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

Elizabeth A Terhune,Kenneth L Jones,Erin E Baschal,Cambria I Wethey,Robin Baschal,G Devon Trahan,Matthew R G Taylor,Morgan R Bland,Anna M Monley,Melissa T Cuevas,Nancy Hadley Miller

doi:10.3390/genes12060922

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.

Highlights

Adolescent idiopathic scoliosis (AIS) is a structural lateral spinal curvature ≥10◦ that affects 2–3% of healthy children [1], with females at the greatest risk for severe progression [2,3,4]
To identify rare and low frequency variants associated with familial AIS, we performed whole exome sequencing on 23 multigenerational IS families (3–5 individuals per family, 86 individuals in total)
Illumina HiSeq reads were mapped to the human reference genome, and a minimum of 50X average coverage was obtained for each sample

Summary

Introduction

Adolescent idiopathic scoliosis (AIS) is a structural lateral spinal curvature ≥10◦ that affects 2–3% of healthy children [1], with females at the greatest risk for severe progression [2,3,4]. To understand the genetics of AIS, traditional approaches including genome wide association studies (GWAS), exome sequencing, and familial linkage studies have been applied to multiple populations. GWAS of unrelated individuals with AIS have identified potential common risk alleles, notably those in or near LBX1 [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23] and GPR126/ADGRG6 [23,24,25,26,27], which are the most well-replicated genetic findings to date across populations. The inability far to relate specific genetic variants to the biology of AIS and the wide variation in which AIS presents are indicative of the complex heterogeneity of this disorder

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Discussion

Conclusion