Relevance to Autism

De novo and rare inherited variants in the TCF20 gene were identifed in ASD patients in Babbs et al., 2014, including a pericentric inversion with a breakpoint within TCF20 in two brothers with ASD that was not observed in their parents, and a de novo frameshift variant in a female patient with ASD and moderate intellectual disability. Two additional de novo loss-of-function variants in the TCF20 gene were identified in individuals with intellectual disability and postnatal overgrowth in Schafgen et al., 2016; one of these cases also presented with ASD. Another de novo LoF variant in TCF20 was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017. Torti et al., 2019 reported 27 individuals with TCF20 variants, all of whom had developmental delay/intellectual disability; ASD or autistic features was observed in 69% of cases, attention deficit or hyperactivity in 67%, craniofacial features (with no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Vetrini et al., 2018 reported pathogenic TCF20 variants in 32 patients and 4 affected parents from 31 unrelated families; patients presented with a phenotype characterized by motor delay (94%), language delay (86%) intellectual disability (75%), dysmorphic features (78%), hypotonia (66%), and ASD and other neurobehavioral abnormalities (66%). Two de novo protein-truncating variants in the TCF20 gene were identified in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified TCF20 as a candidate gene with a false discovery rate (FDR) between 0.01 and 0.05 (0.01 < FDR 0.05). Using proximity-dependent biotinylation (BioID), Zhou et al., 2022 identified a TCF20 complex that interacted with MeCP2 at the chromatin interface; Rett syndrome-causing mutations inMECP2disrupted this interaction. Furthermore, this report demonstrated that reducingTcf20partially rescued the behavioral deficits caused byMECP2 overexpression, and behavioral deficits in Tcf20+/- mice overlapped with those observed in a mouse model of Rett syndrome. Additional de novo loss-of-function variants in the TCF20 gene were reported in ASD probands from the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified TCF20 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

Transcriptional activator that binds to the regulatory region of MMP3 and thereby controls stromelysin expression. It stimulates the activity of various transcriptional activators such as JUN, SP1, PAX6 and ETS1, suggesting a function as a coactivator.

External Links

References

Model Summary

Mice with TCF20 knockdown in the brain and het or null KOs, show reduced number of neurons due to reduced neuronal cell proliferation, impaired neuronal differentiation, abnormal brain functions, abnormal DNA methylation and gene expression, reduced ultrasonic vocalization, increased anxiety, increased repetitive digging, decreased social interaction and social memory. Overexpression of downstream factors of TCF20, TDG or TCF-4, rescues the deficient neurogenesis of TCF20 knockdown brains.

References