Abstract
BackgroundRetinal dystrophies (RD) are a group of hereditary diseases that lead to debilitating visual impairment and are usually transmitted as a Mendelian trait. Pathogenic mutations can occur in any of the 100 or more disease genes identified so far, making molecular diagnosis a rather laborious process. In this work we explored the use of whole exome sequencing (WES) as a tool for identification of RD mutations, with the aim of assessing its applicability in a diagnostic context.Methodology/Principal FindingsWe ascertained 12 Spanish families with seemingly recessive RD. All of the index patients underwent mutational pre-screening by chip-based sequence hybridization and resulted to be negative for known RD mutations. With the exception of one pedigree, to simulate a standard diagnostic scenario we processed by WES only the DNA from the index patient of each family, followed by in silico data analysis. We successfully identified causative mutations in patients from 10 different families, which were later verified by Sanger sequencing and co-segregation analyses. Specifically, we detected pathogenic DNA variants (∼50% novel mutations) in the genes RP1, USH2A, CNGB3, NMNAT1, CHM, and ABCA4, responsible for retinitis pigmentosa, Usher syndrome, achromatopsia, Leber congenital amaurosis, choroideremia, or recessive Stargardt/cone-rod dystrophy cases.Conclusions/SignificanceDespite the absence of genetic information from other family members that could help excluding nonpathogenic DNA variants, we could detect causative mutations in a variety of genes known to represent a wide spectrum of clinical phenotypes in 83% of the patients analyzed. Considering the constant drop in costs for human exome sequencing and the relative simplicity of the analyses made, this technique could represent a valuable tool for molecular diagnostics or genetic research, even in cases for which no genotypes from family members are available.
Highlights
Retinal dystrophies (RD), comprising the wide spectrum of retinal degeneration, are rare genetic conditions leading to visual deficiency and in some instances to blindness [1]
Diagnoses were based on ophthalmologic examination and pedigree data, according to previously described/established clinical and classification criteria [26,27,28,29,30]
Precise clinical information or family history can facilitate this procedure, the number of known mutations that medical geneticists have to consider in the screening process is likely in the range of a few thousands, over more than 100 different genes
Summary
Retinal dystrophies (RD), comprising the wide spectrum of retinal degeneration, are rare genetic conditions leading to visual deficiency and in some instances to blindness [1] These diseases affect roughly one person out of 4,000 and are the result of the progressive loss or dysfunction of photoreceptors, the light-sensing cells of the eye [2]. Mutations causing RD can occur in any of these genes, as well as in other disease genes that still await identification, and can be transmitted as dominant, recessive, or X-linked alleles. This very elevated genetic heterogeneity is possibly the highest detected so far among all Mendelian diseases and leads to a very high carrier frequency of heterozygous mutant alleles, i.e. possibly more than 1 in 4–5 individuals [3]. In this work we explored the use of whole exome sequencing (WES) as a tool for identification of RD mutations, with the aim of assessing its applicability in a diagnostic context
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