Exome Sequencing Identifies a Rare HSPG2 Variant Associated with Familial Idiopathic Scoliosis

Abstract

Idiopathic scoliosis occurs in 3% of individuals and has an unknown etiology. The objective of this study was to identify rare variants that contribute to the etiology of idiopathic scoliosis by using exome sequencing in a multigenerational family with idiopathic scoliosis. Exome sequencing was completed for three members of this multigenerational family with idiopathic scoliosis, resulting in the identification of a variant in the HSPG2 gene as a potential contributor to the phenotype. The HSPG2 gene was sequenced in a separate cohort of 100 unrelated individuals affected with idiopathic scoliosis and also was examined in an independent idiopathic scoliosis population. The exome sequencing and subsequent bioinformatics filtering resulted in 16 potentially damaging and rare coding variants. One of these variants, p.Asn786Ser, is located in the HSPG2 gene. The variant p.Asn786Ser also is overrepresented in a larger cohort of idiopathic scoliosis cases compared with a control population (P = 0.024). Furthermore, we identified additional rare HSPG2 variants that are predicted to be damaging in two independent cohorts of individuals with idiopathic scoliosis. The HSPG2 gene encodes for a ubiquitous multifunctional protein within the extracellular matrix in which loss of function mutation are known to result in a musculoskeletal phenotype in both mouse and humans. Based on these results, we conclude that rare variants in the HSPG2 gene potentially contribute to the idiopathic scoliosis phenotype in a subset of patients with idiopathic scoliosis. Further studies must be completed to confirm the effect of the HSPG2 gene on the idiopathic scoliosis phenotype.

Genetics and pathogenesis of idiopathic scoliosis

“…Two other common variants of interest have recently been found to be associated with IS, but have yet to be replicated (Table 2) [63, 68]. New methodologies such as exome-sequencing have made it possible to identify rare variants associated with idiopathic scoliosis [47–49, 81]. The importance of these findings in the general idiopathic scoliosis population, however, remains to be seen.…”

“…Baschal et al [47] sequenced the exomes of three affected individuals in a multigenerational family with dominant Mendelian inheritance of IS. They identified a rare missense variant in HSPG2 , coding for an extracellular matrix protein, also known as perlecan.…”

Clinical Observations and Treatment Approaches for Scoliosis in Prader–Willi Syndrome

“…32, 2q36.1, 8q12, 10q24.31, 17q25.3, and 19p13.3) that may involve genes affecting growth and musculoskeletal development [28]. For example, next-generation sequencing, genotyping, linkage analysis, GWAS and gene expression studies in tissues have identified 23 genes that are related to scoliosis [29][30][31][32][33][34]. These genes code for extracellular matrix proteins, collagen, bone formation, mineralization and metabolism, growth and sex hormones, and homeobox genes required for differentiation of skeletal elements and structural integrity of the vertebrae.…”

Benchmarking challenging small variants with linked and long reads

“…39 Rare variants in the HSPG2 gene are linked to cases of idiopathic scoliosis. 40 STRC has a pseudogene with high genomic and coding sequence homology making it very difficult to characterize by normal short read sequencing methods. 41 The PMS2 gene has multiple pseudogenes, making it difficult to reliably detect mutations or characterize by sequencing.…”