Whole-exome Sequencing Identifies Novel Candidate PCNT Variants in a Child With Overlapping MOPD II Features: A Case Report

Summary

Two novel candidate PCNT variants (c.5675A>G and c.9734G>T) were identified in a 7-year-old boy with severe growth failure, developmental delay, and dysmorphic features. The findings are consistent with an atypical, suspected PCNT-related primordial dwarfism phenotype. Both variants remain classified as variants of uncertain significance pending further validation

Abstract

A 7-year-old Chinese boy presented with severe postnatal growth failure (height <3rd percentile at age 7 years), global developmental delay, moderate intellectual disability, and characteristic dysmorphic features including hypertelorism, short palpebral fissures, low-set ears, and a broad nasal bridge. A single electrocardiogram demonstrated a borderline corrected QT interval (QT_c = 450 ms). No arrhythmias, QT-prolonging medications, electrolyte abnormalities, or relevant family cardiac history were identified. This finding warrants longitudinal cardiology follow-up and should not be interpreted as definitive Long QT syndrome. Whole-exome sequencing identified two novel missense variants in the PCNT gene (NM_006031.5): c.5675A>G (p.Glu1892Gly) in exon 28 and c.9734G>T (p.Arg3245Ile) in exon 45. Both variants were absent from gnomAD, ExAC, the 1000 Genomes Project database, and Chinese population databases, fulfilling ACMG criterion PM2. Although classified as variants of uncertain significance (VUS) because of limited functional evidence and conflicting in silico predictions, the variants occur in a gene associated with primordial dwarfism and are accompanied by partial phenotypic overlap with Microcephalic Osteodysplastic Primordial Dwarfism Type II (MOPD II). However, parental segregation analysis was unavailable; therefore, the variant phase could not be confirmed, and a recessive disease mechanism could not be established. These findings support the presence of candidate PCNT variants in an atypical primordial dwarfism phenotype and illustrate the utility of whole-exome sequencing for generating testable molecular hypotheses in genetically heterogeneous growth disorders. A definitive molecular diagnosis cannot be established at present, and the isolated borderline QT_c finding requires further clinical evaluation.

Introduction

Microcephalic Osteodysplastic Primordial Dwarfism Type II (MOPD II) is an exceptionally rare autosomal recessive disorder (estimated prevalence <1:1,000,000) characterized by severe intrauterine and postnatal growth failure, progressive microcephaly, skeletal dysplasia, and distinctive craniofacial features^1,2. MOPD II was molecularly linked to biallelic pathogenic variants in the PCNT gene (pericentrin) in 2008³. Despite this genetic characterization, clinical diagnosis remains challenging because of significant phenotypic heterogeneity, age-dependent expressivity, and substantial overlap with other primordial dwarfism syndromes, including Seckel syndrome and Meier-Gorlin syndrome⁴. Conventional diagnostic approaches that rely solely on clinical criteria often yield inconclusive results, particularly in young patients who have not yet developed the complete phenotypic spectrum⁵.

Whole-exome sequencing (WES) has emerged as a valuable diagnostic approach for genetically heterogeneous disorders, offering distinct advantages over sequential single-gene testing. WES enables the simultaneous interrogation of more than 20,000 protein-coding genes. This approach provides definitive molecular diagnoses in approximately 25%–40% of previously undiagnosed growth disorders, thereby reducing diagnostic delays⁶. Unlike karyotyping or chromosomal microarray analysis, which primarily detect large structural variants, WES efficiently identifies single-nucleotide variants (SNVs) and small insertions/deletions (InDels) that may underlie monogenic disorders⁷. In clinically ambiguous cases, WES prioritizes candidate variants for subsequent segregation studies and functional validation rather than providing a standalone definitive molecular diagnosis. This approach is particularly relevant given the broad mutational spectrum of the PCNT gene, which encompasses numerous variants distributed across its 47 exons and exhibits incomplete genotype–phenotype correlations³.

