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

• DOI: 10.1016/j.ajhg.2016.06.025
• Publication Date: 2016-08-12T08:19:07Z
• Authors: Elisabeth M. Lodder; Pasquelena De Nittis; Charlotte D. Koopman; Wojciech Wiszniewski; Carolina Fisching...; Najim Lahrouchi; Nicolas Guex; Valerio Napolioni; Federico Tessadori; Leander Beekman; Eline A. Nannenberg; Lamiae Boualla; Nico A. Blom; Wim de Graaff; Maarten Kamermans; Dario Cocciadiferro; Natascia Malerba; Barbara Mandriani; Zeynep Hande Coba...; Richard J. Fish; Mohammad K. Eldomery; Ilham Ratbi; Arthur A.M. Wilde; Teun de Boer; William F. Simonds; Marguerite Neerma...; V. Reid Sutton; Fernando Kok; James R. Lupski; Alexandre Reymond; Connie R. Bezzina; Jeroen Bakkers; Giuseppe Merla
• Keywords: Male; Heterozygote; Parasympathetic system; Adolescent; Developmental Disabilities; Heart rate; G-protein signaling; Intellectual disability; Mutation, Missense; Hypotonia; Genes, Recessive; Retinal Diseases; Heart Rate; Journal Article; Genetics; Bradycardia; Animals; Humans; ddc:576.5; Genetics(clinical); Child; GTP-Binding Protein beta Subunits; Pedigree; 3. Good health; Phenotype; Whole-exome sequencing; Mutation; Gastroesophageal Reflux; Muscle Hypotonia; Female; Gene Deletion

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.