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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Child
  • DNA Copy Number Variations
  • Disease Models, Animal
  • Female
  • Genetic Association Studies
  • Heart Septal Defects / diagnosis*
  • Heart Septal Defects / genetics*
  • Humans
  • Infant
  • Loss of Function Mutation*
  • Male
  • Mice
  • Nerve Tissue Proteins / genetics*
  • Phenotype*
  • Polymorphism, Single Nucleotide
  • Receptors, Immunologic / genetics*
  • Tetralogy of Fallot / diagnosis*
  • Tetralogy of Fallot / genetics*


  • Nerve Tissue Proteins
  • Receptors, Immunologic
  • roundabout protein