Abstract
BackgroundRetinal dystrophies (RDs) are one of the most genetically heterogeneous monogenic disorders with ~270 associated loci identified by early 2019. The recent application of next‐generation sequencing (NGS) has greatly improved the molecular diagnosis of RD patients. Genetic characterization of RD cohorts from different ethnic groups is justified, as it would improve the knowledge of molecular basis of the disease. Here, we present the results of genetic analysis in a large cohort of 143 unrelated Mexican subjects with a variety of RDs.MethodsA targeted NGS approach covering 199 RD genes was employed for molecular screening of 143 unrelated patients. In addition to probands, 258 relatives were genotyped by Sanger sequencing for familial segregation of pathogenic variants.ResultsA solving rate of 66% (95/143) was achieved, with evidence of extensive loci (44 genes) and allelic (110 pathogenic variants) heterogeneity. Forty‐eight percent of the identified pathogenic variants were novel while ABCA4, CRB1, USH2A, and RPE65 carried the greatest number of alterations. Novel deleterious variants in IDH3B and ARL6 were identified, supporting their involvement in RD. Familial segregation of causal variants allowed the recognition of 124 autosomal or X‐linked carriers.ConclusionOur results illustrate the utility of NGS for genetic diagnosis of RDs of different populations for a better knowledge of the mutational landscape associated with the disease.
Highlights
Retinal dystrophies (RDs) are an extensive group of inherited disorders arising from mutations in genes with a role in development, function, and maintenance of specific retinal cells (Tsui, Song, Lin, & Tsang, 2018)
This study represents the largest cohort of molecularly analyzed RD subjects from Mexico and Latin America, and our results demonstrate extensive genic and allelic heterogeneity underlying these disorders in our population
As it has been shown in previous studies (Bernardis et al, 2016; Bravo-Gil et al, 2016; Glöckle et al, 2014; Patel et al, 2016), the molecular diagnostic yield varied among subtypes of RD in our cohort, with cone-rod dystrophy (CRD) (86% solving rate), autosomal recessive retinitis pigmentosa (ARRP) (78%), macular dystrophy (MD) (82%), and Leber congenital amaurosis (LCA) (71%) being the commonest molecularly solved disorders
Summary
The human retina is a specialized neural tissue in which the interaction of a variety of cell types allows the transduction of light stimuli into neural signals. Retinal dystrophies (RDs) are an extensive group of inherited disorders arising from mutations in genes with a role in development, function, and maintenance of specific retinal cells (Tsui, Song, Lin, & Tsang, 2018). NGS has been recently applied for the recognition of pathogenic variants in cohorts of RDs patients from different ethnicities, with rates of molecularly solved cases ranging from 50% to 75% (Bernardis et al, 2016; Birtel et al, 2018; BoulangerScemama et al, 2015; Bravo-Gil et al, 2016; Di Iorio et al, 2017; Ge et al, 2015; Patel et al, 2016; Riera et al, 2017; Wang et al, 2014; Zhao et al, 2015). Molecular characterization of additional RD cohorts is warranted as they will allow the expansion of the spectrum of pathogenic variants linked to human retinal degeneration, will permit the identification of additional genotype–phenotype correlations, and will recognize ethnic-specific founder effects which would facilitate subsequent molecular analysis in patients from such populations. A diagnostic rate of 66% was obtained (95/143 probands) and a total of 110 distinct pathogenic variants (53 of them novel) in 44 known RD genes were identified
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