Frontotemporal dementia and/or amyotrophic lateral sclerosis 1

Summary

Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (MONDO:0007105) is a disease caused by C9orf72 (GenCC Definitive), with 5 cohort genes and 2 clinical trials.

At a glance

• Causal gene: C9orf72 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 815
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	frontotemporal dementia and/or amyotrophic lateral sclerosis 1
Mondo ID	MONDO:0007105
OMIM	105550
DOID	DOID:0060213
NCIT	C168756
UMLS	C5779877
MedGen	1830423
GARD	0018396
Is cancer (heuristic)	no

Also known as: ALSFTD · amyotrophic lateral sclerosis and/or frontotemporal dementia · C9ORF72 frontotemporal dementia with motor neuron disease · C9orf72 frontotemporal dementia with motor neuron disease · frontotemporal dementia and/or amyotrophic lateral sclerosis 1 · frontotemporal dementia and/or amyotrophic lateral sclerosis type 1 · frontotemporal dementia and/or motor neuron disease · frontotemporal dementia with motor neuron disease caused by mutation in C9ORF72 · frontotemporal dementia with motor neuron disease caused by mutation in C9orf72 · FTDALS1 · FTDMND

Data availability: 815 ClinVar variants · 3 GenCC gene-disease records · 147 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › spinal cord disorder › anterior horn disorder › amyotrophic lateral sclerosis › familial amyotrophic lateral sclerosis › frontotemporal dementia and/or amyotrophic lateral sclerosis 1

Related subtypes (29): amyotrophic lateral sclerosis type 1, spinocerebellar ataxia type 2, amyotrophic lateral sclerosis type 15, frontotemporal dementia and/or amyotrophic lateral sclerosis 7, amyotrophic lateral sclerosis type 4, amyotrophic lateral sclerosis type 21, amyotrophic lateral sclerosis type 3, amyotrophic lateral sclerosis type 6, amyotrophic lateral sclerosis type 7, amyotrophic lateral sclerosis type 8, amyotrophic lateral sclerosis type 9, amyotrophic lateral sclerosis type 10, amyotrophic lateral sclerosis type 11, amyotrophic lateral sclerosis type 12, frontotemporal dementia and/or amyotrophic lateral sclerosis 6, amyotrophic lateral sclerosis type 18, amyotrophic lateral sclerosis type 20, amyotrophic lateral sclerosis type 19, frontotemporal dementia and/or amyotrophic lateral sclerosis 2, amyotrophic lateral sclerosis type 22, frontotemporal dementia and/or amyotrophic lateral sclerosis 3, frontotemporal dementia and/or amyotrophic lateral sclerosis 4, juvenile amyotrophic lateral sclerosis, amyotrophic lateral sclerosis type 23, frontotemporal dementia and/or amyotrophic lateral sclerosis 8, frontotemporal dementia and/or amyotrophic lateral sclerosis 5, amyotrophic lateral sclerosis 26 with or without frontotemporal dementia, amyotrophic lateral sclerosis 27, juvenile, amyotrophic lateral sclerosis 28

