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Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort.

ABSTRACT: BACKGROUND:Gene discovery has provided remarkable biological insights into amyotrophic lateral sclerosis (ALS). One challenge for clinical application of genetic testing is critical evaluation of the significance of reported variants. METHODS:We use whole exome sequencing (WES) to develop a clinically relevant approach to identify a subset of ALS patients harboring likely pathogenic mutations. In parallel, we assess if DNA methylation can be used to screen for pathogenicity of novel variants since a methylation signature has been shown to associate with the pathogenic C9orf72 expansion, but has not been explored for other ALS mutations. Australian patients identified with ALS-relevant variants were cross-checked with population databases and case reports to critically assess whether they were "likely causal," "uncertain significance," or "unlikely causal." RESULTS:Published ALS variants were identified in >10% of patients; however, in only 3% of patients (4/120) could these be confidently considered pathogenic (in SOD1 and TARDBP). We found no evidence for a differential DNA methylation signature in these mutation carriers. CONCLUSIONS:The use of WES in a typical ALS clinic demonstrates a critical approach to variant assessment with the capability to combine cohorts to enhance the largely unknown genetic basis of ALS.

SUBMITTER: Garton FC

PROVIDER: S-EPMC5511806 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort.

Garton Fleur C FC Benyamin Beben B Zhao Qiongyi Q Liu Zhijun Z Gratten Jacob J Henders Anjali K AK Zhang Zong-Hong ZH Edson Janette J Furlong Sarah S Morgan Sarah S Heggie Susan S Thorpe Kathryn K Pfluger Casey C Mather Karen A KA Sachdev Perminder S PS McRae Allan F AF Robinson Matthew R MR Shah Sonia S Visscher Peter M PM Mangelsdorf Marie M Henderson Robert D RD Wray Naomi R NR McCombe Pamela A PA

Molecular genetics & genomic medicine 20170612 4

<h4>Background</h4>Gene discovery has provided remarkable biological insights into amyotrophic lateral sclerosis (ALS). One challenge for clinical application of genetic testing is critical evaluation of the significance of reported variants.<h4>Methods</h4>We use whole exome sequencing (WES) to develop a clinically relevant approach to identify a subset of ALS patients harboring likely pathogenic mutations. In parallel, we assess if DNA methylation can be used to screen for pathogenicity of nov ...[more]

PMID: 28717666

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Project description:Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterised by the degeneration of motor neurons, which are responsible for voluntary movement. There remains limited understanding of disease aetiology, with median survival of ALS of three years and no effective treatment. Identifying genes that contribute to ALS susceptibility is an important step towards understanding aetiology. The vast majority of published human genetic studies, including for ALS, have used samples of European ancestry. The importance of trans-ethnic studies in human genetic studies is widely recognised, yet a dearth of studies of non-European ancestries remains. Here, we report analyses of novel whole-exome sequencing (WES) data from Chinese ALS and control individuals.WES data were generated for 610 ALS cases and 460 controls drawn from Chinese populations. We assessed evidence for an excess of rare damaging mutations at the gene level and the gene set level, considering only singleton variants filtered to have allele frequency less than 5?×?10-5 in reference databases. To meta-analyse our results with a published study of European ancestry, we used a Cochran-Mantel-Haenszel test to compare gene-level variant counts in cases vs controls.No gene passed the genome-wide significance threshold with ALS in Chinese samples alone. Combining rare variant counts in Chinese with those from the largest WES study of European ancestry resulted in three genes surpassing genome-wide significance: TBK1 (p?=?8.3?×?10-12), SOD1 (p?=?8.9?×?10-9) and NEK1 (p?=?1.1?×?10-9). In the Chinese data alone, SOD1 and NEK1 were nominally significantly associated with ALS (p?=?0.04 and p?=?7?×?10-3, respectively) and the case/control frequencies of rare coding variants in these genes were similar in Chinese and Europeans (SOD1: 1.5%/0.2% vs 0.9%/0.1%, NEK1 1.8%/0.4% vs 1.9%/0.8%). This was also true for TBK1 (1.2%/0.2% vs 1.4%/0.4%), but the association with ALS in Chinese was not significant (p?=?0.14).While SOD1 is already recognised as an ALS-associated gene in Chinese, we provide novel evidence for association of NEK1 with ALS in Chinese, reporting variants in these genes not previously found in Europeans.

Dataset Information

Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort.

Publications

Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort.

Similar Datasets

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