Identification of susceptibility loci for scoliosis in FIS families with triple curves

Marosy, Beth; Justice, Cristina M.; Vu, Cuong Manh; Zorn, A.; Nzegwu, Nneka; Wilson, Alexander F.; Miller, Nancy H.

doi:10.1002/ajmg.a.33222

Cited by 17 publications

(16 citation statements)

References 48 publications

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“…The current literature includes multiple studies that have used linkage and association analyses. Genome-wide linkage analyses have effectively localized candidate regions; however, progress has been burdened by heterogeneity both within and between study populations and by insufficient statistical power ( Wise et al 2000 ; Chan et al 2002 ; Salehi et al 2002 ; Justice et al 2003 ; Miller et al 2005 , 2006 ; Alden et al 2006 ; Ocaka et al 2008 ; Gurnett et al 2009 ; Raggio et al 2009 ; Clough et al 2010 ; Marosy et al 2010 ; Edery et al 2011 ). Association studies, including genome-wide association studies (GWAS), have implicated select genes, including CHD7 , LBX1 , and GPR126 ( Gao et al 2007 ; Sharma et al 2011 ; Takahashi et al 2011 ; Kou et al 2013 ).…”

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confidence: 99%

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

Baschal

Wethey

Swindle

et al. 2015

G3 Genes|Genomes|Genetics

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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.

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confidence: 99%

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

Baschal

Wethey

Swindle

et al. 2015

G3 Genes|Genomes|Genetics

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“…Recently, a genome-wide association study was performed in a Japanese population and three SNPs (single nucleotide polymorphisms), near LBX1 on 10q24.31, were associated with adolescent idiopathic scoliosis [Takahashi et al, 2011;Gao et al, 2013]. Indeed, LBX1 has been identified as a candidate gene for familial idiopathic scoliosis [Marosy et al, 2010]. Here, we describe the first case of the isolated microduplication of this gene.…”

Section: Introductionmentioning

confidence: 80%

“…Variable penetrance, underlying parental mosaicism, or the function of regulatory genes could explain the heterogeneity of these genetic alterations. Although LBX1 has been related to idiopathic scoliosis [Marosy et al, 2010;Takahashi et al, 2011;Gao et al, 2013], there are no cases with SHFM3 with described scoliosis, vertebrae malformations, or myopathy. Furthermore, 15% of SHFM3 patients have intellectual disability, usually severe [Elliott and Evans, 2006].…”

Section: Discussionmentioning

confidence: 99%

Microduplication 10q24.31 in a Spanish girl with scoliosis and myopathy: The critical role of LBX

Fernández-Jaén

Suela²,

Fernández-Mayoralas

et al. 2014

American J of Med Genetics Pt A

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LBX1 plays a cardinal role in neuronal and muscular development in animal models. Its function in humans is unknown; it has been reported as a candidate gene for idiopathic scoliosis. Our goal is to document the first clinical case of a microduplication at 10q24.31 (chr10:102927883-103053612, hg19), affecting exclusively LBX1. The patient, a 12-year-old girl, showed attention problems, dyspraxia, idiopathic congenital scoliosis, and marked hypotrophy of paravertebral muscles. Her paternal aunt had a severe and progressive myopathy with a genetic study that revealed the same duplication. We propose to consider genetic studies, particularly of LBX1, in patients with scoliosis and/or hypotrophy-hypoplasia of paravertebral muscles of unknown etiology.

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“…Nevertheless, an association between a polymorphism of the FBN1 gene and AIS was not found [179]. Twenty-one candidate genes on chromosomes 6 and 10 were found in families with triple IS spine deformities [180]. Salehi et al [181] reported on the link between familial IS and 17p11 (D17S947-D17S798) gene polymorphism.…”

Section: Genetic Factors Study Of Ais In Twins Demonstratedmentioning

confidence: 99%

Ultrastructure of Intervertebral Disc and Vertebra-Disc Junctions Zones as a Link in Etiopathogenesis of Idiopathic Scoliosis

Burger

Noshchenko

Patel

et al. 2014

Advances in Orthopedic Surgery

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Background Context. There is no general accepted theory on the etiology of idiopathic scoliosis (IS). An important role of the vertebrae endplate physes (VEPh) and intervertebral discs (IVD) in spinal curve progression is acknowledged, but ultrastructural mechanisms are not well understood.Purpose. To analyze the current literature on ultrastructural characteristics of VEPh and IVD in the context of IS etiology.Study Design/Setting. A literature review.Results. There is strong evidence for multifactorial etiology of IS. Early wedging of vertebra bodies is likely due to laterally directed appositional bone growth at the concave side, caused by a combination of increased cell proliferation at the vertebrae endplate and altered mechanical properties of the outer annulus fibrosus of the adjacent IVD. Genetic defects in bending proteins necessary for IVD lamellar organization underlie altered mechanical properties. Asymmetrical ligaments, muscular stretch, and spine instability may also play roles in curve formation.Conclusions. Development of a reliable, cost effective method for identifying patients at high risk for curve progression is needed and could lead to a paradigm shift in treatment options. Unnecessary anxiety, bracing, and radiation could potentially be minimized and high risk patient could receive surgery earlier, rendering better outcomes with fewer fused segments needed to mitigate curve progression.

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Identification of susceptibility loci for scoliosis in FIS families with triple curves

Cited by 17 publications

References 48 publications

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

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

Microduplication 10q24.31 in a Spanish girl with scoliosis and myopathy: The critical role of LBX

Ultrastructure of Intervertebral Disc and Vertebra-Disc Junctions Zones as a Link in Etiopathogenesis of Idiopathic Scoliosis

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