This case report describes a 7-year-old Chinese boy in whom WES identified two novel candidate PCNT missense variants (c.5675A>G and c.9734G>T). The patient presented with profound postnatal growth failure, global developmental delay, and characteristic craniofacial dysmorphism, yet notably lacked overt microcephaly at the initial evaluation, a feature that typically characterizes classic MOPD II. Nevertheless, MOPD II remained a leading diagnostic consideration because microcephaly in PCNT-related disorders often demonstrates age-dependent progression, with some affected individuals developing significant head growth deceleration only during late childhood or adolescence⁴. Furthermore, the combination of severe short stature, characteristic craniofacial features, intellectual disability, and delayed skeletal maturation closely aligns with the core phenotypic spectrum of PCNT-related primordial dwarfism. This case highlights the utility of WES in generating testable molecular hypotheses in atypical clinical presentations and underscores the importance of longitudinal phenotypic monitoring in resolving diagnostic uncertainty.

Case Presentation:

A 7-year-old boy was referred to the Department of Genetics at Changsha Maternal and Child Health Care Hospital in April 2019 because of profound growth failure and global developmental delay. He was born to healthy, non-consanguineous parents (father's height: 173 cm; mother's height: 160 cm). There was no family history of similar conditions or consanguinity, although the maternal grandmother had a history of diabetes mellitus.

The perinatal history was notable for delivery at 38 weeks of gestation with a birth weight of 2.5 kg. Although the initial clinical record categorized this birth weight as normal, it corresponds to approximately the 10th percentile for gestational age, consistent with small for gestational age (SGA) rather than the severe intrauterine growth restriction typically observed in classic MOPD II. From early childhood, the patient exhibited significant postnatal growth failure with a growth velocity of only 2–3 cm/year. At 7 years of age (April 2019), height was 103.5 cm (–4.04 SD), weight was 16.7 kg (<3rd percentile), and occipitofrontal circumference (OFC) was 51.5 cm (Z-score: –1.2), according to the 2009 Chinese National Growth Standards and age- and sex-specific OFC growth charts.

Skeletal survey radiographs, including anteroposterior views of the left hand and wrist, were obtained in April 2019. Radiographic interpretation by a pediatric radiologist using the Greulich–Pyle atlas demonstrated a bone age of 6 years at a chronological age of 7 years and 1 month. The skeletal survey revealed no evidence of characteristic MOPD II skeletal abnormalities, such as femoral neck dysplasia, metaphyseal flaring, or advanced carpal bone age. Brain magnetic resonance imaging (MRI) demonstrated normal brain structure and myelination without overt malformations, helping to exclude other syndromic causes of severe growth failure and neurodevelopmental delay.

The patient demonstrated delayed motor and language milestones. Formal cognitive assessment using the Wechsler Intelligence Scale for Children (WISC), performed at a chronological age of 7 years and 1 month, yielded a Full-Scale Intelligence Quotient (FSIQ) of 50. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), this score is consistent with mild-to-moderate intellectual disability (mild: 50–69; moderate: 35–49). Physical examination revealed hypertelorism, short palpebral fissures, low-set ears, and a broad nasal bridge. Overt microcephaly was not documented at the initial evaluation. A baseline 12-lead electrocardiogram demonstrated a borderline corrected QT interval (QT_c) of 450 ms (Figure 1A, B). The patient had no history of syncope, palpitations, or documented arrhythmias. There was no exposure to QT-prolonging medications, serum electrolyte concentrations were within normal limits, and the family history was negative for sudden cardiac death or inherited arrhythmias. Repeat electrocardiography and a formal pediatric cardiology consultation were recommended.

Figure 1: Representative electrocardiogram (ECG) obtained from the patient at the initial clinical evaluation. (A) Standard 12-lead ECG recorded at a paper speed of 25 mm/s and a calibration of 10 mm/mV. The tracing demonstrates a normal sinus rhythm with a heart rate of 97 beats/min. The PR interval measures 116 ms, the QRS duration measures 78 ms, and the corrected QT interval (QT_c), calculated using Bazett's formula, measures 450 ms. (B) Magnified view of leads II, V5, and V6, highlighting the T-wave morphology and QT interval. Note: The ECG represents a single baseline recording obtained during the initial clinical evaluation. Please click here to view a larger version of this figure.

Endocrine evaluation confirmed delayed bone age. A growth hormone provocation test demonstrated a normal peak growth hormone response (12.39 ng/mL), excluding growth hormone deficiency as the primary cause of short stature. Thyroid function was normal (TSH: 1.76 mIU/L; FT4: 21.93 pmol/L), and pituitary MRI demonstrated normal morphology (4.5 × 9.1 × 3.1 mm). Following this evaluation, recombinant human growth hormone (rhGH) therapy was initiated on July 28, 2019, along with lifestyle interventions, including dietary protein optimization, regular jumping exercises (e.g., rope skipping), and improved sleep hygiene.