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

301 uncertain significance, 206 likely benign, 32 benign, 21 pathogenic, 19 conflicting classifications of pathogenicity, 10 benign/likely benign, 8 likely pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
31151	NM_001256054.1(C9orf72):c.-45+163GGGGCC[>24]	C9orf72	Pathogenic	no assertion criteria provided
183034	NG_031977.1:g.(5321_5338)ins(60_?)	LOC109504728	Pathogenic	no assertion criteria provided
1069495	NM_003900.5(SQSTM1):c.1170del (p.Asp391fs)	SQSTM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071292	NM_003900.5(SQSTM1):c.1210A>G (p.Met404Val)	SQSTM1	Pathogenic	criteria provided, multiple submitters, no conflicts
1076912	NM_003900.5(SQSTM1):c.244G>T (p.Glu82Ter)	SQSTM1	Pathogenic	criteria provided, single submitter
1323651	NM_003900.5(SQSTM1):c.415del (p.Arg139fs)	SQSTM1	Pathogenic	criteria provided, multiple submitters, no conflicts
1387627	NM_003900.5(SQSTM1):c.301+1G>T	SQSTM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458052	NM_003900.5(SQSTM1):c.1231G>A (p.Gly411Ser)	SQSTM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459183	NM_003900.5(SQSTM1):c.1165G>C (p.Glu389Gln)	SQSTM1	Pathogenic	criteria provided, multiple submitters, no conflicts
1912117	NM_003900.5(SQSTM1):c.815_818del (p.Val271_Ser272insTer)	SQSTM1	Pathogenic	criteria provided, single submitter
1948518	NM_003900.5(SQSTM1):c.259_260insATGCCTTTTCCAGTGACGAGGAATTGACGAGGAAT (p.Met87fs)	SQSTM1	Pathogenic	criteria provided, single submitter
1962648	NM_003900.5(SQSTM1):c.979dup (p.Glu327fs)	SQSTM1	Pathogenic	criteria provided, single submitter
2083476	NM_003900.5(SQSTM1):c.820G>T (p.Glu274Ter)	SQSTM1	Pathogenic	criteria provided, single submitter
2136359	NM_003900.5(SQSTM1):c.1175del (p.Pro392fs)	SQSTM1	Pathogenic	criteria provided, single submitter
2166073	NM_003900.5(SQSTM1):c.901G>T (p.Glu301Ter)	SQSTM1	Pathogenic	criteria provided, single submitter
265782	NM_003900.5(SQSTM1):c.286C>T (p.Arg96Ter)	SQSTM1	Pathogenic	criteria provided, multiple submitters, no conflicts
2943392	NM_003900.5(SQSTM1):c.1111C>T (p.Gln371Ter)	SQSTM1	Pathogenic	criteria provided, single submitter
2948186	NM_003900.5(SQSTM1):c.763dup (p.Val255fs)	SQSTM1	Pathogenic	criteria provided, single submitter
2949509	NM_003900.5(SQSTM1):c.973C>T (p.Gln325Ter)	SQSTM1	Pathogenic	criteria provided, single submitter
2952106	NM_003900.5(SQSTM1):c.309dup (p.Glu104fs)	SQSTM1	Pathogenic	criteria provided, single submitter
3750300	NM_003900.5(SQSTM1):c.571G>T (p.Gly191Ter)	SQSTM1	Pathogenic	criteria provided, single submitter
3753178	NM_003900.5(SQSTM1):c.616_617del (p.Trp206fs)	SQSTM1	Pathogenic	criteria provided, single submitter
3757914	NM_003900.5(SQSTM1):c.686C>A (p.Ser229Ter)	SQSTM1	Pathogenic	criteria provided, single submitter
451357	NM_003900.5(SQSTM1):c.823_824del (p.Ser275fs)	SQSTM1	Pathogenic	criteria provided, multiple submitters, no conflicts
2942752	NM_003900.5(SQSTM1):c.185_205+48delinsCACTACAGAGGTCCTGGTCTGTGCGGGGGCCTCCAGGCCTTCTGCGCTGCAGCCACTGCGCTGTGTCCCCTGTGATTGTCAATCTCCCTAAAGATGGCCCAGAGCAGTGCGGCCTGAATC	LOC129995449	Likely pathogenic	criteria provided, single submitter
1473565	NM_003900.5(SQSTM1):c.970-2A>G	SQSTM1	Likely pathogenic	criteria provided, single submitter
1985646	NM_003900.5(SQSTM1):c.205+2T>C	SQSTM1	Likely pathogenic	criteria provided, single submitter
2940935	NM_003900.5(SQSTM1):c.206-2A>G	SQSTM1	Likely pathogenic	criteria provided, single submitter
2951682	NM_003900.5(SQSTM1):c.1181_*644del (p.Leu394fs)	SQSTM1	Likely pathogenic	criteria provided, single submitter
3749705	NM_003900.5(SQSTM1):c.1145dup (p.Leu382fs)	SQSTM1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
C9orf72	Definitive	Autosomal dominant	frontotemporal dementia and/or amyotrophic lateral sclerosis 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
C9orf72	Orphanet:100069	Semantic dementia
C9orf72	Orphanet:100070	Progressive non-fluent aphasia
C9orf72	Orphanet:275864	Behavioral variant of frontotemporal dementia
C9orf72	Orphanet:275872	Frontotemporal dementia with motor neuron disease
C9orf72	Orphanet:401901	Huntington disease-like syndrome due to C9ORF72 expansions
C9orf72	Orphanet:803	Amyotrophic lateral sclerosis
SQSTM1	Orphanet:275864	Behavioral variant of frontotemporal dementia
SQSTM1	Orphanet:275872	Frontotemporal dementia with motor neuron disease
SQSTM1	Orphanet:603	Distal myopathy, Welander type
SQSTM1	Orphanet:803	Amyotrophic lateral sclerosis

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
C9orf72	HGNC:28337	ENSG00000147894	Q96LT7	Guanine nucleotide exchange factor C9orf72	gencc,clinvar
SQSTM1	HGNC:11280	ENSG00000161011	Q13501	Sequestosome-1	clinvar
CANX	HGNC:1473	ENSG00000127022	P27824	Calnexin	clinvar
ZNF354C	HGNC:16736	ENSG00000177932	Q86Y25	Zinc finger protein 354C	clinvar
LTC4S	HGNC:6719	ENSG00000213316	Q16873	Leukotriene C4 synthase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
C9orf72	Guanine nucleotide exchange factor C9orf72	Acts as a guanine-nucleotide releasing factor (GEF) for Rab GTPases by promoting the conversion of inactive RAB-GDP to the active form RAB-GTP.
SQSTM1	Sequestosome-1	Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes.
CANX	Calnexin	Calcium-binding protein that interacts with newly synthesized monoglucosylated glycoproteins in the endoplasmic reticulum.
ZNF354C	Zinc finger protein 354C	Transcriptional repressor that inhibits endothelial angiogenic sprouting.
LTC4S	Leukotriene C4 synthase	Catalyzes the conjugation of leukotriene A4 with reduced glutathione (GSH) to form leukotriene C4 with high specificity.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.2

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	2	3.3×	0.343
Enzyme (other)	1	2.4×	0.530
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
C9orf72	Other/Unknown	no		C9orf72
SQSTM1	Transcription factor	no		PB1_dom, Znf_ZZ, UBA-like_sf
CANX	Other/Unknown	no		Calret/calnex, Calreticulin/calnexin_P_dom_sf, ConA-like_dom_sf
ZNF354C	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
LTC4S	Enzyme (other)	yes	4.4.1.20	Membr-assoc_MAPEG, 5_LipOase_AP, FLAP/GST2/LTC4S_CS

Expression context

Cohort genes with no expression data: 0.

5 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mucosa of paranasal sinus	1
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
calcaneal tendon	1
islet of Langerhans	1
stromal cell of endometrium	1
cardiac muscle of right atrium	1
cortical plate	1
left ventricle myocardium	1
apex of heart	1
male germ line stem cell (sensu Vertebrata) in testis	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
C9orf72	250	ubiquitous	marker	monocyte, leukocyte, mucosa of paranasal sinus
SQSTM1	241	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
CANX	148	ubiquitous	marker	stromal cell of endometrium, islet of Langerhans, calcaneal tendon
ZNF354C	195	ubiquitous	marker	cardiac muscle of right atrium, left ventricle myocardium, cortical plate
LTC4S	133	ubiquitous	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, apex of heart

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CANX	8,019
SQSTM1	7,269
C9orf72	3,126
LTC4S	758
ZNF354C	458

