Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD

单倍率不足 自闭症 外显子组测序 智力残疾 遗传学 全球发育迟缓 语音延迟 错义突变 遗传咨询 自闭症谱系障碍 神经发育障碍 移码突变 表型 拷贝数变化 注意缺陷多动障碍 生物 心理学 基因 精神科 基因组
作者
Jorge L. Granadillo,Alexander P.A. Stegmann,Hui Guo,Kun Xia,Brad Angle,Kelly Bontempo,Judith D. Ranells,Patricia Newkirk,Carrie Costin,Joleen Viront,Constanze T Stumpel,Margje Sinnema,Bianca Panis,Rolph Pfundt,Ingrid P.C. Krapels,Merel Klaassens,Joost Nicolai,Jinliang Li,Yuwu Jiang,Gian Marco Ghiggeri,Ana Pinheiro Machado Canton,Ana Cláudia Latronico,Luciana Ribeiro Montenegro,Bruno Leheup,Céline Bonnet,Shivarajan Amudhavalli,Caitlin E. Lawson,Kirsty McWalter,Aida Telegrafi,Richard Pearson,Malin Kvarnung,Xia Wang,Weimin Bi,Jill A. Rosenfeld,Marwan Shinawi
出处
期刊:Journal of Medical Genetics [BMJ]
卷期号:57 (10): 717-724 被引量:18
标识
DOI:10.1136/jmedgenet-2019-106470
摘要

Background Rare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes. TNRC6B encodes a protein important for RNA silencing. Heterozygous truncating variants have been reported in three patients from large cohorts with autism, but no full phenotypic characterisation was described. Methods Clinical and molecular characterisation was performed on 17 patients with TNRC6B variants. Clinical data were obtained by retrospective chart review, parent interviews, direct patient interaction with providers and formal neuropsychological evaluation. Results Clinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygous TNRC6B variants were identified in 12 male and five female unrelated subjects by exome sequencing (14), a targeted panel (2) and a chromosomal microarray (1). The variants were nonsense (7), frameshift (5), splice site (2), intragenic deletions (2) and missense (1). Conclusions Variants in TNRC6B cause a novel genetic disorder characterised by recurrent neurocognitive and behavioural phenotypes featuring DD/ID, autism, ADHD and other behavioural abnormalities. Our data highly suggest that haploinsufficiency is the most likely pathogenic mechanism. TNRC6B should be added to the growing list of genes of the RNA-induced silencing complex associated with ID/DD, autism and ADHD.
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