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
Alexander P A Stegmann
Hui Guo
Kun Xia
Brad Angle, Advocate Aurora Health
Kelly Bontempo, Advocate Aurora Health
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 Marco
Ana Canton
Ana Claudia Latronico
Luciana Montenegro
Bruno Leheup
Celine Bonnet
Shivarajan M Amudhavalli
Caitlin E Lawson
Kirsty McWalter
Aida Telegrafi
Richard Pearson
Malin Kvarnung
Xia Wang
Weimin Bi
Jill Anne Rosenfeld
Marwan Shinawi

Advocate Lutheran General Hospital

Advocate Lutheran General Hospital


BACKGROUND: Rare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes.

METHODS: Clinical and molecular characterisation was performed on 17 patients with

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

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.