Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability-猫眼课题宝

DOI：

10.1136/jmedgenet-2020-107462

发表时间：

2021-06

期刊：

Journal of Medical Genetics

影响因子：

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

Natalie B Tan;A. Pagnamenta;Matteo P. Ferla;J. Gadian;B. Chung;Marcus C. Y. Chan;J. Fung;Edwin Cook;Stephen J. Guter;Felix Boschann;André Heinen;J. Schallner;C. Mignot;B. Keren;S. Whalen;C. Sarret;Dana Mittag;L. Demmer;Rachel Stapleton;K. Saida;N. Matsumoto;N. Miyake;R. Sheffer;Hagar Mor-Shaked;C. Barnett;Alicia B. Byrne;H. Scott;A. Kraus;G. Cappuccio;N. Brunetti‐Pierri;R. Iorio;F. Di Dato;L. Pais;A. Yeung;T. Tan;Jenny C. Taylor;J. Christodoulou;S. White

目的结合蛋白（G蛋白）是介导多种细胞功能的信号通路，由Gα和Gβγ两个单位组成。所有五种Gβ蛋白均已报告人类疾病。最近在一个患有发育迟缓/智力残疾（DD/ID）和畸形的个体中报告了GNB 2的从头错义变体。我们的目的是确认GNB 2作为一个神经发育疾病基因，并阐明GNB 2相关的神经发育表型在患者队列。方法我们通过外显子组测序在索引病例中发现了GNB 2变体，并通过国际数据共享计划寻找具有GNB 2变体的个体。根据美国医学遗传学和基因组学学会关于序列变异解释的指导原则，评估了变异的计算机模拟，沿着多条证据线。结果我们鉴定了12个GNB 2基因有5个错义突变的无关个体，其中4个是复发性的：p。（Ala73Thr），p.（Gly77Arg），p.（Lys 89 Glu）和p.（Lys89Thr）。所有的人都有DD/ID与变量畸形和神经功能。这些变异体位于与Gα亚基的普遍保守的共享界面，建模表明削弱了这种相互作用。结论GNB 2错义突变导致了一种具有不同综合征特征的先天性神经发育障碍，拓宽了与G蛋白编码基因突变相关的多系统表型谱。

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.

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

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