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

Abstract

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.

The epileptology of GNB5 encephalopathy

“…1 There is one additional published family from Turkey with six affected individuals; the DEE was described in one child and mirrors our cases. In addition to our five new cases, we obtained additional epilepsy phenotyping data on four individuals from three published families to delineate the picture of GNB5-DEE.…”

“…1 All nine of our children had biallelic variants predicted to result in protein truncation and a profound DEE. 1 All nine of our children had biallelic variants predicted to result in protein truncation and a profound DEE.…”

“…1 All nine of our children had biallelic variants predicted to result in protein truncation and a profound DEE. 1,4 Two siblings without seizures were homozygous for a variant that was predicted to affect splicing, but this was not proven in vitro. Homozygosity for the same missense variant has been seen in three families with nonepileptic, milder phenotypes, with either speech delay or mild intellectual disability.…”

“…6 Gβ5 downregulates central nervous system G-protein signaling via interactions with G-protein-coupled receptors. 1 Here we delineate the epileptology of GNB5 developmental and epileptic encephalopathy in five new and four previously reported patients, 1 enabling earlier recognition of GNB5 developmental and epileptic encephalopathy (DEE). 4 GNB5 knockout mice have impaired neurologic, cardiac, and retinal function.…”

“…1 Twenty-two affected individuals from 10 families were reported in 2016-2018. 1 Twenty-two affected individuals from 10 families were reported in 2016-2018.…”