ABCA4 Deep Intronic Variants Contributed to Nearly Half of Unsolved Stargardt Cases With a Milder Phenotype

Overview

Journal Invest Ophthalmol Vis Sci

Date 2025 Jan 30

PMID 39883546

Authors

Yingwei Wang

Pangfeng Wang

Zhen Yi

Jiamin Ouyang

Yi Jiang

Shiqiang Li

Xiaoyun Jia

Xueshan Xiao

James Fielding Hejtmancik

Wenmin Sun

Qingjiong Zhang

Affiliations

Soon will be listed here.

Abstract

Purpose: The purpose of this study was to investigate the contribution and natural progression of ABCA4 deep intronic variants (DIVs) among a Chinese Stargardt disease (STGD) cohort.

Methods: For unsolved STGD probands, DIVs in ABCA4 were detected by next-generation sequencing, and splicing effects were evaluated by in silico tools and validated through minigene experiments. Comprehensive ocular examinations, especially fundus changes, were carried out and analyzed. These and long-term follow-up data were compared with data of patients carrying biallelic coding variants of ABCA4.

Results: Seven DIVs in ABCA4 were identified in 18 of 40 (45.0%) unsolved STGD probands, involving 2 novel and 5 known variants. Four DIVs were confirmed to effect splicing through minigene assay. The c.161-395G>A was the most prevalent DIV allele (30.6%, 11/36). In the early 5-year duration, localized maculopathy was predominant, accounting for 51.9% (14/27) of fundus recordings. Expanded macular lesion within the vascular arch, with or without flecks, was observed in 75.0% (12/16) of recordings beyond the 5-year duration, whereas generalized retinal dystrophy was rarely observed. Compared with those in the non-DIV group, the patients in the DIV group manifested milder fundus change at all disease stages (P < 0.05). Follow-up visits utilizing wide-field fundus autofluorescence (FAF) further validated the slower development of lesions. Optical coherence tomography angiography (OCTA) documented a gradual reduction in perfusion in each layer's capillaries and high-reflective deposits below the sub-RPE layer.

Conclusions: DIVs contribute to nearly half of STGD cases with missing heritability, totally occupying 7.8% of all STGD families. Based on optimized grading criteria, patients with DIV alleles manifested localized macular lesions with slow progress. The amount of residual correctly spliced mRNA might play a role, suggesting that adding or enhancing normal ABCA4 expression might be a potential approach of intervention.

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