title: Whole genome analyses reveal no pathogenetic single nucleotide or structural differences between monozygotic twins discordant for amyotrophic lateral sclerosis.
abstract: The contribution of genetic and environmental factors to the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) remains unclear. To investigate the genetic component of the disease, we performed whole genome sequencing on ALS discordant monozygotic twins. Illumina whole genome sequencing on white blood cell DNA of five ALS-discordant monozygotic twin pairs (10 samples in total) yielded ∼30x coverage per individual. All single nucleotide variants, indels, and structural variants (copy number variants, inversions and translocations) were called and evaluated for functional consequence, evolutionary conservation, population frequency and overlap with known ALS associated variants and genes. Results showed that no validated discordant coding or regulatory single nucleotide variants or indels were found, and nor were any genome-wide discordant structural variants detected. Concordant variants of particular interest were: 1) two rare, highly-conserved heterozygous non-synonymous variants in SYT9 and EWSR1, genes previously associated with ALS (out of 2044 rare heterozygous variants detected); 2) three rare homozygous missense variants; and 3) three novel copy number deletions that overlapped genes. In conclusion, no convincing coding or regulatory nucleotide or genome-wide structural differences were found between ALS discordant monozygotic twins. The results suggest that more work is needed to elucidate possible environmental, epigenetic, oligogenic and somatic genetic factors that could underlie susceptibility to sporadic ALS.
authors.affiliation: a The Genome Institute, Washington University School of Medicine, St. Louis , Missouri , USA.
authors.forename: Karyn
authors.initials: K
authors.lastname: Meltz Steinberg
authors.affiliation: a The Genome Institute, Washington University School of Medicine, St. Louis , Missouri , USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Nicholas
authors.affiliation: a The Genome Institute, Washington University School of Medicine, St. Louis , Missouri , USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Koboldt
authors.affiliation: b Department of Medical Genomics , Royal Prince Alfred Hospital and Sydney Medical School, The University of Sydney , New South Wales , Australia.
authors.forename: Bing
authors.initials: B
authors.lastname: Yu
authors.affiliation: a The Genome Institute, Washington University School of Medicine, St. Louis , Missouri , USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Mardis
authors.affiliation: c The Stacey MND Laboratory, Discipline of Pathology, Sydney Medical School, The Brain & Mind Research Institute, The University of Sydney , New South Wales , Australia.
authors.forename: Roger
authors.initials: R
authors.lastname: Pamphlett
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D002148:Calmodulin-Binding Proteins / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D016678:Genome; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins / Q000235:genetics; D050857:Synaptotagmins / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics*
chemical_list: D002148:Calmodulin-Binding Proteins; C500986:EWSR1 protein, human; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins; C494308:SYT9 protein, human; D050857:Synaptotagmins
keywords: Amyotrophic lateral sclerosis; gene variant; genetics; genomics; monozygotic twin study; motor neuron disease; whole genome sequencing