Retinal disorders

Gene: XXYLT1

I don't know

Kraatari-Tiri et al. 2026 (PMID 42530953) identified XXYLT1 as putative IRD gene via recessive GWAS in a Finnish clinical/ control population (FinnGen), with replication in Finnish and UK IRD cohorts. GWAS was the discovery method only; the lead SNP is the causal variant itself (c.505-1G>C) and 9/13 significant loci were known IRD genes, so the curation-relevant evidence rests on downstream segregation and functional data.

Five patients from four families in a Finnish clinical cohort were homozygous for the Finnish founder variant c.505-1G>C (canonical intron 1 splice acceptor) and presented with cone-rod dystrophy; RNA studies confirmed exon 2 skipping and loss of function. Prior genetic testing and exclusion of other putative causative variants in this cohort varied from no prior genetic testing (39%) to exome sequencing (18%). A separate consanguineous UK family carried biallelic c.766G>A p.(Glu256Lys) and presented with macular dystrophy, segregating in two affected relatives; no functional validation was performed and in silico predictions were largely deleterious with an intermediate REVEL (0.567). Other potential genetic aetiologies had been excluded by standard of care genetic testing. Homozygous knockout mice (xxylt1 -/-) show abnormal retinal morphology, cited as an International Mouse Phenotyping Consortium (IMPC) hit, with the mechanism not established (NOTCH signalling disruption proposed) and extra-ocular mouse features not recapitulated in patients.

Recommended rating: Amber. Although 5 families are cited with consistent phenotype, 4 of these share the same homozygous founder allele. Thus, independent-family evidence does not reach three independent observations (one founder allele plus one missense family), and the animal-model route to a green rating is not met as the knockout lacks detailed characterisation or mechanistic support.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.

Created: 31 Jul 2026, 4:14 p.m. | Last Modified: 31 Jul 2026, 4:14 p.m.

Panel Version: 9.10

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cone-rod dystrophy (MONDO:0015993); Inherited retinal dystrophy (MONDO:0019118)

Publications

• 42530953

Green List (high evidence)

Biallelic XXYLT1 variants were identified in 7 affected individuals from 5 unrelated families (4 Finnish and 1 UK) with autosomal recessive inherited retinal disease. The recurrent splice variant was supported by RNA studies demonstrating aberrant splicing and loss of function, while the independent UK family harboured a distinct homozygous missense variant. These findings support XXYLT1 is a novel cause of autosomal recessive inherited retinal disease.
Sources: Literature

Created: 31 Jul 2026, 12:27 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Retinal dystrophy

Publications

• PMID: 42530953

Mode of pathogenicity
Other