Xeroderma Pigmentosum via the DDB2 Gene

Xeroderma pigmentosum (XP) results in skin changes (e.g. blistering due to sunburn (60% of cases), persistent erythema, freckling, and hyper/hypopigmentation), early onset skin cancers and internal cancers, ocular problems (e.g. severe keratitis, eyelid atrophy, and conjunctival inflammatory masses), and neurologic abnormalities (e.g. microcephaly, diminished/absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and cognitive impairment) (Kraemer and DiGiovanna. GeneReviews. 2012). The types of cancers involved are usually non-melanoma skin cancers (basal and squamous cell) and cutaneous melanoma. The incidence of skin cancer is 1000 times the rate of the general population (Webb. BMJ 23;336(7641):444-6, 2008). 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. DNA Repair (Amst) 3;7(5):744-50, 2008), and a higher prevalence of 1 in 22,000 live births in Japan (Hirai et al. Mutat Res 10;601(1-2):171-8, 2006). Higher prevalence is also seen in North Africa, and the Middle East, possibly due to increased 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 mutation and unknown factors (Lehmann et al. Orphanet Journal of Rare Diseases 6:70, 2011).

Xeroderma pigmentosum is an autosomal recessive disorder caused by mutations in the XPA, ERCC3, XPC, ERCC2, DDB2, 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 is involved in removing 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 and DiGiovanna. GeneReviews. 2012). The majority of mutations in the DDB2 gene are missense mutations. Less common types of DDB2 mutations include splice site and small deletions (Human Gene Mutation Database).

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 and Sugasawa. DNA Repair 10:673-683, 2011; Kraemer and DiGiovanna. GeneReviews. 2012). 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 mutations do not have severe sunlight lesions and neurological abnormalities, and this may have to do with their type of NER pathway involvement. Mutations in the POLH gene do not cause aberrant nucleotide excision repair, but have difficulty replicating DNA containing ultraviolet-induced damage (Lehmann et al. Proceedings of the National Academy of Sciences of the United States of America 72:219-223, 1975).

DNA testing confirms diagnosis in ~77% of XP patients. Mutations in the DDB2 gene are rare (Kraemer and DiGiovanna. GeneReviews. 2012).

This test provides full coverage of all coding exons of the DDB2 gene 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 full 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).