title: GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability.
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.
authors: Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors: Elisabeth M
authors: EM
authors: Lodder
authors: Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, viale Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy.
authors: Pasquelena
authors: P
authors: De Nittis
authors: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands; Hubrecht Institute- Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands.
authors: Charlotte D
authors: CD
authors: Koopman
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Wojciech
authors: W
authors: Wiszniewski
authors: Medical Genetics Service, Hospital de Clinicas de Porto Alegre, 2350 Porto Alegre, Brazil.
authors: Carolina Fischinger
authors: CF
authors: Moura de Souza
authors: Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors: Najim
authors: N
authors: Lahrouchi
authors: Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors: Nicolas
authors: N
authors: Guex
authors: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
authors: Valerio
authors: V
authors: Napolioni
authors: Hubrecht Institute- Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands.
authors: Federico
authors: F
authors: Tessadori
authors: Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors: Leander
authors: L
authors: Beekman
authors: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors: Eline A
authors: EA
authors: Nannenberg
authors: Centre de Génomique Humaine, Faculté de Médecine et Pharmacie, Mohammed V University of Rabat, 8007, Rabat, Morocco.
authors: Lamiae
authors: L
authors: Boualla
authors: Department of Pediatric Cardiology, Emma Children's Hospital, Academic Medical Centre, 1105 AZ Amsterdam, the Netherlands.
authors: Nico A
authors: NA
authors: Blom
authors: Retinal Signal Processing Lab, Netherlands Institute for Neuroscience, 1105 BA Amsterdam, the Netherlands.
authors: Wim
authors: W
authors: de Graaff
authors: Retinal Signal Processing Lab, Netherlands Institute for Neuroscience, 1105 BA Amsterdam, the Netherlands; Department of Genome Analysis, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors: Maarten
authors: M
authors: Kamermans
authors: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, viale Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy; PhD Program in Experimental and Regenerative Medicine, Faculty of Medicine, University of Foggia, 71121 Foggia, Italy.
authors: Dario
authors: D
authors: Cocciadiferro
authors: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, viale Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy; PhD Program in Experimental and Regenerative Medicine, Faculty of Medicine, University of Foggia, 71121 Foggia, Italy.
authors: Natascia
authors: N
authors: Malerba
authors: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, viale Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy; PhD Program in Molecular Genetics Applied to Medical Sciences, Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy.
authors: Barbara
authors: B
authors: Mandriani
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Zeynep Hande Coban
authors: ZHC
authors: Akdemir
authors: Department of Genetic Medicine and Development, University Medical Centre (CMU), 1211 Geneva, Switzerland.
authors: Richard J
authors: RJ
authors: Fish
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Mohammad K
authors: MK
authors: Eldomery
authors: Centre de Génomique Humaine, Faculté de Médecine et Pharmacie, Mohammed V University of Rabat, 8007, Rabat, Morocco.
authors: Ilham
authors: I
authors: Ratbi
authors: Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors: Arthur A M
authors: AAM
authors: Wilde
authors: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands.
authors: Teun
authors: T
authors: de Boer
authors: Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892-2560, USA.
authors: William F
authors: WF
authors: Simonds
authors: Department of Genetic Medicine and Development, University Medical Centre (CMU), 1211 Geneva, Switzerland.
authors: Marguerite
authors: M
authors: Neerman-Arbez
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors: V Reid
authors: VR
authors: Sutton
authors: Child Neurology Division, Department of Neurology, School of Medicine, University of Sao Paulo, 01246903 Sao Paulo, Brazil.
authors: Fernando
authors: F
authors: Kok
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: James R
authors: JR
authors: Lupski
authors: Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
authors: Alexandre
authors: A
authors: Reymond
authors: Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
authors: Connie R
authors: CR
authors: Bezzina
authors: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands; Hubrecht Institute- Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands. Electronic address: j.bakkers@hubrecht.eu.
authors: Jeroen
authors: J
authors: Bakkers
authors: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, viale Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy. Electronic address: g.merla@operapadrepio.it.
authors: Giuseppe
authors: G
authors: Merla
mesh_terms: D000293:Adolescent; D000818:Animals; D001919:Bradycardia / Q000235:genetics* / Q000503:physiopathology*; D002648:Child; D002658:Developmental Disabilities / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D044387:GTP-Binding Protein beta Subunits / Q000172:deficiency / Q000235:genetics*; D005764:Gastroesophageal Reflux / Q000235:genetics / Q000503:physiopathology; D017353:Gene Deletion; D005808:Genes, Recessive / Q000235:genetics*; D006339:Heart Rate / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D009123:Muscle Hypotonia / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012164:Retinal Diseases / Q000235:genetics / Q000503:physiopathology; D012640:Seizures / Q000235:genetics; D012849:Sinoatrial Node / Q000503:physiopathology*; D013577:Syndrome; D055815:Young Adult; D015027:Zebrafish / Q000235:genetics / Q000502:physiology; D029961:Zebrafish Proteins
chemical_list: C490611:GNB5 protein, human; D044387:GTP-Binding Protein beta Subunits; D029961:Zebrafish Proteins; C000618000:gnb5b protein, zebrafish
keywords: G-protein signaling; heart rate; hypotonia; intellectual disability; parasympathetic system; whole-exome sequencing