ABCA4-Associated Retinal Degeneration in 8 Families from the Three Provinces of Northeast China: Identification and Characterization of Potentially Novel Variants.

ABSTRACT Background This study characterizes the clinical and genetic features of ABCA4 ‐associated inherited retinal diseases (IRDs) in eight unrelated probands from the three provinces of Northeast China. All patients harbored biallelic pathogenic ABCA4 variants, with detailed variant profiles provided in Table 2. Methods Eight unrelated Chinese pedigrees (31 individuals, including 8 probands and 23 family members) with ABCA4 ‐related IRDs. All participants underwent comprehensive ophthalmic examinations. Genetic variants were identified using a targeted next‐generation sequencing (NGS) panel for IRDs. For all candidate pathogenic variants, in silico pathogenicity predictions were performed using REVEL, PolyPhen‐2, MutationTaster, SIFT, and LRT (Likelihood Ratio Test). The pathogenicity of the variants was classified in accordance with the guidelines of the American College of Medical Genetics and Genomics (ACMG), integrating computational evidence and segregation analysis. All candidate variants were validated by bidirectional Sanger sequencing, and co‐segregation analysis was performed in available family members. Results Sixteen ABCA4 variants were identified, including six novel potentially deleterious variants (three predicted loss‐of‐function). ACMG classifications comprised six pathogenic variants, eight likely pathogenic variants, and two variants of uncertain significance (VUS). Phenotypically, six probands presented with Stargardt disease type 1 (STGD1), one with early‐onset severe retinal dystrophy (EOSRD, compound heterozygous ABCA4 variants), and one with an unclassified IRD. The three provinces of Northeast China STGD1 patients displayed a higher proportion of mild‐severity variants yet presented with an earlier median onset age (10.6 years) and more severe visual impairment (77.2% with best‐corrected visual acuity < 0.1) when compared to global cohorts. However, this observation may reflect referral bias to a tertiary center and requires validation in larger, multi‐ethnic cohorts. Conclusions Targeted NGS identified six potentially novel ABCA4 variants in the Northeast Chinese population, including three predicted loss‐of‐function variants. This study reports a case of ABCA4 associated EOSRD, thereby broadening the documented ABCA4 variant spectrum in this population.