Schwartz–Jampel Syndrome Type 1 in a Balouch Patient: A Novel Compound Heterozygous <i>HSPG2</i> Variant Revealed by Whole-Exome Sequencing

Abstract

Introduction: Schwartz–Jampel syndrome type 1 (SJS1) is a rare autosomal recessive (AR) skeletal dysplasia caused by pathogenic variants in the heparan sulfate proteoglycan 2 (HSPG2) gene, which encodes the extracellular matrix proteoglycan perlecan. Case Presentation: We describe a 13-year-old Iranian male presenting with progressive joint contractures, skeletal deformities, and muscle weakness. He was born to consanguineous parents and had a positive family history of similar manifestations. Physical examination revealed finger contractures, congenital hip dislocation, and myopia. Whole-exome sequencing (WES; a comprehensive technique that interrogates nearly all coding regions of the genome) identified a novel compound heterozygous HSPG2 variant (NM_005529.7: c.1928G>A; p.Arg643His and c.4378G>T; p.Glu1460Ter). The missense variant was extremely rare in the heterozygous state in the Balouch population, whereas the nonsense variant was predicted to cause premature protein truncation and loss of downstream functional domains. In silico predictions using multiple bioinformatics tools such as SIFT, PolyPhen-2, and Mutation Taster supported the deleterious effect of these variants. Conclusions: This case expands the HSPG2 mutational spectrum by reporting a novel pathogenic variant in a patient of Balouch descent. Identifying new HSPG2 variants is important for improving genotype-phenotype correlations. This helps with more accurate genetic counseling and sets the stage for future targeted treatments. The findings underscore the utility of combining WES with population-specific allele frequency data and detailed phenotypic assessment to achieve accurate molecular diagnoses. In the future, such discoveries may help create personalized management strategies.