PT - JOURNAL ARTICLE AU - Jorge Luis Granadillo AU - Alexander P.A. Stegmann AU - Hui Guo AU - Kun Xia AU - Brad Angle AU - Kelly Bontempo AU - Judith D Ranells AU - Patricia Newkirk AU - Carrie Costin AU - Joleen Viront AU - Constanze T Stumpel AU - Margje Sinnema AU - Bianca Panis AU - Rolph Pfundt AU - Ingrid P C Krapels AU - Merel Klaassens AU - Joost Nicolai AU - Jinliang Li AU - Yuwu Jiang AU - Elysa Marco AU - Ana Canton AU - Ana Claudia Latronico AU - Luciana Montenegro AU - Bruno Leheup AU - Celine Bonnet AU - Shivarajan M. Amudhavalli AU - Caitlin E Lawson AU - Kirsty McWalter AU - Aida Telegrafi AU - Richard Pearson AU - Malin Kvarnung AU - Xia Wang AU - Weimin Bi AU - Jill Anne Rosenfeld AU - Marwan Shinawi TI - Pathogenic variants in <em>TNRC6B</em> cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD AID - 10.1136/jmedgenet-2019-106470 DP - 2020 Oct 01 TA - Journal of Medical Genetics PG - 717--724 VI - 57 IP - 10 4099 - http://jmg.bmj.com/content/57/10/717.short 4100 - http://jmg.bmj.com/content/57/10/717.full SO - J Med Genet2020 Oct 01; 57 AB - 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.