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

Am J Hum Genet. 2016 Sep 1;99(3):704-710. doi: 10.1016/j.ajhg.2016.06.025. Epub 2016 Aug 11.


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.

Keywords: G-protein signaling; heart rate; hypotonia; intellectual disability; parasympathetic system; whole-exome sequencing.

MeSH terms

  • Adolescent
  • Animals
  • Bradycardia / genetics*
  • Bradycardia / physiopathology*
  • Child
  • Developmental Disabilities / genetics*
  • Developmental Disabilities / physiopathology
  • Female
  • GTP-Binding Protein beta Subunits / deficiency
  • GTP-Binding Protein beta Subunits / genetics*
  • Gastroesophageal Reflux / genetics
  • Gastroesophageal Reflux / physiopathology
  • Gene Deletion
  • Genes, Recessive / genetics*
  • Heart Rate / genetics
  • Heterozygote
  • Humans
  • Male
  • Muscle Hypotonia / genetics
  • Mutation / genetics*
  • Mutation, Missense / genetics
  • Pedigree
  • Phenotype
  • Retinal Diseases / genetics
  • Retinal Diseases / physiopathology
  • Seizures / genetics
  • Sinoatrial Node / physiopathology*
  • Syndrome
  • Young Adult
  • Zebrafish / genetics
  • Zebrafish / physiology
  • Zebrafish Proteins


  • GNB5 protein, human
  • GTP-Binding Protein beta Subunits
  • Zebrafish Proteins
  • gnb5b protein, zebrafish