Am J Hum Genet.: co-auth.: A. Reymond

Am J Hum Genet. 2016 Aug 10. pii: S0002-9297(16)30229-4. doi: 10.1016/j.ajhg.2016.06.025. [Epub ahead of print]

GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability.


GNB5 encodes the G protein β subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision.

Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.


G-protein signaling; heart rate; hypotonia; intellectual disability; parasympathetic system; whole-exome sequencing

PMID: 27523599