title: Exome sequencing of case-unaffected-parents trios reveals recessive and de novo genetic variants in sporadic ALS.
abstract: The contribution of genetic variants to sporadic amyotrophic lateral sclerosis (ALS) remains largely unknown. Either recessive or de novo variants could result in an apparently sporadic occurrence of ALS. In an attempt to find such variants we sequenced the exomes of 44 ALS-unaffected-parents trios. Rare and potentially damaging compound heterozygous variants were found in 27% of ALS patients, homozygous recessive variants in 14% and coding de novo variants in 27%. In 20% of patients more than one of the above variants was present. Genes with recessive variants were enriched in nucleotide binding capacity, ATPase activity, and the dynein heavy chain. Genes with de novo variants were enriched in transcription regulation and cell cycle processes. This trio study indicates that rare private recessive variants could be a mechanism underlying some case of sporadic ALS, and that de novo mutations are also likely to play a part in the disease.
authors.affiliation: The Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Karyn Meltz
authors.initials: KM
authors.lastname: Steinberg
authors.affiliation: Department of Medical Genomics, Royal Prince Alfred Hospital and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Bing
authors.initials: B
authors.lastname: Yu
authors.affiliation: The Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Koboldt
authors.affiliation: The Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: The Stacey MND Laboratory, Department of Pathology, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Roger
authors.initials: R
authors.lastname: Pamphlett
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D014644:Genetic Variation; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation