Clinical manifestations and genetic variation analysis in six Chinese pedigrees affected with Stargardt disease
10.3760/cma.j.cn511374-20241220-00669
- VernacularTitle:Stargardt病6个家系的临床表现及基因变异分析
- Author:
Lijuan ZHANG
1
;
Tao MA
1
;
Ruiqi ZHANG
1
;
Ximei ZHANG
1
Author Information
1. 山西省眼科医院、山西医科大学，太原 030002
- Publication Type:Journal Article
- Keywords:
Mutation, gene;
Multilocus sequence typing;
Genetic variation;
Stargardt disease;
ABCA4 gene;
Macular atrophy;
Whole exome sequencing
- From:
Chinese Journal of Medical Genetics
2025;42(5):547-555
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore the correlation between the clinical manifestations and genetic variations in six Chinese Stargardt disease pedigrees.Methods: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 the ABCA4 gene were verified by 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). Results:From June 2021 to June 2023, 7 patients 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 6 to 15 years old. All patients exhibited moderate-to-severe visual impairment with macular atrophy, and yellow white spots were seen in all patients except patient Ⅱ 2 in family 5. Optical coherence tomography (OCT) results showed that the in all patients the macular fovea was significantly thinner, and IS/OS or ellipsoid zone had disappeared. Autofluorescence showed low autofluorescence in the macula, with abnormal 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. Pedigree analysis showed that all six pedigrees had autosomal recessive inheritance, family 1, 2, 3, 4, 6 had compound heterozygous variants of the ABCA4, and family 5 had homozygous variants. A total of 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. Those carrying nonsense or frameshift mutations include patient 1 (family 1, Ⅱ 1), patient 2 (family 1, Ⅱ 2), patient 4 (family 3, Ⅱ 1), patient 6 (family 5, Ⅱ 2), and patient 7 (family 6, Ⅱ 1), whose clinical manifestations were more severe than those of patient 3 (family 2, Ⅱ 2) and patient 5 (family 4, Ⅱ 1) carrying missense mutations in terms of best corrected visual acuity(BCVA) damage. Conclusion:The ABCA4 gene variation may be the genetic cause of the Stargardt disease in this study, and the discovery of the ABCA4 gene disease variants p. Glu1704Gly, p. Gly1965Glu, p. Ser1531Phe has enriched the mutational spectrum of of Stargardt disease.
