The Genetic Landscape of Inherited Retinal Diseases in a Mexican Cohort: Genes, Mutations and Phenotypes

Abstract

In this work, we aimed to provide the genetic diagnosis of a large cohort of patients affected with inherited retinal dystrophies (IRDs) from Mexico. Our data add valuable information to the genetic portrait in rare ocular diseases of Mesoamerican populations, which are mostly under-represented in genetic studies. A cohort of 144 unrelated probands with a clinical diagnosis of IRD were analyzed by next-generation sequencing using target gene panels (overall including 346 genes and 65 intronic sequences). Four unsolved cases were analyzed by whole-exome sequencing (WES). The pathogenicity of new variants was assessed by in silico prediction algorithms and classified following the American College of Medical Genetics and Genomics (ACMG) guidelines. Pathogenic or likely pathogenic variants were identified in 105 probands, with a final diagnostic yield of 72.9%; 17 cases (11.8%) were partially solved. Eighteen patients were clinically reclassified after a genetic diagnostic test (17.1%). In our Mexican cohort, mutations in 48 genes were found, with ABCA4, CRB1, RPGR and USH2A as the major contributors. Notably, over 50 new putatively pathogenic variants were identified. Our data highlight cases with relevant clinical and genetic features due to mutations in the RAB28 and CWC27 genes, enrich the novel mutation repertoire and expand the IRD landscape of the Mexican population.

Retinitis Pigmentosa in the Puerto Rican Population: A Geographic Distribution

“…This is a higher incidence than has been identified in other populations. 10,12 Studies have also identified BBS7 mutations in Spanish and Mexican cohorts. 12 However, the p. Thr211Ile variant has not been previously identified in other populations.…”

“…Previous studies have identified that mutations in the CRB1 gene are one of the major contributors to RP in the Mexican population. 10 Mutations in CRB1 contributed to 7% of pathogenic mutations associated with inherited retinal dystrophies. 10 In our cohort, mutations in CRB1 were associated with 11% of cases.…”

“… 10 Mutations in CRB1 contributed to 7% of pathogenic mutations associated with inherited retinal dystrophies. 10 In our cohort, mutations in CRB1 were associated with 11% of cases. The relatively higher frequencies in our cohort could be explained by consanguinity.…”

Dawn and dusk peaks of outer segment phagocytosis, and visual cycle function require Rab28

“…RAB28 null and hypomorphic alleles cause autosomal recessive cone-rod dystrophy (arCRD) with eight pathogenic alleles attributed to date. [18][19][20][21][22][23] In Caenorhabditis elegans, we have shown that Rab28 is an intraflagellar transport (IFT) and BBSome-associated ciliary protein, 24 which regulates extracellular vesicle biogenesis in a subset of ciliated neurons. 25 In addition, we employed zebrafish knockout and transgenic reporter models to probe Rab28's localization and, we previously described the localization, GTP/GDP nucleotide regulation, and a protein interactome of Rab28 in cone photoreceptors.…”

“…In 2012, the small ciliary GTPase Rab28 was identified as the first Rab GTPase associated with human cone‐rod dystrophy (CRD). RAB28 null and hypomorphic alleles cause autosomal recessive cone‐rod dystrophy (arCRD) with eight pathogenic alleles attributed to date 18‐23 . In Caenorhabditis elegans , we have shown that Rab28 is an intraflagellar transport (IFT) and BBSome‐associated ciliary protein, 24 which regulates extracellular vesicle biogenesis in a subset of ciliated neurons 25 .…”