Whole-exome sequencing (WES) performed using peripheral blood DNA identified two novel missense variants in the PCNT gene (NM_006031.5): c.5675A>G (p.Glu1892Gly) in exon 28 and c.9734G>T (p.Arg3245Ile) in exon 45. Both variants were absent from major population databases (gnomAD, ExAC, the 1000 Genomes Project database, and the Chinese-specific Shenzhou Genome Database). In silico prediction tools yielded divergent results. The c.5675A>G variant was predicted to be deleterious by SIFT and possibly damaging by PolyPhen-2 (CADD PHRED score: 18.82), whereas c.9734G>T was predicted to be tolerated or benign (CADD score: 7.87). CNV-seq analysis identified no pathogenic copy number variants (Figure 2). According to the ACMG/AMP guidelines, both variants were classified as Variants of Uncertain Significance (VUS). Parental DNA samples were unavailable; therefore, segregation analysis to determine the phase of the two variants could not be performed.

Figure 2: Copy number variant sequencing (CNV-seq) analysis. Genome-wide CNV-seq plot generated from peripheral blood DNA obtained from the patient. The x-axis represents genomic coordinates (chromosomes 1–22, X, and Y), and the y-axis represents the log₂ read-depth ratio. Horizontal dashed lines indicate the thresholds for copy number gain (>0.3) and copy number loss (<–0.3). No chromosomal aneuploidies or pathogenic copy number variants above the 100 kb detection threshold were identified. Please click here to view a larger version of this figure.

Diagnosis, assessment, and plan:

Comprehensive clinical, radiological, endocrine, cardiac, and genomic evaluation supported a diagnosis of suspected PCNT-related primordial dwarfism with overlapping features of Microcephalic Osteodysplastic Primordial Dwarfism Type II (MOPD II). The diagnostic assessment included standardized anthropometric measurements, a neurodevelopmental evaluation demonstrating global developmental delay and moderate intellectual disability, baseline 12-lead electrocardiography, a skeletal survey, an endocrine evaluation, brain magnetic resonance imaging (MRI), copy number variant sequencing (CNV-seq), and whole-exome sequencing (WES) (Figure 3). CNV-seq excluded pathogenic copy number variants and large chromosomal abnormalities, whereas WES identified two candidate missense variants in the PCNT gene. According to the ACMG/AMP guidelines, both variants were classified as Variants of Uncertain Significance (VUS). Because parental DNA samples were unavailable, segregation analysis could not be performed to determine whether the variants were present in trans, precluding confirmation of a recessive molecular diagnosis.

Figure 3: Brain magnetic resonance imaging (MRI) demonstrating normal intracranial findings. (A) Sagittal T1-weighted contrast-enhanced image demonstrating normal midline intracranial structures and brainstem without abnormal enhancement. (B) Coronal T1-weighted contrast-enhanced image demonstrating normal brain parenchyma and sellar region without evidence of an intracranial mass lesion. Please click here to view a larger version of this figure.

Following the initial evaluation, recombinant human growth hormone (rhGH) therapy was initiated on July 28, 2019, along with lifestyle interventions, including dietary protein optimization, regular jumping exercises (e.g., rope skipping), and improved sleep hygiene. Genetic counseling was provided to the family regarding the current VUS classification, the theoretical recurrence risk associated with an autosomal recessive disorder, and available reproductive options, including prenatal diagnosis and preimplantation genetic testing.

Because no curative therapy is currently available for PCNT-related disorders, long-term management focuses on multidisciplinary surveillance. Annual magnetic resonance angiography (MRA) of the brain, beginning at 5 years of age, was recommended for patients with MOPD II because of the recognized risk of cerebrovascular complications, including moyamoya disease, in accordance with published vascular surveillance recommendations. Repeat 12-lead electrocardiography and a formal pediatric cardiology evaluation were recommended to determine whether the borderline QT_c interval was reproducible. Pharmacological intervention was not indicated at the time of evaluation but would be reconsidered if persistent QT_c prolongation (>460 ms) or symptomatic arrhythmias developed. Continued endocrine follow-up, developmental assessment, speech therapy, occupational therapy, and individualized educational support were also recommended. Growth hormone therapy should continue to be evaluated cautiously because of its uncertain efficacy and the theoretical vascular risks reported in PCNT-related disorders.

