Early onset or syndromic epilepsy

Gene: FBXL4

Comment on phenotypes: Seizures

Created: 14 Apr 2021, 2:46 p.m. | Last Modified: 14 Apr 2021, 2:46 p.m.

Panel Version: 2.319

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

AR Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) - characterised by early infantile onset of encephalopathy, hypotoni, lactic acidosis and severe global dev delay. Gai et al, 2013 - 9 children from 7 unrelated families - seizures called a variable feature. Van Rij et al, 2016 - compound het for 2 stop mutations, no mention of epliepsy but died at 2 days of age. Huemer et al, 2015 - retrospecitve review in 28 individuals with FBXL4 defic - 9/28 with epilepsy. Gene reviews Almannai et al, 2017 - seizures in ~33% of cases - fits with Huemer data. Dai et al, 2017 - 10 patients had FBXL4 mutations - 5 no seizures, 2 yes and 3 not applicable (probably due to very early death). Do see epilepsy in ~1/3 but not the major feature of disease.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), 615471

Publications

• 23993193

Green List (high evidence)

Comment on list classification: Changed from Amber to Green. Enough evidence to support gene-disease association and relevance to this panel to rate this gene Green

Created: 13 Nov 2018, 5:44 p.m.

FBXL4 defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome, seizures are part of the clinical phenotype and can start at age four months (Dai et al 2017 PMID: 27743463). Seizure types reported include complex partial seizures (Baroy et al 2016 PMID:27182039) and absence and generalized seizures (Gai et al 2013 PMID:23993194). The clinical manifestations of FBXL4-Related mtDNA Depletion Syndrome with seizures occurs at a frequency of approximately 33% of cases (Almannai et al 2017 PMID:28383868)

Created: 13 Nov 2018, 5:42 p.m.

Comment on publications: FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals to date. Added publications suggested to support upgrading of the gene to Green.

Created: 13 Nov 2018, 5:34 p.m.

Comment on phenotypes: added OMIM, orphanet phenotype and MIMid

Created: 13 Nov 2018, 5:02 p.m.

Comment on mode of inheritance: Added MOI from external review and checked with PMID

Created: 13 Nov 2018, 5 p.m.

Green List (high evidence)

Seizures are a common feature of this mitochondrial disorder.

Created: 13 Aug 2018, 12:31 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), MIM#615471

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