Xeroderma Pigmentosum

Kenneth H Kraemer; John J DiGiovanna; Deborah Tamura

Xeroderma Pigmentosum

Kraemer KH, DiGiovanna JJ, Tamura D.

Publication Details

Estimated reading time: 38 minutes

Summary

Clinical characteristics.

Xeroderma pigmentosum (XP) is characterized by:

Acute sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure) with marked freckle-like pigmentation of the face before age two years;
Sunlight-induced ocular involvement (photophobia, severe keratitis, atrophy of the skin of the lids, ocular surface neoplasms);
Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma) within the first decade of life.

Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, progressive cognitive impairment, and ataxia). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).

Diagnosis/testing.

The diagnosis of XP is established in a proband on the basis of clinical findings and family history and/or by the identification of biallelic pathogenic variants in DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, POLH, XPA, or XPC.

Management.

Treatment of manifestations: Premalignant skin lesions such as actinic keratoses can be treated by freezing with liquid nitrogen; larger areas can be treated with field treatments such as topical 5-fluorouracil or imiquimod preparations. Rarely, therapeutic dermatome shaving or dermabrasion has been used; skin neoplasms can be treated (as in persons without XP) with electrodesiccation and curettage or surgical excision; skin cancers that are recurrent or in locations at high risk for recurrence are best treated with Mohs micrographic surgery. Oral isotretinoin or acitretin can prevent new skin neoplasms but have many side effects. Neoplasms of the eyelids, conjunctiva, and cornea can be treated surgically; corneal injury associated with eyelid abnormality can be decreased with eye drops or soft contact lenses; corneal transplantation may improve the visual impairment resulting from severe keratitis. Hearing loss may be treated with hearing aids.

Prevention of primary manifestations: Avoid sun and other UV exposure to the skin and eyes. Measure UV light with a light meter in an affected individual's home, school, and/or work environment so that high levels of environmental UV can be identified and eliminated.

Surveillance: Skin examinations by a physician every three to 12 months; eye exams for signs of UV exposure and damage every six months; routine eye and neurologic examinations for progressive neurologic abnormalities every 12 months; audiograms every six to12 months.

Agents/circumstances to avoid: UV exposure from sunlight and artificial sources of UV radiation; cigarette smoke.

Evaluation of relatives at risk: If family-specific pathogenic variants have been identified, molecular genetic testing of at-risk sibs can permit early diagnosis and rigorous sun protection from an early age.

Pregnancy management: Systemic retinoids (isotretinoin, acitretin) may be used as skin cancer chemopreventive agents. These drugs are known to be teratogenic to a developing fetus and pose a high risk for birth defects. Women of reproductive age who are taking a systemic retinoid must use effective contraception and be monitored with regular pregnancy tests.

Genetic counseling.

XP is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an XP-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the XP-related pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for XP are possible.

Diagnosis

Moriwaki et al [2017] (full text) published diagnostic criteria focused on Japanese individuals with xeroderma pigmentosum (XP).

Suggestive Findings

XP should be suspected in individuals with the following clinical findings and family history.

Clinical findings

Skin
- Acute sun sensitivity (severe sunburn with blistering or persistent erythema on minimal sun exposure)
- Marked freckle-like pigmentation (lentigos) on the face before age two years
- Skin cancer within the first decade of life
Eye
- Photophobia with prominent conjunctival injection
- Severe keratitis, sometimes resulting in corneal opacification and vascularization
- Increased pigmentation of the lids with loss of lashes
- Atrophy of the skin of the lids resulting in ectropion, entropion, or in severe cases complete loss of the lids
- Ocular surface neoplasms
Nervous system
- Diminished or absent deep tendon stretch reflexes. EMG and nerve conduction velocities may show an axonal (or mixed) neuropathy.
- Progressive sensorineural hearing loss. Audiometry may reveal early high-tone hearing loss.
- Acquired microcephaly. CT and MRI of the brain may show enlarged ventricles with thinning of the cortex and thickening of the bones of the skull.
- Progressive cognitive impairment
- Ataxia

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of XP is established in a proband on the basis of clinical findings and family history (see Suggestive Findings) and/or by the identification of biallelic pathogenic variants in one of the genes listed in Table 1.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of XP has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

A xeroderma pigmentosum multigene panel that includes all of the genes listed in Table 1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

NOTE: Some regions of the world have increased prevalence of XP and the proportion of XP attributed to pathogenic variants in a specific gene may vary by country of origin of the proband associated with particular founder variants in that region. See Prevalence.

