Amyotrophic lateral sclerosis/motor neuron disease

Gene: C9orf72

Red List (low evidence)

C9orf72 (chromosome 9 open reading frame 72)
EnsemblGeneIds (GRCh38): ENSG00000147894
EnsemblGeneIds (GRCh37): ENSG00000147894
OMIM: 614260, Gene2Phenotype
C9orf72 is in 8 panels

3 reviews

Ellen McDonagh (Genomics England Curator)

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.

Nayana Lahiri (South London GMC)

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

Andrew Douglas (University of Southampton / Wessex Clinical Genetics Service)

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

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Eligibility statement prior genetic testing
  • Expert
  • Radboud University Medical Center, Nijmegen
  • Illumina TruGenome Clinical Sequencing Services
Phenotypes
  • Amyotrophic Lateral Sclerosis/Frontotemporal Dementia
  • Amyotrophic lateral sclerosis and/or frontotemporal dementia, 105550 -3
  • Hexanucleotide repeat expansion
  • Frontotemporal Dementia, Amyotrophic Lateral Sclerosis
  • amyotrophic lateral sclerosis
  • frontotemporal dementia
  • Frontotemporal Dementia, Amyotrophic Lateral Sclerosis
Tags
nucleotide-repeat-expansion
OMIM
614260
Clinvar variants
Variants in C9orf72
Penetrance
Complete
Publications
Mode of Pathogenicity
Other - please provide details in the comments
Panels with this gene

History Filter Activity

19 Dec 2016, Gel status: 1

panel promoted to version 1

Alice Gardham (Genomics England)

Promoted to version 1 on 19th December 2016 following external review and internal curation

13 Jun 2016, Gel status: 1

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

13 Jun 2016, Gel status: 1

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

13 Jun 2016, Gel status: 2

Set Phenotypes

Ellen McDonagh (Genomics England Curator)

Phenotypes for C9orf72 were set to Amyotrophic Lateral Sclerosis/Frontotemporal Dementia; Amyotrophic lateral sclerosis and/or frontotemporal dementia, 105550 -3; Hexanucleotide repeat expansion; Frontotemporal Dementia, Amyotrophic Lateral Sclerosis; amyotrophic lateral sclerosis; frontotemporal dementia; Frontotemporal Dementia, Amyotrophic Lateral Sclerosis

13 Jun 2016, Gel status: 2

Set mode of pathogenicity

Ellen McDonagh (Genomics England Curator)

Mode of pathogenicity for C9orf72 was changed to Other - please provide details in the comments

13 Jun 2016, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Mode of inheritance for C9orf72 was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

13 Jun 2016, Gel status: 2

Set Phenotypes

Ellen McDonagh (Genomics England Curator)

Phenotypes for C9orf72 were set to Amyotrophic Lateral Sclerosis/Frontotemporal Dementia; Amyotrophic lateral sclerosis and/or frontotemporal dementia, 105550 -3; Hexanucleotide repeat expansion; Frontotemporal Dementia, Amyotrophic Lateral Sclerosis; amyotrophic lateral sclerosis; frontotemporal dementia

13 Jun 2016, Gel status: 2

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for C9orf72 were set to PMID: 21944778; 21944779; 25638642; 27059391; 23597494

18 Aug 2015, Gel status: 2

Set Phenotypes

Ellen McDonagh (Genomics England Curator)

Phenotypes for gene C9orf72 were set to Amyotrophic Lateral Sclerosis/Frontotemporal Dementia;Amyotrophic lateral sclerosis and/or frontotemporal dementia, 105550 -3; Hexanucleotide repeat expansion

18 Aug 2015, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene C9orf72 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

18 Aug 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

C9orf72 was added to Amyotrophic lateral sclerosis/motor neuron diseasepanel. Source: Eligibility statement prior genetic testing

18 Aug 2015, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene C9orf72 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

18 Aug 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

C9orf72 was added to Amyotrophic lateral sclerosis/motor neuron diseasepanel. Source: Expert

18 Aug 2015, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene C9orf72 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

18 Aug 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

C9orf72 was added to Amyotrophic lateral sclerosis/motor neuron diseasepanel. Source: Radboud University Medical Center, Nijmegen

18 Aug 2015, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene C9orf72 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

18 Aug 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

C9orf72 was added to Amyotrophic lateral sclerosis/motor neuron diseasepanel. Source: Illumina TruGenome Clinical Sequencing Services

18 Aug 2015, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene C9orf72 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

18 Aug 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

C9orf72 was added to Amyotrophic lateral sclerosis/motor neuron diseasepanel. Source: Expert

18 Aug 2015, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene C9orf72 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

18 Aug 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

C9orf72 was added to Amyotrophic lateral sclerosis/motor neuron diseasepanel. Source: Radboud University Medical Center, Nijmegen

18 Aug 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

C9orf72 was added to Amyotrophic lateral sclerosis/motor neuron diseasepanel. Sources: Illumina TruGenome Clinical Sequencing Services,Radboud University Medical Center, Nijmegen,Expert