Xeroderma Pigmentosum via the XPA Gene

Xeroderma pigmentosum (XP) results in skin changes (blistering due to sunburn in 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 et al. 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). Increased rates are also seen in North Africa, and the Middle East, possibly due to increased consanguinity. XP presents with complete penetrance and shows a wide variety of clinical heterogeneity within and between XP groups. This may be due to length of sunlight exposure, complementation group, nature of mutation 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 (DiGiovanna et al. 2012. PubMed ID: 22217736). 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. The XP variant phenotype which is caused by POLH variants leads to affected individuals who have an increased skin cancer incidence and eye abnormalities like most XP patients. Cells with POLH variants do not have dysfunctional nucleotide excision repair. Specific genotype-phenotype correlations exist for the XP forms (Kraemer et al. 2016. PubMed ID: 20301571).

The XPC and DDB2 (XPE) protein products are initially 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’ cleavage 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/ DDB2 variants do not have severe sunlight lesions and neurological abnormalities, and this may have to do with their type of NER pathway involvement.

The XPA gene encodes a zinc finger protein of 31.3 kd that plays a key role in NER by maintaining single stranded regions. A pathogenic founder variant in XPA, c.390-1G>C, is estimated to occur at a frequency of up to 1% in Japanese populations. Individuals homozygous for this change have severe and progressive neurological degeneration (Kraemer et al. 2016. PubMed ID: 20301571). To date, causative variants reported in XPA implicated in xeroderma pigmentosum group A include missense, nonsense, splicing, small frameshift deletions, indels and duplications. No gross deletions and duplications have been reported (Human Genome Mutation Database).

Pathogenic variants in XPA account for 9% of XP cases in the US, 20% in Europe, and are more common in Japan accounting for 55% of cases (Kraemer et al. 2016. PubMed ID: 20301571).

This test provides full coverage of all coding exons of the XPA gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.