Xeroderma Pigmentosum via the ERCC1 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
12011 ERCC1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
12011ERCC181479 81479 $890 Order Options and Pricing

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

For Reflex to PGxome pricing 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 (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).

Genetics

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). ERCC4 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 majority of XPF patients have relatively mild symptoms including sun sensitivity, skin freckling and adult-onset basal or squamous cell carcinoma (Gregg et al. 2011. PubMed ID: 21612988).

ERCC1 (complementation group XPF) encodes for a 110-kd protein of 323 amino acids. The ERCC1 protein product functions in nucleotide excision repair, and forms a heterodimer with the XPF endonuclease ERCC4. To date, only 5 variants (1 missense, 3 nonsense, 1 splicing) in ERCC1 have been reported to be causative for xeroderma pigmentosum. One individual affected with severe XP/Cockayne syndrome was reported to have a homozygous pathogenic variant in ERCC1, and other affected individuals had compound heterozygous pathogenic variants (Gregg et al. 2011. PubMed ID: 21612988; Kashiyama et al. 2013. PubMed ID: 23623389; Human Gene Mutation Database).

Clinical Sensitivity - Sequencing with CNV PGxome

Pathogenic variants in ERCC1 are rare and only a small fraction have been reported in individuals with xeroderma pigmentosum (Kraemer et al. 2016. PubMed ID: 20301571).

Testing Strategy

This test provides full coverage of all coding exons of the ERCC1 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. 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 ERCC1. This test is specifically designed for heritable germline variants and is not appropriate for the detection of somatic variants in tumor tissue.

Gene

Official Gene Symbol OMIM ID
ERCC1 126380
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Cerebrooculofacioskeletal Syndrome 4 AR 610758

Related Test

Name
Xeroderma Pigmentosum (XP) Panel

Citations

  • DiGiovanna et al. 2012. PubMed ID: 22217736
  • Gregg et al. 2011. PubMed ID: 21612988
  • Hirai et al. 2006. PubMed ID: 16905156
  • Human Gene Mutation Database (Biobase).
  • Kashiyama et al. 2013. PubMed ID: 23623389
  • Kleijer et al. 2008. PubMed ID: 18329345
  • Kraemer et al. 2016. PubMed ID: 20301571
  • Lehmann et al. 2011. PubMed ID: 22044607
  • Naegeli et al. 2011. PubMed ID: 21684221
  • Webb et al. 2008. PubMed ID: 18292171

Ordering/Specimens

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Requisition Form

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  • 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

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