Abstract
Purpose :
Mutations in the ABCA4 gene are the most frequent cause of inherited macular disease, with phenotypes ranging from early onset fast progressing retinal degeneration to late onset mild cases of central atrophy. Phenotypic variability is caused by extensive genetic variation in the ABCA4 gene, and correlated with the combined effect of the two disease alleles on the ABCA4 function. In genetic screening, 5-10% of the Stargardt patients remain with only one ABCA4 disease allele identified after sequencing the ABCA4 gene. The aim of this study was to identify missing causal variants in ABCA4 monoallelic STGD1 patients from a large, well-characterized ABCA4 disease cohort.
Methods :
Sequencing was performed on Illumina TruSeq platform. Pathogenicity of variants was assessed according to ACMG guidelines, combining information from allele frequency data in patients vs the general population, predictive algorithms (e.g., CADD), previous publications, and segregation analysis in families. Patient phenotypes were assessed from clinical and retinal imaging data.
Results :
In 61/706 (8.6%) patients only one definitely pathogenic ABCA4 variant was identified in screening of the ABCA4 coding sequences. Subsequent sequencing of the non-coding intronic sequences has revealed several rare deep-intronic candidate variants in about half of the monoallelic STGD1 patients, while many cases remain genetically ‘unsolved’ without plausible candidate variants. Several rare ABCA4 missense variants (p.I1562T, p.V643G, p.V643M, p.G1591R, p.T897I) have been classified as benign or of uncertain significance despite moderate pathogenicity predictions, because they are not enriched in STGD1 patients. In our cohort, four 'unsolved' monoallelic STGD1 patients harbored the c.4685T>C (p.I1562T) variant opposite from a functionally deleterious ABCA4 mutation. They were diagnosed in 5th-7th decade and showed mild macular lesions with foveal sparing. We suggest that the rare p.I1562T variant shared between these 4 patients exhibiting similar mild late onset STGD1 phenotype, might be causal when in combination with a null allele. We do not exclude the role of other possible yet to be identified cis or trans modifying variants.
Conclusions :
Rare missense variants previously considered benign or of uncertain significance may contribute to late-onset ABCA4 disease with mild macular symptoms and foveal sparing.
This is a 2021 ARVO Annual Meeting abstract.