Summary

Major challenges in molecular diagnostics of ABCA4-related retinopathy include non-coding variants typically not targeted by genetic tests, small copy number variants (CNV), and challenging interpretation of common hypomorphic variants, eg, ABCA4 p.(Asn1868Ile). We investigated the contribution of these challenging variants in the molecular diagnosis of ABCA4 disease in a cohort of 7500 IRD patients, analyzed with an NGS platform boosted with established ABCA4 non-coding variants and high-resolution CNV detection. Key findings included the following:

• Two disease-causing ABCA4variants were detected in 8.8% of cases; 3% had a non-coding variant, 1.5% had CNV
• The hypomorphic variant p.(Asn1868Ile) was identified in 57% of the cases with clinically diagnosed ABCA4-related retinopathy and only one disease-causing ABCA4variant; the allele frequency was higher among these cases (32.8%) vs controls in the gnomAD database (4.2%) (OR: 11.087, 95% CI: 8.953–13.73, p<0.001)
• The median age at testing was significantly higher in individuals with the hypomorphic (Asn1868Ile) variant compared to the individuals with two disease causing variants (56 vs 37 years).

Non-coding variants, CNVs and common hypomorphic alleles are important regions to include in the genetic diagnostics of ABCA4-related retinal disease.

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Authors:

Johanna Känsäkoski, Kati Kämpjärvi, Sari Tuupanen, Kirsty Wells, Laura Sarantaus, Pernilla von Nandelstadh, Katja Merkkiniemi, Hanna Västinsalo, Emma Mårtensson, Raquel Perez Carro, Eeva-Marja Sankila, Juha W Koskenvuo, Samuel Myllykangas, Tero-Pekka Alastalo