Xeroderma Pigmentosum (XP) Panel

Xeroderma pigmentosum (XP) results in skin changes (blistering due to sunburn (60% of cases), persistent erythema, freckling, and hyper/hypopigmentation), early onset skin cancers and internal cancers, ocular problems (severe keratitis, eyelid atrophy, and conjunctival inflammatory masses), and neurologic abnormalities (microcephaly, diminished/absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and cognitive impairment) (Kraemer et al. 2016. PubMed ID: 20301571). The types of cancers involved are usually non-melanoma skin cancers (basal and squamous cell) and cutaneous melanoma. The incidence of skin cancer is 1,000 times the rate of the general population (Webb. 2008. PubMed ID: 18292171). Sun exposure must be limited because skin cancer can appear within the first decade of life due to ultraviolet radiation; removal of early pre-cancerous lesions is beneficial. XP occurs in approximately 1 in 250,000 live births in the United States, 2.3 in 1,000,000 live births in Western Europe (Kleijer et al. 2008. PubMed ID: 18329345), and a higher prevalence of 1 in 22, 000 live births in Japan (Hirai et al. 2006. PubMed ID: 16905156). Higher prevalence is also seen in North Africa, and the Middle East, possibly due to consanguinity. XP presents with complete penetrance, but shows a wide variety of clinical heterogeneity within and between XP groups. Heterogeneity may be due to length of sunlight exposure, complementation group, nature of pathogenic variants and unknown factors (Lehmann et al. 2011. PubMed ID: 22044607).

Xeroderma pigmentosum is an autosomal recessive disorder caused by biallelic pathogenic variants in the XPA, ERCC3, XPC, ERCC2, DDB2, ERCC1/ERCC4, and ERCC5 genes, which belong to the XPA, XPB, XPC, XPD, XPE, XPF, and XPG complementation groups, respectively. The products of these genes are involved in DNA repair, specifically nucleotide excision repair (NER). This mechanism of repair involves removal of UV-induced dipyrimidine photoproducts and chemical crosslinks. If the damage is left unchecked, cells have the potential for cancer development. Specific genotype-phenotype correlations exist for the XP forms (Kraemer et al. 2016. PubMed ID: 20301571). The XP variant phenotype, which is caused by POLH pathogenic variants, leads to affected individuals who have an increased skin cancer incidence and eye abnormalities like most XP patients. Pathogenic variants in the POLH gene do not cause aberrant nucleotide excision repair, but result in difficulty replicating DNA containing ultraviolet-induced damage (Lehmann et al. 2011. PubMed ID: 22044607).

The XPC and DDB2 (XPE) protein products are required for initial damage detection. Afterwards the products XPB and XPD open up DNA around the photoproduct. XPA verifies correct protein assembly and then the XPG and XPF nucleases cleave the DNA on either side of the damage for correct repair via the DNA polymerase η (encoded by POLH) (Naegeli et al. 2011. PubMed ID: 21684221; Kraemer et al. 2016. PubMed ID: 20301571). XPF and ERCC1 form a heterodimeric structure-specific endonuclease which is necessary for 5’ cleaving of UV-damaged DNA at the incision step of NER (Kashiyama et al. 2013. PubMed ID: 23623389). Two types of NER are performed within the cell, namely, global genome repair and transcription coupled repair. The former is involved in global genome maintenance, whereas the latter is involved in repair of DNA from transcriptionally active genes. All aforementioned protein products are involved in transcription-coupled repair and most of these gene products are also involved with global genome repair, with the exception of XPC and XPE. Interestingly, patients with XPC or XPE variants do not have severe sunlight lesions and neurological abnormalities, and this may have to do with their type of NER pathway involvement.

See individual gene test descriptions for additional information on molecular biology of gene products and mutation spectra.

The proportion of Xeroderma Pigmentosum (XP) (in the US) that is attributed to pathogenic variants in DDB2, ERCC2, ERCC3, ERCC5, POLH, XPA and XPC are 3%, 28%, 1%, 3%, 7%, 9%, 43%, respectively. Causative variants in the XPA gene are more common in Japan and rare in the United States and Europe (Kraemer et al. 2016. PubMed ID: 20301571).

Pathogenic variants in ERCC1 and ERCC4 are rare, but have been reported in individuals affected with severe XP/Cockayne syndrome (Kashiyama et al. 2013. PubMed ID: 23623389), and cerebro-oculo-facio-skeletal syndrome (COFS) (Jaspers et al. 2007. PubMed ID: 17273966).

Some individuals have a phenotype with both features of XP and Cockayne syndrome (increased skin cancer in XP and dysmyelination in CS). These XP/CS individuals have pathogenic variants in either the ERCC2, ERCC3 or ERCC5 genes (Rapin et al. 2000. PubMed ID: 11185579).

Copy number variations are a rare form of pathogenic variation among the genes in this test panel. Therefore, clinical sensitivity for CNV detection is predicted to be low.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).