Mutation Spectrum of Macular Dystrophy Patients Who Had No Known Family History in East Asia

Abstract

Purpose : Inherited retinal degenerations (IRDs) consist of a number of severe retinal degenerative diseases with great genetic and clinical heterogeneity. Among them, macular dystrophies are caused by pathogenic variants in a single gene and lead to photoreceptors degradation in macula. However, the clinical phenotype of macular dystrophies is highly variable and still poorly understood. Here we report the results of genetic diagnosis for our macular dystrophy patients who were the only known patient in their families, and report the genotype-phenotype correlation in our cohort.

Methods : The reported cases were recruited in the Taiwan Inherited retinal diseases Project (TIP). The blood sample was collected and the genomic DNA was sequenced by panel-based next-generation sequencing (NGS) with 211 genes associated with inherited retinal degenerations. NGS data were annotated and filtered by allele frequency and pathogenicity prediction algorithms. The pathogenicity of remained variants was further classified by the ACMG standard and guideline.

Results : Among the first 400 recruited families, 30 probands of macular dystrophy who had no known family history were recruited in TIP and phenotype of each proband was characterized. Our panel-based NGS test provided a molecular diagnosis in 21 out of the 30 probands without family history (detection rate = 70.0%), and the disease-causing variants in ABCA4 were identified in 15 probands (15/21, 71.4%). The majority of probands with ABCA4 variants (5/15, 33.3%) carried the variant c.1804C>T with a severe effect on ABCA4 function and phenotypic abnormality.

Conclusions : In this study, the panel-based NGS was proven to have high diagnostic rate for molecular diagnosis of macular dystrophy patients who had no known family history in East Asia. The variant c.1804C>T in ABCA4 is the major disease-causing variant in our cohort and reveals a severe phenotypic abnormality. These findings confirm the value of NGS technique to diagnose macular dystrophy patients without family history at early stage of disease, and might be useful for genetic consultation and the advent of therapeutic possibilities in near future.

This is a 2020 ARVO Annual Meeting abstract.