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Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability
  1. Natalie B Tan1,2,3,
  2. Alistair T Pagnamenta4,
  3. Matteo P Ferla4,
  4. Jonathan Gadian5,
  5. Brian HY Chung6,
  6. Marcus CY Chan6,
  7. Jasmine LF Fung6,
  8. Edwin Cook7,
  9. Stephen Guter7,
  10. Felix Boschann8,
  11. Andre Heinen9,
  12. Jens Schallner10,
  13. Cyril Mignot11,
  14. Boris Keren11,
  15. Sandra Whalen12,
  16. Catherine Sarret13,
  17. Dana Mittag14,
  18. Laurie Demmer14,
  19. Rachel Stapleton15,
  20. Ken Saida16,
  21. Naomichi Matsumoto16,
  22. Noriko Miyake16,
  23. Ruth Sheffer17,
  24. Hagar Mor-Shaked17,
  25. Christopher P Barnett18,
  26. Alicia B Byrne19,20,
  27. Hamish S Scott19,
  28. Alison Kraus21,22,
  29. Gerarda Cappuccio23,24,
  30. Nicola Brunetti-Pierri23,24,
  31. Raffaele Iorio23,
  32. Fabiola Di Dato23,
  33. Lynn S Pais25,
  34. Alison Yeung1,2,3,
  35. Tiong Y Tan1,2,3,
  36. Jenny C Taylor4,
  37. John Christodoulou1,2,3,
  38. Susan M White1,2,3
  1. 1 Victorian Clinical Genetics Services, Parkville, Victoria 3052, Australia
  2. 2 Murdoch Children's Research Institute, Parkville, Victoria 3052, Australia
  3. 3 Department of Paediatrics, The University of Melbourne, Parkville 3052, Victoria, Australia
  4. 4 NIHR Oxford BRC, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  5. 5 Department of Paediatric Neurology, John Radcliffe Hospital, Oxford, UK
  6. 6 Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong
  7. 7 Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago 60608, Illinois, USA
  8. 8 Institute of Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany
  9. 9 Carl Gustav Carus Faculty of Medicine, Children's Hospital, Technical University Dresden, Dresden, Germany
  10. 10 Department of Neuropediatrics, Carl Gustav Carus Faculty of Medicine, Children's Hospital, Technical University Dresden, Dresden, Germany
  11. 11 Département de Génétique, Hôpital Pitié-Salpêtrière, APHP.Sorbonne Université, Paris, France
  12. 12 UF de Génétique Clinique, Centre de Référence Maladies Rares Anomalies du développement et syndromes malformatifs, APHP.Sorbonne Université, Hôpital Armand Trousseau, Paris, France
  13. 13 Service de génétique médicale, Hôpital Estaing, Centre hospitalo-universitaire de Clermont-Ferrand, 63003 Clermont-Ferrand, France
  14. 14 Division of Genetics, Levine Children’s Hospital, Carolinas Medical Center, Atrium Health, Charlotte 28232-2861, North Carolina, USA
  15. 15 Genetic Health Service NZ, Christchurch Hospital, Christchurch 8140, New Zealand
  16. 16 Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
  17. 17 Department of Human Genetics, Hadassah University Hospital, Jerusalem, Israel
  18. 18 South Australian Clinical Genetics Service, Women’s and Children’s Hospital, North Adelaide 5006, South Australia, Australia
  19. 19 Department of Genetics and Molecular Pathology, Centre for Cancer Biology, Adelaide, South Australia, Australia
  20. 20 UniSA Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia
  21. 21 Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds 0113 392 4455, UK
  22. 22 Castle Hill Hospital, Cottingham, Hull 01482 622470, UK
  23. 23 Department of Translational Medicine, Section of Pediatrics, Federico II University Hospital, Naples, Italy
  24. 24 Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy
  25. 25 Center for Mendelian Genomics, Eli and Edythe L Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
  1. Correspondence to A/Professor Susan M White, Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville 3052, Victoria, Australia; sue.white{at}; Professor John Christodoulou, Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville 3052, Victoria, Australia; john.christodoulou{at}


Purpose Binding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A de novo missense variant in GNB2 was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm GNB2 as a neurodevelopmental disease gene, and elucidate the GNB2-associated neurodevelopmental phenotype in a patient cohort.

Methods We discovered a GNB2 variant in the index case via exome sequencing and sought individuals with GNB2 variants via international data-sharing initiatives. In silico modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants.

Results We identified 12 unrelated individuals with five de novo missense variants in GNB2, four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction.

Conclusion Missense variants in GNB2 cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.

  • GNB2
  • G-beta protein
  • intellectual disability
  • developmental delay

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  • Correction notice This article has been corrected since it was published online first. The name of author Susan M White and the shading and layout of table 1 have been amended.

  • Contributors All coauthors have contributed to the preparation of the manuscript and approve the final submission.

  • Funding Funding for the UDP-Vic was provided by philanthropic donation and the Murdoch Children’s Research Institute. The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. NBT is supported by an NHMRC Postgraduate Scholarship (APP2005458) and acknowledges the Australian NHMRC Centre for Research Excellence in Neurocognitive Disorders (APP1079342) for their support. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. Data were also generated through the Deciphering Developmental Disorders (DDD) Study. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). This study makes use of DECIPHER ( which is funded by Wellcome. See Nature PMID: 25533962 or for full acknowledgement. This work was also supported by: the Wellcome Trust (203141/Z/16/Z); the NIHR Biomedical Research Centre Oxford with funding from the Department of Health's NIHR Biomedical Research Centre's funding scheme; AMED under the grant numbers JP20ek0109280, JP20dm0107090, JP20ek0109301, JP20ek0109348 and JP20kk0205012; JSPS KAKENHI under grant numbers JP17H01539 and JP19H03621; Autism Speaks; the NIH under grant numbers U54 HG003067 and U01 MH100233; the Telethon Foundation (GSP15001) and Telethon Undiagnosed Diseases Program (TUDP); NHMRC grant APP1123341; and the Australian Genomic Health Alliance NHMRC Targeted Call for Research into Preparing Australia for the Genomics Revolution in Healthcare (GNT1113531). ABB acknowledges the Australian Government Research Training Program Scholarship and the Australian Genomics Health Alliance PhD Award. BC, MCYC and JL-FF acknowledge the Duchess of Kent Children's Hospital for assistance in patient recruitment and the Autism Sequencing Consortium for sequencing and provision of raw exome data.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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