Tan Natalie B, Pagnamenta Alistair T, Ferla Matteo P, Gadian Jonathan, Chung Brian Hy, Chan Marcus Cy, Fung Jasmine Lf, Cook Edwin, Guter Stephen, Boschann Felix, Heinen Andre, Schallner Jens, Mignot Cyril, Keren Boris, Whalen Sandra, Sarret Catherine, Mittag Dana, Demmer Laurie, Stapleton Rachel, Saida Ken, Matsumoto Naomichi, Miyake Noriko, Sheffer Ruth, Mor-Shaked Hagar, Barnett Christopher P, Byrne Alicia B, Scott Hamish S, Kraus Alison, Cappuccio Gerarda, Brunetti-Pierri Nicola, Iorio Raffaele, Di Dato Fabiola, Pais Lynn S, Yeung Alison, Tan Tiong Y, Taylor Jenny C, Christodoulou John, White Susan M
Victorian Clinical Genetics Services, Parkville, Victoria 3052, Australia.
Murdoch Children's Research Institute, Parkville, Victoria 3052, Australia.
J Med Genet. 2022 May;59(5):511-516. doi: 10.1136/jmedgenet-2020-107462. Epub 2021 Jun 28.
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 missense variant in was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm as a neurodevelopmental disease gene, and elucidate the -associated neurodevelopmental phenotype in a patient cohort.
We discovered a variant in the index case via exome sequencing and sought individuals with variants via international data-sharing initiatives. 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.
We identified 12 unrelated individuals with five missense variants in , 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.
Missense variants in cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.
结合蛋白（G蛋白）介导参与多种细胞功能的信号通路，由Gα和Gβγ亚基组成。已报道所有五种Gβ蛋白均与人类疾病有关。最近有报道称，一名患有发育迟缓/智力残疾（DD/ID）和畸形的个体存在一个错义变体。我们旨在确认该基因作为一种神经发育疾病基因，并在患者队列中阐明与之相关的神经发育表型。
我们通过外显子组测序在索引病例中发现了一个变体，并通过国际数据共享计划寻找携带该变体的个体。对这些变体进行了建模评估，并依据美国医学遗传学与基因组学学会关于序列变体解释的指南提供了多条证据。
我们鉴定出12名无关个体，他们在该基因中存在五个错义变体，其中四个是反复出现的：p.(Ala73Thr)、p.(Gly77Arg)、p.(Lys89Glu)和p.(Lys89Thr)。所有个体均患有DD/ID，并伴有不同程度的畸形和神经外特征。这些变体位于与Gα亚基普遍保守的共享界面处，建模结果表明这会削弱这种相互作用。
该基因中的错义变体会导致一种具有可变综合征特征的先天性神经发育障碍，拓宽了与编码G蛋白基因变体相关的多系统表型谱。
