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Publications

Journal Article Ahead of print

PubMed: 42530953 DOI: 10.1001/jamaophthalmol.2026.2795

XXYLT1 and Mendelian Retinal Dystrophy.

JAMA Ophthalmol

Authors: Minna Kraatari-Tiri, Hina Ishtiaq, Jaakko Tyrmi, Siying Lin, Andriana Valkama, Timo Tiirikka, Sara Äikäs, Laura Lähteenoja, Genevieve Wright, Elena Schiff, Aleksandr Jestin, Andrew R Webster, Omar A Mahroo, Michel Michaelides, Jukka Moilanen, Katri Pylkäs, Johannes Kettunen, Gavin Arno, Aura Falck, Tuomo Mantere, Elisa Rahikkala

Affiliations

  • Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
  • Research Unit of Clinical Medicine and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
  • Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
  • Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
  • Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
  • Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
  • National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital, London, United Kingdom.
  • University College London Institute of Ophthalmology, University College London, London, United Kingdom.
  • Northern Finland Laboratory Centre Nordlab, Oulu, Finland.
  • Department of Ophthalmology, Oulu University Hospital, Oulu, Finland.
  • Section of Ophthalmology, King's College London, St Thomas' Hospital Campus, London, United Kingdom.
  • Biocenter Oulu, University of Oulu, Oulu, Finland.
  • Laboratory of Cancer Genetics and Tumor Biology, Translational Medicine Research Unit, University of Oulu, Oulu, Finland.
  • Greenwood Genetic Center, Greenwood, South Carolina.
  • Department of Genomics, Laboratory Division, Turku University Hospital, Turku, Finland.

Abstract

IMPORTANCE

Substantial unexplained heritability remains for pathogenic inherited retinal disease (IRD) variants. Application of genome-wide association studies (GWAS) could help identify causal genes in rare diseases.

OBJECTIVE

To leverage a GWAS for the discovery of IRD-associated genes.

DESIGN, SETTING, AND PARTICIPANTS

This GWAS analysis was combined with replication of findings in 2 independent IRD cohorts. The study was conducted from January 2024 to December 2025 in a multicenter setting through FinnGen, 100 000 Genomes Project, and the National Health Service Genomic Medicine Service combined with clinical cohort from the Oulu University Hospital. Using IRD criteria from the International Classification of Diseases, 9th and 10th Revisions, 540 individuals with IRD and 473 945 control individuals were identified in the FinnGen study. For validation of FinnGen results, 49 patients were recruited from Oulu University Hospital. Results were further validated in 2 individuals identified from the UK cohort.

MAIN OUTCOMES AND MEASURES

The GWAS and proteomics analysis were performed in the FinnGen cohort. Sanger and whole-genome sequencing and RNA approaches were used in a clinical IRD cohort to validate pathogenicity of the identified XXYLT1 variant.

RESULTS

This GWAS identified 13 recessive loci reaching genome-wide significance (defined as P < 5 × 10-8). Of these, 4 (near or within XXYLT1, ANKRD10, DYM, and CBLN4) had not been associated with IRD, including the XXYLT1 c.505-1G>C founder variant. This variant was further genotyped in the clinical replication cohort, leading to identification of 5 more homozygous individuals from 4 families. The phenotype was consistent with a cone-rod or macular dystrophy, with visual deterioration, cystoid macular edema and/or schisislike macular abnormalities. The effect of the XXYLT1 c.505-1G>C variant was further investigated using RNA sequencing and complementary DNA amplicon sequencing, demonstrating exon 2 skipping and a loss-of-function effect. These findings were replicated in an independent population identifying 2 patients from the UK harboring a homozygous XXYLT1 c.766G>A, p.(Glu256Lys) missense variant.

CONCLUSIONS AND RELEVANCE

This GWAS identified an association between XXYLT1 and IRD. These results affirm that GWAS in a founder population can be used as a potential tool for the discovery of rare mendelian disease genes and that XXYLT1 should be considered in clinical IRD gene panels.

MeSH

Retinal Dystrophies, Genes, Genome, Eye Diseases, Retinaldehyde