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

Jorge Luis Granadillo, P. Alexander 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, Elysa MarcoAna Canton, Ana Claudia Latronico, Luciana Montenegro, Bruno Leheup, Celine Bonnet, M. Shivarajan Amudhavalli, Caitlin E. Lawson, Kirsty McWalter, Aida Telegrafi, Richard Pearson, Malin Kvarnung, Xia Wang, Weimin Bi, Jill Anne Rosenfeld, Marwan Shinawi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number106470
JournalJournal of Medical Genetics
DOIs
StateAccepted/In press - Jan 1 2020

Keywords

  • ADHD
  • autism
  • autosomal dominant
  • De novo
  • developmental delay

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    Granadillo, J. L., Stegmann, P. A., Guo, H., Xia, K., Angle, B., Bontempo, K., Ranells, J. D., Newkirk, P., Costin, C., Viront, J., Stumpel, C. T., Sinnema, M., Panis, B., Pfundt, R., Krapels, I. P. C., Klaassens, M., Nicolai, J., Li, J., Jiang, Y., ... Shinawi, M. (Accepted/In press). Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD. Journal of Medical Genetics, [106470]. https://doi.org/10.1136/jmedgenet-2019-106470