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C9orf72 Gene Curation

C9orf72 Gene Curation

Owned by Andrea Oza
Last updated: 2024-05-06
3 min read

Gene-disease assertions not curated here (add link or write note):

Disease

Frontotemporal dementia and/or amyotrophic lateral sclerosis 1

Disease

Frontotemporal dementia and/or amyotrophic lateral sclerosis 1

Inheritance

Autosomal dominant

Prevalence

Orphanet

Medline Plus Genetics

 1/20,000 (ALS)

Source: ORPHA:803

Rapid or full curation?

Rapid
Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, accessed 8.23.23

Clinical Validity Scoring Notes and points

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).

Source:

Clinical Validity Points Total

18

Source: ClinGen Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, accessed 8.23.23

Clinical Validity Classification

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Definitive

Source: ClinGen Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, accessed 8.23.23

Molecular Mechanism

Loss of function

Gain of function

Dominant negative

Unknown

Other

Unknown

Source: ClinGen Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, accessed 8.23.23

Triplet repeat expansion - GGGGCC hexanucleotide repeat in noncoding region C9orf72. There are two alternatively spliced transcript, and depending on the transcript the repeat is located in the promoter region or in intron 1 (PMID: 21944778)

https://broadinstitute.atlassian.net/browse/BCL-178

Normal: 2-24

Intermediate / Grey Zone: 25-60

Pathogenic: 61 to >6000

Cutoff: 25

For full literature review notes: see https://broadinstitute.atlassian.net/browse/BCL-178

 

Penetrance

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Age dependent and reduced

Source:28522837

Age of Onset

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

 

Severity

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

 

Clinical Features

 

Sources:

HPO Terms

https://hpo.jax.org/app/

 

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

 

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 05.06.2024

 

 

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