C9orf72 was first reported in relation to autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis 1 in 2011 (PMID: 21944779, 21944778). Evidence supporting the gene-disease relationship includes case-level data, segregation data, case-control data and experimental data. Five variants (short tandem repeat expansions, missense and splice site) that have been reported in 8 probands in 7 publications (PMIDs: 21944778, 21944779, 22154785, 27790088, 26742954, 23597494, 27595458) are included in this curation. A GGGGCC hexanucleotide repeat expansion has been found to segregate with disease in at least 22 additional family members and is overrepresented in affected individuals in 9 independent case-control cohorts included here (PMID: 21944778, 21944779, 2215478, 22418734, 22300876, 23284068, 23254636, 23597494). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is currently unknown, however evidence supports 3 potential mechanisms, including RNA-based toxicity of the transcribed repeat; protein-based toxicity via translation of the expanded RNA to form dipeptide repeat proteins; and haploinsufficiency (PMID: 21944779, 24129584, 23393093, 25731823). This gene-disease association is also supported by expression studies, functional alteration assays and animal models. (PMIDs: 24166615, 24559645, 22366792, 27334615, 25977373, 27112499). More experimental evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) has been reached. In summary, C9orf72 is definitively associated with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen ALS Gene Curation Expert Panel on the meeting date 26/08/2021 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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