Table 1.

Molecular Genetic Testing Used in Xeroderma Pigmentosum

Clinical Characteristics

Clinical Description

The findings from 106 individuals with XP examined at the National Institutes of Health (US) in a long-term study from 1971 to 2009 by Bradford et al [2011] and Fassihi et al [2016] are summarized in Table 2 and the text following.

Table 2.

Xeroderma Pigmentosum: Frequency of Select Features

Cutaneous findings. More than half of individuals with XP have a history of acute sunburn reaction on minimal UV exposure. The remainder of individuals with XP tan without excessive burning [Sethi et al 2013]. In all individuals, numerous freckle-like hyperpigmented macules appear on sun-exposed skin.

The median onset of the cutaneous symptoms is between ages one and two years.
These abnormalities are limited to sun-exposed areas.
Continued sun exposure causes the skin to become dry and parchment-like with increased pigmentation; hence the name xeroderma pigmentosum ("dry pigmented skin").
Most individuals with XP develop xerosis (dry skin) and poikiloderma (the constellation of hyper- and hypopigmentation, atrophy, and telangiectasia).
Premalignant actinic keratoses develop at an early age.
XP is an example of accelerated photoaging. The appearance of sun-exposed skin in children with XP is similar to that occurring in farmers and sailors after many years of extreme sun exposure [Rizza et al 2021].

Ocular abnormalities are almost as common as the cutaneous abnormalities [Brooks et al 2013]. Beginning in the first decade of life, findings are usually limited to the anterior, UV-exposed portions of the eyes including the conjunctiva, cornea, and lids.

Dry eyes are a common finding in XP and may be seen in patients in the first decade of life.
Epithelioma, squamous cell carcinoma, and melanoma of UV-exposed portions of the eye are common.
The ocular manifestations may be more severe in heavily pigmented individuals.
Benign conjunctival inflammatory masses that develop can spread to obscure the cornea [Mahindra et al 2008].
Corneal findings include photophobia, severe keratitis, corneal opacification, and neovascularization.
Lid findings include atrophy of the skin of the lids resulting in ectropion, entropion, or (in severe cases) complete loss of the lids. Lentigines, freckling on the lids, and lash loss are also common findings.

Neurologic findings. Progressive neurologic abnormalities that worsen slowly were reported in approximately 25% of 106 affected individuals.

The onset may be early in infancy or, in some individuals, delayed until the second decade or later [Rapin et al 2000, Shanbhag et al 2018].
The neurologic abnormalities may be mild (e.g., isolated hyporeflexia) or severe, including acquired microcephaly, progressive intellectual impairment, sensorineural hearing loss beginning with high frequencies, spasticity, ataxia, and/or seizures.
During an upper respiratory infection some individuals may develop difficulty swallowing or, rarely, vocal cord paralysis [Ohto et al 2004].
Reduced nerve conduction velocity may also be present on nerve conduction studies [Lehky et al 2021].

Cutaneous neoplasia. If aggressive UV avoidance is not begun early, accumulated sunlight-induced DNA damage is likely to result in skin cancer within the first decade of life. Bradford et al [2011] found that individuals with XP younger than age 20 years were at increased risk for the following cancers:

Non-melanoma (basal cell and squamous cell) skin cancer at UV-exposed sites. The >10,000-fold increased risk was associated with a median age of onset of nine years, nearly 60 years earlier than in the US general population.
Cutaneous melanoma. The >2,000-fold increased risk was associated with a median age of onset of 22 years, more than 30 years earlier than in the US general population.
Surprisingly, those with XP who had the most severe sun sensitivity had a later onset of skin cancer – perhaps because they used greater sun protection.

Other neoplasias

A substantial number of people with XP have oral cavity neoplasms, particularly squamous cell carcinoma of the tip of the tongue, a presumed sun-exposed location [Kraemer et al 1994, Butt et al 2010].
Gliomas of the brain and spinal cord, tumors of the lung, uterus, breast, pancreas, stomach, kidney, and testicles, and leukemia have been reported in a few individuals with XP [DiGiovanna et al 1998, Bradford et al 2011, Lai et al 2013, Fassihi et al 2016, Sarasin et al 2019b, Oetjen et al 2020].
Because some of the carcinogens in cigarette smoke bind to DNA, resulting in damage that is repaired by the nucleotide excision repair system, this unrepaired DNA damage may contribute to the development of lung cancer in individuals with XP who smoke. The risk for lung cancer due to exposure from secondhand smoke has not been determined.

