TNRC6B – Global developmental delay with speech and behavioral abnormalities

TNRC6B-associated global developmental delay with speech and behavioral abnormalities is an autosomal dominant disorder caused by heterozygous TNRC6B variants. Multiple unrelated probands present with developmental delay/intellectual disability, speech and motor delays, attention deficit/hyperactivity disorder and behavioral abnormalities in the absence of family history, consistent with de novo occurrence. The overall gene–disease relationship is classified as Strong based on 20 unrelated probands, all de novo, with concordant functional data supporting disrupted TNRC6B function.

Genetic Evidence

TNRC6B deficiency has been reported in 17 unrelated individuals carrying heterozygous truncating, splice, deletion or missense variants ([PMID:32152250]) plus two further de novo variants c.335C>T (p.Pro112Leu) and c.1632delC (p.Leu546fsTer63) in Chinese patients ([PMID:38404251]). A separate case revealed a synonymous c.3141G>A (p.Lys1047=) variant in one child with seizures and developmental delay, confirmed pathogenic via minigene assay ([PMID:39115759]). Collectively, 20 probands harbor 7 nonsense, 5 frameshift, 2 splice, 2 intragenic deletions, 1 missense and 1 synonymous variant, all de novo, consistent with a haploinsufficiency mechanism.

Functional Evidence

Splicing assays demonstrated that c.3141G>A induces exon 7 skipping, resulting in TNRC6B loss-of-function ([PMID:39115759]). TNRC6B is required for RNA silencing; truncating variants likely abrogate miRNA-mediated repression, consistent with haploinsufficiency.

Conflicting Evidence

No studies to date have reported benign segregation or alternative disease mechanisms for TNRC6B in this phenotype.

Integration and Clinical Utility

The convergence of de novo occurrence in 20 patients, diverse loss-of-function alleles, and functional splicing disruption provides strong evidence that TNRC6B haploinsufficiency causes global developmental delay with speech and behavioral abnormalities. TNRC6B should be included in diagnostic gene panels for developmental delay/intellectual disability, and functional assays (e.g., minigene) are recommended for synonymous or splice-region variants.

Key Take-home: De novo TNRC6B haploinsufficiency underlies a clinically recognizable autosomal dominant syndrome of developmental delay, speech/motor deficits and behavioral abnormalities, amenable to genetic diagnosis and counseling.

References

• Molecular biology reports • 2024 • Identification of the synonymous variant c.3141G>A in TNRC6B gene that altered RNA splicing by minigene assay PMID:39115759
• Journal of medical genetics • 2020 • Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD PMID:32152250
• Molecular genetics & genomic medicine • 2024 • Novel variants in TNRC6B cause global developmental delay with speech and behavioral abnormalities, short stature, low body weight, café-au-lait spots, and metabolic abnormality PMID:38404251

Evidence Based Scoring (AI generated)