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

Genes

Matthew R. G. Taylor¹  Robin Baschal²  Nancy Hadley Miller²  Cambria I. Wethey²  Elizabeth A. Terhune²  Melissa T. Cuevas²  Erin E. Baschal²  Morgan R. Bland²  Anna M. Monley²  Kenneth L. Jones³  G. Devon Trahan³ 

[1] Department of Medicine, Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;

关键词: idiopathic scoliosis;    exome sequencing;    spine;    polygenic;    variants;    musculoskeletal disease;   

DOI  :  10.3390/genes12060922

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown