title: Exome sequencing identifies a rare HSPG2 variant associated with familial idiopathic scoliosis.
abstract: 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.
authors.affiliation: Department of Orthopedics, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, 80045.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Baschal
authors.affiliation: Department of Orthopedics, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, 80045.
authors.forename: Cambria I
authors.initials: CI
authors.lastname: Wethey
authors.affiliation: Department of Orthopedics, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, 80045.
authors.forename: Kandice
authors.initials: K
authors.lastname: Swindle
authors.affiliation: Musculoskeletal Research Center, Children's Hospital Colorado, Aurora, Colorado, 80045.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Baschal
authors.affiliation: Department of Biochemistry, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, 80045.
authors.forename: Katherine
authors.initials: K
authors.lastname: Gowan
authors.affiliation: Department of Chemical Pathology and Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Nelson L S
authors.initials: NL
authors.lastname: Tang
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, 63130.
authors.forename: David M
authors.initials: DM
authors.lastname: Alvarado
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, 63130.
authors.forename: Gabe E
authors.initials: GE
authors.lastname: Haller
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, 63130 Saint Louis Shriners Hospital for Children, St. Louis, Missouri, 63131.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Dobbs
authors.affiliation: Department of Cardiology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, 80045.
authors.forename: Matthew R G
authors.initials: MR
authors.lastname: Taylor
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, 63130 Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, 63130.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Gurnett
authors.affiliation: Department of Biochemistry, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, 80045.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Jones
authors.affiliation: Department of Orthopedics, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, 80045 Musculoskeletal Research Center, Children's Hospital Colorado, Aurora, Colorado, 80045 Nancy.Hadley-Miller@ucdenver.edu.
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Miller
mesh_terms: D059472:Exome / Q000235:genetics*; D014644:Genetic Variation; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics*; D006801:Humans; D008297:Male; D010641:Phenotype; D012600:Scoliosis / Q000235:genetics*; D017421:Sequence Analysis
chemical_list: D019812:Heparan Sulfate Proteoglycans; C071927:perlecan
keywords: HSPG2; exome sequencing; idiopathic scoliosis; perlecan