RT Journal Article SR Electronic T1 Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 717 OP 724 DO 10.1136/jmedgenet-2019-106470 VO 57 IS 10 A1 Jorge Luis Granadillo A1 Alexander P.A. Stegmann A1 Hui Guo A1 Kun Xia A1 Brad Angle A1 Kelly Bontempo A1 Judith D Ranells A1 Patricia Newkirk A1 Carrie Costin A1 Joleen Viront A1 Constanze T Stumpel A1 Margje Sinnema A1 Bianca Panis A1 Rolph Pfundt A1 Ingrid P C Krapels A1 Merel Klaassens A1 Joost Nicolai A1 Jinliang Li A1 Yuwu Jiang A1 Elysa Marco A1 Ana Canton A1 Ana Claudia Latronico A1 Luciana Montenegro A1 Bruno Leheup A1 Celine Bonnet A1 Shivarajan M. Amudhavalli A1 Caitlin E Lawson A1 Kirsty McWalter A1 Aida Telegrafi A1 Richard Pearson A1 Malin Kvarnung A1 Xia Wang A1 Weimin Bi A1 Jill Anne Rosenfeld A1 Marwan Shinawi YR 2020 UL http://jmg.bmj.com/content/57/10/717.abstract 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.