Amyotrophic lateral sclerosis/motor neuron disease

Gene: C9orf72

Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism

Created: 8 Nov 2021, 11:14 a.m. | Last Modified: 8 Nov 2021, 11:14 a.m.

Panel Version: 1.45

Comment on list classification: Made red due to reviewer's comments, and tier 1/tier 2 variants will not be relevent within this gene.

Created: 13 Jun 2016, 10:41 a.m.

This gene is in the genetic guide to dementia and motor neurone disease section in the UCLH National Hospital for Neurology and Neurosurgery & Institute of Neurology (NHNN) Neurogenetics genetic testing manual, for testing of Amyotrophic lateral sclerosis: "The GGGGCC hexanucleotide repeat expansion in intron-1 of the C9orf72 gene is the most common cause of familial (50% of cases) and sporadic ALS (10% of cases). Interestingly a similar percentage of FTD cases were found to be caused by the same expansion."

Created: 13 Jun 2016, 9:07 a.m.

Red List (low evidence)

non-coding hexanucleotide repeat expansion is associated with ALS and FTD in a dominant inheritance pattern with variable penetrance. I agree that an expanded repeat may not be detected by current NGS technology and would recommend, as is already suggested in eligability criteria, that this is tested prior to recruitment. Reporting of coding sequence variants in the gene would be unlikely to be clinically useful at present.
Associated with FTD and ALS.

Created: 9 Jun 2016, 7:23 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Frontotemporal Dementia, Amyotrophic Lateral Sclerosis

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice

Red List (low evidence)

The GGGGCC non-coding hexanucleotide expansion in C9orf72, which can cause familial ALS and FTD in an autosomal dominant fashion (high evidence), is not expected to be detected via current NGS technology. Although the repeat expansion may act partly through a loss-of-function mechanism at the epigenetic level, I am not aware of any coding sequence mutations in this gene that have yet been associated with ALS or FTD. Reporting of coding sequence variants in this gene would therefore be unlikely to be clinically useful at present. However, such variant data would of course be of considerable research interest.

Created: 22 Apr 2016, 7:38 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
amyotrophic lateral sclerosis; frontotemporal dementia

Publications

• PMID: 21944778
• 21944779
• 25638642
• 27059391
• 23597494