title: Rare Variants in Neurodegeneration Associated Genes Revealed by Targeted Panel Sequencing in a German ALS Cohort.
abstract: Amyotrophic lateral sclerosis (ALS) is a progressive fatal multisystemic neurodegenerative disorder caused by preferential degeneration of upper and lower motor neurons. To further delineate the genetic architecture of the disease, we used comprehensive panel sequencing in a cohort of 80 German ALS patients. The panel covered 39 confirmed ALS genes and candidate genes, as well as 238 genes associated with other entities of the neurodegenerative disease spectrum. In addition, we performed repeat length analysis forC9orf72. Our aim was to (1) identify potentially disease-causing variants, to (2) assess a proposed model of polygenic inheritance in ALS and to (3) connect ALS with other neurodegenerative entities. We identified 79 rare potentially pathogenic variants in 27 ALS associated genes in familial and sporadic cases. Five patients had pathogenicC9orf72repeat expansions, a further four patients harbored intermediate length repeat expansions. Our findings demonstrate that a genetic background of the disease can actually be found in a large proportion of seemingly sporadic cases and that it is not limited to putative most frequently affected genes such asC9orf72orSOD1. Assessing the polygenic nature of ALS, we identified 15 patients carrying at least two rare potentially pathogenic variants in ALS associated genes including pathogenic or intermediateC9orf72repeat expansions. Multiple variants might influence severity or duration of disease or could account for intrafamilial phenotypic variability or reduced penetrance. However, we could not observe a correlation with age of onset in this study. We further detected potentially pathogenic variants in other neurodegeneration associated genes in 12 patients, supporting the hypothesis of common pathways in neurodegenerative diseases and linking ALS to other entities of the neurodegenerative spectrum. Most interestingly we found variants inGBE1andSPG7which might represent differential diagnoses. Based on our findings, we recommend two-staged genetic testing for ALS in Germany in patients with familial and sporadic ALS, comprisingC9orf72repeat analysis followed by comprehensive panel sequencing including differential diagnoses that impair motor neuron function to meet the complexity of ALS genetics.
authors: CeGaT GmbH, Center for Genomics and Transcriptomics Tübingen, Germany.
authors: Stefanie
authors: S
authors: Krüger
authors: CeGaT GmbH, Center for Genomics and Transcriptomics Tübingen, Germany.
authors: Florian
authors: F
authors: Battke
authors: CeGaT GmbH, Center for Genomics and Transcriptomics Tübingen, Germany.
authors: Andrea
authors: A
authors: Sprecher
authors: CeGaT GmbH, Center for Genomics and TranscriptomicsTübingen, Germany; Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of TübingenTübingen, Germany.
authors: Marita
authors: M
authors: Munz
authors: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of TübingenTübingen, Germany; German Research Center for Neurodegenerative DiseasesTübingen, Germany.
authors: Matthis
authors: M
authors: Synofzik
authors: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of TübingenTübingen, Germany; German Research Center for Neurodegenerative DiseasesTübingen, Germany.
authors: Ludger
authors: L
authors: Schöls
authors: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of TübingenTübingen, Germany; German Research Center for Neurodegenerative DiseasesTübingen, Germany.
authors: Thomas
authors: T
authors: Gasser
authors: Department of Neurology, BG-Kliniken Bergmannsheil GmbH, Ruhr-University Bochum Bochum, Germany.
authors: Torsten
authors: T
authors: Grehl
authors: Department of Neurology, University of RostockRostock, Germany; German Research Center for Neurodegenerative DiseasesRostock, Germany.
authors: Johannes
authors: J
authors: Prudlo
authors: CeGaT GmbH, Center for Genomics and TranscriptomicsTübingen, Germany; Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of TübingenTübingen, Germany.
authors: Saskia
authors: S
authors: Biskup
keywords: amyotrophic lateral sclerosis; genetic heterogeneity; neurodegeneration; next generation sequencing; polygenic inheritance