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

Elisabeth M Lodder, Pasquelena De Nittis, Charlotte D Koopman, Wojciech Wiszniewski, Carolina Fischinger Moura de Souza, Najim Lahrouchi, Nicolas Guex, Valerio Napolioni, Federico Tessadori, Leander Beekman, Eline A Nannenberg, Lamiae Boualla, Nico A Blom, Wim de Graaff, M. Kamermans, Dario Cocciadiferro, Natascia Malerba, Barbara Mandriani, Zeynep Hande Coban Akdemir, Richard J FishMohammad K Eldomery, Ilham Ratbi, Arthur A M Wilde, Teun de Boer, William F Simonds, Marguerite Neerman-Arbez, V Reid Sutton, Fernando Kok, James R Lupski, Alexandre Reymond, Connie R Bezzina, Jeroen Bakkers, Giuseppe Merla

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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.

Original languageEnglish
Pages (from-to)704-710
JournalAmerican Journal of Human Genetics
Volume99
DOIs
Publication statusPublished - 2016

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