Abstract
We combined deep phenotype data and whole-genome sequencing results from the UK 100,000 Genomes Project (100KGP) to characterize the genetic spectrum of infantile nystagmus and albinism, and to explore genotype–phenotype correlations in this cohort. Participants were enrolled in the study based on the clinical codes for albinism or infantile nystagmus. Whole genome sequencing data was retrieved and variants in known nystagmus/albinism genes (PanelApp R39 panel) were analysed alongside genome-wide findings. We ascertained 473 affected individuals (388 families). Positive genetic findings were obtained in 218 participants (46%), including 176 (37%) with definitive diagnoses. Pathogenic variants were found in 16 of 38 panel genes, most commonly in TYR (56 families) and OCA2 (21 families). Recurrent variants (24% of 103 different variants) were identified in six genes. An additional 36 off-panel genes accounted for diagnoses in 45 families, including four dual genetic diagnoses in three families. Phenotypically, refractive errors and foveal hypoplasia-related diagnoses were significantly enriched (odds ratio ~2.8 for refractive disorders). Strabismus and neurodevelopmental features were also over-represented in the cohort. We show that whole-genome sequencing provided a high diagnostic yield in infantile nystagmus/albinism and uncovered a broad allelic spectrum. Integrating comprehensive phenotype data identified distinct genotype–phenotype relationships.
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Acknowledgements
The authors thank all families from the 100kGP and Genomic Medicine Service for their involvement in this study. This study was conducted under the project ID 991 entitled ‘Understanding the genetic and phenotypic landscape of congenital nystagmus’ through access to data in the National Genomic Research Library, which is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The National Genomic Research Library holds data provided by patients and collected by the NHS as part of their care and data collected as part of their participation in research. The National Genomic Research Library is funded by the National Institute for Health and Care Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. M.R.F is supported by National Institute for Health and Care Research Academic Clinical fellowship (NIHR ACF-2022-11-004). This study was supported by the Medical Research Council (MRC), UK (grant numbers MC_PC_17171 and MC_PC_19043), the Ulverscroft Foundation, and Fight for Sight. Additional support was provided by the NIHR Leicester Biomedical Research Centre. The funders had no role in the design, conduct, data collection, analysis, or interpretation of this study.
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Fassad, M.R., Vasudevan, P.C., Barwell, J. et al. Whole-genome sequencing uncovers diverse genetic causes and phenotypic signatures in infantile nystagmus and albinism. npj Genom. Med. (2026). https://doi.org/10.1038/s41525-026-00580-1
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DOI: https://doi.org/10.1038/s41525-026-00580-1