Overall, there is an estimated 34-fold increase in internal neoplasms in XP, and tumors arise 50 years earlier compared to the US general population [Nikolaev et al 2022].

Other medical concerns

Women with XP are at increased risk for premature menopause (menopause before age 40 years) and may require assisted reproductive technology to experience pregnancy [Authors, personal communication]. A study of reproductive health in women with XP identified premature menopause in 31% of the participants, the majority of whom had pathogenic variants in XPC [Merideth et al 2019].
Individuals with XP are at risk for thyroid nodules and carcinoma. Kouatcheu et al [2021] reported on 29 individuals seen prospectively as part of a natural history study and found that 18 had thyroid nodules and two were diagnosed with papillary thyroid cancer. In addition, researchers studying XP in northern Africa have noted thyroid nodules and thyroid cancer in multiple individuals with XP [Ben Rekaya et al 2013, Hadj-Rabia et al 2013, Jerbi et al 2016]. A 74-fold increased frequency of thyroid cancers was estimated by Nikolaev et al [2022].

Life span. The median age at death (29 years) in persons with XP with neurodegeneration was younger than that in persons with XP without neurodegeneration (37 years) (p=0.02). The three most common causes of death were skin cancer, neurologic degeneration, and internal cancer [Bradford et al 2011]. Early diagnosis and use of sun protection have been shown to extend the life span in Japanese patients [Nakano et al 2016].

Phenotype Correlations by Gene

Table 3.

Xeroderma Pigmentosum: Phenotype Correlations by Gene

Genotype-Phenotype Correlations

No genotype-phenotype correlations, besides those shown in Table 3, have been identified.

Nomenclature

Xeroderma pigmentosum was first described in Vienna by Moriz Kaposi in the textbook of dermatology he published in 1870 with his father-in-law, Ferdinand Hebra. The disorder was first called xeroderma or parchment skin. See discussion in Kraemer et al [1987] and in DiGiovanna & Kraemer [2012].

Previously, an individual with XP with any neurologic abnormality was said to have DeSanctis-Cacchione syndrome. With clarification of the spectrum of XP disease, this term is now reserved for XP with severe neurologic disease, dwarfism, and immature sexual development. The complete DeSanctis-Cacchione syndrome has been recognized in very few individuals; however, many individuals with XP have one or more of its neurologic features.

"Pigmented xerodermoid" is now known to be identical to the XP variant.

Before the genes responsible for XP were identified, complementation groups were used to categorize functional defects in affected individuals. In an XP complementation analysis, cells from affected individuals were fused in the laboratory to determine whether their defects were different, in which case they would be able to supply all functions necessary to restore a normal cellular phenotype. Complementation is therefore a test of function and enabled the categorization of affected individuals as having the same or different defects. Subsequently, each complementation group was found to result from a defect in a distinct gene [DiGiovanna & Kraemer 2012]. Testing to assign complementation group is not available on a clinical basis, but the complementation group names are used clinically to describe the different phenotypes associated with underlying genes (see Table 1).

Prevalence

Prevalence is estimated at 1:1,000,000 in the United States and Europe [Kleijer et al 2008].

Certain populations have a higher prevalence. This is usually related to the presence of founder variants (see Table 9):

In Japan prevalence is estimated at 1:22,000 [Hirai et al 2006].
In North Africa (Tunisia, Algeria, Morocco, Libya, and Egypt) [Ben Rekaya et al 2009, Messaoud et al 2010, Soufir et al 2010] and the Middle East (Turkey, Israel, and Syria) [Kraemer & Slor 1985, Jerbi et al 2016] prevalence is increased, as high as 1:10,000, especially in communities in which consanguinity and endogamy are common [Sarasin et al 2019a].

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with germline pathogenic variants in DDB2, POLH, XPA, or XPC.

In addition to the xeroderma pigmentosum (XP) phenotypes discussed in this GeneReview, pathogenic variants in ERCC1, ERCC2, ERCC3, ERCC4, and ERCC5 are known to be associated with cerebrooculofacioskeletal (COFS) syndrome, Fanconi anemia, and trichothiodystrophy (TTD) (Figure 1, Table 4). (Note: COFS syndrome and TTD should be considered in the differential diagnosis of XP; see Table 5.)

Figure 1.

