Submission Details

De novo truncating variants in TNRC6B were first reported in humans with autosomal dominant complex neurodevelopmental disorder in 2014 (Iossifov et al., PMID: 25363768). Individuals with pathogenic variants in this gene have presented with neurodevelopmental phenotypes including intellectual disability, autism spectrum disorder, motor and speech delay, and attention deficit-hyperactivity disorder. Evidence supporting this gene-disease relationship was derived from case-level data. Protein truncating variants in this gene have been reported in over 25 individuals with neurodevelopmental disorders;10 probands from 3 publications (PMIDs: 25363768, 29463886, 32152250) are included in this curation, though additional genetic evidence is available in the literature (PMIDs: 27479843, 30564305, 33057194, 28191889). At least six de novo TNRC6B missense variants have been reported in individuals with neurodevelopmental disorders (PMIDs: 28135719, 31981491) but were not scored because their functional significance is unknown. The mechanism for disease is predicted to be haploinsufficiency based on the predominance of protein truncating variants among individuals with neurodevelopmental disorders. To date, there is no experimental evidence to directly support the role of this gene in neurodevelopmental disorders. In summary, there is sufficient genetic evidence to support a definitive gene-disease relationship between TNRC6B and complex neurodevelopmental disorder. The classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 1/6/21 (SOP Version 8).