Familial idiopathic scoliosis: gene discovery and functional studies Idiopathic scoliosis (IS) is a structural lateral curvature of the spine of =10 of unknown etiology. IS affects 3% of otherwise normal children, with females at the greatest risk for severe progression. Current treatment options are limited to observation, physical therapy, bracing, and surgery, and are primarily directed to addressing the physical and cosmetic deformity. IS occurs clinically in both sporadic and familial forms, but neither the genetic nor th molecular etiology for the disorder is currently understood. The discovery of IS genes and pathways would greatly enhance the overall understanding of the pathogenesis of this disorder and aid in the development of targeted diagnostics and therapeutics. Genetic studies in IS have identified multiple regions that potentially contribute to the disorder; however, very few genes have been directly implicated in the pathogenesis of IS. Historically, the ability to screen for rae variants with large individual effects at the genome-wide level has been economically prohibitive. Advances in Next Generation (NextGen) DNA sequencing technology allow for economical short-read DNA sequencing, focusing on the protein coding aspects of the genome (the exome). We will bring NextGen technology to our unique familial idiopathic scoliosis (FIS) study cohort of 725 families with 2505 individuals. Our innovative strategy for the detection of variants related to FIS etiology is to focus on families with a high disease burden, and, thus, are likely to harbor rare variants with large effects. The central hypothesis of this proposal is that multiple rare pathogenic coding variants are responsible for the FIS phenotype and will be identified by exome sequencing and functional experiments in cells and mouse models.
Our specific aims are: 1) to perform exome sequencing in 27 extended multigenerational families to discover new FIS genes (discovery cohort), 2) to validate these newly identified FIS genes in a second population of 200 FIS families (validation cohort), and 3) to investigate the function of identified variants in both cell culture and mouse model systems, directed to validation of human- specific FIS variants and mechanistic insight into the etiology of FIS. Our group has invested over 20 years studying and collecting large families affected by severe FIS. This proposal is a novel approach directed to FIS gene discovery. The primary goal of this work is to identify genes that contribute to the FIS phenotype, which will provide entry points for the investigation of the mechanisms underlying disease susceptibility and severe progression of deformity. The discoveries from this work will ultimately give us insight into the biological processes that influence the development of the immature skeleton and could aid in the advancement of personalized therapeutic interventions for FIS.

Public Health Relevance

Idiopathic scoliosis (IS) is the most common deformity of the spine in children, with an estimated annual cost of over $3 billion per year. Individuals with IS face lifelong issues, including cosmetic deformity, bracing, and surgery, with females at the greatest risk for severe disease. Family history is a known risk factor for IS, but the genetic causes of the disease are not well understood. We will use cutting-edge DNA sequencing to discover new IS genes, shedding much needed light on the disease process, advancing diagnostics, and paving the way for developing novel therapies.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Washabaugh, Charles H
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University of Colorado Denver
Schools of Medicine
United States
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Baschal, Erin E; Terhune, Elizabeth A; Wethey, Cambria I et al. (2018) Idiopathic Scoliosis Families Highlight Actin-Based and Microtubule-Based Cellular Projections and Extracellular Matrix in Disease Etiology. G3 (Bethesda) 8:2663-2672