Relationship between genotype and phenotype in the xeroderma pigmentosum-Cockayne syndrome-trichothiodystrophy spectrum Modified from DiGiovanna & Kraemer [2012]

Table 4.

Allelic Disorders

Complex phenotypes

Allelic complex phenotypes in the differential diagnosis of XP are summarized in Table 5.
One individual with phenotypic features of Cockayne syndrome, XP, and Fanconi anemia had biallelic pathogenic variants in ERCC4 [Kashiyama et al 2013].
Niedernhofer et al [2006] described a male age 15 years with biallelic ERCC4 pathogenic variants and cachexia, dwarfism, microcephaly, marked sun sensitivity from birth, visual impairment (due to optic atrophy), hearing loss, mild learning disabilities, progressive growth failure, facial features characteristic of premature aging, mild ataxia, and poor coordination. Niedernhofer et al [2006] proposed that this represented a new progeroid syndrome (see OMIM 610965). Whether XFE progeroid syndrome represents a distinct condition or is part of the spectrum of XP, Fanconi anemia, or XP / Cockayne syndrome has not been determined.

Sporadic tumors. Investigation of the association between an increased cancer risk and heterozygosity for an allelic variant causing XP is an active area of research. In addition, sporadic tumors occurring as single tumors in the absence of any other findings of XP may harbor somatic variants in XP-related genes.

Differential Diagnosis

Other nucleotide excision repair disorders associated with cutaneous photosensitivity to consider in the differential diagnosis of xeroderma pigmentosum (XP) are summarized in Table 5 (see also Figure 1) [Horibata et al 2004, Berneburg & Kraemer 2007, Kraemer et al 2007, Stefanini & Kraemer 2008, Kraemer & Ruenger 2012, Ruenger et al 2012].

Table 5.

Autosomal Recessive Nucleotide Excision Repair Disorders Exhibiting Cutaneous Photosensitivity

Other. In addition to disorders sharing deficient nucleotide excision repair, other conditions exhibiting cutaneous photosensitivity may be considered in the differential diagnosis of XP, especially in individuals with a paucity of other clinical findings. These include the following:

Rothmund-Thomson syndrome (RTS). RTS is characterized by a rash that progresses to poikiloderma; sparse hair, eyelashes, and/or eyebrows; small size; skeletal and dental abnormalities; juvenile cataracts; and an increased risk for cancer, especially osteosarcoma. A variety of benign and malignant hematologic abnormalities have been reported in affected individuals. The rash of RTS typically develops between ages three and six months (occasionally as late as age 2 years) as erythema, swelling, and blistering on the face, subsequently spreading to the buttocks and extremities. RTS is caused by pathogenic variants in ANAPC1 or RECQL4 and is inherited in an autosomal recessive manner.
Hartnup disorder (OMIM 234500). Affected individuals may have reduced levels of niacin with resulting pellagra-like symptoms of photosensitivity with dermatitis, diarrhea, and dementia. However, individuals with Hartnup disorder are not reported to have increased frequency of skin cancer, as is seen in those with XP. Hartnup disorder is caused by pathogenic variants in SLC6A19 and is inherited in an autosomal recessive manner.
The cutaneous findings of Carney complex may be confused with those of XP; however, Carney complex is characterized by lentigines without evidence of the usually associated signs of sunlight-induced skin damage such as atrophy and telangiectasia (i.e., poikiloderma), and cutaneous findings are not limited to sun-exposed sites [Correa et al 2015].

Management

Evaluations Following Initial Diagnosis

General clinical care guidelines for individuals with xeroderma pigmentosum (XP) have been proposed by the Japanese Dermatological Association [Moriwaki et al 2017] (full text).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with XP, the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 6.

Recommended Evaluations Following Initial Diagnosis in Individuals with Xeroderma Pigmentosum

Treatment of Manifestations

Table 7.

Treatment of Manifestations in Individuals with Xeroderma Pigmentosum

Prevention of Primary Manifestations

Treatment of XP depends on early diagnosis and immediate, aggressive avoidance of sun and other UV exposure. This involves avoiding or minimizing outdoor exposure at times when UV radiation is present (when the sun is out or during daytime through clouds).

