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
Source: PubMed


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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Available from: Richard Weleber, Jul 03, 2014
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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 "
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    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.
    Cancer informatics 09/2014; Cancer Informatics 2014(Suppl. 2):67-82. DOI:10.4137/CIN.S13779
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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]. "
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    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.
    Molecular vision 06/2014; 20:753-9. · 1.99 Impact Factor
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    • "When this filter was applied on Freeman Sheldon syndrome, an autosomal dominant disorder whose disease gene is known, as a proof of concept it was clear that had the gene not been known, a small number of genetically independent cases might be required to arrive at a gene that harbors a pathogenic allele in each of the affected individuals (Ng et al. 2009b). One limitation is that a heterozygous variant is much more challenging to call by next-gen sequencing compared to a homozygous variant, so it was predicted that autosomal recessive diseases caused by homozygous mutations are going to be easier to solve by next-generation sequencing and that prediction was vindicated by the publication of several disease genes based on simplex cases (it was later shown that autosomal dominant genes can also be solved based on simplex cases, especially de novo mutations when trio analysis is used) (Aldahmesh et al. 2011; Becker et al. 2011a; Chiang et al. 2012; Shaheen et al. 2011; Sobreira et al. 2010). As of January 2013,[100 novel autosomal recessive genes have been identified using next-generation sequencing, a remarkable leap toward the goal of solving all known Mendelian recessive disorders before the turn of the decade (Fig. 1). "
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    ABSTRACT: Autozygosity, or the inheritance of two copies of an ancestral allele, has the potential to not only reveal phenotypes caused by biallelic mutations in autosomal recessive genes, but to also facilitate the mapping of such mutations by flagging the surrounding haplotypes as tractable runs of homozygosity (ROH), a process known as autozygosity mapping. Since SNPs replaced microsatellites as markers for the purpose of genomewide identification of ROH, autozygosity mapping of Mendelian genes has witnessed a significant acceleration. Historically, successful mapping traditionally required favorable family structure that permits the identification of an autozygous interval that is amenable to candidate gene selection and confirmation by Sanger sequencing. This requirement presented a major bottleneck that hindered the utilization of simplex cases and many multiplex families with autosomal recessive phenotypes. However, the advent of next-generation sequencing that enables massively parallel sequencing of DNA has largely bypassed this bottleneck and thus ushered in an era of unprecedented pace of Mendelian disease gene discovery. The ability to identify a single causal mutation among a massive number of variants that are uncovered by next-generation sequencing can be challenging, but applying autozygosity as a filter can greatly enhance the enrichment process and its throughput. This review will discuss the power of combining the best of both techniques in the mapping of recessive disease genes and offer some tips to troubleshoot potential limitations.
    Human Genetics 08/2013; 132(11). DOI:10.1007/s00439-013-1344-x · 4.82 Impact Factor
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