Purpose: Binding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Ga and Gß?units. Human diseases have been reported for all five Gß 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 Ga 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.
Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability / Tan, N. B.; Pagnamenta, A. T.; Ferla, M. P.; Gadian, J.; Chung, B. H. Y.; Chan, M. C. Y.; Fung, J. L. F.; Cook, E.; Guter, S.; Boschann, F.; Heinen, A.; Schallner, J.; Mignot, C.; Keren, B.; Whalen, S.; Sarret, C.; Mittag, D.; Demmer, L.; Stapleton, R.; Saida, K.; Matsumoto, N.; Miyake, N.; Sheffer, R.; Mor-Shaked, H.; Barnett, C. P.; Byrne, A. B.; Scott, H. S.; Kraus, A.; Cappuccio, G.; Brunetti Pierri, N.; Iorio, R.; Di Dato, F.; Pais, L. S.; Yeung, A.; Tan, T. Y.; Taylor, J. C.; Christodoulou, J.; White, S.. - In: JOURNAL OF MEDICAL GENETICS. - ISSN 0022-2593. - (2021), p. jmedgenet-2020-107462. [10.1136/jmedgenet-2020-107462]
Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability
Cappuccio G.;Brunetti Pierri N.;Iorio R.;Di Dato F.;
2021
Abstract
Purpose: Binding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Ga and Gß?units. Human diseases have been reported for all five Gß 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 Ga 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
