Submission Details

The relationship between FAR1 and FAR1 Upregulation, a newly described autosomal dominant disorder, was evaluated using the ClinGen Clinical Validity Framework as of August, 2021. FAR1 encodes a peroxisomal membrane protein that is required for the reduction of fatty acids to fatty alcohols. The disorder is characterized by spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia (PMID: 33239752). The clinical phenotypes seen in affected individuals overlap with those of the autosomal recessive condition, FAR1 deficiency, caused by biallelic variants in FAR1. However, the biochemical phenotypes are in contrast - while FAR1 deficiency is associated with plasmalogen deficiency, FAR1 upregulation is characterized by elevated plasmalogen levels. FAR1 protein levels are subject to plasmalogen-dependent feedback regulation (PMID: 33239752). FAR1 was first reported in relation to autosomal dominant FAR1 Upregulation in 2020 (Ferdinandusseet al, 2020; PMID: 33239752), and so far this is the only report. Variants in this gene that cause FAR1 upregulation (n = 3) all affect the same residue (Arg480) and arise de novo. Evidence supporting this gene-disease relationship includes case-level data and experimental data.

Summary of Case Level Data (9.2 points): Eighteen unrelated patients from around the world in 1 publication (PMID: 33239752, 37335441, 39074165, 36781603) have been reported with de novo heterozygous variants in FAR1. Of note, all variants reported involve the same codon - Arg480.

The mechanism is reported to be gain of function (PMID: 33239752).

Summary of experimental data (1 point): FAR1 has a functional role in plasmalogen synthesis as outlined in PMIDs: 15220348 and 24108123.

In summary, the evidence to support the gene-disease relationship of FAR1 and FAR1 upregulation is moderate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Peroxisomal GCEP on January 12, 2023. It was reevaluated on June 6, 2025 (SOP v 10). Although additional cases were published (PMIDs: 37335441, 39074165, 36781603), the classification did not change.

Lumping and Splitting Considerations: OMIM entities: Cataracts, spastic paraparesis, and speech delay (MIM# 619338), Peroxisomal fatty acyl-CoA reductase 1 disorder (MIM# 616154). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanisms, inheritance patterns AND phenotypic presentation. Therefore, we have split curations for the disease entities, FAR1 deficiency and FAR1 upregulation (terms introduced by the peroxisomal GCEP).