Frontotemporal dementia and/or amyotrophic lateral sclerosis 8

Summary

Frontotemporal dementia and/or amyotrophic lateral sclerosis 8 (MONDO:0030872) is a disease caused by CYLD (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: CYLD (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 88

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	frontotemporal dementia and/or amyotrophic lateral sclerosis 8
Mondo ID	MONDO:0030872
OMIM	619132
UMLS	C5436881
MedGen	1728824
GARD	0018395
Is cancer (heuristic)	no

Also known as: frontotemporal dementia and/or amyotrophic lateral sclerosis 8 · FTDALS8

Data availability: 88 ClinVar variants · 2 GenCC gene-disease records.

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 8

Related subtypes (29): amyotrophic lateral sclerosis type 1, frontotemporal dementia and/or amyotrophic lateral sclerosis 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 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

88 retrieved; paginated sample, class counts are floors:

82 uncertain significance, 2 pathogenic, 2 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
267232	NM_001378743.1(CYLD):c.1112C>A (p.Ser371Ter)	CYLD	Pathogenic	criteria provided, multiple submitters, no conflicts
267249	NM_001378743.1(CYLD):c.2299A>T (p.Lys767Ter)	CYLD	Pathogenic	criteria provided, multiple submitters, no conflicts
2681079	NM_001378743.1(CYLD):c.1111del (p.Ser371fs)	CYLD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5259	NM_001378743.1(CYLD):c.2806C>T (p.Arg936Ter)	CYLD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
319497	NM_001378743.1(CYLD):c.59T>G (p.Ile20Ser)	CYLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
992597	NM_001378743.1(CYLD):c.2155A>G (p.Met719Val)	CYLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1327096	NM_001378743.1(CYLD):c.170A>G (p.His57Arg)	CYLD	Uncertain significance	criteria provided, single submitter
133955	NM_001378743.1(CYLD):c.1933G>A (p.Val645Ile)	CYLD	Uncertain significance	criteria provided, multiple submitters, no conflicts
2413065	NM_001378743.1(CYLD):c.932C>T (p.Thr311Met)	CYLD	Uncertain significance	criteria provided, multiple submitters, no conflicts
2428841	NM_001378743.1(CYLD):c.635T>C (p.Leu212Ser)	CYLD	Uncertain significance	criteria provided, multiple submitters, no conflicts
2681037	NM_001378743.1(CYLD):c.55C>T (p.Arg19Trp)	CYLD	Uncertain significance	criteria provided, single submitter
2681038	NM_001378743.1(CYLD):c.2462A>G (p.Asn821Ser)	CYLD	Uncertain significance	criteria provided, single submitter
2681039	NM_001378743.1(CYLD):c.1827-3C>A	CYLD	Uncertain significance	criteria provided, single submitter
2681040	NM_001378743.1(CYLD):c.439C>T (p.Arg147Cys)	CYLD	Uncertain significance	criteria provided, multiple submitters, no conflicts
2681041	NM_001378743.1(CYLD):c.1141G>T (p.Ala381Ser)	CYLD	Uncertain significance	criteria provided, single submitter
2681042	NM_001378743.1(CYLD):c.157C>T (p.Arg53Cys)	CYLD	Uncertain significance	criteria provided, single submitter
2681043	NM_001378743.1(CYLD):c.125C>T (p.Pro42Leu)	CYLD	Uncertain significance	criteria provided, single submitter
2681044	NM_001378743.1(CYLD):c.1016C>T (p.Ala339Val)	CYLD	Uncertain significance	criteria provided, single submitter
2681045	NM_001378743.1(CYLD):c.727A>G (p.Thr243Ala)	CYLD	Uncertain significance	criteria provided, single submitter
2681047	NM_001378743.1(CYLD):c.2578G>C (p.Glu860Gln)	CYLD	Uncertain significance	criteria provided, single submitter
2681048	NM_001378743.1(CYLD):c.2650G>T (p.Ala884Ser)	CYLD	Uncertain significance	criteria provided, single submitter
2681049	NM_001378743.1(CYLD):c.1763T>C (p.Ile588Thr)	CYLD	Uncertain significance	criteria provided, multiple submitters, no conflicts
2681050	NM_001378743.1(CYLD):c.608A>C (p.Glu203Ala)	CYLD	Uncertain significance	criteria provided, single submitter
2681051	NM_001378743.1(CYLD):c.2434A>G (p.Lys812Glu)	CYLD	Uncertain significance	criteria provided, single submitter
2681052	NM_001378743.1(CYLD):c.1331C>G (p.Ser444Cys)	CYLD	Uncertain significance	criteria provided, single submitter
2681053	NM_001378743.1(CYLD):c.2644G>A (p.Asp882Asn)	CYLD	Uncertain significance	criteria provided, single submitter
2681054	NM_001378743.1(CYLD):c.241G>T (p.Val81Phe)	CYLD	Uncertain significance	criteria provided, single submitter
2681055	NM_001378743.1(CYLD):c.1433T>C (p.Val478Ala)	CYLD	Uncertain significance	criteria provided, single submitter
2681056	NM_001378743.1(CYLD):c.640A>G (p.Ser214Gly)	CYLD	Uncertain significance	criteria provided, single submitter
2681057	NM_001378743.1(CYLD):c.685C>T (p.Pro229Ser)	CYLD	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 2 · 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
CYLD	Strong	Autosomal dominant	frontotemporal dementia and/or amyotrophic lateral sclerosis 8	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYLD	Orphanet:211	Familial cylindromatosis
CYLD	Orphanet:867	Familial multiple trichoepithelioma

