Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Chimalpopoca 14, Col. Obrera, Cuauhtemoc, Mexico City, CP06800, Mexico.
Laboratorio 5, Edificio A-4, Carrera de Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Laboratorio 5, Edificio A-4, Mexico City, Mexico.
Mol Genet Genomics. 2024 Aug 20;299(1):79. doi: 10.1007/s00438-024-02174-x.
The purpose of this study was to analyze and molecularly describe the largest group of patients with ABCA4-associated retinal degeneration in Latin America. Pathogenic variants in ABCA4, a member of the ATP Binding Cassette (ABC) transporters superfamily, is one of the most common causes of inherited visual deficiency in humans. Retinal phenotypes associated with genetic defects in ABCA4 are collectively known as ABCA4-associated retinal degenerations (ABCA4R), a group of recessively inherited disorders associated with a high allelic heterogeneity. While large groups of Caucasian and Asiatic individuals suffering from ABCA4R have been well characterized, molecular information from certain ethnic groups is limited or unavailable, precluding a more realistic knowledge of ABCA4-related mutational profile worldwide. In this study, we describe the molecular findings of a large group of 211 ABCA4R index cases from Mexico. Genotyping was performed using either next generation sequencing (NGS) of a retinal dystrophy genes panel or exome. ABCA4 targeted mutation testing was applied to a subgroup of subjects in whom founder mutations were suspected. A total of 128 different ABCA4 pathogenic variants were identified, including 22 previously unpublished variants. The most common type of genetic variation was single nucleotide substitutions which occurred in 92.7% (408/440 alleles). According to the predicted protein effect, the most frequent variant type was missense, occurring in 83.5% of disease-causing alleles (368/440). Mutations such as p.Ala1773Val are fully demonstrated as a founder effect in native inhabitants of certain regions of Mexico. This study also gives us certain indications of other founder effects that need to be further studied in the near future. This is the largest molecularly characterized ABCA4R Latin American cohort, and our results supports the value of conducting genetic screening in underrepresented populations for a better knowledge of the mutational profile leading to monogenic diseases.
本研究旨在分析和分子描述拉丁美洲最大的 ABCA4 相关视网膜变性患者群体。ABCA4 是 ATP 结合盒（ABC）转运蛋白超家族的成员之一，是导致人类遗传性视力缺陷的最常见原因之一。与 ABCA4 基因缺陷相关的视网膜表型统称为 ABCA4 相关视网膜变性（ABCA4R），这是一组隐性遗传疾病，具有高度等位基因异质性。虽然已经对患有 ABCA4R 的大量白种人和亚洲人群进行了很好的描述，但某些人群的分子信息有限或无法获得，这使得我们无法更真实地了解全球范围内与 ABCA4 相关的突变谱。在这项研究中，我们描述了来自墨西哥的 211 例 ABCA4R 索引病例的分子发现。使用视网膜营养不良基因panel 的下一代测序（NGS）或外显子组对基因型进行检测。对怀疑存在 founder 突变的亚组患者应用 ABCA4 靶向突变检测。共鉴定出 128 种不同的 ABCA4 致病性变异，包括 22 种以前未发表的变异。最常见的遗传变异类型是单核苷酸替换，占 92.7%（408/440 个等位基因）。根据预测的蛋白效应，最常见的变异类型是错义突变，占致病等位基因的 83.5%（368/440）。p.Ala1773Val 等突变被充分证明是墨西哥某些地区土着居民的 founder 效应。本研究还为我们提供了其他 founder 效应的一些迹象，这些效应需要在不久的将来进一步研究。这是拉丁美洲最大的 ABCA4R 分子特征化队列，我们的研究结果支持在代表性不足的人群中进行遗传筛查的价值，以便更好地了解导致单基因疾病的突变谱。
