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J Med Genet. 2017 Dec;54(12):825-829. doi: 10.1136/jmedgenet-2017-104611. Epub 2017 Jun 7.

Loss of function in ROBO1 is associated with tetralogy of Fallot and septal defects.

Author information

1
Medical Genetics Branch, National Human Genome Research Institute, The National Institutes of Health, Bethesda, Maryland, USA.
2
Division of Genetics and Metabolism, Children's National Health System, Washington, DC, USA.
3
Genetic Health Service New Zealand (Central Hub), Wellington, New Zealand.
4
Division of Pediatric Cardiology, Department of Pediatrics, Chiangmai University, Chiang Mai, Thailand.
5
Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
6
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.
7
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.
8
Division of Genetic Medicine, Seattle Children's Hospital, Seattle, Washington, USA.
9
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
10
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
11
Department of Medicine, Columbia University Medical Center, New York, New York, USA.

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.

KEYWORDS:

Congenital Heart Disease; ROBO1; tetralogy of Fallot

PMID:
28592524
DOI:
10.1136/jmedgenet-2017-104611
[Indexed for MEDLINE]

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