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.
- autosomal dominant
- De novo
- developmental delay
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JLG and AP.S contributed equally.
Contributors Study concept and design: JLG and MSH. Recruitment of patients and collection of clinical information: APAS, HG, KX, BA, KB, JR, PN, CC, JV, CTRMS, MS, BP, RPF, IPCK, MK, JN, JL, YJ, EM, AC, ACL, LM, BL, CB, AS, CEL, KM, AT, RP, MKv, XW, WB, JAR and MSH. Acquisition of data: JLG, APAS, HG, JL, LM, CB, KW, JAR and MSH. Analysis and interpretation of data: JLG and MSH. Drafting of the manuscript: JLG and MSH. Critical revision of the manuscript: JLG, APAS, HG, KB, JR, CTRMS, MS, IPCK, MK, JN, AC, BL, KM, AT, RP, WB, JAR and MSH. Study supervision: MSH.
Competing interests KM, AT and RP are employed by GeneDx, and XW, WB, JAR receive salary support from Baylor Genetics Laboratory. Both laboratories offer extensive genetic laboratory testing, including exome sequencing and derive revenue from this activity.
Patient consent for publication Parental/guardian consent obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. As indicated above, all data relevant to the study are included in the Supplementary Table.