Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures.
Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein subunit beta-1, Gβ. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p = 7.1 × 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gβ binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gβγ interaction (resulting in a constitutively active Gβγ) or through the disruption of residues relevant for interaction between Gβγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA; Department of Medicine, Austin Health and Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3050, Australia. Electronic address: slavep@unimelb.edu.au.
Slavé
S
Petrovski
Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France.
Sébastien
S
Küry
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195, USA.
Candace T
CT
Myers
Division of Clinical Genetics, Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
Kwame
K
Anyane-Yeboa
Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France.
Benjamin
B
Cogné
Division of Medical Genetics, Northwell Health, Manhasset, NY 11030, USA.
Martin
M
Bialer
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Fan
F
Xia
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
Parisa
P
Hemati
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
James
J
Riviello
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195, USA.
Michele
M
Mehaffey
Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France.
Thomas
T
Besnard
Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Emily
E
Becraft
Section of Genetics, Department of Pediatrics, University of Oklahoma, Oklahoma City, OK 73019, USA.
Alexandrea
A
Wadley
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
Anya Revah
AR
Politi
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
Sophie
S
Colombo
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
Xiaolin
X
Zhu
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
Zhong
Z
Ren
School of Women's and Children's Health, University of New South Wales, Kensington, NSW 2052, Australia.
Ian
I
Andrews
Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia; Priority Research Centre GrowUpWell, University of Newcastle, Callaghan, NSW 2308, Australia.
Tracy
T
Dudding-Byth
Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC 3081, Australia.
Amy L
AL
Schneider
Department of Neurosciences, Royal Children's Hospital, Herston School of Medicine, University of Queensland, Brisbane, QLD 4072, Australia.
Geoffrey
G
Wallace
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195, USA.
Aaron B I
ABI
Rosen
Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Susan
S
Schelley
Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Gregory M
GM
Enns
Service de Stomatologie, Centre Hospitalier Universitaire Nantes, Nantes 44093, France.
Pierre
P
Corre
Department of Neurology, University of Minnesota, Minneapolis, MN 55454, USA.
Joline
J
Dalton
Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France.
Sandra
S
Mercier
Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France.
Xénia
X
Latypova
Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France.
Sébastien
S
Schmitt
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
Edwin
E
Guzman
Division of Medical Genetics, Northwell Health, Manhasset, NY 11030, USA.
Christine
C
Moore
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
Louise
L
Bier
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
Erin L
EL
Heinzen
Department of Neurology, University of Minnesota, Minneapolis, MN 55454, USA.
Peter
P
Karachunski
Division of Genetics, Department of Pediatrics, Albany Medical Center, Albany, NY 12208, USA.
Natasha
N
Shur
Phoenix Children's Hospital and Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ 85724, USA.
Theresa
T
Grebe
Cook Children's Physician Network, Fort Worth, TX 76102, USA.
Alice
A
Basinger
Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Joanne M
JM
Nguyen
Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France.
Stéphane
S
Bézieau
Section of Genetics, Department of Pediatrics, University of Oklahoma, Oklahoma City, OK 73019, USA.
Klaas
K
Wierenga
Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Jonathan A
JA
Bernstein
Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC 3081, Australia; Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3050, Australia; Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, VIC 3050, Australia.
Ingrid E
IE
Scheffer
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Jill A
JA
Rosenfeld
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195, USA.
Heather C
HC
Mefford
Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France.
Bertrand
B
Isidor
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA. Electronic address: dg2875@cumc.columbia.edu.
David B
DB
Goldstein
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000209:etiology* / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D044387:GTP-Binding Protein beta Subunits / Q000737:chemistry / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000209:etiology* / Q000473:pathology; D008297:Male; D009123:Muscle Hypotonia / Q000209:etiology* / Q000473:pathology; D010641:Phenotype; D011487:Protein Conformation; D012640:Seizures / Q000209:etiology* / Q000473:pathology; D015398:Signal Transduction; D055815:Young Adult
C516790:GNB1 protein, human; D044387:GTP-Binding Protein beta Subunits