Longitudinal follow-up data were unavailable because the patient was lost to follow-up after the initial 2019 evaluation. Consequently, subsequent endocrine monitoring, including assessment of rhGH efficacy and insulin-like growth factor 1 (IGF-1) concentrations, developmental progress, repeat cardiac evaluation, and additional genetic counseling, could not be documented. The long-term clinical course and response to treatment, therefore, remain unknown.

The diagnostic assessment was limited by the unavailability of parental DNA samples for segregation analysis and the absence of functional studies to determine the biological effects of the identified PCNT variants. Consequently, the phase of the two variants (cis versus trans) could not be established, compound heterozygosity could not be confirmed, and both variants remain classified as Variants of Uncertain Significance (VUS). In addition, whole-exome sequencing cannot exclude pathogenic variants located within deep intronic or regulatory regions; therefore, whole-genome sequencing may be considered in future investigations. Given the recognized risk of cerebrovascular and metabolic complications associated with PCNT-related disorders, long-term multidisciplinary surveillance remains appropriate.

Protocol

This study was conducted in strict accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Changsha Hospital for Maternal & Child Health Care (Approval No.CSSFYBJYEC-SOP-005-F07V2.0). Written informed consent was obtained from the patient’s parents for both participation in this study and the publication of clinical data and accompanying images. All patient data and images presented in this manuscript have been strictly de-identified to protect patient privacy. The research tools used in this protocol are listed in the Table of Materials.

1. Initial clinical assessment and phenotypic characterization

1. Anthropometric measurements were obtained with the patient standing barefoot in an upright position using calibrated digital stadiometers and electronic scales.
2. Height and weight were plotted against the 2009 Chinese National Growth Standards to assess growth status. Occipitofrontal circumference (OFC) was measured using a non-stretchable measuring tape and plotted on age- and sex-specific growth charts to assess for microcephaly, defined as an OFC below –2 SD or below the 3^rd percentile.
3. A comprehensive dysmorphology examination was performed by a board-certified clinical geneticist to document craniofacial features. Neurodevelopmental assessment was conducted using the Wechsler Intelligence Scale for Children (WISC).
4. The Full-Scale Intelligence Quotient (FSIQ) was calculated and interpreted according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), diagnostic criteria for intellectual disability (mild: 50–69; moderate: 35–49; severe: 20–34; profound: <20).

2. Cardiovascular and skeletal evaluation

1. A standard 12-lead electrocardiogram (ECG) was obtained using a paper speed of 25 mm/s and a calibration of 10 mm/mV. The QT interval was measured manually in leads II and V5, and the corrected QT interval (QT_c) was calculated using Bazett’s formula (QT_c = QT/√RR). QT_c prolongation was defined according to pediatric reference values as >440 ms in males.
2. Skeletal survey radiographs, including anteroposterior and lateral views of the left hand and wrist, were obtained. Bone age was assessed by a pediatric radiologist using the Greulich–Pyle atlas to evaluate skeletal maturation and assess for skeletal dysplasia.

