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Intellectual disability

Gene: FGF13

Amber List (moderate evidence)
FGF13 (fibroblast growth factor 13)
EnsemblGeneIds (GRCh38): ENSG00000129682
EnsemblGeneIds (GRCh37): ENSG00000129682
OMIM: 300070, Gene2Phenotype
FGF13 is in 3 panels

2 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: New gene added by Zornitza Stark. Three variants (c.31C>T, c.41G>C, c.32G>C) identified by WES/WGS in seven individuals from five unrelated families who presented with severe infantile-onset seizures and severe-to-profound ID. Supportive functional data.

Sufficient number of unrelated cases with relevant phenotype; however, early-onset epilepsy represents the main feature of the disorder and ID appears to be a secondary manifestation (see supplemental note in PMID:33245860 for clinical details). Therefore, rating Amber on this panel but will add the FGF13 gene to 'Genetic epilepsy syndromes'
Created: 22 Jan 2021, 3:56 p.m. | Last Modified: 22 Jan 2021, 3:56 p.m.
Panel Version: 3.726
Created: 22 Jan 2021, 3:56 p.m.
Last Modified: 22 Jan 2021, 3:56 p.m.
Panel version: 3.726

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Two sibling pairs and three unrelated males reported who presented in infancy with intractable focal seizures and severe developmental delay. The variants were located in the N-terminal domain of the A isoform of FGF13/FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants.
Sources: Literature
Created: 7 Jan 2021, 9:58 a.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Intellectual disability; epilepsy

Publications

Mode of pathogenicity
Other

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

Created: 7 Jan 2021, 9:58 a.m.

Panel version: 3.694

Details

Mode of Inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Expert Review Amber
Phenotypes
  • Developmental and epileptic encephalopathy
  • Intellectual disability
  • Infantile-onset seizures
OMIM
300070
Clinvar variants
Variants in FGF13
Penetrance
None
Publications
Mode of Pathogenicity
Other
Panels with this gene

History Filter Activity

22 Jan 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: fgf13 has been classified as Amber List (Moderate Evidence).

22 Jan 2021, Gel status: 0

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: FGF13 were changed from Intellectual disability; epilepsy to Developmental and epileptic encephalopathy; Intellectual disability; Infantile-onset seizures

22 Jan 2021, Gel status: 0

Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

Mode of inheritance for gene: FGF13 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

7 Jan 2021, Gel status: 0

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

Zornitza Stark (Australian Genomics)

gene: FGF13 was added gene: FGF13 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: FGF13 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: FGF13 were set to 33245860 Phenotypes for gene: FGF13 were set to Intellectual disability; epilepsy Mode of pathogenicity for gene: FGF13 was set to Other Review for gene: FGF13 was set to GREEN gene: FGF13 was marked as current diagnostic