Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements

Feng Wang, Hui Wang, Han-Fang Tuan, Duy H Nguyen, Vincent Sun, Vafa Keser, Sara J Bowne, Lori S Sullivan, Hongrong Luo, Ling Zhao, Xia Wang, Jacques E Zaneveld, Jason S Salvo, Sorath Siddiqui, Louise Mao, Dianna K Wheaton, David G Birch, Kari E Branham, John R Heckenlively, Cindy WenKen Flagg, Henry Ferreyra, Jacqueline Pei, Ayesha Khan, Huanan Ren, Keqing Wang, Irma Lopez, Raheel Qamar, Juan C Zenteno, Raul Ayala-Ramirez, Beatriz Buentello-Volante, Qing Fu, David Simpson, Yumei Li, Ruifang Sui, Giuliana Silvestri, Stephen P Daiger, Robert K Koenekoop, Kang Zhang, Rui Chen, Giuliana Silvestri

Research output: Contribution to journalArticlepeer-review

161 Citations (Scopus)

Abstract

Retinitis pigmentosa (RP) is a devastating form of retinal degeneration, with significant social and professional consequences. Molecular genetic information is invaluable for an accurate clinical diagnosis of RP due to its high genetic and clinical heterogeneity. Using a gene capture panel that covers 163 of the currently known retinal disease genes, including 48 RP genes, we performed a comprehensive molecular screening in a collection of 123 RP unsettled probands from a wide variety of ethnic backgrounds, including 113 unrelated simplex and 10 autosomal recessive RP (arRP) cases. As a result, 61 mutations were identified in 45 probands, including 38 novel pathogenic alleles. Interestingly, we observed that phenotype and genotype were not in full agreement in 21 probands. Among them, eight probands were clinically reassessed, resulting in refinement of clinical diagnoses for six of these patients. Finally, recessive mutations in CLN3 were identified in five retinal degeneration patients, including four RP probands and one cone-rod dystrophy patient, suggesting that CLN3 is a novel non-syndromic retinal disease gene. Collectively, our results underscore that, due to the high molecular and clinical heterogeneity of RP, comprehensive screening of all retinal disease genes is effective in identifying novel pathogenic mutations and provides an opportunity to discover new genotype-phenotype correlations. Information gained from this genetic screening will directly aid in patient diagnosis, prognosis, and treatment, as well as allowing appropriate family planning and counseling.
Original languageEnglish
Pages (from-to)331-345
JournalHuman genetics
Volume133
Issue number3
Early online date24 Oct 2013
DOIs
Publication statusPublished - Mar 2014

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