Laurence Faivre, Rosette Lidereau, Catherine Noguès, Yves-Jean Bignon, Fabienne Prieur, Marie-Agnès Collonge-Rame, Laurence Venat-Bouvet, Sandra Fert-Ferrer, Alex Miron, Saundra S Buys, John L Hopper, Mary B Daly, Esther M John, Mary Beth Terry, David Goldgar, Thomas V O Hansen, Lars Jønson, Bent Ejlertsen, Bjarni A Agnarsson, Kenneth Offit, Tomas Kirchhoff, Joseph Vijai, Ana V C Dutra-Clarke, Jennifer A Przybylo, Marco Montagna, Cinzia Casella, Evgeny N Imyanitov, Ramunas Janavicius, Ignacio Blanco, Conxi Lazaro, Kirsten B Moysich, Beth Y Karlan, Jenny Gross, Mary S Beattie, Rita Schmutzler, Barbara Wappenschmidt, Alfons Meindl, Ina Ruehl, Britta Fiebig, Christian Sutter, Norbert Arnold, Helmut Deissler, Raymonda Varon-Mateeva, Karin Kast, Dieter Niederacher, Dorothea Gadzicki, Trinidad Caldés, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomäki, Jacques Simard, Penny Soucy, Amanda B Spurdle, Helene Holland, Georgia Chenevix-Trench, Douglas F Easton, Antonis C Antoniou.
J. Natl. Cancer Inst.
PUBLISHED: 12-17-2010
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Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2.
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Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction.
Antonis C Antoniou, Jonathan Beesley, Lesley McGuffog, Olga M Sinilnikova, Sue Healey, Susan L Neuhausen, Yuan Chun Ding, Timothy R Rebbeck, Jeffrey N Weitzel, Henry T Lynch, Claudine Isaacs, Patricia A Ganz, Gail Tomlinson, Olufunmilayo I Olopade, Fergus J Couch, Xianshu Wang, Noralane M Lindor, Vernon S Pankratz, Paolo Radice, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Monica Barile, Alessandra Viel, Anna Allavena, Valentina Dall'Olio, Paolo Peterlongo, Csilla I Szabo, Michal Zikán, Kathleen Claes, Bruce Poppe, Lenka Foretova, Phuong L Mai, Mark H Greene, Gad Rennert, Flavio Lejbkowicz, Gord Glendon, Hilmi Ozcelik, Irene L Andrulis, , Mads Thomassen, Anne-Marie Gerdes, Lone Sunde, Dorthe Crüger, Uffe Birk Jensen, Maria Caligo, Eitan Friedman, Bella Kaufman, Yael Laitman, Roni Milgrom, Maya Dubrovsky, Shimrit Cohen, Ake Borg, Helena Jernström, Annika Lindblom, Johanna Rantala, Marie Stenmark-Askmalm, Beatrice Melin, Kate Nathanson, Susan Domchek, Ania Jakubowska, Jan Lubiński, Tomasz Huzarski, Ana Osorio, Adriana Lasa, Mercedes Durán, Maria-Isabel Tejada, Javier Godino, Javier Benitez, Ute Hamann, Mieke Kriege, Nicoline Hoogerbrugge, Rob B van der Luijt, Christi J van Asperen, Peter Devilee, E J Meijers-Heijboer, Marinus J Blok, Cora M Aalfs, Frans Hogervorst, Matti Rookus, Margaret Cook, Clare Oliver, Debra Frost, Don Conroy, D Gareth Evans, Fiona Lalloo, Gabriella Pichert, Rosemarie Davidson, Trevor Cole, Jackie Cook, Joan Paterson, Shirley Hodgson, Patrick J Morrison, Mary E Porteous, Lisa Walker, M John Kennedy, Huw Dorkins, Susan Peock, Andrew K Godwin, Dominique Stoppa-Lyonnet, Antoine de Pauw, Sylvie Mazoyer, Valérie Bonadona, Christine Lasset, Hélène Dreyfus, Dominique Leroux, Agnès Hardouin, Pascaline Berthet, Laurence Faivre, Catherine Loustalot, Tetsuro Noguchi, Hagay Sobol, Etienne Rouleau, Catherine Noguès, Marc Frénay, Laurence Venat-Bouvet, John L Hopper, Mary B Daly, Mary B Terry, Esther M John, Saundra S Buys, Yosuf Yassin, Alexander Miron, David Goldgar, Christian F Singer, Anne Catharina Dressler, Daphne Gschwantler-Kaulich, Georg Pfeiler, Thomas V O Hansen, Lars Jønson, Bjarni A Agnarsson, Tomas Kirchhoff, Kenneth Offit, Vincent Devlin, Ana Dutra-Clarke, Marion Piedmonte, Gustavo C Rodriguez, Katie Wakeley, John F Boggess, Jack Basil, Peter E Schwartz, Stephanie V Blank, Amanda Ewart Toland, Marco Montagna, Cinzia Casella, Evgeny Imyanitov, Laima Tihomirova, Ignacio Blanco, Conxi Lazaro, Susan J Ramus, Lara Sucheston, Beth Y Karlan, Jenny Gross, Rita Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Magdalena Lochmann, Norbert Arnold, Simone Heidemann, Raymonda Varon-Mateeva, Dieter Niederacher, Christian Sutter, Helmut Deissler, Dorothea Gadzicki, Sabine Preisler-Adams, Karin Kast, Ines Schönbuchner, Trinidad Caldés, Miguel de la Hoya, Kristiina Aittomäki, Heli Nevanlinna, Jacques Simard, Amanda B Spurdle, Helene Holland, Xiaoqing Chen, Radka Platte, Georgia Chenevix-Trench, Douglas F Easton.
Cancer Res.
PUBLISHED: 11-30-2010
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The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.
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