Exome Sequencing Identifies a Rare HSPG2 Variant Associated with Familial Idiopathic Scoliosis

Idiopathic scoliosis occurs in 3% of individuals and has an unknown etiology. The objective of this study was to identify rare variants that contribute to the etiology of idiopathic scoliosis by using exome sequencing in a multigenerational family with idiopathic scoliosis. Exome sequencing was comp...

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Main Authors:	Baschal, Erin E., Wethey, Cambria I., Swindle, Kandice, Baschal, Robin M., Gowan, Katherine, Tang, Nelson L.S., Alvarado, David M., Haller, Gabe E., Dobbs, Matthew B., Taylor, Matthew R.G., Gurnett, Christina A., Jones, Kenneth L., Miller, Nancy H.
Format:	Online
Language:	English
Published:	Genetics Society of America 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321025/

id	pubmed-4321025
recordtype	oai_dc
spelling	pubmed-43210252015-02-18 Exome Sequencing Identifies a Rare HSPG2 Variant Associated with Familial Idiopathic Scoliosis Baschal, Erin E. Wethey, Cambria I. Swindle, Kandice Baschal, Robin M. Gowan, Katherine Tang, Nelson L.S. Alvarado, David M. Haller, Gabe E. Dobbs, Matthew B. Taylor, Matthew R.G. Gurnett, Christina A. Jones, Kenneth L. Miller, Nancy H. Investigations Idiopathic scoliosis occurs in 3% of individuals and has an unknown etiology. The objective of this study was to identify rare variants that contribute to the etiology of idiopathic scoliosis by using exome sequencing in a multigenerational family with idiopathic scoliosis. Exome sequencing was completed for three members of this multigenerational family with idiopathic scoliosis, resulting in the identification of a variant in the HSPG2 gene as a potential contributor to the phenotype. The HSPG2 gene was sequenced in a separate cohort of 100 unrelated individuals affected with idiopathic scoliosis and also was examined in an independent idiopathic scoliosis population. The exome sequencing and subsequent bioinformatics filtering resulted in 16 potentially damaging and rare coding variants. One of these variants, p.Asn786Ser, is located in the HSPG2 gene. The variant p.Asn786Ser also is overrepresented in a larger cohort of idiopathic scoliosis cases compared with a control population (P = 0.024). Furthermore, we identified additional rare HSPG2 variants that are predicted to be damaging in two independent cohorts of individuals with idiopathic scoliosis. The HSPG2 gene encodes for a ubiquitous multifunctional protein within the extracellular matrix in which loss of function mutation are known to result in a musculoskeletal phenotype in both mouse and humans. Based on these results, we conclude that rare variants in the HSPG2 gene potentially contribute to the idiopathic scoliosis phenotype in a subset of patients with idiopathic scoliosis. Further studies must be completed to confirm the effect of the HSPG2 gene on the idiopathic scoliosis phenotype. Genetics Society of America 2014-12-12 /pmc/articles/PMC4321025/ /pubmed/25504735 http://dx.doi.org/10.1534/g3.114.015669 Text en Copyright © 2015 Baschal et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Unported License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Baschal, Erin E. Wethey, Cambria I. Swindle, Kandice Baschal, Robin M. Gowan, Katherine Tang, Nelson L.S. Alvarado, David M. Haller, Gabe E. Dobbs, Matthew B. Taylor, Matthew R.G. Gurnett, Christina A. Jones, Kenneth L. Miller, Nancy H.
spellingShingle	Baschal, Erin E. Wethey, Cambria I. Swindle, Kandice Baschal, Robin M. Gowan, Katherine Tang, Nelson L.S. Alvarado, David M. Haller, Gabe E. Dobbs, Matthew B. Taylor, Matthew R.G. Gurnett, Christina A. Jones, Kenneth L. Miller, Nancy H. Exome Sequencing Identifies a Rare HSPG2 Variant Associated with Familial Idiopathic Scoliosis
author_facet	Baschal, Erin E. Wethey, Cambria I. Swindle, Kandice Baschal, Robin M. Gowan, Katherine Tang, Nelson L.S. Alvarado, David M. Haller, Gabe E. Dobbs, Matthew B. Taylor, Matthew R.G. Gurnett, Christina A. Jones, Kenneth L. Miller, Nancy H.
author_sort	Baschal, Erin E.
title	Exome Sequencing Identifies a Rare HSPG2 Variant Associated with Familial Idiopathic Scoliosis
title_short	Exome Sequencing Identifies a Rare HSPG2 Variant Associated with Familial Idiopathic Scoliosis
title_full	Exome Sequencing Identifies a Rare HSPG2 Variant Associated with Familial Idiopathic Scoliosis
title_fullStr	Exome Sequencing Identifies a Rare HSPG2 Variant Associated with Familial Idiopathic Scoliosis
title_full_unstemmed	Exome Sequencing Identifies a Rare HSPG2 Variant Associated with Familial Idiopathic Scoliosis
title_sort	exome sequencing identifies a rare hspg2 variant associated with familial idiopathic scoliosis
description	Idiopathic scoliosis occurs in 3% of individuals and has an unknown etiology. The objective of this study was to identify rare variants that contribute to the etiology of idiopathic scoliosis by using exome sequencing in a multigenerational family with idiopathic scoliosis. Exome sequencing was completed for three members of this multigenerational family with idiopathic scoliosis, resulting in the identification of a variant in the HSPG2 gene as a potential contributor to the phenotype. The HSPG2 gene was sequenced in a separate cohort of 100 unrelated individuals affected with idiopathic scoliosis and also was examined in an independent idiopathic scoliosis population. The exome sequencing and subsequent bioinformatics filtering resulted in 16 potentially damaging and rare coding variants. One of these variants, p.Asn786Ser, is located in the HSPG2 gene. The variant p.Asn786Ser also is overrepresented in a larger cohort of idiopathic scoliosis cases compared with a control population (P = 0.024). Furthermore, we identified additional rare HSPG2 variants that are predicted to be damaging in two independent cohorts of individuals with idiopathic scoliosis. The HSPG2 gene encodes for a ubiquitous multifunctional protein within the extracellular matrix in which loss of function mutation are known to result in a musculoskeletal phenotype in both mouse and humans. Based on these results, we conclude that rare variants in the HSPG2 gene potentially contribute to the idiopathic scoliosis phenotype in a subset of patients with idiopathic scoliosis. Further studies must be completed to confirm the effect of the HSPG2 gene on the idiopathic scoliosis phenotype.
publisher	Genetics Society of America
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321025/
_version_	1613185625707511808

Exome Sequencing Identifies a Rare HSPG2 Variant Associated with Familial Idiopathic Scoliosis

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