Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability.

Abstract

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.

• Authors: Natalie B Tan, Alistair T Pagnamenta, Matteo P Ferla, Jonathan Gadian, Brian Hy Chung, Marcus Cy Chan, Jasmine Lf Fung, Edwin Cook, Stephen Guter, Felix Boschann, Andre Heinen, Jens Schallner, Cyril Mignot, Boris Keren, Sandra Whalen, Catherine Sarret, Dana Mittag, Laurie Demmer, Rachel Stapleton, Ken Saida, Naomichi Matsumoto, Noriko Miyake, Ruth Sheffer, Hagar Mor-Shaked, Christopher P Barnett, Alicia B Byrne, Hamish S Scott, Alison Kraus, Gerarda Cappuccio, Nicola Brunetti-Pierri, Raffaele Iorio, Fabiola Di Dato, Lynn S Pais, Alison Yeung, Tiong Y Tan, Jenny C Taylor, John Christodoulou, Susan M White
• Journal: Journal of medical genetics (J Med Genet) Vol. 59 Issue 5 Pg. 511-516 (05 2022) ISSN: 1468-6244 [Electronic] England
• PMID: 34183358 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• GNB2 protein, human
• GTP-Binding Proteins

Topics

• GTP-Binding Proteins (genetics)
• Humans
• Intellectual Disability (genetics)
• Mutation, Missense (genetics)
• Neurodevelopmental Disorders (genetics)
• Phenotype
• Exome Sequencing