@article{ac08882855374e499b5e9879dd944018,
title = "Distal chromosome 16p11.2 duplications containing SH2B1 in patients with scoliosis",
abstract = "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.",
keywords = "16p11.2, copy-number, scoliosis",
author = "Brooke Sadler and Gabe Haller and Lilian Antunes and Xavier Bledsoe and Jose Morcuende and Philip Giampietro and Cathleen Raggio and Nancy Miller and Yared Kidane and Wise, {Carol A.} and Ina Amarillo and Nephi Walton and Mark Seeley and Darren Johnson and Conner Jenkins and Troy Jenkins and Matthew Oetjens and Tong, {R. Spencer} and Druley, {Todd E.} and Dobbs, {Matthew B.} and Gurnett, {Christina A.}",
note = "Funding Information: 1Department of neurology, Washington University in Saint louis School of Medicine, St. louis, Missouri, USa 2Department of Orthopedic Surgery, Washington University in Saint louis School of Medicine, St. louis, Missouri, USa 3Department of Orthopaedic Surgery and rehabilitation, University of iowa roy J and lucille a carver college of Medicine, iowa city, iowa, USa 4Department of genetics, St. christopher{\textquoteright}s Hospital for children, Philadelphia, Pennsylvania, USa 5Orthopedic Surgery, Pediatrics, Hospital for Special Surgery, new York city, new York, USa 6Department of Orthopedics, University of colorado at Denver - anschutz Medical campus, aurora, colorado, USa 7Sarah M. and charles e. Seay center for Musculoskeletal research, texas Scottish rite Hospital for children, Dallas, texas, USa 8Department of Pathology and immunology, Washington University in Saint louis School of Medicine, St. louis, Missouri, USa 9genomic Medicine, geisinger Health System, Danville, Pennsylvania, USa 10Department of Pediatrics, Washington University in Saint louis School of Medicine, St. louis, Missouri, USa 11Department of neurology, Division of Pediatric neurology, Washington University in St. louis School of Medicine, St. louis, Missouri, USa Acknowledgements We would like to thank the genome technology access center in the Department of genetics at Washington University School of Medicine for help with genomic analysis. the center is partially supported by national cancer institute (nci) cancer center Support grant #P30 ca91842 to the Siteman cancer center and by the institute for clinical and translational Sciences (ictS) / clinical and translational Science awards Program (ctSa) grant #Ul1rr024992 from the national center for research resources, a component of the national institutes of Health (niH) and niH roadmap for Medical research. Funded with support from University of Missouri Spinal cord injury research Program, Shriners Hospital for children and the children{\textquoteright}s Discovery institute of Washington University and St. louis children{\textquoteright}s Hospital, and Hope center Dna/rna Purification core at Washington University School of Medicine. computations were performed using the facilities of the Washington University center for High Performance computing, which were partially funded by niH grants 1S10rr022984-01a1 and 1S10OD018091-01. We would like to thank the patients and their families for their participation, as well as Drs Munish gupta, Keith Bridwell, Mike Kelly, Scott luhmann, Brian Kelly, luke Zebala, lawrence lenke and christi abeln. Funding Information: 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 & Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.",
year = "2019",
month = jul,
day = "1",
doi = "10.1136/jmedgenet-2018-105877",
language = "English (US)",
volume = "56",
pages = "427--433",
journal = "Journal of medical genetics",
issn = "0022-2593",
publisher = "BMJ Publishing Group",
number = "7",
}