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

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

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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 (US)
Pages (from-to)704-710
Number of pages7
JournalAmerican Journal of Human Genetics
Volume99
Issue number3
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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