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<jats:sec><jats:title>Introduction</jats:title><jats:p>Adolescent 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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Exome 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 &gt;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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Distal chromosome 16p11.2 microduplications containing the gene <jats:italic>SH2B1</jats:italic> 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<jats:sup>−11</jats:sup>, 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 <jats:italic>SH2B1</jats:italic> compared with 7.6% (10/132) of controls (p=5.6×10<jats:sup>−4</jats:sup>, OR=3.9).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Recurrent 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 <jats:italic>TBX6</jats:italic>. Individuals with distal chromosome 16p11.2 microduplications should be screened for scoliosis to facilitate early treatment.</jats:p></jats:sec>

Original publication




Journal article


Journal of Medical Genetics



Publication Date





427 - 433