C9ORF72
Chr 9ADC9orf72-SMCR8 complex subunit
Also known as: ALSFTD, DENND9, DENNL72, FTDALS, FTDALS1
An expanded GGGGCC repeat in C9orf72 is the commonest genetic cause of ALS and frontotemporal dementia in people of European ancestry: about 39% of familial and 7% of sporadic ALS, 25% of familial and 6% of sporadic FTD (Majounie 2012). 24 or fewer repeats is normal, 25–60 of uncertain significance, and more than 60 pathogenic; some laboratories set the cut-off at 30.
Penetrance is age-dependent and incomplete. Exome and panel sequencing miss the expansion, so it needs repeat-primed PCR. No treatment targets it: two antisense drugs were stopped for lack of benefit.
Primary Disease Associations & Inheritance
Clinical highlights
- Definitive · frontotemporal dementia and/or amyotrophic lateral sclerosis 1 · AD · ClinGen 2021
- Limited · progressive myoclonus epilepsy · AD · Ambry Genetics — not for standalone diagnostic reporting
- C9orf72 ASO programs (e.g. BIIB078, WVE-004)ASODiscontinued
Lower the repeat-containing transcript.
Delivery: IntrathecalPhase 1 programs discontinued after not meeting endpoints — shown for transparency
Therapeutic landscape as of 2026-07. Educational only. Investigational ≠ available; not medical advice or eligibility. Approved entries are precise; investigational program names/phases are conservative and move fast. Curated from FDA/EMA approvals and the clinical-trial literature; verify against current labeling + ClinicalTrials.gov.
ClinicalTrials.govC9orf72: a hexanucleotide repeat causing ALS and FTD
GGGGCC repeat in the promoter / intron 1 — the cause of C9orf72 ALS and frontotemporal dementia. What matters is the number of repeats.
- Normal · ≤24
- Uncertain · 25–60 — uncertain significance; some laboratories call 30 or more pathogenic
- Pathogenic · >60 — usually hundreds to thousands of repeats
In white populations the expansion is found in about 39% of familial and 7% of sporadic ALS, and about 25% of familial and 6% of sporadic FTD; it was not found in 360 Asian and Pacific patients with sporadic ALS (Majounie 2012). Penetrance rises with age — about half by 58 — and population-based estimates are lower.
No treatment targets it yet: two antisense drugs lowered the repeat proteins but were stopped for lack of clinical benefit (2022, 2023). Tofersen treats SOD1 ALS, not C9orf72.
Testing: Exome and panel sequencing miss this expansion. Order repeat-primed PCR (with sizing PCR); Southern blot or PCR-free genome analysis can size large expansions.
Sources: ACMG points to consider 2026 (Table 1); Majounie, Lancet Neurol 2012; Morimoto 2026.
ClinVar Variant Classifications
0 submitted variants in ClinVar
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
TRIAL READY (Clinical Trial Readiness)
ACTIVE NOT RECRUITINGGENetic Fronto Temporal Dementia Initiative in Lille
RECRUITINGSafety and Therapeutic Potential of the FDA-approved Drug Metformin for C9orf72 ALS/FTD
ACTIVE NOT RECRUITINGTracking and Predicting How Brain Damage Spreads in Neurodegenerative Diseases
ENROLLING BY INVITATIONGenetic Frontotemporal Dementia Initiative for Neurodevelopment
RECRUITINGAmyotrophic Lateral Sclerosis Registry in Thailand
RECRUITINGA Study of the Behavioral Variant of Frontotemporal Dementia and Bipolar Disorder: a Neuroimaging and Epigenetics Integrated Approach
RECRUITINGTesting Pulse Stimulation to Improve Motor Function in People With ALS: A Pilot Study
RECRUITINGA Study Evaluating the Safety and Tolerability of QRL-201 in ALS
ACTIVE NOT RECRUITINGNeurofilament Surveillance Project (NSP)
ACTIVE NOT RECRUITINGAmyotrophic Lateral Sclerosis (ALS) Families Project
RECRUITINGNeurofilament Light Chain And Voice Acoustic Analyses In Dementia Diagnosis
RECRUITINGExternal Resources
Links to major genomics databases and tools