| Contributors: |
Lodder, Em; De Nittis, P; Koopman, Cd; Wiszniewski, W; de Souza, Cfm; Lahrouchi, N; Guex, N; Napolioni, V; Tessadori, F; Beekman, L; Nannenberg, Ea; Boualla, L; Blom, Na; de Graaff, W; Kamermans, M; Cocciadiferro, D; Malerba, N; Mandriani, B; Akdemir, Zhc; Fish, Rj; Eldomery, Mk; Ratbi, I; Wilde, Aam; de Boer, T; Simonds, Wf; Neerman-Arbez, M; Sutton, Vr; Kok, F; Lupski, Jr; Reymond, A; Bezzina, Cr; Bakkers, J; Merla, G |
| Description: |
GNB5 encodes the G protein beta 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 re flux, 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. |