3. Genetic diagnostic workup

1. Chromosomal copy number variant sequencing (CNV-seq) was performed using peripheral blood DNA. Low-pass whole-genome sequencing was performed to assess for chromosomal aneuploidies and pathogenic copy-number variants at a detection resolution greater than 100 kb.
2. Whole-exome sequencing (WES) was performed on genomic DNA extracted from peripheral blood leukocytes using a commercial DNA extraction kit. Exome capture was performed using a commercial exome capture kit, followed by sequencing on a next-generation sequencing platform, generating 2 × 150 bp paired-end reads.
3. Sequence reads were aligned to the GRCh38/hg38 reference genome using a validated alignment algorithm, and variant calling was performed using a validated bioinformatics pipeline.
4. Quality-control metrics demonstrated a mean sequencing depth greater than 100×, with more than 98% of targeted exons achieving at least 20× coverage and PCNT exon coverage exceeding 99%.
5. Sanger sequencing was performed to confirm the presence and zygosity of the identified PCNT variants in the proband. Because of the extended interval since the initial clinical evaluation, the original Sanger sequencing chromatograms were no longer available from the institutional archives.
6. Parental DNA samples were unavailable; therefore, segregation analysis could not be performed to determine the phase of the identified variants.
7. Variant interpretation was performed according to the 2015 ACMG/AMP guidelines. The bioinformatics workflow included variant annotation, population frequency assessment using gnomAD (v2.1.1), ExAC, and the Chinese-specific Shenzhou Genome Database, in silico pathogenicity prediction using SIFT, PolyPhen-2, and CADD (v1.6), evolutionary conservation analysis using PhyloP and multiz alignment (UCSC Genome Browser), and protein domain mapping using UniProt and the AlphaFold Protein Structure Database.
8. Published literature and the ClinVar database were also reviewed to assign final variant classifications.

4. Differential diagnosis framework

1. Microcephalic Osteodysplastic Primordial Dwarfism Type II (MOPD II; OMIM #210720) was prioritized because of severe prenatal-onset growth failure, intellectual disability, and characteristic craniofacial features despite the absence of overt microcephaly at the initial evaluation (age- and sex-adjusted OFC Z-score > –2 SD).
2. Seckel syndrome (OMIM #210600) was considered but excluded because of the absence of a bird-headed facial profile and the absence of pathogenic or likely pathogenic variants in associated genes (e.g., ATR and CEP152) identified through analysis of the WES dataset.
3. Meier–Gorlin syndrome (OMIM #224690) was excluded because patellar aplasia or hypoplasia was absent, and no pathogenic or likely pathogenic variants were identified in pre-replication complex genes (e.g., ORC1, ORC4, ORC6, CDC6, CDC45, GMNN, and MCM5) during analysis of the WES dataset.

Results

Comprehensive clinical evaluation and genomic analysis identified a molecular and phenotypic profile consistent with a suspected PCNT-related primordial dwarfism. Whole-exome sequencing (WES) identified two novel missense variants in the PCNT gene (NM_006031.5): c.5675A>G (p.Glu1892Gly) in exon 28 and c.9734G>T (p.Arg3245Ile) in exon 45. Copy number variant sequencing (CNV-seq) identified no pathogenic copy number variants or chromosomal aneuploidies above the 100 kb detection threshold (Figure 2).

The designation of these variants as “novel” is based on their absence from major population databases (gnomAD, ExAC, the 1000 Genomes Project database, and the Chinese-specific Shenzhou Genome Database), the ClinVar database, disease-specific repositories (e.g., LOVD for PCNT), and the published literature available at the time of analysis. In silico analyses yielded divergent predictions. The c.5675A>G variant received a CADD PHRED score of 18.82 and was predicted to be deleterious by SIFT, whereas c.9734G>T received a CADD score of 7.87 and was predicted to be tolerated or benign. PhyloP and multiz alignment analyses performed using the UCSC Genome Browser demonstrated distinct evolutionary conservation patterns. The Glu1892 residue was highly conserved across 100 vertebrate species (PhyloP score: 4.88), whereas the Arg3245 residue was strictly conserved within primates but showed greater variability across other mammalian lineages. Protein domain mapping using UniProt localized both variants to the central coiled-coil rod domain of pericentrin.

Clinically, the patient exhibited profound postnatal growth failure, with a height of 103.5 cm (–4.04 SD) at the initial evaluation, corresponding to below the 3^rd percentile for age. Neurodevelopmental assessment demonstrated global developmental delay and a Full-Scale Intelligence Quotient (FSIQ) of 50. Physical examination identified hypertelorism, short palpebral fissures, low-set ears, and a broad nasal bridge. Electrocardiographic evaluation demonstrated a single borderline corrected QT interval (QT_c) of 450 ms (Figure 1A, B).

According to the ACMG/AMP guidelines and the evidence summarized in Table 1, both PCNT variants were classified as Variants of Uncertain Significance (VUS).

