Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing.

TitleComprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing.
Publication TypeJournal Article
Year of Publication2013
AuthorsWang, X, Wang, H, Sun, V, Tuan, H-F, Keser, V, Wang, K, Ren, H, Lopez, I, Zaneveld, JE, Siddiqui, S, Bowles, S, Khan, A, Salvo, J, Jacobson, SG, Iannaccone, A, Wang, F, Birch, D, Heckenlively, JR, Fishman, GA, Traboulsi, EI, Li, Y, Wheaton, D, Koenekoop, RK, Chen, R
JournalJ Med Genet
Volume50
Issue10
Pagination674-88
Date Published2013 Oct
ISSN1468-6244
KeywordsAlleles, Amino Acid Sequence, Base Sequence, Exome, Female, Genotype, High-Throughput Nucleotide Sequencing, Humans, Leber Congenital Amaurosis, Mutation, Pedigree, Polymorphism, Single Nucleotide, Reproducibility of Results, Retinitis Pigmentosa, Sensitivity and Specificity
Abstract

BACKGROUND: Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are inherited retinal diseases that cause early onset severe visual impairment. An accurate molecular diagnosis can refine the clinical diagnosis and allow gene specific treatments.

METHODS: We developed a capture panel that enriches the exonic DNA of 163 known retinal disease genes. Using this panel, we performed targeted next generation sequencing (NGS) for a large cohort of 179 unrelated and prescreened patients with the clinical diagnosis of LCA or juvenile RP. Systematic NGS data analysis, Sanger sequencing validation, and segregation analysis were utilised to identify the pathogenic mutations. Patients were revisited to examine the potential phenotypic ambiguity at the time of initial diagnosis.

RESULTS: Pathogenic mutations for 72 patients (40%) were identified, including 45 novel mutations. Of these 72 patients, 58 carried mutations in known LCA or juvenile RP genes and exhibited corresponding phenotypes, while 14 carried mutations in retinal disease genes that were not consistent with their initial clinical diagnosis. We revisited patients in the latter case and found that homozygous mutations in PRPH2 can cause LCA/juvenile RP. Guided by the molecular diagnosis, we reclassified the clinical diagnosis in two patients.

CONCLUSIONS: We have identified a novel gene and a large number of novel mutations that are associated with LCA/juvenile RP. Our results highlight the importance of molecular diagnosis as an integral part of clinical diagnosis.

DOI10.1136/jmedgenet-2013-101558
Alternate JournalJ. Med. Genet.
PubMed ID23847139
PubMed Central IDPMC3932025
Grant ListF32 EY019430 / EY / NEI NIH HHS / United States
R01 EY020540 / EY / NEI NIH HHS / United States
R01EY018571 / EY / NEI NIH HHS / United States
S10 RR026550 / RR / NCRR NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
5F32EY19430 / EY / NEI NIH HHS / United States
R01EY020540 / EY / NEI NIH HHS / United States
R01 EY022356 / EY / NEI NIH HHS / United States
R01 EY018571 / EY / NEI NIH HHS / United States
T32 GM008307 / GM / NIGMS NIH HHS / United States
T32 EY007102 / EY / NEI NIH HHS / United States