Whole Genome Sequencing in Adolescent Idiopathic Scoliosis Cohort Indicates Polygenic Disease Involving Multiple Biological Pathways

Adolescent idiopathic scoliosis (AIS) is the most common nondegenerative spinal abnormality. Research indicates a strong correlation between genetics and AIS, with heritability estimates of 87.5%. However, the rarity of shared causative genes among patients, and the difficulty of replication between studies suggest that AIS is a highly complex polygenic disease. In this study, we utilized whole-genome sequencing (WGS) to comprehensively explore the genetic landscape of 119 AIS patients from 103 families. We implemented an automated WGS analysis pipeline powered by RareVision^TMconsisting of automated algorithms and manual curation. We identified clinically relevant candidate variants in 20/119 (16.8%) patients and potentially relevant strong or moderate candidate variants in another 73/119 (61.3%) patients. Candidate variants included coding and noncoding point mutations, along with structural variants and large indels, showing the utility of WGS. Candidate genes included AIS-associated genes (e.g.CHD7,COL11A1/2,FBN1/2,HSPG2,KIF7), as well as genes associated with other musculoskeletal and developmental syndromes where scoliosis is a known symptom (e.g.RYR1,GJB2,MYH2,MYH7). Association analysis showed 4 known AIS single nucleotide polymorphisms (rs12946942, rs10756785, rs3904778, rs7633294) also correlated with AIS in our cohort. Finally, through gene set enrichment analysis, we were able to identify 3 gene clusters involved in skeletal muscle contraction, extracellular matrix composition, and gene expression regulation. In summary, through scalable WGS-based familial testing we were able to (1) find clinically relevant genetic variations in the majority of our patients and (2) create a large dataset that allowed us to identify biological pathways relevant to AIS etiopathogenesis.