Disorders of sex development

Gene: TCF12

Amber List (moderate evidence)

TCF12 (transcription factor 12)
EnsemblGeneIds (GRCh38): ENSG00000140262
EnsemblGeneIds (GRCh37): ENSG00000140262
OMIM: 600480, Gene2Phenotype
TCF12 is in 10 panels

1 review

Arina Puzriakova (Genomics England Curator)

I don't know

Comment on list classification: Variants in TCF12 typically cause craniosynostosis, while evidence for an association with Kallmann Syndrome is currently based on a single study, and therefore warrants further investigation. Furthermore, the presence of incomplete penetrance must be considered. Additional cases would help validate the pathogenicity of TCF12 variants in aberrant GnRH axis development.

Therefore, rating Amber in anticipation of additional publications/clinical evidence (added to watchlist).
Created: 22 Sep 2020, 1:29 p.m. | Last Modified: 22 Sep 2020, 1:30 p.m.
Panel Version: 2.11
Note monoallelic variants in this gene are a well-established cause of craniosynostosis.

- PMID: 32620954 (2020) - 13 unrelated kindreds (11 de novo, 1 AD and 1 AR) comprising 14 affected individuals with an anosmic form of isolated GnRH deficiency (IGD) (Kallman syndrome) due to different LoF variants in TCF12.

Clinical manifestation included anosmia and pubertal failure (with reproductive phenotypes such as micropenis, bilateral cryptorchidism, hypospadias). Two unrelated individuals within the cohort additionally exhibited craniosynostosis, and a further two pedigrees had a family history of craniosynostosis (that did not affect the index cases). Multiplex cases typically presented incomplete penetrance.

Loss of tcf12 in a mutant zebrafish model perturbed GnRH neuronal patterning, with concomitant expression attenuation of tcf3a/b and stub1 (latter mutated in other syndromic forms of IGD). Furthermore, restored STUB1 expression rescued loss of tcf12 in vivo.
Sources: Literature
Created: 22 Sep 2020, 1:08 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Kallmann syndrome



Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
  • Expert Review Amber
  • Literature
  • Kallmann syndrome
Clinvar variants
Variants in TCF12
Panels with this gene

History Filter Activity

22 Sep 2020, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag watchlist tag was added to gene: TCF12.

22 Sep 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: tcf12 has been classified as Amber List (Moderate Evidence).

22 Sep 2020, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Arina Puzriakova (Genomics England Curator)

gene: TCF12 was added gene: TCF12 was added to Disorders of sex development. Sources: Literature Mode of inheritance for gene: TCF12 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: TCF12 were set to 32620954 Phenotypes for gene: TCF12 were set to Kallmann syndrome Review for gene: TCF12 was set to AMBER