ABCA4 p.Glu1574*
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[hide] Exome sequencing of index patients with retinal dy... PLoS One. 2013 Jun 14;8(6):e65574. doi: 10.1371/journal.pone.0065574. Print 2013. Corton M, Nishiguchi KM, Avila-Fernandez A, Nikopoulos K, Riveiro-Alvarez R, Tatu SD, Ayuso C, Rivolta C
Exome sequencing of index patients with retinal dystrophies as a tool for molecular diagnosis.
PLoS One. 2013 Jun 14;8(6):e65574. doi: 10.1371/journal.pone.0065574. Print 2013., [PMID:23940504]
Abstract [show]
BACKGROUND: Retinal dystrophies (RD) are a group of hereditary diseases that lead to debilitating visual impairment and are usually transmitted as a Mendelian trait. Pathogenic mutations can occur in any of the 100 or more disease genes identified so far, making molecular diagnosis a rather laborious process. In this work we explored the use of whole exome sequencing (WES) as a tool for identification of RD mutations, with the aim of assessing its applicability in a diagnostic context. METHODOLOGY/PRINCIPAL FINDINGS: We ascertained 12 Spanish families with seemingly recessive RD. All of the index patients underwent mutational pre-screening by chip-based sequence hybridization and resulted to be negative for known RD mutations. With the exception of one pedigree, to simulate a standard diagnostic scenario we processed by WES only the DNA from the index patient of each family, followed by in silico data analysis. We successfully identified causative mutations in patients from 10 different families, which were later verified by Sanger sequencing and co-segregation analyses. Specifically, we detected pathogenic DNA variants ( approximately 50% novel mutations) in the genes RP1, USH2A, CNGB3, NMNAT1, CHM, and ABCA4, responsible for retinitis pigmentosa, Usher syndrome, achromatopsia, Leber congenital amaurosis, choroideremia, or recessive Stargardt/cone-rod dystrophy cases. CONCLUSIONS/SIGNIFICANCE: Despite the absence of genetic information from other family members that could help excluding nonpathogenic DNA variants, we could detect causative mutations in a variety of genes known to represent a wide spectrum of clinical phenotypes in 83% of the patients analyzed. Considering the constant drop in costs for human exome sequencing and the relative simplicity of the analyses made, this technique could represent a valuable tool for molecular diagnostics or genetic research, even in cases for which no genotypes from family members are available.
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No. Sentence Comment
105 FAMILY ID INDEX PATIENT ID GENE (OMIM entry) NUCLEOTIDE CHANGE PROTEIN CHANGE NOVEL/KNOWN REFERENCE RP-0674 01-0570 ABCA4 c.287delA p.N96Tfs*19 novel (601691) c.6148G.C p.V2050L known [43] RP-0298 95-0103 ABCA4 c.4720G.T p.E1574* known [44] c.950delG p.G317Afs*57 novel RP-1102 07-0366 ABCA4 c.2285C.A (homoz) p.A762E known [45] RP-1164 07-0360 CHM (300390) c.863dupA p.M289Y*18 novel RP-1263 08-0177 USH2A c.920_923dupGCCA p.H308Qfs*16 known [46] (608400) c.12574C.T p.R4192C novel RP-1659 10-1367 CNGB3 c.1148delC p.T383Ifs*13 known [31] (605080) c.1666G.T p.E556* novel RP-1174 04-0834 CNGB3 c.1148delC (homoz) p.T383Ifs*13 known [31] RP-0137 1601 RP1 c.1625C.G p.S542* novel (603937) c.4804C.T p.Q1602* novel RP-0235 2343 RP1 c.5173C.T (homoz) p.Q1725* novel RP-1116 06-1075 NMNAT1 c.507G.A p.W169* known [47] (608700) c.769G.A p.E257K known [47] doi:10.1371/journal.pone.0065574.t001 clinical phenotype of the patients, and/or the sequencing/ mapping methods of NGS itself.
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ABCA4 p.Glu1574* 23940504:105:223
status: NEW