Early onset or syndromic epilepsy

Gene: FAR1

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 8 Feb 2023, 3:49 p.m. | Last Modified: 8 Feb 2023, 3:49 p.m.

Panel Version: 3.36

Green List (high evidence)

PMID 33239752 - 12 patients with de novo FAR1 missense variants Arg480Cys/His/Leu - 8/12 seizures as part of phenotype.

PMID 25439727 - 2 unrelated families - family 1 2 sibs (consanguineous) with hom in frame deletion;family 2 individual compound het for missense and nonsense variant - all 3 had seizures reported as part of phenotype.
PMID 33586168 - child with consanguineous parents - hom nonsense variant - epileptic spasms reported as part of phenotype.
PMID 28454995 - hom missense variant reported - case 156 (Supp info) - diagnosis of peroxisomal fatty Acyl-CoA reductase I disorder but no clinical information included.

12 AD de novo cases 8/12 with epilepsy pheno - ok to classify as green
4 AR families 4/5 (3 families) epilepsy pheno, 1 no clinical info provided. ok to classify as green,

Created: 6 Jul 2022, 3:06 p.m. | Last Modified: 6 Jul 2022, 3:06 p.m.

Panel Version: 2.543

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
cataracts, spastic paraparesis and speech delay & peroxisomal fatty Acyl-CoA reductase I disorder

Publications

• 33239752
• 25439727
• 33586168
• 28454995

The mode of inheritance of this gene has been updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 9:39 a.m. | Last Modified: 1 Feb 2023, 9:39 a.m.

Panel Version: 3.29

Comment on mode of inheritance: As only 2/4 families with biallelic variants in this gene presented with epilepsy, in 2019, the rating was set to Amber for this allelic requirement (no new related evidence since). However, there is now evidence supporting pathogenicity of monoallelic variants affecting the Arg480 residue, and the number of unrelated individuals with seizures (8) reaches the threshold for inclusion with the monoallelic MOI.

FAR1 will be flagged for GMS expert review to determine the most appropriate MOI and rating on this panel.

Created: 28 Jun 2021, 11:17 a.m. | Last Modified: 16 Mar 2022, 3:38 p.m.

Panel Version: 2.500

Associated with relevant phenotype in OMIM and has a 'confirmed' disease confidence rating for 'Severe intellectual disability, epilepsy, and cataracts' in Gene2Phenotype.

Both biallelic and monoallelic variants have been linked to disease; both supported by functional data but showing distinct biochemical phenotypes. Seizures are reported in 3/5 patients (4 families - 2 with same founder variant, neither of which had seizures) with biallelic variants (PMIDs: 25439727; 30561787) and in 8/12 patients with heterozygous de novo variants (PMID: 33239752)

Created: 28 Jun 2021, 11:02 a.m. | Last Modified: 28 Jun 2021, 11:02 a.m.

Panel Version: 2.377

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154

Publications

• 25439727
• 30561787
• 33239752

I don't know

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Demoted from Green to Amber.

Created: 25 Nov 2019, 8:49 p.m. | Last Modified: 25 Nov 2019, 8:50 p.m.

Panel Version: 1.439

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: Amber.

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

Panel Version: 1.189

I don't know

AR peroxisomal fatty acyl-CoA reductase 1 disorder - onset in infancyof severely delayed psychomotor development, growth retardation with microcephaly and seizures. Buchert et al, 2014 -3 patients from 2 families with a severe disorder all had early-onset epilepsy. Bialleleic mutations identified in FAR1 (hom indel in consang family and compound het for a missense and a nonsense) and in vitro expression studies showed that all the mutations resulted in a complete loss of enzyme activity.

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
Peroxisomal fatty acyl-CoA reductase 1 disorder, 616154

Publications

• 25439727

Green List (high evidence)

Gene originally listed on the Intellectual disability panel V2.42.
Associated with relevant phenotypes in OMIM and as confirmed Gen2Phen gene. At least 3 variants reported in 2 unrelated cases, supportive functional studies provided for each variant (PMID 25439727).

Created: 10 Apr 2018, 9:02 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Peroxisomal fatty acyl-CoA reductase 1 disorder 616154

Publications

• 25439727