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 journalArticle

23 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

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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    Lodder, EM. M., De Nittis, P., Koopman, CD. D., Wiszniewski, W., Moura de Souza, CF. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, EA. A., Boualla, L., Blom, NA. A., de Graaff, W., Kamermans, M., Cocciadiferro, D., Malerba, N., Mandriani, B., Akdemir, ZHC. H. C., ... Merla, G. (2016). GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability. American Journal of Human Genetics, 99(3), 704-710. https://doi.org/10.1016/j.ajhg.2016.06.025