Epidermolysis bullosa simplex: genes and variants

Genes linked to Epidermolysis bullosa simplex

• KRT5: Keratin, type II cytoskeletal 5

  It pairs with keratin 14 to form the primary intermediate-filament scaffold of basal epidermal keratinocytes. Dominant pathogenic variants are a major cause of epidermolysis bullosa simplex, while other alleles can cause pigmentary disorders such as Dowling-Degos disease.

  18 disease-causing and 13 uncertain variants in KRT5 are linked to Epidermolysis bullosa simplex.

• KRT14: Keratin, type I cytoskeletal 14

  It pairs with keratin 5 to provide mechanical strength to basal epidermal keratinocytes. Dominant-negative variants are a major cause of epidermolysis bullosa simplex, while other variants can cause pigmentation disorders or ectodermal phenotypes.

  6 disease-causing and 0 uncertain variants in KRT14 are linked to Epidermolysis bullosa simplex.

Where Epidermolysis bullosa simplex variants cluster

• KRT5 Coil 1A (positions 168–203): 7 of 18 disease-causing changes, 6.4× more than its size predicts.
• KRT5 Linker 12 (positions 316–338): 3 of 18 disease-causing changes, 4.3× more than its size predicts.
• KRT14 Coil 2 (positions 284–422): 3 of 6 disease-causing changes, 1.7× more than its size predicts.

Known disease-causing variants in Epidermolysis bullosa simplex

Which prediction tools work for Epidermolysis bullosa simplex

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 97 out of 100
• PolyPhen-2: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Epidermolysis bullosa simplex 2B, generalized intermediate is also caused by KRT5 variants; they fall partly in the same places as the Epidermolysis bullosa simplex variants (5 disease-causing).
• Epidermolysis bullosa simplex 1C, localized is also caused by KRT5 variants; they fall partly in the same places as the Epidermolysis bullosa simplex variants (3 disease-causing).
• Dermatopathia pigmentosa reticularis is also caused by KRT14 variants; they fall mostly in different places as the Epidermolysis bullosa simplex variants (8 disease-causing).
• Epidermolysis bullosa simplex, Koebner type is also caused by KRT14 variants; they fall partly in the same places as the Epidermolysis bullosa simplex variants (7 disease-causing).
• Epidermolysis bullosa simplex 1A, generalized severe is also caused by KRT14 variants; they fall mostly in different places as the Epidermolysis bullosa simplex variants (6 disease-causing).
• Epidermolysis bullosa simplex 1C, localized is also caused by KRT14 variants; they fall mostly in different places as the Epidermolysis bullosa simplex variants (4 disease-causing).
• Epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive is also caused by KRT14 variants; they fall mostly in different places as the Epidermolysis bullosa simplex variants (4 disease-causing).

Diseases related to Epidermolysis bullosa simplex

• Epidermolysis bullosa simplex 1A, generalized severe, also linked to KRT14 and KRT5
• Epidermolysis bullosa simplex, Koebner type, also linked to KRT14 and KRT5
• Epidermolysis bullosa simplex 1C, localized, also linked to KRT14 and KRT5
• Epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive, also linked to KRT14 and KRT5
• Dermatopathia pigmentosa reticularis, also linked to KRT14
• Epidermolysis bullosa simplex 2B, generalized intermediate, also linked to KRT5
• Epidermolysis bullosa, also linked to KRT5
• Epidermolysis bullosa simplex 2A, generalized severe, also linked to KRT5
• Dowling-Degos disease, also linked to KRT5
• Basal cell carcinoma, also linked to KRT5
• Epidermolysis bullosa simplex 2C, localized, also linked to KRT5
• Epidermolysis bullosa simplex with mottled pigmentation, also linked to KRT5

Frequently asked questions

Which genes are linked to Epidermolysis bullosa simplex?

In CATVariant, Epidermolysis bullosa simplex is linked to 2 analyzed proteins: KRT5 (Keratin, type II cytoskeletal 5) and KRT14 (Keratin, type I cytoskeletal 14).

How many genetic variants are linked to Epidermolysis bullosa simplex?

59 variants: 24 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 13 are of uncertain significance or have conflicting reports.

Which uncertain variants in Epidermolysis bullosa simplex look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Epidermolysis bullosa simplex?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.97, based on 24 disease-causing and 30 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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