ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 22q13.2|22q13.3
  • GRCh37/hg19 chr22: 42,556,019-42,679,933
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr22: 42,160,013-42,283,927
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000022.10) (NC_000022.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
27436265 Sch?fgen J et al. Eur J Hum Genet 2016. The first two were de novo, pathogenic, LOF variants, published by a group in Germany in 2016. They reported two independent individuals with ID in whom de novo nonsense and frameshift variants of TCF20 were identified by trio whole exome sequencing (WES). They did whole exome sequencing (WES) on 313 child-parent trios and identified two de novo TCF20 variants in two independent indivaduals. Individual 1 carried a nonsense variant at codon 319 (hg19 chr22:g.42610357G>A, c.955C>T, (p.(Gln319*))). Individual 2 carried a frameshift variant leading to a premature stop codon at position 1350 (hg19 chr22:g.42607475_42607475delT, c.3837del, (p.(Asp1280Ilefs*71))). The two individuals share a phenotype of mild ID, secondary tall stature, postnatal macrocephaly, obesity and muscular hypotonia. Only one of them has ASD and seizures.
25228304 Babbs C et al. J Med Genet 2014. A de novo truncating mutation (c.3518delA encoding p.K1173Rfs*5) of TCF20 was identified by exome sequencing in a woman with ASD and moderate intellectual disability.
28135719 McRae JF et al. Nature 2017. They exome sequenced 4,293 families with individuals with developmental disorders (DDs), and meta-analysed these data with another 3,287 individuals with similar disorders. TCF20 was one of the fourteen genes for which no statistically-compelling prior evidence for DD causation was available achieved genome-wide significance. LOF variants they detected included: frameshift variant, c.594_595insT p.(G199Wfs*56) stop-gained variant, c.3027T>A p.(Y1009*) stop-gained variant, c.5719C>T p.(R1907*) frameshift variant, c.3379del1 p.(Q1127Sfs*10)

Haploinsufficiency phenotype comments:

Lelieveld et al. Nature Neuroscience 2016 (PMID:27479843) reported two frameshift and two nonsense variants among 2104 trios with proband affected by intellectual disability. All variants were de novo. The DDD study Nature 2017 (PMID: 28135719) identified one missense and 5 protein truncating variants from 4293 individuals with developmental delay. All variants were de novo. Torti et al. Genetics in Medicine 2019 (PMID: 30739909) reported 27 patients with 24 novel variants (1 missense, 15 frameshift and 8 nonsense). All patients had developmental delay, 69% with ASD, 67% with AHDH. 18 variants (including the missense) were de novo Vetrini et al. Genome Medicine 2019 (PMID: 30819258) reported 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20 in 32 patients and 4 affected parents from 31 unrelated families. 20 variants were de novo and 5 were inherited from symptomatic parents. The affected individuals presented with developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity