title: De novo FUS mutations are the most frequent genetic cause in early-onset German ALS patients.
abstract: In amyotrophic lateral sclerosis (ALS) patients with known genetic cause, mutations in chromosome 9 open reading frame 72 (C9orf72) and superoxide dismutase 1 (SOD1) account for most familial and late-onset sporadic cases, whereas mutations in fused in sarcoma (FUS) can be identified in just around 5% of familial and 1% of overall sporadic cases. There are only few reports on de novo FUS mutations in juvenile ALS patients. To date, no systematic evaluation on the frequency of de novo FUS mutations in early-onset ALS patients has been conducted. Here, we screened a cohort of 14 early-onset sporadic ALS patients (onset age <35 years) to determine the frequency of mutations in C9orf72, SOD1, and FUS in this defined patient cohort. All patients were recruited prospectively by a single center in a period of 38 months. No mutations were detected in SOD1 or C9orf72; however, we identified 6 individuals (43%) carrying a heterozygous FUS mutation including 1 mutation that has not been described earlier (c.1504delG [p.Asp502Thrfs*27]). Genetic testing of parents was possible in 5 families and revealed that the mutations in these patients arose de novo. Three of the 6 identified patients presented with initial bulbar symptoms. Our study identifies FUS mutations as the most frequent genetic cause in early-onset ALS. Genetic testing of FUS thus seems indicated in sporadic early-onset ALS patients especially if showing predominant bulbar symptoms and an aggressive disease course.
authors.affiliation: Department of Neurology, University Hospital of Ulm, Ulm, Germany. Electronic address: annemarie.huebers@uni-ulm.de.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Hübers
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Just
authors.affiliation: Department of Neurology, University Hospital of Ulm, Ulm, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Rosenbohm
authors.affiliation: Department of Neurology, University Hospital of Ulm, Ulm, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Müller
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Marroquin
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Goebel
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Högel
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany; Institute of Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Department of Neurology, University Hospital of Ulm, Ulm, Germany.
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.affiliation: Department of Neurology, University Hospital of Ulm, Ulm, Germany.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: a.volk@uke.de.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Volk
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D015331:Cohort Studies; D018450:Disease Progression; D056726:Genetic Association Studies; D005820:Genetic Testing; D005858:Germany; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D011446:Prospective Studies; D034702:RNA-Binding Protein FUS / Q000235:genetics*; D055815:Young Adult
chemical_list: C000599550:FUS protein, human; D034702:RNA-Binding Protein FUS
keywords: Amyotrophic lateral sclerosis (ALS); De novo mutation; Early onset; Fused in sarcoma (FUS); Genetic testing