PT - JOURNAL ARTICLE AU - Brooke Sadler AU - Gabe Haller AU - Lilian Antunes AU - Xavier Bledsoe AU - Jose Morcuende AU - Philip Giampietro AU - Cathleen Raggio AU - Nancy Miller AU - Yared Kidane AU - Carol A Wise AU - Ina Amarillo AU - Nephi Walton AU - Mark Seeley AU - Darren Johnson AU - Conner Jenkins AU - Troy Jenkins AU - Matthew Oetjens AU - R Spencer Tong AU - Todd E Druley AU - Matthew B Dobbs AU - Christina A Gurnett TI - Distal chromosome 16p11.2 duplications containing <em>SH2B1</em> in patients with scoliosis AID - 10.1136/jmedgenet-2018-105877 DP - 2019 Jul 01 TA - Journal of Medical Genetics PG - 427--433 VI - 56 IP - 7 4099 - http://jmg.bmj.com/content/56/7/427.short 4100 - http://jmg.bmj.com/content/56/7/427.full SO - J Med Genet2019 Jul 01; 56 AB - 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 &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.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.