CYLD

Chr 16AD

CYLD lysine 63 deubiquitinase

Also known as: BRSS, CDMT, CYLD1, CYLDI, EAC, FTDALS8, MFT, MFT1

NCBI Gene: 1540 ENSG00000083799 UniProt: Q9NQC7

This gene is encodes a cytoplasmic protein with three cytoskeletal-associated protein-glycine-conserved (CAP-GLY) domains that functions as a deubiquitinating enzyme. Mutations in this gene have been associated with cylindromatosis, multiple familial trichoepithelioma, and Brooke-Spiegler syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

?Frontotemporal dementia and/or amyotrophic lateral sclerosis 8MIM #619132

Brooke-Spiegler syndromeMIM #605041

Cylindromatosis, familialMIM #132700

Trichoepithelioma, multiple familial, 1MIM #601606

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

3.5

Missense Z· constrained

0.20

LOEUF· LoF intolerant

Clinical Summary— CYLD

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Gene-Disease Validity (ClinGen)

Brooke-Spiegler syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.20LOEUF

pLI 1.000

Z-score 5.65

OE 0.09 (0.04–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

3.55Z-score

OE missense 0.55 (0.50–0.61)

277 obs / 500.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.09 (0.04–0.20)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.55 (0.50–0.61)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97

0≤1.21.6

LoF obs/exp: 4 / 44.8Missense obs/exp: 277 / 500.1Syn Z: 0.32

0.2997th %ile

GOF

0.3491th %ile

LOF

0.69top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.20

GOF1 literature citation

DN1 literature citation

Literature Evidence

DNTherefore, although complete loss of CYLD may be compensated for by other endogenous NF-kB inhibitors, CYLD(ex7/8) acts in a dominant negative manner.PMID:20836156

GOFHere, we conclude that loss of CYLD catalytic activity potentiates its oncogenic gain of function through increased cell survival and migration.PMID:29807073

LOFIdentification of the familial cylindromatosis tumour-suppressor genePMID:10835629

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.