| XP group / genotype | Causal gene | Core pathway role | Neurological involvement | High-signal recent evidence |
|---|---|---|---|---|
| XPA | **XPA** | Damage verification/scaffold in NER pre-incision complex; coordinates repair factors in GG-NER and TC-NER | **Yes, often prominent**; among the groups with the greatest neurologic burden and measurable progression | UK prospective cohort: XPA had frequent neurologic symptoms and significant SARA progression (~0.63 points/year); mutation severity correlated with faster progression. 2024 XP-A natural-history/genotype study linked variant class/location to severe, intermediate, or mild neurodegeneration. Management overview relevant for surveillance/supportive care. (pqac-00000025, pqac-00000011, pqac-00000001) |
| XPB | **ERCC3 (XPB)** | TFIIH DNA translocase/helicase activity for DNA opening during NER; also transcription factor function | **Variable / can occur**; less common due to rarity, but neurologic disease can occur, especially in combined NER/transcription phenotypes | NER overview places XPB in TFIIH-mediated unwinding; UK cohort included very few XPB cases, limiting precision, but background notes combined GG-NER/TC-NER defect groups are more prone to neurodegeneration. Management overview relevant. (pqac-00000001, pqac-00000030, pqac-00000031) |
| XPC | **XPC** | Primary lesion recognition in **global-genome NER (GG-NER)**; damage sensing/handover to TFIIH | **Usually no or mild/variable**; neurologic involvement uncommon but not absent | UK cohort: only 2/22 XPC patients (9.1%) had neurologic symptoms. 2024 XP-C rescue study identified PIK3C3 knockdown as an experimental synthetic-rescue strategy. 2023 skin-cancer genomics showed strong mutational burden/signature effects in XP-C tumors. Management overview relevant. (pqac-00000026, pqac-00000012, pqac-00000008, pqac-00000001) |
| XPD | **ERCC2 (XPD)** | TFIIH 5'→3' helicase/translocase for lesion verification and DNA opening in NER | **Yes, often prominent**; one of the groups with fastest neurologic progression | UK prospective cohort: XPD showed high neurologic burden and fastest reported SARA progression (~0.91 points/year), with frequent cognitive impairment, neuropathy, hearing loss, and MRI abnormalities. Mechanistic work also supports XPD as core NER motor protein. Management overview relevant. (pqac-00000025, pqac-00000026, pqac-00000027, pqac-00000001) |
| XPE | **DDB2 (XPE)** | UV-photoproduct recognition in GG-NER (especially CPD/6-4PP recognition with DDB complex), facilitates XPC recruitment | **Usually no / low frequency** | UK cohort found no neurologic complaints in XPE in this series. 2023 tumor-genome study showed XP-E tumors can have very high mutation burden, supporting strong skin-cancer susceptibility despite limited neurologic disease. Management overview relevant. (pqac-00000024, pqac-00000008, pqac-00000001) |
| XPF | **ERCC4 (XPF)** | Structure-specific endonuclease; 5' incision in NER with ERCC1 | **Variable**; can be mild in founder intronic forms, but neurologic disease exists in some XP-F/overlap cases | 2023 PNAS identified deep intronic **ERCC4/XPF** founder mutations in 17 Japanese XP-F cases; one founder allele accounts for ~10% of Japanese XP, with early-onset skin cancers and generally typical XP-F cutaneous disease, and ASOs restored XPF expression/repair in cells. UK cohort had few XPF cases, limiting neurologic estimates. Management overview relevant. (pqac-00000032, pqac-00000033, pqac-00000036, pqac-00000031, pqac-00000001) |
| XPG | **ERCC5 (XPG)** | Structure-specific endonuclease; 3' incision in NER; also stabilizes repair complex | **Yes, often prominent** | UK cohort: XPG grouped with XPA/XPD as having high SARA scores, frequent cognitive impairment, hearing loss, MRI abnormalities, and substantial disability. Management overview relevant. (pqac-00000025, pqac-00000026, pqac-00000027, pqac-00000001) |
| XPV | **POLH** | **Translesion synthesis (TLS)** polymerase eta; error-free bypass of UV photolesions, especially CPDs; not a core NER factor | **Usually no / low frequency, but subtle abnormalities reported** | UK cohort reported no neurologic complaints in XPV, though some exam/ancillary abnormalities were detected. 2023 skin-cancer genomics showed XP-V tumors have distinctive mutational spectra and high TMB linked to POLH deficiency. Management overview relevant. (pqac-00000024, pqac-00000027, pqac-00000008, pqac-00000009, pqac-00000001) |


*Table: This table summarizes the main xeroderma pigmentosum complementation groups, their causal genes, core repair roles, and whether neurologic involvement is typical or variable. It emphasizes high-yield 2023-2024 evidence plus a practical management overview source useful for clinical interpretation.*