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYLD	HGNC:2584	ENSG00000083799	Q9NQC7	Ubiquitin carboxyl-terminal hydrolase CYLD	gencc,clinvar
CYLD-AS2	HGNC:56848	ENSG00000260616		CYLD antisense RNA 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYLD	Ubiquitin carboxyl-terminal hydrolase CYLD	Deubiquitinase that specifically cleaves ‘Lys-63’- and linear ‘Met-1’-linked polyubiquitin chains and is involved in NF-kappa-B activation and TNF-induced necroptosis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Protease	1	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYLD	Protease	yes		CAP-Gly_domain, Peptidase_C19_UCH, USP_CS
CYLD-AS2	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
lateral nuclear group of thalamus	1
lymph node	1
bone marrow	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYLD	294	ubiquitous	marker	lateral nuclear group of thalamus, calcaneal tendon, lymph node
CYLD-AS2	112		yes	male germ line stem cell (sensu Vertebrata) in testis, bone marrow, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYLD	3,507
CYLD-AS2	0

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CYLD	Q9NQC7	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TNFR1-induced proapoptotic signaling	1	439.2×	0.005	CYLD
TNFR1-induced NF-kappa-B signaling pathway	1	335.9×	0.005	CYLD
Negative regulators of DDX58/IFIH1 signaling	1	326.3×	0.005	CYLD
NOD1/2 Signaling Pathway	1	317.2×	0.005	CYLD
Regulation of TNFR1 signaling	1	223.9×	0.005	CYLD
Ub-specific processing proteases	1	53.1×	0.019	CYLD

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of interleukin-18-mediated signaling pathway	1	16852.0×	0.001	CYLD
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	5617.3×	0.001	CYLD
ripoptosome assembly involved in necroptotic process	1	5617.3×	0.001	CYLD
protein linear deubiquitination	1	5617.3×	0.001	CYLD
nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	1	2808.7×	0.002	CYLD
regulation of intrinsic apoptotic signaling pathway	1	2407.4×	0.002	CYLD
negative regulation of p38MAPK cascade	1	2106.5×	0.002	CYLD
regulation of necroptotic process	1	1872.4×	0.002	CYLD
positive regulation of protein localization	1	1404.3×	0.002	CYLD
regulation of B cell differentiation	1	1296.3×	0.002	CYLD
necroptotic process	1	1053.2×	0.003	CYLD
positive regulation of T cell receptor signaling pathway	1	766.0×	0.003	CYLD
regulation of tumor necrosis factor-mediated signaling pathway	1	702.2×	0.003	CYLD
homeostasis of number of cells	1	674.1×	0.003	CYLD
protein K63-linked deubiquitination	1	624.1×	0.003	CYLD
regulation of cilium assembly	1	601.9×	0.003	CYLD
negative regulation of JNK cascade	1	561.7×	0.003	CYLD
regulation of microtubule cytoskeleton organization	1	543.6×	0.003	CYLD
negative regulation of non-canonical NF-kappaB signal transduction	1	510.7×	0.003	CYLD
negative regulation of type I interferon production	1	495.6×	0.003	CYLD
positive regulation of T cell differentiation	1	455.5×	0.003	CYLD
positive regulation of extrinsic apoptotic signaling pathway	1	455.5×	0.003	CYLD
obsolete negative regulation of NF-kappaB transcription factor activity	1	358.6×	0.004	CYLD
regulation of mitotic cell cycle	1	240.7×	0.006	CYLD
protein deubiquitination	1	177.4×	0.007	CYLD
negative regulation of canonical NF-kappaB signal transduction	1	172.0×	0.007	CYLD
regulation of inflammatory response	1	168.5×	0.007	CYLD
negative regulation of inflammatory response	1	137.0×	0.008	CYLD
negative regulation of canonical Wnt signaling pathway	1	117.8×	0.009	CYLD
Wnt signaling pathway	1	99.7×	0.011	CYLD

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYLD	0	0
CYLD-AS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CYLD	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	1	CYLD
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CYLD-AS2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CYLD	3	—
CYLD-AS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.