Nationwide genetic analysis of more than 600 families with inherited eye diseases in Argentina

Abstract

This study corresponds to the first large-scale genetic analysis of inherited eye diseases (IED) in Argentina and describes the comprehensive genetic profile of a large cohort of patients. Medical records of 22 ophthalmology and genetics services throughout 13 Argentinian provinces were analyzed retrospectively. Patients with a clinical diagnosis of an ophthalmic genetic disease and a history of genetic testing were included. Medical, ophthalmological and family history was collected. A total of 773 patients from 637 families were included, with 98% having inherited retinal disease. The most common phenotype was retinitis pigmentosa (RP, 62%). Causative variants were detected in 379 (59%) patients. USH2A, RPGR, and ABCA4 were the most common disease-associated genes. USH2A was the most frequent gene associated with RP, RDH12 early-onset severe retinal dystrophy, ABCA4 Stargardt disease, PROM1 cone-rod dystrophy, and BEST1 macular dystrophy. The most frequent variants were RPGR c.1345 C > T, p.(Arg449*) and USH2A c.15089 C > A, p.(Ser5030*). The study revealed 156/448 (35%) previously unreported pathogenic/likely pathogenic variants and 8 possible founder mutations. We present the genetic landscape of IED in Argentina and the largest cohort in South America. This data will serve as a reference for future genetic studies, aid diagnosis, inform counseling, and assist in addressing the largely unmet need for clinical trials to be conducted in the region.

Fig. 1. Map of Argentina, provinces in shades of blue participated in the present study.

The blue gradient represents the percentage of previously unreported/total variants in each province, with darker tones corresponding to higher percentage and lighter, lower. Of note, the province with the highest percentage (60%, Jujuy) contained only a few variants and cases, possibly representing a bias.

Fig. 2. Clinical diagnoses of 773 patients with inherited eye diseases in Argentina.

RP retinitis pigmentosa, EOSRD early-onset severe retinal dystrophy, MD macular dystrophy, CHM choroideremia, CORD cone-rod dystrophy, IRD inherited retinal dystrophy, BBS Bardet–Biedl syndrome, FEVR familial exudative vitreoretinopathy, XLRS X-linked retinoschisis, MAC microphthalmia-anophthalmia-coloboma spectrum, PHPV persistent hyperplastic primary vitreous, CSNB congenital stationary night blindness, PPRCA pigmented paravenous retinochoroidal atrophy, OA optic atrophy. Albinism & related conditions include oculo-cutaneous albinism, ocular albinism, and foveal hypoplasia.

Fig. 3. Inheritance patterns and most common genes in the cohort.

A Pie graph representing the genotypes found in our cohort. B Bar graph showing the most frequently seen genes in the cohort, ranked by the number of affected families. The remaining genes were present in one or two families nationwide.

Fig. 4. Most common genes in pediatric patients and most frequently found variants in the complete cohort.

A Bar graph showing the most frequently found genes in patients under 18 years of age, ranked by the number of affected families. B Bar graph showing the most frequently found variants in the cohort, ranked by the number of alleles. The remaining variants were present in up to three families nationwide.