DSG1

Chr 18ARAD

desmoglein 1

Also known as: CDHF4, DG1, DSG, EPKHE, EPKHIA, PPKS1, SPPK1

NCBI Gene: 1828 ENSG00000134760 UniProt: Q02413

The protein is a cadherin-like transmembrane glycoprotein that forms desmosomes, which are cell-cell junctions that resist mechanical stress and mediate cellular adhesion. Mutations cause congenital erythroderma with palmoplantar keratoderma, hypotrichosis, and hyper-IgE (autosomal recessive) or palmoplantar keratoderma striata (autosomal dominant). This gene is highly constrained against loss-of-function mutations, indicating that such variants are likely to be pathogenic.

Summary from RefSeq, OMIM, UniProt

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Primary Disease Associations & Inheritance

Erythroderma, congenital, with palmoplantar keratoderma, hypotrichosis, and hyper IgEMIM #615508

Keratosis palmoplantaris striata I, ADMIM #148700

Active trials

Pubs (1 yr)

P/LP submissions

P/LP missense

0.33

LOEUF· LoF intol.

LOF

Mechanism· G2P

Clinical Summary— DSG1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.93). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

23 unique Pathogenic / Likely Pathogenic· 302 VUS of 500 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.33LOEUF

pLI 0.927

Z-score 5.00

OE 0.18 (0.11–0.33)

Highly constrained

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

Missense Constraint

-0.34Z-score

OE missense 1.04 (0.97–1.11)

592 obs / 569.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE0.18 (0.11–0.33)

0≤0.351.4

Missense OE1.04 (0.97–1.11)

0≤0.61.4

Synonymous OE1.13

0≤1.21.6

LoF obs/exp: 8 / 43.6Missense obs/exp: 592 / 569.1Syn Z: -1.40

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveDSG1-related palmoplantar keratoderma, striateLOFAD

strongDSG1-related severe dermatitis, multiple allergies and metabolic wastingLOFAR

0.5476th %ile

GOF

0.7028th %ile

LOF

0.55top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 35% of P/LP variants are LoF · LOEUF 0.33

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFRickman et al. (1999) concluded that haploinsufficiency was probably a mechanism of the dominant disorder in the family. The rather mild clinical symptoms could have been a consequence of the partial efficiency of missplicing and the fact that affected individuals were heterozygotes, so that only a PMID:10332028

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