Variant	HGVS notation	ACMG criteria applied	Evidence summary			Final classification
Variant 1	NM_006031.5:c.5675A>G p.(Glu1892Gly)	PM2, PP3	PM2: Absent from population databases (gnomAD, ExAC, the 1000 Genomes Project database, and the Chinese-specific Shenzhou Genome Database). PP3: Computational evidence supported a deleterious effect based on SIFT and a CADD PHRED score of 18.82. PhyloP and multiz alignment analyses demonstrated strong evolutionary conservation of the Glu1892 residue (PhyloP score: 4.88).			VUS
Variant 2	NM_006031.5:c.9734G>T p.(Arg3245Ile)	PM2, PP3	PM2: Absent from population databases (gnomAD, ExAC, the 1000 Genomes Project database, and the Chinese-specific Shenzhou Genome Database). PP3: Computational analyses yielded limited evidence. Although evolutionary conservation within primates and structural assessment suggested a possible effect on the central coiled-coil domain, the CADD score (7.87) and in silico predictions provided insufficient evidence to support pathogenicity beyond a VUS classification.			VUS
Abbreviations: ACMG, American College of Medical Genetics and Genomics; CADD, Combined Annotation Dependent Depletion; HGVS, Human Genome Variation Society; PM2, absent from population databases; PP3, computational evidence; VUS, Variant of Uncertain Significance.

Table 1: ACMG/AMP classification of the identified PCNT variants. Summary of the two PCNT missense variants identified by whole-exome sequencing, including HGVS nomenclature, ACMG/AMP criteria applied, supporting evidence, and final variant classification.

Discussion

This case report describes a 7-year-old Chinese boy harboring two novel missense variants in the PCNT gene (c.5675A>G/p.Glu1892Gly and c.9734G>T/p.Arg3245Ile) who presented with profound postnatal growth failure (height 103.5 cm, –4.04 SD at age 7 years), global developmental delay, intellectual disability (Full-Scale IQ = 50 on the Wechsler Intelligence Scale), and characteristic craniofacial dysmorphism but lacked several canonical features of classic MOPD II. Compared with the classic diagnostic phenotype, the patient did not demonstrate severe intrauterine growth restriction (birth weight 2.5 kg, classified as small for gestational age), characteristic skeletal dysplasia, or overt microcephaly. Skeletal evaluation demonstrated delayed bone age (6 years) without characteristic radiographic abnormalities, and the age- and sex-adjusted occipitofrontal circumference remained above the diagnostic threshold for microcephaly (Z-score: –1.2) at the initial evaluation. In addition, CNV-seq analysis identified no pathogenic copy number variants or chromosomal aneuploidies exceeding 100 kb, supporting the subsequent evaluation of a monogenic etiology.

Although the phenotype differs from the classic diagnostic criteria for MOPD II, PCNT-related disorders exhibit considerable phenotypic heterogeneity and age-dependent expressivity. Previous cohort studies have demonstrated that microcephaly and skeletal manifestations may be mild or become more apparent during late childhood or adolescence, and some affected individuals present primarily with severe postnatal growth failure and characteristic craniofacial features without classic intrauterine growth restriction or skeletal dysplasia^3,4. Accordingly, the findings are best interpreted as an atypical, suspected PCNT-related primordial dwarfism phenotype with overlapping features of MOPD II, rather than as a definitive diagnosis of classic MOPD II.

The normal peak growth hormone response (12.39 ng/mL), observed despite profound short stature, is consistent with the current understanding that growth impairment in PCNT-related disorders is primarily associated with abnormalities in skeletal development and growth plate function rather than pituitary hormone deficiency. This observation further emphasizes the importance of comprehensive genomic evaluation in patients with severe short stature and normal endocrine testing.

The divergent in silico predictions obtained for the two PCNT variants illustrate the limitations of computational pathogenicity assessment for missense variants in large multidomain proteins. The c.5675A>G variant received stronger computational support for pathogenicity (CADD PHRED score 18.82; SIFT deleterious), whereas c.9734G>T was consistently predicted to be tolerated or benign (CADD score 7.87). These findings demonstrate that computational prediction alone is insufficient for variant classification, particularly for large scaffold proteins with complex structural and functional domains. Pericentrin, encoded by PCNT, is an essential centrosomal scaffold protein involved in mitotic spindle organization, DNA damage response, and cell-cycle regulation⁸. Experimental studies have further shown that loss of pericentrin disrupts centriole association at spindle poles, resulting in premature centriole separation and centrosome abnormalities⁹.

