ArticleHuman molecular genetics2012
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.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 39 citations in OpenAlex.
- Unraveling Molecular and Genetic Insights into Neurodegenerative Diseases: Advances in Understanding Alzheimer's, Parkinson's, and Huntington's Diseases and Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2023Review
- Article
- Characterizing sensitivity and coverage of clinical WGS as a diagnostic test for genetic disorders.BMC medical genomics · 2021Article
- Frequency of SCA8, SCA10, SCA12, SCA36, FXTAS and C9orf72 repeat expansions in SCA patients negative for the most common SCA subtypes.BMC neurology · 2018Article
- Neuroblast differentiation during development and in neuroblastoma requires KIF1Bβ-mediated transport of TRKA.Genes & development · 2017Article
- Lessons learned from the search for genes responsible for rare Mendelian disorders.Molecular genetics & genomic medicine · 2016Article
- Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine.NPJ genomic medicine · 2016Article
- Using the ENCODE Resource for Functional Annotation of Genetic Variants.Cold Spring Harbor protocols · 2015Review
- Application of next-generation sequencing technologies in Neurology.Annals of translational medicine · 2014Review
- Next generation sequencing and the future of genetic diagnosis.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2014Review
- Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy.European journal of human genetics : EJHG · 2014Article
- Searching for Grendel: origin and global spread of the C9ORF72 repeat expansion.Acta neuropathologica · 2014Article
- C9ORF72 mutations in neurodegenerative diseases.Molecular neurobiology · 2014Review
- Next-generation sequencing in understanding complex neurological disease.Expert review of neurotherapeutics · 2013Review
- Microsatellite tandem repeats are abundant in human promoters and are associated with regulatory elements.PloS one · 2013Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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 five 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 1 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 frontotemporal dementia. 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 a cause of familial ALS.
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