Distal chromosome 16p11.2 duplications containing SH2B1 in patients with scoliosis

Abstract

IntroductionAdolescent idiopathic scoliosis (AIS) is a common musculoskeletal disorder with strong evidence for a genetic contribution. CNVs play an important role in congenital scoliosis, but their role in idiopathic scoliosis has been largely unexplored.MethodsExome sequence data from 1197 AIS cases and 1664 in-house controls was analysed using coverage data to identify rare CNVs. CNV calls were filtered to include only highly confident CNVs with >10 average reads per region and mean log-ratio of coverage consistent with single-copy duplication or deletion. The frequency of 55 common recurrent CNVs was determined and correlated with clinical characteristics.ResultsDistal chromosome 16p11.2 microduplications containing the gene SH2B1 were found in 0.7% of AIS cases (8/1197). We replicated this finding in two additional AIS cohorts (8/1097 and 2/433), resulting in 0.7% (18/2727) of all AIS cases harbouring a chromosome 16p11.2 microduplication, compared with 0.06% of local controls (1/1664) and 0.04% of published controls (8/19584) (p=2.28×10−11, OR=16.15). Furthermore, examination of electronic health records of 92 455 patients from the Geisinger health system showed scoliosis in 30% (20/66) patients with chromosome 16p11.2 microduplications containing SH2B1 compared with 7.6% (10/132) of controls (p=5.6×10−4, OR=3.9).ConclusionsRecurrent distal chromosome 16p11.2 duplications explain nearly 1% of AIS. Distal chromosome 16p11.2 duplications may contribute to scoliosis pathogenesis by directly impairing growth or by altering expression of nearby genes, such as TBX6. Individuals with distal chromosome 16p11.2 microduplications should be screened for scoliosis to facilitate early treatment.

Exome sequencing analysis identifies frequent oligogenic involvement andFLNBvariants in adolescent idiopathic scoliosis

“…In one study, more than 6% of patients with AIS were found to harbour a clinically important copy number abnormality, and some of these abnormalities may play a role in AIS pathogenesis 44. In another comprehensive, large-scale study, distal chromosome 16p11.2 duplications were identified in approximately 1% of patents with AIS, who also presented an OR that was much higher than any other OR previously reported for AIS 45. The enrichment of CNVs is intriguing, and further studies examining the combination of single-nucleotide variants and CNVs may help to better elucidate the oligogenic model and genetic basis of AIS.…”

The role of 22q11.2 deletion syndrome in the relationship between congenital heart disease and scoliosis

“…Recent studies have suggested a general role for CNVs in the development of AIS [11,12]. Sadler et al reported that 16p11.2 duplications explain nearly 1% of AIS cases, in a study restricted to patients without major development impairment or major congenital anomalies [12].…”

“…Recent studies have suggested a general role for CNVs in the development of AIS [11,12]. Sadler et al reported that 16p11.2 duplications explain nearly 1% of AIS cases, in a study restricted to patients without major development impairment or major congenital anomalies [12]. Given that the 22q11.2DS population is characterized by broad phenotypic heterogeneity, with developmental impairment and congenital anomalies (eg, CHD) as common features, many patients with 22q11.2DS and scoliosis may have been excluded from the Sadler et al study.…”

“…There is a higher concordance of scoliosis in monozygotic twins (73%) and dizygotic twins (36%) than in unrelated individuals [10]. Notably, recent reports indicate that rare pathogenic copy number variants (CNVs) play a role in the development of AIS [11,12], as they do in CHD [13]. Also, in nature AIS only occurs in fully upright bipedal man [14][15][16].…”

Rare andde novoduplications containingSHOXin clubfoot

“…CNV analysis was performed using the software package FishingCNV that is designed to identify rare CNVs from exome sequencing data without the need for a paired control. We previously used this programme to successfully identify CNVs in an adolescent idiopathic scoliosis cohort 17. This programme uses an algorithm to prioritise rare variants, and compares coverage depth in a test sample against the background distribution, as well as principal components analysis to remove batch effects.…”