title: FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study.
abstract: We aimed to identify the genetic cause of the devastating neurodegenerative disease amyotrophic lateral sclerosis (ALS) in a German family with two affected individuals, and to assess the prevalence of variants in the identified risk gene, FIG4, in a central European ALS cohort. Whole-exome sequencing (WES) and an overlapping data analysis strategy were performed in an ALS family with autosomal dominant inheritance and incomplete penetrance. Additionally, 200 central European ALS patients were analyzed using whole-exome or targeted sequencing. All patients were subjected to clinical, electrophysiological, and neuroradiological characterization to explore genotype-phenotype relationships. WES analysis of the ALS family identified the rare heterozygous frameshift variant FIG4:c.759delG, p.(F254Sfs*8) predicted to delete the catalytic domain and active center from the encoded phosphoinositide 5-phosphatase with a key role in endosomal vesicle trafficking. Additionally, novel or rare heterozygous FIG4 missense variants predicted to be deleterious were detected in five sporadic ALS patients revealing an overall FIG4 variant frequency of 3% in our cohort. Four of six variants identified were previously associated with ALS or the motor and sensory neuropathy Charcot-Marie-Tooth disease type 4J (CMT4J), whereas two variants were novel. In FIG4 variant carriers, disease duration was longer and upper motor neuron predominance was significantly more frequent compared with ALS patients without FIG4 variants. Our study provides evidence for FIG4 as an ALS risk gene in a central European cohort, adds new variants to the mutational spectrum, links ALS to CMT4J on a genetic level, and describes a distinctive ALS phenotype for FIG4 variant carriers.
authors.affiliation: Department of Human Genetics, Hannover Medical School, Hannover, Germany.|Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Alma
authors.initials: A
authors.lastname: Osmanovic
authors.affiliation: Department of Human Genetics, Hannover Medical School, Hannover, Germany.|Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Isolde
authors.initials: I
authors.lastname: Rangnau
authors.affiliation: Department of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Kosfeld
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.|Department of Neurology, University Hospital Magdeburg, Magdeburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Abdulla
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Claas
authors.initials: C
authors.lastname: Janssen
authors.affiliation: Department of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Auber
authors.affiliation: Department of Neuroradiology, Hannover Medical School, Hannover, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Raab
authors.affiliation: Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany.|Center for Structural Systems Biology, German Electron Synchrotron (DESY), Hamburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Preller
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Petri
authors.affiliation: Department of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Ruthild G
authors.initials: RG
authors.lastname: Weber
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000235:genetics*; D020134:Catalytic Domain; D005060:Europe; D059472:Exome; D005260:Female; D005420:Flavoproteins / Q000737:chemistry / Q000235:genetics*; D016368:Frameshift Mutation; D005787:Gene Frequency; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000235:genetics*
chemical_list: D005420:Flavoproteins; C522215:FIG4 protein, human; D010744:Phosphoric Monoester Hydrolases