Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis
Casey Eye Institute Molecular Diagnostic Laboratory, Portland, Oregon, USA.Nature Genetics (Impact Factor: 29.35). 07/2012; 44(9):972-4. DOI: 10.1038/ng.2370
Leber congenital amaurosis (LCA) is an autosomal recessive retinal dystrophy that manifests with genetic heterogeneity. We sequenced the exome of an individual with LCA and identified nonsense (c.507G>A, p.Trp169*) and missense (c.769G>A, p.Glu257Lys) mutations in NMNAT1, which encodes an enzyme in the nicotinamide adenine dinucleotide (NAD) biosynthesis pathway implicated in protection against axonal degeneration. We also found NMNAT1 mutations in ten other individuals with LCA, all of whom carry the p.Glu257Lys variant.
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- "is one of the most recently identified LCA genes (LCA9). Thus far, eight studies listed 45 distinct mutations, all located in the coding region or intron-exon boundaries of NMNAT1 (Chiang et al., 2012; Falk et al., 2012; Koenekoop et al., 2012; Perrault et al., 2012; Corton et al., 2013; Coppieters et al., 2014; Jin et al., 2014; Siemiatkowska et al., 2014). Here, we demonstrate for the first time that both regulatory 5'UTR variations and SVs of NMNAT1 add to the complex molecular pathogenesis of LCA. "
ABSTRACT: Leber Congenital Amaurosis (LCA) is a severe autosomal recessive retinal dystrophy leading to congenital blindness. A recently identified LCA gene is NMNAT1, located in the LCA9 locus. Although most mutations in blindness genes are coding variations, there is accumulating evidence for hidden non-coding defects or structural variations (SVs). The starting point of this study was an LCA9-associated consanguineous family in which no coding mutations were found in the LCA9 region. Exploring the UTRs of NMNAT1 revealed a novel homozygous 5'UTR variant, c.-70A>T. Moreover, an adjacent 5'UTR variant, c.-69C>T, was identified in a second consanguineous family displaying a similar phenotype. Both 5'UTR variants resulted in decreased NMNAT1 mRNA abundance in patients' lymphocytes, and caused decreased luciferase activity in human retinal pigment epithelial RPE-1 cells. Second, we unraveled pseudohomozygosity of a coding NMNAT1 mutation in two unrelated LCA patients by the identification of two distinct heterozygous partial NMNAT1 deletions. Molecular characterization of the breakpoint junctions revealed a complex Alu-rich genomic architecture. Our study uncovered hidden genetic variation in NMNAT1-associated LCA and emphasized a shift from coding to non-coding regulatory mutations and repeat-mediated SVs in the molecular pathogenesis of heterogeneous recessive disorders such as hereditary blindness. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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- "Furthermore, by performing WES on a metastatic, castration-resistant prostate cancer patient, Van Allen et al. discovered somatic genomic mutations in the PI3K pathway and a BRCA2 germline variant that may predispose individuals to cancer.119 An increasing number of studies employ whole genome and exome sequencing to successfully identify disease-causing mutations that provide attractive treatment targets using gene therapy, therapeutic drugs, or transplantation.120–122 "
ABSTRACT: The advent of next-generation sequencing technologies has greatly promoted advances in the study of human diseases at the genomic, transcriptomic, and epigenetic levels. Exome sequencing, where the coding region of the genome is captured and sequenced at a deep level, has proven to be a cost-effective method to detect disease-causing variants and discover gene targets. In this review, we outline the general framework of whole exome sequence data analysis. We focus on established bioinformatics tools and applications that support five analytical steps: raw data quality assessment, preprocessing, alignment, post-processing, and variant analysis (detection, annotation, and prioritization). We evaluate the performance of open-source alignment programs and variant calling tools using simulated and benchmark datasets, and highlight the challenges posed by the lack of concordance among variant detection tools. Based on these results, we recommend adopting multiple tools and resources to reduce false positives and increase the sensitivity of variant calling. In addition, we briefly discuss the current status and solutions for big data management, analysis, and summarization in the field of bioinformatics.
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- "Until now, mutations in 204 genes were found to be involved in the pathogenesis of IRDs (RetNet). Recently, NMNAT1, a gene involved in nicotinamide adenine dinucleotide (NAD) synthesis, was found to be responsible for a subset of LCA cases, mainly with macular lesions [6-9]. "
ABSTRACT: Purpose The gene encoding nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) was recently found to be mutated in a subset of patients with Leber congenital amaurosis (LCA) with macular atrophy. The aim of this study was to determine the occurrence and frequency of NMNAT1 mutations and associated phenotypes in different types of inherited retinal dystrophies. Methods DNA samples of 161 patients with LCA without genetic diagnosis were analyzed for variants in NMNAT1 using Sanger sequencing. Variants in exon 5 of NMNAT1, which harbors the majority of the previously identified mutations, were screened in 532 additional patients with retinal dystrophies. This cohort encompassed 108 persons with isolated or autosomal recessive cone-rod dystrophy (CRD), 271 with isolated or autosomal recessive retinitis pigmentosa (RP), and 49 with autosomal dominant RP, as well as 104 persons with LCA in whom the causative mutation was previously identified. Results Compound heterozygous alterations were found in six patients with LCA and in one person with early-onset RP. All except one carried the common p.E257K variant on one allele. Macular atrophy was absent in one patient, who carried this variant in combination with a truncating mutation on the other allele. The p.E257K alteration was also found in a heterozygous state in five individuals with LCA and one with RP while no mutation was detected on the other allele. Two individuals with LCA carried other NMNAT1 variants in a heterozygous state, whereas no NMNAT1 variants in exon 5 were identified in individuals with CRD. The p.E257K variant was found to be enriched in a heterozygous state in individuals with LCA (0.94%) compared to Caucasian controls (0.18%), although the difference was statistically insignificant (p=0.12). Conclusions Although macular atrophy can occur in LCA and CRD, no NMNAT1 mutations were found in the latter cohort. NMNAT1 variants were also not found in a large group of patients with sporadic or autosomal recessive RP. The enrichment of p.E257K in a heterozygous state in patients with LCA versus controls suggests that this allele could act as a modifier in other genetic subtypes of LCA.