Whole exome sequencing (WES) continues to yield significant efficiencies in clinical identification of inherited retinal degenerations.

Research results reported by investigators based at the Department of Genetics & Microbiology, University of Barcelona, Spain, have shown that whole exome sequencing (WES) continues to provide efficient returns in the identification of the genetic diagnosis for a range of inherited retinal disorders. The Spanish research group worked on a cohort of 33 families with a variety of retinal disorders and used WES to define a genetic diagnosis in 18 families while proposing a viable candidate gene in a further 10 cases. Two thirds of the mutations identified were described as novel and included 4 chromosomal rearrangements. In addition, the results obtained prompted a clinical re-evaluation of some patients resulting in a change of diagnosis from a non-syndromic inherited retinal degeneration to a syndromic diagnosis. Four new candidate genes for non-syndromic pathologies were also identified including SEMA6B, CEP78, CEP250 and SCLT1.


The value of WES has advanced in recent years, driven considerably by reductions in the cost of next generation sequencing technologies, the availability of several well maintained databases, and an increasingly sophisticated bioinformatics toolkit available for sequence analysis. The difference in size between a whole genome (3 billion base pairs) and a whole exome (30 million base pairs) makes the sequencing task less expensive, more manageable and more focused on sequences more likely to harbour the genetic lesion. In general, it is estimated that approximately 85% of disease causing mutations are located in the coding regions of the genome. While there are currently over 6,000 monogenic diseases recorded, the molecular basis of almost two-thirds of them has yet to be reported. WES can provide a powerful tool in uncovering pathogenic variants, not only in monogenic disorders but also in the far larger pool of heterogeneous or complex disorders. Combining WES with already known pathways and mutations should lead to more efficient clinical application of genetic variants in new patients.


In the Spanish study, the WES analysis had a coverage of approximately 60X on the genes in the cohort of 33 families, among which the researchers identified 21 previously unreported mutations in genes known to cause inherited retinal degenerations. The group reported that the WES approach was very efficient, compared to other NGS based methods, and was advantageous in respect of (i) identifying pre-symptomatic patients with potential severe late-onset disorders, (ii) uncovering new clinical associations with milder alleles of syndromic genes, and; (iii) in proposing new candidate-genes for inherited retinopathies. In concluding their study the researchers comment that WES is “a highly informative and effective approach for patient molecular diagnosis in retinal dystrophies provided there is qualified genetic counselling. Genomic data from carefully clinically diagnosed patients are required to build a comprehensive human genomic landscape and elucidate how the interactions and complex tradeoffs between mutations, additional genetic variants – and environmental factors – tip the scales towards pathogenicity or resilience to disease.”

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