Xeroderma pigmentosum: genes and variants

Genes linked to Xeroderma pigmentosum

• ERCC2: General transcription and DNA repair factor IIH helicase subunit XPD

  Its XPD helicase activity unwinds damaged DNA during nucleotide-excision repair and also supports transcription initiation within TFIIH. Biallelic pathogenic variants cause xeroderma pigmentosum, trichothiodystrophy, or combined DNA-repair syndromes depending on the functional defect.

  5 disease-causing and 20 uncertain variants in ERCC2 are linked to Xeroderma pigmentosum.

• XPA: DNA repair protein complementing XP-A cells

  It verifies bulky DNA lesions and organizes the nucleotide-excision-repair machinery around damaged sites. Biallelic loss-of-function variants cause xeroderma pigmentosum group A with extreme ultraviolet sensitivity, early skin cancers, and often progressive neurologic disease.

  5 disease-causing and 11 uncertain variants in XPA are linked to Xeroderma pigmentosum.

• ERCC5: DNA excision repair protein ERCC-5

  It makes one of the two strand incisions required to remove bulky DNA lesions during nucleotide-excision repair and also supports repair-associated transcriptional responses. Biallelic pathogenic variants can cause xeroderma pigmentosum group G, Cockayne syndrome, or combined phenotypes.

  4 disease-causing and 0 uncertain variants in ERCC5 are linked to Xeroderma pigmentosum.

• XPC: DNA repair protein complementing XP-C cells

  It detects helix-distorting lesions throughout the genome and initiates global-genome nucleotide-excision repair. Biallelic loss-of-function variants cause xeroderma pigmentosum group C with severe ultraviolet sensitivity and greatly increased skin-cancer risk.

  2 disease-causing and 26 uncertain variants in XPC are linked to Xeroderma pigmentosum.

• ERCC4: DNA repair endonuclease XPF

  Together with ERCC1, it makes structure-specific DNA incisions required for nucleotide-excision repair and interstrand-crosslink repair. Biallelic pathogenic variants can cause xeroderma pigmentosum, Fanconi anemia, or severe progeroid DNA-repair disease.

  0 disease-causing and 8 uncertain variants in ERCC4 are linked to Xeroderma pigmentosum.

Where Xeroderma pigmentosum variants cluster

• ERCC2 Mediates interaction with MMS19 (positions 438–637): 4 of 5 disease-causing changes, 3.0× more than its size predicts.

Known disease-causing variants in Xeroderma pigmentosum

Which prediction tools work for Xeroderma pigmentosum

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

• REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 96 out of 100
• phyloP: 91 out of 100
• SIFT: 89 out of 100
• PolyPhen-2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Cerebrooculofacioskeletal syndrome 2 is also caused by ERCC2 variants; they fall mostly in different places as the Xeroderma pigmentosum variants (15 disease-causing).
• Xeroderma pigmentosum, group D is also caused by ERCC2 variants; they fall mostly in different places as the Xeroderma pigmentosum variants (11 disease-causing).
• Trichothiodystrophy 1, photosensitive is also caused by ERCC2 variants; they fall mostly in different places as the Xeroderma pigmentosum variants (9 disease-causing).
• Xeroderma pigmentosum, group G is also caused by ERCC5 variants; they fall mostly in different places as the Xeroderma pigmentosum variants (4 disease-causing).

Diseases related to Xeroderma pigmentosum

• Ovarian cancer, also linked to ERCC2, ERCC4, ERCC5 and XPC
• Cerebrooculofacioskeletal syndrome 2, also linked to ERCC2 and ERCC5
• Acute myeloid leukemia, also linked to ERCC4
• Fanconi anemia, also linked to ERCC4
• Xeroderma pigmentosum, group D, also linked to ERCC2
• Trichothiodystrophy 1, photosensitive, also linked to ERCC2
• Xeroderma pigmentosum, group G, also linked to ERCC5
• Xeroderma pigmentosum group A, also linked to XPA
• Fanconi anemia complementation group Q, also linked to ERCC4
• Xeroderma pigmentosum, group F, also linked to ERCC4
• Cockayne syndrome, also linked to ERCC4
• Basal cell carcinoma, also linked to XPA

Frequently asked questions

Which genes are linked to Xeroderma pigmentosum?

In CATVariant, Xeroderma pigmentosum is linked to 5 analyzed proteins: ERCC2 (General transcription and DNA repair factor IIH helicase subunit XPD), XPA (DNA repair protein complementing XP-A cells), ERCC5 (DNA excision repair protein ERCC-5), XPC (DNA repair protein complementing XP-C cells) and ERCC4 (DNA repair endonuclease XPF).

How many genetic variants are linked to Xeroderma pigmentosum?

121 variants: 16 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 65 are of uncertain significance or have conflicting reports.

Which uncertain variants in Xeroderma pigmentosum 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 Xeroderma pigmentosum?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.96, based on 15 disease-causing and 66 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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