Brian P Hafler1. 1. Departments of Genetics and Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.
Abstract
PURPOSE: Inherited retinal dystrophies are a significant cause of vision loss and are characterized by the loss of photoreceptors and the retinal pigment epithelium (RPE). Mutations in approximately 250 genes cause inherited retinal degenerations with a high degree of genetic heterogeneity. New techniques in next-generation sequencing are allowing the comprehensive analysis of all retinal disease genes thus changing the approach to the molecular diagnosis of inherited retinal dystrophies. This review serves to analyze clinical progress in genetic diagnostic testing and implications for retinal gene therapy. METHODS: A literature search of PubMed and OMIM was conducted to relevant articles in inherited retinal dystrophies. RESULTS: Next-generation genetic sequencing allows the simultaneous analysis of all the approximately 250 genes that cause inherited retinal dystrophies. Reported diagnostic rates range are high and range from 51% to 57%. These new sequencing tools are highly accurate with sensitivities of 97.9% and specificities of 100%. Retinal gene therapy clinical trials are underway for multiple genes including RPE65, ABCA4, CHM, RS1, MYO7A, CNGA3, CNGB3, ND4, and MERTK for which a molecular diagnosis may be beneficial for patients. CONCLUSION: Comprehensive next-generation genetic sequencing of all retinal dystrophy genes is changing the paradigm for how retinal specialists perform genetic testing for inherited retinal degenerations. Not only are high diagnostic yields obtained, but mutations in genes with novel clinical phenotypes are also identified. In the era of retinal gene therapy clinical trials, identifying specific genetic defects will increasingly be of use to identify patients who may enroll in clinical studies and benefit from novel therapies.
PURPOSE:Inherited retinal dystrophies are a significant cause of vision loss and are characterized by the loss of photoreceptors and the retinal pigment epithelium (RPE). Mutations in approximately 250 genes cause inherited retinal degenerations with a high degree of genetic heterogeneity. New techniques in next-generation sequencing are allowing the comprehensive analysis of all retinal disease genes thus changing the approach to the molecular diagnosis of inherited retinal dystrophies. This review serves to analyze clinical progress in genetic diagnostic testing and implications for retinal gene therapy. METHODS: A literature search of PubMed and OMIM was conducted to relevant articles in inherited retinal dystrophies. RESULTS: Next-generation genetic sequencing allows the simultaneous analysis of all the approximately 250 genes that cause inherited retinal dystrophies. Reported diagnostic rates range are high and range from 51% to 57%. These new sequencing tools are highly accurate with sensitivities of 97.9% and specificities of 100%. Retinal gene therapy clinical trials are underway for multiple genes including RPE65, ABCA4, CHM, RS1, MYO7A, CNGA3, CNGB3, ND4, and MERTK for which a molecular diagnosis may be beneficial for patients. CONCLUSION: Comprehensive next-generation genetic sequencing of all retinal dystrophy genes is changing the paradigm for how retinal specialists perform genetic testing for inherited retinal degenerations. Not only are high diagnostic yields obtained, but mutations in genes with novel clinical phenotypes are also identified. In the era of retinal gene therapy clinical trials, identifying specific genetic defects will increasingly be of use to identify patients who may enroll in clinical studies and benefit from novel therapies.
Authors: Morag E Shanks; Susan M Downes; Richard R Copley; Stefano Lise; John Broxholme; Karl Az Hudspith; Alexandra Kwasniewska; Wayne Il Davies; Mark W Hankins; Emily R Packham; Penny Clouston; Anneke Seller; Andrew Om Wilkie; Jenny C Taylor; Jiannis Ragoussis; Andrea H Németh Journal: Eur J Hum Genet Date: 2012-09-12 Impact factor: 4.246
Authors: Cristy A Ku; Vince A Chiodo; Sanford L Boye; Abigail Hayes; Andrew F X Goldberg; William W Hauswirth; Visvanathan Ramamurthy Journal: Hum Mol Genet Date: 2014-09-30 Impact factor: 6.150
Authors: Lucie P Pellissier; Peter M Quinn; C Henrique Alves; Rogier M Vos; Jan Klooster; John G Flannery; J Alexander Heimel; Jan Wijnholds Journal: Hum Mol Genet Date: 2015-02-20 Impact factor: 6.150
Authors: Nicola G Ghazi; Emad B Abboud; Sawsan R Nowilaty; Hisham Alkuraya; Abdulrahman Alhommadi; Huimin Cai; Rui Hou; Wen-Tao Deng; Sanford L Boye; Abdulrahman Almaghamsi; Fahad Al Saikhan; Hassan Al-Dhibi; David Birch; Christopher Chung; Dilek Colak; Matthew M LaVail; Douglas Vollrath; Kirsten Erger; Wenqiu Wang; Thomas Conlon; Kang Zhang; William Hauswirth; Fowzan S Alkuraya Journal: Hum Genet Date: 2016-01-29 Impact factor: 4.132
Authors: Thomas L Edwards; Jasleen K Jolly; Markus Groppe; Alun R Barnard; Charles L Cottriall; Tanya Tolmachova; Graeme C Black; Andrew R Webster; Andrew J Lotery; Graham E Holder; Kanmin Xue; Susan M Downes; Matthew P Simunovic; Miguel C Seabra; Robert E MacLaren Journal: N Engl J Med Date: 2016-04-27 Impact factor: 91.245
Authors: Sanford L Boye; James J Peterson; Shreyasi Choudhury; Seok Hong Min; Qing Ruan; K Tyler McCullough; Zhonghong Zhang; Elena V Olshevskaya; Igor V Peshenko; William W Hauswirth; Xi-Qin Ding; Alexander M Dizhoor; Shannon E Boye Journal: Hum Gene Ther Date: 2015-08-06 Impact factor: 4.793
Authors: Robert E MacLaren; Markus Groppe; Alun R Barnard; Charles L Cottriall; Tanya Tolmachova; Len Seymour; K Reed Clark; Matthew J During; Frans P M Cremers; Graeme C M Black; Andrew J Lotery; Susan M Downes; Andrew R Webster; Miguel C Seabra Journal: Lancet Date: 2014-01-16 Impact factor: 79.321
Authors: Lea D Bennett; Georgiana Metz; Martin Klein; Kirsten G Locke; Areeba Khwaja; David G Birch Journal: Invest Ophthalmol Vis Sci Date: 2019-03-01 Impact factor: 4.799