Review
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Med Genet. May 27, 2015; 5(2): 14-22
Published online May 27, 2015. doi: 10.5496/wjmg.v5.i2.14
Clinical applications of high-throughput genetic diagnosis in inherited retinal dystrophies: Present challenges and future directions
Gemma Marfany, Roser Gonzàlez-Duarte
Gemma Marfany, Roser Gonzàlez-Duarte, Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain
Gemma Marfany, Roser Gonzàlez-Duarte, CIBER, Instituto de Salud Carlos III, 08028 Barcelona, Spain
Gemma Marfany, Roser Gonzàlez-Duarte, IBUB, Institut de Biomedicina de la Universitat de Barcelona, 08028 Barcelona, Spain
Author contributions: Marfany G and Gonzàlez-Duarte R conceived the review, designed the contents, searched the literature, wrote the manuscript and elaborated the tables.
Supported by Grants SAF2013-49069-C2-1-R (Marfany G and Gonzàlez-Duarte R); BFU2010-15656 (Marfany G) (Ministerio de Ciencia e Innovación); SGR2014-0932 (Generalitat de Catalunya); CIBERER (U718); Retina Asturias (Gonzàlez-Duarte R); and ONCE (Gonzàlez-Duarte R).
Conflict-of-interest: The authors declare no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Roser Gonzàlez-Duarte, PhD, Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Avinguda Diagonal 643, 08028 Barcelona, Spain. rgonzalez@ub.edu
Telephone: +34-93-4021034 Fax: +34-93-4034420
Received: November 20, 2014
Peer-review started: November 24, 2014
First decision: December 12, 2014
Revised: January 23, 2015
Accepted: February 4, 2015
Article in press: February 9, 2015
Published online: May 27, 2015
Processing time: 189 Days and 13.1 Hours
Abstract

The advent of next generation sequencing (NGS) techniques has greatly simplified the molecular diagnosis and gene identification in very rare and highly heterogeneous Mendelian disorders. Over the last two years, these approaches, especially whole exome sequencing (WES), alone or combined with homozygosity mapping and linkage analysis, have proved to be successful in the identification of more than 25 new causative retinal dystrophy genes. NGS-approaches have also identified a wealth of new mutations in previously reported genes and have provided more comprehensive information concerning the landscape of genotype-phenotype correlations and the genetic complexity/diversity of human control populations. Although whole genome sequencing is far more informative than WES, the functional meaning of the genetic variants identified by the latter can be more easily interpreted, and final diagnosis of inherited retinal dystrophies is extremely successful, reaching 80%, particularly for recessive cases. Even considering the present limitations of WES, the reductions in costs and time, the continual technical improvements, the implementation of refined bioinformatic tools and the unbiased comprehensive genetic information it provides, make WES a very promising diagnostic tool for routine clinical and genetic diagnosis in the future.

Keywords: Next generation sequencing; Identification of novel causative genes; Inherited retinal dystrophies; Genetic diagnosis; Whole exome sequencing

Core tip: This review focuses on the application of next generation sequencing (NGS)-based methods [whole genome sequencing, whole exome sequencing (WES), targeted exome sequencing] for genetic diagnosis and novel gene identification in hereditary retinal dystrophies. Advances over the last two years concerning NGS accuracy, reliability, development of bioinformatics tools, together with the drop in costs and time required for the analysis have allowed thirty novel genes to be identified, plus a large number of new mutations in previously reported genes. NGS techniques (particularly WES) are revolutionizing genetic diagnosis and have clear applications in clinical practice, helping to pave the way for personalized medicine. Present challenges and future directions are also discussed.