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Title: Whole-genome sequencing reveals a coding non-pathogenic variant tagging a non-coding pathogenic hexanucleotide repeat expansion in C9orf72 as cause of amyotrophic lateral sclerosis
Authors: Herdewyn, Sarah ×
Zhao, Hui
Moisse, Matthieu
Race, Valérie
Matthijs, Gert
Reumers, Joke
Kusters, Benno
Schelhaas, Helenius J
van den Berg, Leonard H
Goris, An
Robberecht, Wim
Lambrechts, Diether
Van Damme, Philip #
Issue Date: Jun-2012
Publisher: IRL Press
Series Title: Human Molecular Genetics vol:21 issue:11 pages:2412-2419
Abstract: Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has a familial cause in 10 % of patients. Despite significant advances in the genetics of the disease, many families remain unexplained. We performed whole-genome sequencing in 5 family members from a pedigree with autosomal dominant classical ALS. A family-based elimination approach was used to identify novel coding variants segregating with the disease. This list of variants was effectively shortened by genotyping these variants in 2 additional unaffected family members and 1500 unrelated population-specific controls. A novel rare coding variant in SPAG8 on chromosome 9p13.3 segregated with the disease and was not observed in controls. Mutations in SPAG8 were not encountered in 34 other unexplained ALS pedigrees, including one with linkage to chromosome 9p13.2-23.3. The shared haplotype containing the SPAG8 variant in this small pedigree was 22.7 Mb and overlapped with the core 9p21 linkage locus for ALS and FTD. Based on differences in coverage depth of known variable tandem repeat regions between affected and non-affected family members, the shared haplotype was found to contain an expanded hexanucleotide (GGGGCC)(n) repeat in C9orf72 in the affected members. Our results demonstrate that rare coding variants identified by whole-genome sequencing can tag a shared haplotype containing a non-coding pathogenic mutation and that changes in coverage depth can be used to reveal tandem repeat expansions. It also confirms (GGGGCC)n repeat expansions in C9orf72 as cause of familial ALS.
ISSN: 0964-6906
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Neuroimmunology
Department of Human Genetics - miscellaneous
Laboratory for Neurobiology (Vesalius Research Center)
Laboratory of Translational Genetics (Vesalius Research Center) (+)
Research Group Experimental Neurology
× corresponding author
# (joint) last author

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