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

TitleNext generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements.
Publication TypeJournal Article
Year of Publication2014
AuthorsWang, Feng, Wang Hui, Tuan Han-Fang, Nguyen Duy H., Sun Vincent, Keser Vafa, Bowne Sara J., Sullivan Lori S., Luo Hongrong, Zhao Ling, Wang Xia, Zaneveld Jacques E., Salvo Jason S., Siddiqui Sorath, Mao Louise, Wheaton Dianna K., Birch David G., Branham Kari E., Heckenlively John R., Wen Cindy, Flagg Ken, Ferreyra Henry, Pei Jacqueline, Khan Ayesha, Ren Huanan, Wang Keqing, Lopez Irma, Qamar Raheel, Zenteno Juan C., Ayala-Ramirez Raul, Buentello-Volante Beatriz, Fu Qing, Simpson David A., Li Yumei, Sui Ruifang, Silvestri Giuliana, Daiger Stephen P., Koenekoop Robert K., Zhang Kang, and Chen Rui
JournalHuman genetics
Volume133
Issue3
Pagination331-45
Date Published2014 Mar
ISSN1432-1203
KeywordsAlleles, Computational Biology, Exons, Genes, Recessive, Genetic Association Studies, Genetic Testing, Genotype, High-Throughput Nucleotide Sequencing, Humans, Membrane Glycoproteins, Molecular Chaperones, Mutation, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Reproducibility of Results, Retinitis Pigmentosa, Sequence Analysis, DNA
AbstractRetinitis 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.
DOI10.1007/s00439-013-1381-5
Alternate JournalHum. Genet.


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