Severe microcephaly

Gene: GTF3C3

Green List (high evidence)

Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Created: 17 Mar 2025, 4:27 p.m. | Last Modified: 17 Mar 2025, 4:27 p.m.

Panel Version: 8.151

- PMID: 39636576 (2025) - 12 individuals from 7 unrelated families were identified with homozygous or compound heterozygous missense variants in GTF3C3 (8 unpublished individuals combined with newly ascertained information from 4 published individuals). The cohort presented with intellectual disability, variable nonfamilial facial features, motor impairments, seizures, and cerebellar/corpus callosum malformations.

- PMID: 40040844 (2025) - 4 patients from 3 unrelated families with biallelic variants in this gene and microcephaly, developmental delay, intellectual disability, seizures and distinctive dysmorphic facies. Knockout zebrafish recapitulated the key clinical symptoms including microcephaly, brain anomalies and seizure susceptibility.

Created: 17 Mar 2025, 4:26 p.m. | Last Modified: 17 Mar 2025, 4:26 p.m.

Panel Version: 8.150

Comment on publications: PMID: 40040844 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

Created: 17 Mar 2025, 4:16 p.m. | Last Modified: 17 Mar 2025, 4:16 p.m.

Panel Version: 8.150

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 39636576
• 40040844

I don't know

Three unrelated individuals with variants in GTF3C3 all reported to have ID.
PMID: 30552426 reported on a patient with epilepsy and intellectual disability.
PMID: 28940097 reported on an individual who had a homozygous splice site variant which was shown to cause skipping of exon 10 and parts of exon 11 (in-frame deletion) in a patient with profound microcephaly, characteristic facial appearance and failure to thrive.
PMID: 28097321 reported on a homozygous missense variant in GTF3C3 in two affected sisters with a phenotype including mild ID, seizures and dysmorphisms and classified it as a moderately confident candidate gene.
GTF3C3 has no disease gene phenotype associations in OMIM or Gene2Phenotype and limited clinical information is provided on the degree of ID. All the cases identified have variable phenotype in terms of skeletal features and epilepsy. Therefore GTF3C3 will remain as Amber and be added to the watchlist.

Created: 29 Jul 2019, 1:41 p.m. | Last Modified: 29 Jul 2019, 1:41 p.m.

Panel Version: 2.989

I don't know

Papuc et al. (PMID: 30552426) report on one further patient with epilepsy and intellectual disability (all participants of the study had moderate to profound ID) due to biallelic GTF3C3 mutations.

This individual had the following variants (NM_012086.4): c.2419C>T / p.(Arg807Cys) and c.503C>T / p.(Ala168Val). A healthy sister of the proband was heterozygous for the first variant but not the second one. The first variant affects only 1 (of 2) Refseq isoforms while the second affects both. Both variants were predicted pathogenic in silico and absent from ExAC.

The phenotype of previously published individuals (from PMIDs 28940097, 28097321) is briefly summarized. According to the authors, Tcf4 - a yeast ortholog of GTF3C3 - has been shown to interact with BRF1 for regulation of RNA polymerase III-mediated transcription. Arguments are provided for phenotypic similarities to the BRF1-related phenotype, cerebellofaciodental syndrome (MIM 616202).

The gene is not associated with any phenotype in OMIM, nor in G2P. It is not included in gene panels for ID offered by diagnostic laboratories.

As a result it could be considered for upgrade probably to amber (or green).

Created: 19 Dec 2018, 11:41 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Global developmental delay; Intellectual disability; Seizures

Publications

• 30552426
• 28940097
• 28097321

I don't know

Two unrelated families with bi-allelic variants in this gene, ID is part of the phenotype. Consider inclusion as Amber.

Created: 22 Jun 2018, 11:09 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 28940097, 28097321

Variants in this GENE are reported as part of current diagnostic practice