ERCC5 is a clinically valid cause of xeroderma pigmentosum, specifically the rare XP complementation group G, with autosomal recessive inheritance and an overall Definitive gene-disease classification based on multiple independent affected individuals, formal complementation and functional rescue data, recurrent biallelic pathogenic ERCC5 variants, and long-standing replication from 1993 through 2024 PMID:8317483, PMID:7951246, PMID:12060391, PMID:22417308, PMID:23370536, PMID:40626125. The supplied evidence consistently places ERCC5 gene dysfunction within nucleotide excision repair deficiency, with ERCC5-related xeroderma pigmentosum showing marked UV sensitivity and a clinically important spectrum ranging from predominantly cutaneous disease to xeroderma pigmentosum with neurodevelopmental or neurodegenerative involvement, and in some individuals overlap with Cockayne syndrome features PMID:8317483, PMID:12060391, PMID:38975443.
Human genetic evidence for ERCC5 and xeroderma pigmentosum includes early formal proof from an XP-G patient in whom two ERCC5 alleles were shown to inactivate complementation in vivo PMID:7951246. Across the supplied reports, ERCC5-associated xeroderma pigmentosum was documented in at least 15 affected individuals from multiple unrelated families, including 2 severe XP/CS-spectrum patients in 1993 PMID:8317483, 1 XP-G patient with biallelic ERCC5 defects in 1994 PMID:7951246, 1 informative pedigree with transmission from both parents to an affected child and not the unaffected sibling in 1997 PMID:9447232, 3 additional XP-G patients in 2002 PMID:12060391, 1 Japanese XP-G case in 2012 PMID:22417308, 3 additional XPG-defective patients in 2013 PMID:23370536, 2 mildly affected Brazilian siblings PMID:23255472, 2 Tunisian siblings PMID:30838033, and 1 adult with compound heterozygous ERCC5 variants and neuropsychiatric presentation in 2024 PMID:38975443. Additional cohort-level support comes from Chinese xeroderma pigmentosum series identifying ERCC5-diagnosed XP-G families within sequenced clinical cohorts PMID:25256075, PMID:27982466.
The ERCC5 variant spectrum in xeroderma pigmentosum is broad and includes nonsense, frameshift, splice, and missense alleles. Reported ERCC5 variants in affected individuals include c.33G>T (p.Glu11Ter), c.406C>T (p.Gln136Ter), c.194T>C (p.Leu65Pro), c.83C>A (p.Ala28Asp), c.922_923del (p.Leu308fs), c.1975del (p.Ser659fs), c.2332del (p.Leu778fs), c.2333T>C (p.Leu778Pro), c.2375C>T (p.Ala792Val), c.2413G>A (p.Gly805Arg), c.2573T>C (p.Leu858Pro), c.2606_2607del (p.Val869fs), c.2620G>A (p.Ala874Thr), c.2751del (p.Lys917fs), c.2775del (p.Gly926fs), c.2878G>T (p.Glu960Ter), c.2880-2A>G, c.2904G>C (p.Trp968Cys), and c.3146del (p.Asp1049ValfsTer12) PMID:9447232, PMID:12060391, PMID:22417308, PMID:23370536, PMID:23255472, PMID:30838033, PMID:38975443. ERCC5 genotype-phenotype correlation is supported in the supplied dataset: biallelic truncating ERCC5 alleles were associated with more severe XP/CS manifestations, whereas at least some missense ERCC5 alleles with residual activity were associated with milder xeroderma pigmentosum without major neurologic disease PMID:12060391, PMID:9096355, PMID:11841555, PMID:23255472.
