RT Journal Article
SR Electronic
T1 Recurrent <em>de novo</em> missense variants in <em>GNB2</em> can cause syndromic intellectual disability
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 511
OP 516
DO 10.1136/jmedgenet-2020-107462
VO 59
IS 5
A1 Natalie B Tan
A1 Alistair T Pagnamenta
A1 Matteo P Ferla
A1 Jonathan Gadian
A1 Brian HY Chung
A1 Marcus CY Chan
A1 Jasmine LF Fung
A1 Edwin Cook
A1 Stephen Guter
A1 Felix Boschann
A1 Andre Heinen
A1 Jens Schallner
A1 Cyril Mignot
A1 Boris Keren
A1 Sandra Whalen
A1 Catherine Sarret
A1 Dana Mittag
A1 Laurie Demmer
A1 Rachel Stapleton
A1 Ken Saida
A1 Naomichi Matsumoto
A1 Noriko Miyake
A1 Ruth Sheffer
A1 Hagar Mor-Shaked
A1 Christopher P Barnett
A1 Alicia B Byrne
A1 Hamish S Scott
A1 Alison Kraus
A1 Gerarda Cappuccio
A1 Nicola Brunetti-Pierri
A1 Raffaele Iorio
A1 Fabiola Di Dato
A1 Lynn S Pais
A1 Alison Yeung
A1 Tiong Y Tan
A1 Jenny C Taylor
A1 John Christodoulou
A1 Susan M White
YR 2022
UL http://jmg.bmj.com/content/59/5/511.abstract
AB 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.