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

Brooke Sadler, Gabe Haller, Lilian Antunes, Xavier Bledsoe, Jose Morcuende, Philip Giampietro, Cathleen Raggio, Nancy Miller, Yared Kidane, Carol A. Wise, Ina Amarillo, Nephi Walton, Mark Seeley, Darren Johnson, Conner Jenkins, Troy Jenkins, Matthew Oetjens, R. Spencer Tong, Todd E. Druley, Matthew B. DobbsChristina A. Gurnett

Research output: Contribution to journalArticle

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 â '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 â '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.

Original languageEnglish (US)
JournalJournal of Medical Genetics
DOIs
StatePublished - Jan 1 2019

Fingerprint

Chromosome Duplication
Scoliosis
Chromosomes
Exome
Electronic Health Records

Keywords

  • 16p11.2
  • copy-number
  • scoliosis

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Sadler, B., Haller, G., Antunes, L., Bledsoe, X., Morcuende, J., Giampietro, P., ... Gurnett, C. A. (2019). Distal chromosome 16p11.2 duplications containing SH2B1 in patients with scoliosis. Journal of Medical Genetics. https://doi.org/10.1136/jmedgenet-2018-105877

Distal chromosome 16p11.2 duplications containing SH2B1 in patients with scoliosis. / Sadler, Brooke; Haller, Gabe; Antunes, Lilian; Bledsoe, Xavier; Morcuende, Jose; Giampietro, Philip; Raggio, Cathleen; Miller, Nancy; Kidane, Yared; Wise, Carol A.; Amarillo, Ina; Walton, Nephi; Seeley, Mark; Johnson, Darren; Jenkins, Conner; Jenkins, Troy; Oetjens, Matthew; Tong, R. Spencer; Druley, Todd E.; Dobbs, Matthew B.; Gurnett, Christina A.

In: Journal of Medical Genetics, 01.01.2019.

Research output: Contribution to journalArticle

Sadler, B, Haller, G, Antunes, L, Bledsoe, X, Morcuende, J, Giampietro, P, Raggio, C, Miller, N, Kidane, Y, Wise, CA, Amarillo, I, Walton, N, Seeley, M, Johnson, D, Jenkins, C, Jenkins, T, Oetjens, M, Tong, RS, Druley, TE, Dobbs, MB & Gurnett, CA 2019, 'Distal chromosome 16p11.2 duplications containing SH2B1 in patients with scoliosis', Journal of Medical Genetics. https://doi.org/10.1136/jmedgenet-2018-105877
Sadler, Brooke ; Haller, Gabe ; Antunes, Lilian ; Bledsoe, Xavier ; Morcuende, Jose ; Giampietro, Philip ; Raggio, Cathleen ; Miller, Nancy ; Kidane, Yared ; Wise, Carol A. ; Amarillo, Ina ; Walton, Nephi ; Seeley, Mark ; Johnson, Darren ; Jenkins, Conner ; Jenkins, Troy ; Oetjens, Matthew ; Tong, R. Spencer ; Druley, Todd E. ; Dobbs, Matthew B. ; Gurnett, Christina A. / Distal chromosome 16p11.2 duplications containing SH2B1 in patients with scoliosis. In: Journal of Medical Genetics. 2019.
@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 {\^a} '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 {\^a} '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.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1136/jmedgenet-2018-105877",
language = "English (US)",
journal = "Journal of Medical Genetics",
issn = "0022-2593",
publisher = "BMJ Publishing Group",

}

TY - JOUR

T1 - Distal chromosome 16p11.2 duplications containing SH2B1 in patients with scoliosis

AU - Sadler, Brooke

AU - Haller, Gabe

AU - Antunes, Lilian

AU - Bledsoe, Xavier

AU - Morcuende, Jose

AU - Giampietro, Philip

AU - Raggio, Cathleen

AU - Miller, Nancy

AU - Kidane, Yared

AU - Wise, Carol A.

AU - Amarillo, Ina

AU - Walton, Nephi

AU - Seeley, Mark

AU - Johnson, Darren

AU - Jenkins, Conner

AU - Jenkins, Troy

AU - Oetjens, Matthew

AU - Tong, R. Spencer

AU - Druley, Todd E.

AU - Dobbs, Matthew B.

AU - Gurnett, Christina A.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 â '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 â '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.

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 >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 â '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 â '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.

KW - 16p11.2

KW - copy-number

KW - scoliosis

UR - http://www.scopus.com/inward/record.url?scp=85062228635&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062228635&partnerID=8YFLogxK

U2 - 10.1136/jmedgenet-2018-105877

DO - 10.1136/jmedgenet-2018-105877

M3 - Article

C2 - 30803986

AN - SCOPUS:85062228635

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

ER -