Loss of function in ROBO1 is associated with tetralogy of Fallot and septal defects.
J Med Genet
; 54(12): 825-829, 2017 12.
Article
em En
| MEDLINE
| ID: mdl-28592524
ABSTRACT
BACKGROUND:
Congenital heart disease (CHD) is a common birth defect affecting approximately 1% of newborns. Great progress has been made in elucidating the genetic aetiology of CHD with advances in genomic technology, which we leveraged in recovering a new pathway affecting heart development in humans previously known to affect heart development in an animal model.METHODS:
Four hundred and sixteen individuals from Thailand and the USA diagnosed with CHD and/or congenital diaphragmatic hernia were evaluated with chromosomal microarray and whole exome sequencing. The DECIPHER Consortium and medical literature were searched for additional patients. Murine hearts from ENU-induced mouse mutants and transgenic mice were evaluated using both episcopic confocal histopathology and troponin I stained sections.RESULTS:
Loss of function ROBO1 variants were identified in three families; each proband had a ventricular septal defect, and one proband had tetralogy of Fallot. Additionally, a microdeletion in an individual with CHD was found in the medical literature. Mouse models showed perturbation of the Slit-Robo signalling pathway, causing septation and outflow tract defects and craniofacial anomalies. Two probands had variable facial features consistent with the mouse model.CONCLUSION:
Our findings identify Slit-Robo as a significant pathway in human heart development and CHD.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fenótipo
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Tetralogia de Fallot
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Receptores Imunológicos
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Mutação com Perda de Função
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Defeitos dos Septos Cardíacos
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Proteínas do Tecido Nervoso
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Child
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Female
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Humans
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Infant
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Male
Idioma:
En
Revista:
J Med Genet
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos