Submission Details

The TCF20 gene is located on chromosome 22 at 22q13.2 and encodes the transcription factor 20 protein. TCF20 regulates gene transcription by acting as a coactivator for a variety of other transcription factors. TCF20 was first associated with autosomal dominant developmental delay with variable intellectual impairment and behavioral abnormalities in 2014 (Babbs et al., PMID 25228304). More than 50 unrelated cases have been reported. The core phenotype of this disorder includes developmental delay / intellectual disability; autism spectrum disorder or other neurobehavioral concerns (e.g. ADHD); dysmorphic facial features; congenital hypotonia; variable neurological disturbances including ataxia, seizures, and movement and sleep disorders; and variable additional features affecting other organ systems. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Haploinsufficiency has been suggested as the mechanism for disease, but a potential dominant-negative mechanism has not been ruled out. This curation included eight unique variants (five frameshift, two stop-gained, one missense) identified in eight unrelated probands from four publications (Babbs et al., 2014 PMID 25228304; Schäfgen et al., 2016 PMID 27436265; Vetrini et al., 2019 PMID 30819258; Torti et al., 2019 PMID 30739909). In the majority of reported cases, variants occurred de novo, but rare cases of a variant inherited from an affected parent have been reported. Notably, two independent evaluations demonstrated that variant transcripts predicted to undergo nonsense-mediated decay (NMD) escaped from NMD. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by TCF20 expression in the brain, a shared structure and biochemical function with another gene associated with a similar phenotype (RAI1) (Vetrini et al., 2019 PMID 30819258), a role in neurogenesis and neural differentiation, and behavioral abnormalities related to autism observed in a heterozygous knockout mouse model (Feng et al., 2020 PMID 32510763). In summary, TCF20 is definitively associated with autosomal dominant developmental delay with variable intellectual impairment and behavioral abnormalities. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on 7.28.2020 (SOP Version 7).