Whole Exome Sequencing of 23 Multigeneration Idiopathic Scoliosis Families Reveals Enrichments in Cytoskeletal Variants, Suggests Highly Polygenic Disease

Abstract

Adolescent idiopathic scoliosis (AIS) is a lateral spinal curvature >10° with rotation that affects 2-3% of healthy children across populations. AIS is known to have a significant genetic component, and despite a handful of risk loci identified in unrelated individuals by GWAS and next-generation sequencing methods, the underlying etiology of the condition remains largely unknown. In this study, we performed exome sequencing of affected individuals within 23 multigenerational families, with the hypothesis that the occurrence of rare, low frequency, disease-causing variants will co-occur in distantly related, affected individuals. Bioinformatic filtering of uncommon, potentially damaging variants shared by all sequenced family members revealed 1448 variants in 1160 genes across the 23 families, with 132 genes shared by two or more families. Ten genes were shared by >4 families, and no genes were shared by all. Gene enrichment analysis showed an enrichment of variants in cytoskeletal and extracellular matrix related processes. These data support a model that AIS is a highly polygenic disease, with few variant-containing genes shared between affected individuals across different family lineages. This work presents a novel resource for further exploration in familial AIS genetic research.

Keywords: cytoskeleton; exome sequencing; extracellular matrix; idiopathic scoliosis; musculoskeletal disease; polygenic; spine; variants.

Figure 2

Summary information for total gene list (n = 1160) of familial AIS-associated variants across families with a minor allele frequency (MAF) <0.05 passing bioinformatic filtering, as described in the Methods. (A) Variant type with n variants and % of total provided. (B) Minor allele frequency of all variants using ExAC. (C) Variant counts by chromosome. (D) Top GO Cellular Component, 2018 terms using EnrichR. See Table 2 for top GO terms using DAVID. (E) Volcano plot of top enriched KEGG terms over expected.

Figure 1

Project overview of subject enrollment, sample collection and extraction, exome sequencing, and bioinformatic filtering strategy.