Etiology

XP results from pathogenic variants in one of eight genes involved in the recognition and repair of ultraviolet radiation (UVR)-induced DNA damage in a pathway called nucleotide excision repair (NER). There are two subtypes of NER:

  • Transcription-coupled repair (TCR)-NER: repairs actively transcribed DNA

  • Global genome repair (GGR)-NER: repairs DNA not undergoing transcription.

Eight causative proteins (XPA, XPB, XPC, XPD, XPE, XPF, XPG, and XPV) and their genes (XPA, XPB [ERCC3], XPC, XPD [ERCC2], XPE [DDB2], XPF [ERCC4], XPG [ERCC5], and XPV [POLH]) have been identified:[15][16]

  • XPA to XPG are involved in different steps of the NER in the presence of DNA damage[17][18]

  • XPV is involved in the post-replication repair of damaged DNA.[17][18]

Depending on the pathogenic variant of the specific gene, XP can be classified into seven complementation groups (XPA to XPG) and an XP variant (XPV).There is considerable clinical overlap between XP subtypes and within complementation groups, which is strongly dependent on distinct locations and types of pathogenic variants in the causative genes.[3][4]​​ See Classification.

XP is an autosomal recessive inherited disorder with 100% penetrance; a pathogenic variant must be present in both copies of the gene (one from the father and one from the mother) for a person to be affected.

Pathophysiology

​​Defects in the genes involved in the recognition and repair of UVR-induced DNA damage lead to increased cellular susceptibility to UVR-induced killing, and genetic instability leading to accumulation of UVR-induced photoproducts and unrepaired DNA damage. This results in the cutaneous features, disease progression, and increased susceptibility to skin cancer seen in XP.[14][19][20]​​

The main causes of neurodegeneration are oxidative stress and cumulative oxidative DNA damage in neurons.[21][22]

Classification

Subtypes of XP

XP is classified into eight laboratory subtypes (group A-G genetic complementation groups and a variant type V) of which each responsible gene (listed below) has been identified:[2]

  • XPA

  • XPB (ERCC3)

  • XPC

  • XPD (ERCC2)

  • XPE (DDB2)

  • XPF (ERCC4)

  • XPG (ERCC5)

  • XPV (POLH).

There is considerable clinical overlap between the subtypes and within complementation groups.[3][4]

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