The phenotype associated with ERCC5-related xeroderma pigmentosum includes childhood-onset sun sensitivity, pigmentary change of sun-exposed skin, cutaneous photosensitivity, xerosis/dry skin, and early skin cancer susceptibility, with squamous cell carcinoma specifically reported in adulthood in mild ERCC5 cases PMID:22417308, PMID:27462567. Neurologic involvement is variable in ERCC5 disease: some ERCC5 patients had no neurologic abnormalities PMID:22417308, PMID:25256075, whereas others had developmental impairment, cognitive impairment, lower-limb spasticity, delusions, or severe early neurodegeneration PMID:12060391, PMID:38975443. The 2024 review summarized 19 xeroderma pigmentosum cases, 24 XP/CS cases, and 16 COFS cases with ERCC5 mutations, underscoring that ERCC5 can underlie a broad but recognizable DNA-repair disorder spectrum in which classic xeroderma pigmentosum remains a major diagnostic presentation PMID:40626125.
Functional evidence for ERCC5 is extensive and concordant with the human phenotype. ERCC5 encodes the XPG 3' endonuclease required for nucleotide excision repair, and biochemical studies demonstrated that catalytic residues and the helix-loop-helix region are necessary for DNA binding, incision activity, and restoration of UV resistance PMID:9188507, PMID:9346928, PMID:10026181. Patient-derived ERCC5 fibroblasts repeatedly showed UV hypersensitivity, reduced unscheduled DNA synthesis, reduced post-UV survival, or reduced host-cell reactivation, and complementation by ERCC5 cDNA corrected repair defects PMID:22417308, PMID:23370536, PMID:7951246. Functional analyses of specific ERCC5 missense alleles showed residual activity for some variants linked to mild xeroderma pigmentosum and more profound impairment for variants associated with XP/CS PMID:10026181, PMID:11841555, PMID:23255472, PMID:23370536. Animal data are also supportive: Xpg-deficient mice showed postnatal growth failure, shortened lifespan, premature cellular senescence, and increased spontaneous mutation burden, consistent with a key role for ERCC5 in genome maintenance PMID:10022922, PMID:11738939, PMID:15661658.
Several caveats are important when interpreting ERCC5 in xeroderma pigmentosum. First, the ERCC5-associated phenotype spans classic xeroderma pigmentosum, XP/Cockayne overlap, and COFS-spectrum presentations, so careful phenotypic assignment is necessary when reviewing published ERCC5 cases PMID:8317483, PMID:9096355, PMID:40626125. Second, some studies in the supplied set concern ERCC5 polymorphisms and common cancer risk rather than monogenic xeroderma pigmentosum, and these do not weaken the recessive disease association PMID:15494739, PMID:16823510. Third, some reported ERCC5 variants appeared in functional or non-XP cancer studies without evidence that they cause xeroderma pigmentosum, so clinical interpretation should prioritize biallelic variants observed in affected XP patients and supported by repair assays PMID:16550608, PMID:36033436. No conflicting evidence was provided in the supplied dataset.
In aggregate, the evidence supports ERCC5 gene analysis as highly clinically useful in patients with suspected autosomal recessive xeroderma pigmentosum, especially when UV hypersensitivity is accompanied by mixed cutaneous and neurologic findings or when complementation group G is suspected. ERCC5 has been implicated by multiple independent biallelic pathogenic variants, segregation within families, reproducible cellular DNA-repair defects, and mechanistic studies that align tightly with disease biology PMID:9447232, PMID:12060391, PMID:22417308, PMID:23370536. Key take-home: ERCC5 is a definitive autosomal recessive xeroderma pigmentosum gene, and biallelic loss-of-function or functionally damaging missense ERCC5 variants should be considered diagnostic when they fit the characteristic UV-sensitive, skin-cancer-prone XP phenotype with or without neurologic involvement.
Gene–Disease AssociationDefinitiveMultiple unrelated probands and families with biallelic ERCC5 variants, segregation, formal complementation evidence, recurrent damaging variants, and extensive concordant cellular and animal functional data replicated over decades. Genetic EvidenceDefinitiveAt least 15 affected individuals from multiple unrelated families with autosomal recessive ERCC5 variants, including truncating, splice, and missense alleles with consistent XP phenotypes and genotype-phenotype correlation. Functional EvidenceDefinitiveERCC5/XPG is a core nucleotide excision repair endonuclease; patient cells show UV hypersensitivity and defective repair rescued by ERCC5 cDNA, and animal models demonstrate genome instability and growth failure consistent with disease biology. |