Xeroderma Pigmentosum via the POLH Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8319 POLH 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8319POLH81479 81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

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).

Genetics

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 XP variant phenotype which is caused by POLH mutations leads to affected individuals who have an increased skin cancer incidence and eye abnormalities like most XP patients. The majority of mutations in POLH are missense, nonsense and small deletions. Less common types of mutations include splice site, small insertions, and large deletions (Human Gene Mutation Database). 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).

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.

Clinical Sensitivity - Sequencing with CNV PGxome

About 21% of XP patients have causative mutations in the POLH gene (Kraemer and DiGiovanna. GeneReviews. 2012).

Large deletions have been reported in several cases (Human Gene Mutation Database).

Testing Strategy

This test provides full coverage of all coding exons of the POLH 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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Individuals with a clinical presentation of XP. People with a family history of XP wanting to know their XP mutation status can also be tested. Carriers are asymptomatic, but the possibility of increased cancer risk is currently being assessed. Earlier diagnosis may improve patient prognosis through regular screening and treatment for early-onset malignancies. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in POLH. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

Gene

Official Gene Symbol OMIM ID
POLH 603968
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Xeroderma Pigmentosum, Variant Type AR 278750

Citations

  • Hirai Y, Kodama Y, Moriwaki S-I, Noda A, Cullings HM, MacPhee DG, Kodama K, Mabuchi K, Kraemer KH, Land CE, Nakamura N. 2006. Heterozygous individuals bearing a founder mutation in the XPA DNA repair gene comprise nearly 1% of the Japanese population. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 601: 171–178. PubMed ID: 16905156
  • Kleijer WJ, Laugel V, Berneburg M, Nardo T, Fawcett H, Gratchev A, Jaspers NGJ, Sarasin A, Stefanini M, Lehmann AR. 2008. Incidence of DNA repair deficiency disorders in western Europe: Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. DNA Repair 7: 744–750. PubMed ID: 18329345
  • Kraemer KH, DiGiovanna JJ. 2013. Xeroderma Pigmentosum. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301571
  • Lehmann AR, McGibbon D, Stefanini M. 2011. Xeroderma pigmentosum. Orphanet J Rare Dis 6: 5. PubMed ID: 22044607
  • Lehmann et al. (1975). "Xeroderma pigmentosum cells with normal levels of excision repair have a defect in DNA synthesis after UV-irradiation." Proceedings of the National Academy of Sciences of the United States of America 72:219-223. PubMed ID: 1054497
  • Naegeli H, Sugasawa K. 2011. The xeroderma pigmentosum pathway: Decision tree analysis of DNA quality. DNA Repair 10: 673–683. PubMed ID: 21684221
  • Webb S. 2008. Xeroderma pigmentosum. BMJ 336: 444–446. PubMed ID: 18292171

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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