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.

Rare Coding Variants in Patients with Non-Syndromic Vestibular Dysfunction

“…The DNA from these patients were collected and extracted from blood or saliva using the QIAamp DNA Mini Kit (Qiagen, Venlo, the Netherlands) and Oragene saliva kits, respectively. Cohort 3: European–American families with AIS were enrolled as previously described [ 10 , 11 , 12 ]. The families were selected for sequencing if the proband had no co-occurring congenital deformity or genetic disorder and was diagnosed with AIS based on a standing anteroposterior spinal radiograph showing ≥10° curvature by the Cobb method with pedicle rotation.…”

Computerized-Assisted Scoliosis Diagnosis Based on Faster R-CNN and ResNet for the Classification of Spine X-Ray Images

“…Verification of the target positioning of the spine area is shown in Table 2 . In the table, no disease, mild scoliosis disease, moderate scoliosis disease, and severe scoliosis disease [ 15 – 19 ] are represented by 1, 2, 3, and 4, respectively. Model 1, Model 2, Model 3, and Model 4 are four models generated by the fourfold cross-validation.…”

Zebrafish: an important model for understanding scoliosis

“…Compared to CS, IS is more complicated due to the lack of apparent causes. Exome sequencing analysis of the family population with IS revealed that some mutation sites were related to cilia, microtubule skeletons, extracellular matrices and muscles [ 12 , 48 , 52 , 80 – 86 ]. Recently, a potential relationship between cilia and scoliosis was suggested using a zebrafish model.…”