A single electrocardiogram demonstrated a borderline corrected QT interval of 450 ms. This finding was not accompanied by symptoms, electrolyte abnormalities, exposure to QT-prolonging medications, or a family history of inherited arrhythmia¹⁰. Although experimental studies have suggested potential roles for centrosomal proteins in cardiovascular biology, including vascular smooth muscle cell regulation and cardiomyocyte cell-cycle control, the clinical significance of the borderline QT_c observed in this patient remains uncertain¹¹. Repeat electrocardiography, ambulatory monitoring, and formal pediatric cardiology assessment would be required to determine whether this finding is reproducible and clinically relevant¹².

Several limitations should be considered when interpreting this case. As a single-patient report, the findings cannot establish definitive genotype–phenotype relationships. Parental DNA samples were unavailable, precluding segregation analysis and confirmation of the trans configuration of the two PCNT variants. Consequently, compound heterozygosity could not be confirmed, and both variants remain classified as Variants of Uncertain Significance (VUS). Functional studies evaluating the biological effects of these variants were not performed, leaving their molecular consequences unresolved. Although WES provides broad coverage of coding regions, pathogenic variants located within deep intronic or regulatory regions cannot be excluded. In addition, longitudinal follow-up data were unavailable because the patient was lost to follow-up after the initial evaluation, preventing assessment of treatment response, developmental outcomes, and repeat cardiac evaluation.

Despite these limitations, the identification of candidate variants in exons 28 and 45 contributes additional clinical and molecular information to the expanding spectrum of PCNT-related disorders and highlights the value of comprehensive genomic testing in patients with severe growth failure and developmental delay⁴. These findings also support multidisciplinary management, including surveillance for vascular complications in accordance with published vascular surveillance recommendations¹⁰ and continued cardiology follow-up for the observed borderline QT_c interval. Genetic counseling should clearly communicate the current VUS classification and the uncertainty surrounding disease causality until additional segregation or functional evidence becomes available. Future studies should focus on functional characterization of these variants using patient-derived fibroblasts to evaluate centrosomal localization and mitotic spindle defects¹³, systematic cardiac assessment in larger PCNT cohorts, and continued data sharing through repositories such as ClinVar to facilitate future variant classification.

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
12-lead electrocardiograph	GE Healthcare	MAC 5500 HD (Software v2.0)	Cardiac evaluation and QT interval measurement
ABI 3730xl Genetic Analyzer	Applied Biosystems	Firmware v3.0	Sanger sequencing validation
ANNOVAR	Children's Hospital of Philadelphia (CHOP)	v2021-02-01	Variant annotation
BigDye Terminator v3.1 Cycle Sequencing Kit	Thermo Fisher Scientific	Cat. No. 4337456	Sanger sequencing reactions
BWA-MEM	Broad Institute	v0.7.17	Sequence alignment
ClinVar	National Center for Biotechnology Information (NCBI)	Accessed June 2026	Clinical variant database
Combined Annotation Dependent Depletion (CADD)	University of Washington	v1.6	In silico pathogenicity prediction
Digital radiography (DR) system	Siemens Healthineers	Ysio Max (syngo.via v4.0)	Skeletal survey and bone age assessment
Ensembl Variant Effect Predictor (VEP)	EMBL-EBI	v104	Variant annotation
GATK HaplotypeCaller	Broad Institute	v4.2.6.1	Variant calling
Genome Aggregation Database (gnomAD)	Broad Institute	v2.1.1 / v3.1.2	Population frequency database
GRCh38/hg38 reference genome	Genome Reference Consortium	Build 38, Patch 13	Sequence alignment reference
Low-pass whole-genome sequencing library preparation kit	Berry Genomics	Commercially provided	CNV-seq library preparation
NovaSeq 6000 Sequencing System	Illumina	Reagent Kit v1.5 (300 cycles)	Whole-exome sequencing
PolyPhen-2	Harvard Medical School	v2.3.10	In silico pathogenicity prediction
QIAamp DNA Blood Mini Kit	QIAGEN	Cat. No. 51104	Genomic DNA extraction
SIFT	J. Craig Venter Institute	v5.2.2	In silico pathogenicity prediction
SureSelect Human All Exon V6 Kit	Agilent Technologies	Cat. No. G9904B	Exome capture and library preparation