[Clinical manifestations and genetic variation analysis in six Chinese pedigrees affected with Stargardt disease]

To explore the correlation between clinical manifestations and genetic variations in six Chinese Stargardt disease pedigrees.

Six Stargardt disease pedigrees due to ABCA4 gene variants that visited Shanxi Eye Hospital from June 2021 June 2023 were selected as the study subjects. A retrospective study method was used to collect the clinical and family history data of all members of these pedigrees. Peripheral venous blood samples of the examinees were collected, and genomic DNA was extracted for trio-WES. Candidate variants of the ABCA4 gene were verified by family Sanger sequencing. According to the "Standards and Guidelines for the Classification of Sequence Variants" (hereinafter referred to as the "ACMG Guidelines") formulated by American College of Medical Genetics and Genomics (ACMG), the variant sites of the ABCA4 gene were classified for pathogenicity. This study has been approved by the Medical Ethics Committee of Shanxi Eye Hospital (Ethics No. SXYYLL-20200620).

From June 2021 to June 2023, 7 patients (patient 1 to 7) from families with Stargardt disease with ABCA4 variants were selected as the study subjects. The age of the patients was between 7 to 53 years old, and the age of onset was between their 6 to 15 years old. All patients had exhibited moderate-to-severe visual impairment with macular atrophy, and yellow white spots were seen in all patients except patient II2 in family 5. Optical coherence tomography (OCT) results showed that all patients' macular fovea was significantly thinner, with IS/OS or ellipsoid zone disappeared. Autofluorescence showed low autofluorescence in the macula, and abnormalities dot autofluorescence in the paramacular and periphery retina. ERG grouping classified three pedigrees as Group 3, two as Group 1, and one as Group 2. Genetic analysis results showed that all pedigrees had autosomal recessive inheritance, five had compound heterozygous variants in the ABCA4, and one had homozygous variants. In total 11 pathogenic mutations were detected in the ABCA4 gene, of which 3 were found for the first time, including p.Glu1704Gly, p.Gly1965Glu and p.Ser1531Phe. Patients carrying nonsense or frameshift mutations include patient 1 (family 1, II1), patient 2 (family 1, II2), patient 4 (family 3, II1), patient 6 (family 5, II2), and patient 7 (family 6, II1), whose clinical manifestations are more severe than those of patient 3 (family 2, II2) and patient 5 (family 4, II1), whom carried missense mutations in terms of best corrected visual acuity (BCVA) damage.

The ABCA4 gene variations may be the genetic cause of the Stargardt disease in this study, and the discovery of the ABCA4 gene p.Glu1704Gly, p.Gly1965Glu, p.Ser1531Phe variants has enriched the mutational spectrum of Stargardt disease.