Introduction 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.
Methods 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 >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.
Results Distal 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).
Conclusions 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 TBX6. Individuals with distal chromosome 16p11.2 microduplications should be screened for scoliosis to facilitate early treatment.
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Contributors BS, GH, MD and CAG conceived of the study; BS and GH carried out statistical analyses, LA compiled exome data; XB compiled supplemental table data; CAW, YK, JM, PG, CR and NM compiled and provided additional exome data from University of Iowa, University of Colorado and University of Texas; IA provided additional advice on CNV location methods; NW, MS, DJ, CJ, TJ and MO provided and analysed Geisinger dataset for CNVs and phenotypic data, and ST and TD validated CNVs. All authors edited the manuscript.
Funding Research reported in this publication was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases under Award Number R01AR067715, Eunice Kennedy Shriver National Institutes of Child Health and Human Development of the National Institutes of Health under the Award Number P01HD084387, the Marfan Foundation Faculty Grant award #81831, Washington University Institute of Clinical and Translational Sciences grant UL1 TR002345 from the National Center for Advancing Translational Sciences of the National Institutes of Health, Washington University Musculoskeletal Research Center (NIH/NIAMS P30 AR057235) and the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number U54 HD087011 to the Intellectual and Developmental Disabilities Research Center at Washington University.
Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Competing interests None declared.
Ethics approval The institutional review board at each institution approved this study.
Provenance and peer review Not commissioned; externally peer reviewed.
Author note Accession number for the AIS exome data reported in this paper are dbGAP: phs001677.