Exome sequencing analysis identifies frequent oligogenic involvement and FLNB variants in adolescent idiopathic scoliosis.
J Med Genet
; 57(6): 405-413, 2020 06.
Article
em En
| MEDLINE
| ID: mdl-32381728
BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a genetically heterogeneous disease characterised by three-dimensional deformity of the spine in the absence of a congenital spinal anomaly or neurological musculoskeletal disorder. The clinical variability and incomplete penetrance of some genes linked with AIS indicate that this disease constitutes an oligogenic trait. OBJECTIVE: We aimed to explore the oligogenic nature of this disease and identify novel AIS genes. METHODS: We analysed rare damaging variants within AIS-associated genes by using exome sequencing in 40 AIS trios and 183 sporadic patients. RESULTS: Multiple variants within AIS-associated genes were identified in eight AIS trios, and five individuals harboured rare damaging variants in the FLNB gene. The patients showed more frequent oligogenicity than the controls. In the gene-based burden test, the top signal resided in FLNB. In functional studies, we found that the AIS-associated FLNB variants altered the protein's conformation and subcellular localisation and its interaction with other proteins (TTC26 and OFD1) involved in AIS. The most compelling evidence of an oligogenic basis was that the number of rare damaging variants was recognised as an independent prognostic factor for curve progression in Cox regression analysis. CONCLUSION: Our data indicate that AIS is an oligogenic disease and identify FLNB as a susceptibility gene for AIS.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Escoliose
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Predisposição Genética para Doença
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Estudos de Associação Genética
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Filaminas
Tipo de estudo:
Prognostic_studies
Limite:
Adolescent
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Child
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Female
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Humans
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Male
Idioma:
En
Revista:
J Med Genet
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China