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

Enhuan Yi; Huali Qin; Ling Che; Ni Gan; Xiangwen Peng

doi:10.3791/71153

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Case Report

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

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DOI:

10.3791/71153

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August 14th, 2026

Enhuan Yi^*¹ , Huali Qin^*¹ , Ling Che^*¹ , Ni Gan^*¹ , Xiangwen Peng¹

¹Hunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control, Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University

^* These authors contributed equally

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 features¹^,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 substan....