Identification of Copy Number Variants in a Southern Chinese Cohort of Patients with Congenital Scoliosis.

Wenjing Lai,Bo Gao,Prudence W H Cheung,Xin Feng,Jason Pui Yin Cheung,Ming Yue,You-Qiang Song,Keith D K Luk,Vanessa N T Choi

doi:10.3390/genes12081213

Abstract

Congenital scoliosis (CS) is a lateral curvature of the spine resulting from congenital vertebral malformations (CVMs) and affects 0.5–1/1000 live births. The copy number variant (CNV) at chromosome 16p11.2 has been implicated in CVMs and recent studies identified a compound heterozygosity of 16p11.2 microdeletion and TBX6 variant/haplotype causing CS in multiple cohorts, which explains about 5–10% of the affected cases. Here, we studied the genetic etiology of CS by analyzing CNVs in a cohort of 67 patients with congenital hemivertebrae and 125 family controls. We employed both candidate gene and family-based approaches to filter CNVs called from whole exome sequencing data. This identified 12 CNVs in four scoliosis-associated genes (TBX6, NOTCH2, DSCAM, and SNTG1) as well as eight recessive and 64 novel rare CNVs in 15 additional genes. Some candidates, such as DHX40, NBPF20, RASA2, and MYSM1, have been found to be associated with syndromes with scoliosis or implicated in bone/spine development. In particular, the MYSM1 mutant mouse showed spinal deformities. Our findings suggest that, in addition to the 16p11.2 microdeletion, other CNVs are potentially important in predisposing to CS.

Highlights

Among all musculoskeletal disorders, scoliosis is one of the most common diseases, affecting around 3% of the world population, which can occur as an isolated defect or as a concomitant symptom in other diseases or syndromes [1]
We found 64 novel, rare copy number variant (CNV) in 14 genes that occurred in multiple patients but are very rare in our control group and the general population, suggesting a potential role for genetic susceptibility in the development of congenital scoliosis (CS)
After excluding the homozygous CNVs that existed in both patients and controls, we identified unique homozygous CNVs in eight patients with CS

Summary

Introduction

Scoliosis is one of the most common diseases, affecting around 3% of the world population, which can occur as an isolated defect or as a concomitant symptom in other diseases or syndromes [1]. Scoliosis is categorized into several main groups, including congenital scoliosis (CS), idiopathic scoliosis (IS), neuromuscular scoliosis, and degenerative scoliosis. One of the most significant differences between CS and IS is that IS does not have an association with congenital vertebral malformation (CVM), whereas CVM is the major cause leading to CS. CVM can be classified into several subclasses, including failure of vertebral formation (e.g., hemivertebrae, wedged vertebrae), failure of vertebral segmentation (e.g., unilateral bar, block vertebrae), and mixed type. Of all CVMs, congenital hemivertebrae is the most common anomaly that causes CS [4,5]

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