| First Author | Kruszka P | Year | 2017 |
| Journal | J Med Genet | PubMed ID | 28592524 |
| Mgi Jnum | J:244438 | Mgi Id | MGI:5913217 |
| Doi | 10.1136/jmedgenet-2017-104611 | Citation | Kruszka P, et al. (2017) Loss of function in ROBO1 is associated with tetralogy of Fallot and septal defects. J Med Genet 54(12):825-829 |
| abstractText | 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. |
