Loss of function in ROBO1 is associated with tetralogy of Fallot and septal defects. Issue 12 (7th June 2017)

• Record Type: Journal Article
• Authors: Kruszka, Paul; Tanpaiboon, Pranoot; Neas, Katherine; Crosby, Kathleen; Berger, Seth I; Martinez, Ariel F; Addissie, Yonit A; Pongprot, Yupada; Sittiwangkul, Rekwan; Silvilairat, Suchaya; Makonkawkeyoon, Krit; Yu, Lan; Wynn, Julia; Bennett, James T; Mefford, Heather C; Reynolds, William T; Liu, Xiaoqin; Mommersteeg, Mathilda T M; Chung, Wendy K; Lo, Cecilia W; Muenke, Maximilian
• Is Part Of: Journal of medical genetics. Volume 54:Issue 12(2017)
• Page Start: 825
• Page End: 829
• Publication Date: 2017-06-07
• Subjects: Congenital Heart Disease -- ROBO1 -- tetralogy of Fallot; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2017-104611
• Languages: English
• ISSNs: 1468-6244

Abstract

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.