Intra-cohort edges

A	B	Sources
C9orf72	SQSTM1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SQSTM1	Q13501	26
LTC4S	Q16873	20
C9orf72	Q96LT7	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CANX	P27824	77.15
ZNF354C	Q86Y25	66.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 69. Enrichment computed across 5 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Biosynthesis of DHA-derived sulfido conjugates	1	2855.0×	0.010	LTC4S
Biosynthesis of protectin and resolvin conjugates in tissue regeneration (PCTR and RCTR)	1	2855.0×	0.010	LTC4S
Virus Assembly and Release	1	1427.5×	0.010	CANX
Assembly of Viral Components at the Budding Site	1	1427.5×	0.010	CANX
Biosynthesis of maresin conjugates in tissue regeneration (MCTR)	1	1427.5×	0.010	LTC4S
p75NTR signals via NF-kB	1	475.8×	0.013	SQSTM1
Biosynthesis of Lipoxins (LX)	1	475.8×	0.013	LTC4S
Biosynthesis of DHA-derived SPMs	1	475.8×	0.013	LTC4S
Biosynthesis of specialized proresolving mediators (SPMs)	1	475.8×	0.013	LTC4S
Maturation of spike protein	1	475.8×	0.013	CANX
Signaling by Interleukins	2	32.1×	0.013	SQSTM1, CANX
Synthesis of 5-eicosatetraenoic acids	1	317.2×	0.016	LTC4S
Mitophagy	1	259.6×	0.016	SQSTM1
Interleukin-27 signaling	1	259.6×	0.016	CANX
Interleukin-35 Signalling	1	237.9×	0.016	CANX
Pexophagy	1	237.9×	0.016	SQSTM1
p75NTR recruits signalling complexes	1	219.6×	0.016	SQSTM1
NF-kB is activated and signals survival	1	219.6×	0.016	SQSTM1
Translation of Structural Proteins	1	219.6×	0.016	CANX
Cytokine Signaling in Immune system	2	20.4×	0.016	SQSTM1, CANX
NRIF signals cell death from the nucleus	1	178.4×	0.018	SQSTM1
Calnexin/calreticulin cycle	1	178.4×	0.018	CANX
Synthesis of Leukotrienes (LT) and Eoxins (EX)	1	142.8×	0.020	LTC4S
Arachidonate metabolism	1	142.8×	0.020	LTC4S
Interleukin-12 family signaling	1	119.0×	0.023	CANX
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1	105.7×	0.025	CANX
Translation of Structural Proteins	1	102.0×	0.025	CANX
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	1	98.5×	0.025	CANX
PINK1-PRKN Mediated Mitophagy	1	89.2×	0.026	SQSTM1
Nuclear events mediated by NFE2L2	1	84.0×	0.026	SQSTM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
brown fat cell proliferation	1	1123.5×	0.014	SQSTM1
protein targeting to vacuole involved in autophagy	1	1123.5×	0.014	SQSTM1
response to mitochondrial depolarisation	1	561.7×	0.014	SQSTM1
negative regulation of exocytosis	1	481.5×	0.014	C9orf72
regulation of actin filament organization	1	481.5×	0.014	C9orf72
regulation of Ras protein signal transduction	1	374.5×	0.014	SQSTM1
aggrephagy	1	337.0×	0.014	SQSTM1
regulation of TORC1 signaling	1	337.0×	0.014	C9orf72
protein folding in endoplasmic reticulum	1	280.9×	0.014	CANX
protein localization to perinuclear region of cytoplasm	1	280.9×	0.014	SQSTM1
leukotriene metabolic process	1	259.3×	0.014	LTC4S
leukotriene biosynthetic process	1	259.3×	0.014	LTC4S
negative regulation of sprouting angiogenesis	1	259.3×	0.014	ZNF354C
autophagosome-lysosome fusion	1	240.7×	0.014	C9orf72
negative regulation of toll-like receptor 4 signaling pathway	1	224.7×	0.014	SQSTM1
regulation of synaptic vesicle cycle	1	224.7×	0.014	C9orf72
membraneless organelle assembly	1	224.7×	0.014	SQSTM1
regulation of autophagosome assembly	1	224.7×	0.014	C9orf72
pexophagy	1	210.7×	0.014	SQSTM1
negative regulation of immune response	1	210.7×	0.014	C9orf72
regulation of protein complex stability	1	210.7×	0.014	SQSTM1
autophagy	2	44.1×	0.014	C9orf72, SQSTM1
late endosome to lysosome transport	1	198.3×	0.015	C9orf72
regulation of mitochondrion organization	1	168.5×	0.016	SQSTM1
cellular response to stress	1	168.5×	0.016	SQSTM1
negative regulation of ferroptosis	1	160.5×	0.016	SQSTM1
autophagy of mitochondrion	1	146.5×	0.017	SQSTM1
positive regulation of long-term synaptic potentiation	1	134.8×	0.018	SQSTM1
temperature homeostasis	1	129.6×	0.018	SQSTM1
stress granule assembly	1	120.4×	0.018	C9orf72

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 4

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LTC4S	2	3
C9orf72	0	0
SQSTM1	0	0
CANX	0	0
ZNF354C	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FIBOFLAPON	3	LTC4S
AZD-9898	1	LTC4S

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
LTC4S	37	Binding:36, ADMET:1
SQSTM1	20	Binding:20
CANX	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LTC4S	4.4.1.20	leukotriene-C4 synthase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
FIBOFLAPON	3	LTC4S
AZD-9898	1	LTC4S

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	LTC4S
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	C9orf72, SQSTM1, CANX, ZNF354C

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
C9orf72	0	—
SQSTM1	20	—
CANX	2	—
ZNF354C	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02964637	Not specified	RECRUITING	Diagnosing Frontotemporal Lobar Degeneration
NCT06051123	Not specified	RECRUITING	Effects of Probiotics in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia Spectrum Disorder (ALS-FTDSD) Patients