Retinal disorders

Gene: FSD1L

Green List (high evidence)

Comment on list classification: There are more than 3 unrelated families reported in literature where affected individuals have a syndromic phenotype including retinal disease, and habrour biallelic FDS1L variants. In milder cases, retinitis pigmentosa was reported as the only symptom. Hence, this gene should be promoted to Green at the next update.

Created: 9 Mar 2026, 2:15 p.m. | Last Modified: 9 Mar 2026, 2:20 p.m.

Panel Version: 8.91

PMID: 41720098 Serpieri et al., 2026
Report of eleven individuals (including five fetuses) from six unrelated families harbouring biallelic FSD1L variants. Seq method: exome sequencing. Consanguinity was confirmed in 4/6 families, and suspected in the fifth.
Phenotype spectrum: severe intellectual disability (5/5 assessed from 3 families), epilepsy (5 individuals from 3 families), severe hydrocephalus (3 families), vision deficit due to optic nerve hypoplasia/atrophy (3 families), spastic tetraparesis (2 families) corpus callosum hypoplasia/agenesis on MRI (5/5 families assessed),

Variants detected - largely nonsense type:
Family A - homozygous c.409T>G (p.Leu137Val);
Family B - 3 affected fetuses homozygous for c.1411C>T (p.Gln471Ter);
Family C - sibs compound het for c.1228T>G (p.Phe410Val) and c.1251_1252insTAA (p.Thr418Ter);
Family D - affected individuals (1 fetal case) homozygous for c.1366G>C (p.Asp456His) - shown to impact splicing (r.406_442del), resulting in predicted p.Ser136LeufsTer19 change;
Family E - affected child with homozygous c.835C>T (p.Arg279Ter) change;
Family F - fetus homozygous for c.1260G>A (p.Trp420Ter);

Functional evidence: Fsd1l depletion in mouse embryos recapitulated the ventricular dilation observed in affected fetuses.

PMID 41720099 Lin et al., 2026
FSD1L variants detected:
Family A: 2 sibs compound het for c.1049G>A (p.Arg350Gln) and c.1428del (p.Phe476Leufs∗22)
Family B: individual comp het for c.488G>A (p.Arg163His), c.488G>A & c.745C>T (p.Arg249∗)
Family C: 2 sibs compound het for c.488G>A (p.Arg163His) & c.226_227del (p.Ser77Argfs∗4)
Family D: individual compound het for c.1037_1038delinsT (p.Pro346Leufs∗8) and c.1025+624_1025+649del
Sibs from family A had mild neurological involvement (mild ID, spastic diplegia in one sibling).
Authors note that "specific combination and functional severity of the two alleles likely determines the clinical outcome", with non-LoF variants causing a milder effect (e.g., isolated retinal phenotype).

FSD1L is not yet associated with a phenotype in OMIM or Gene2Phenotype.

Created: 9 Mar 2026, 2:04 p.m. | Last Modified: 9 Mar 2026, 2:14 p.m.

Panel Version: 8.88

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
retinitis pigmentosa, MONDO:0019200; neurodevelopmental disorder, MONDO:0700092

Publications

• 41720098
• 41720099

Green List (high evidence)

Lin, Cancellieri, Cao et al (PMID 41720099) describe 6 affected individuals from 4 families with retinitis pigmentosa. 2 affected siblings had both retinitis pigmentosa and a mild neurodevelopmental phenotype; the remaining four individuals had apparent isolated retinal dystrophy, including one individual who underwent a full neurological evaluation, including brain neuroimaging, which revealed no evidence of central nervous system involvement. This suggests that FSD1L-associated disease may therefore span a broad phenotypic spectrum, ranging from severe neurodevelopmental syndromes to, at its mildest, non-syndromic retinal dystrophy.
Sources: Literature

Created: 23 Feb 2026, 7:09 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Retinitis pigmentosa; retinal dystrophy

Publications

• 41720099

Mode of pathogenicity
Other