Clinical suspicion of XP should prompt immediate sun-protective measures until the diagnosis is confirmed or an alternative explanation is determined.
Individuals should be educated to protect all body surfaces from UV radiation by wearing protective clothing including hats, long sleeves, long pants and gloves, broad-spectrum, high-SPF sunscreens, UV-absorbing glasses, and long hair styles. Multiple layers of clothing are preferred. The eyes should be protected by wearing UV-absorbing glasses with side shields. Some individuals have custom-made hats with UV-absorbing face shields to permit visibility outdoors while protecting the face from UV.

Because the cells of individuals with XP are hypersensitive to UVA and UVB (found in sunlight) and UVC (found in some artificial light sources), it is useful to measure UV light in an individual's home, school, or work environment with a light meter so that high levels of environmental UV (e.g., halogen lamps) can be identified and eliminated if possible. While no standards exist for perfectly safe UV exposure in individuals with XP, the use of UV meters can alert individuals to unexpected sources of high levels of environmental UV. Unlike UVB, UVA is not blocked by window glass. Windows in areas where individuals with XP will be spending large amounts of time should have UV blocking film applied.

Low vitamin D levels can result from aggressive avoidance of sun exposure. Vitamin D is produced in the skin by a reaction involving exposure to UV radiation. Active adults with XP and skin cancers received sufficient vitamin D in their diet in the past to result in normal serum concentrations of the active form (1,25 dihydroxy vitamin D) [Sollitto et al 1997]. However, children protected from sunlight very early in life have had low serum concentration of 25 hydroxy vitamin D; one child became susceptible to bone fractures [Ali et al 2009; Author, personal observation]. Serum vitamin D levels should be monitored and dietary supplementation with oral vitamin D is recommended for persons with low serum concentration of serum vitamin D [Reichrath 2007; Author, personal communication].

Surveillance

Table 8.

Recommended Surveillance for Individuals with Xeroderma Pigmentosum

Agents/Circumstances to Avoid

UV exposure from sunlight and artificial sources of UV radiation should be avoided (see Prevention of Primary Manifestations).

Artificial sources of UV. Certain light sources (e.g., mercury arc, halogen, and other lamps) can be unrecognized sources of UV. Although such light sources are often shielded, in open areas such as gymnasiums they can be a source of UV if the shield has been breached. UV meters are readily available to enable monitoring of areas to identify unexpected UV sources.

Cigarette smoke. Because cells from individuals with XP are also hypersensitive to environmental mutagens, such as benzo[a]pyrene found in cigarette smoke, prudence dictates that individuals with XP should be protected against these agents. One individual with XP who smoked cigarettes for more than ten years died of bronchogenic carcinoma of the lungs at age 35 years [Kraemer et al 1994]. The authors have cared for another individual with XP who smoked and developed lung cancer in the fifth decade of life.

Evaluation of Relatives at Risk

It is appropriate to evaluate the apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Treatment of XP depends on early diagnosis and immediate, aggressive avoidance of sun and other UV exposure (see Prevention of Primary Manifestations).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The systemic retinoids isotretinoin and acitretin are used as skin cancer chemopreventive agents in individuals who are actively developing large numbers of skin cancers, and thus may be used by some women with XP [Kraemer et al 1988]. Systemic retinoids are known to be teratogenic to a developing fetus and pose a high risk for birth defects. Therefore, women who are using systemic retinoids should be appropriately counseled about pregnancy risks and the need for effective contraception; regular monitoring with pregnancy tests is indicated. Systemic retinoids should be administered only by physicians who are knowledgeable regarding their risks and benefits.

To access isotretinoin in the US, women and their prescribing providers must be enrolled in the iPLEDGE program to minimize the potential for fetal exposure. Pregnancy avoidance is initiated before therapy, continues during therapy, and extends post-treatment until the drug is cleared from the body. While both isotretinoin and acitretin may be effective in preventing skin cancers, acitretin may take longer to be eliminated from the body, requiring an extended period (3 years) of post-therapy pregnancy avoidance to minimize teratogenic risk.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Xeroderma pigmentosum (XP) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

The parents of an individual with XP are presumed to be heterozygous for an XP-related pathogenic variant.
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an XP-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
- One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
- Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

If both parents are known to be heterozygous for an XP-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

Unless an individual with XP has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for an XP-related pathogenic variant.
The offspring of an individual with XP and an individual who is heterozygous for an XP-related pathogenic variant in the same gene as the proband have a 50% chance of having XP. This is a consideration in populations with a founder variant or with a high rate of consanguinity (see Prevalence and Table 9).

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an XP-related pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the XP-related pathogenic variants in the family (see Christen-Zaech et al [2009] for discussion).

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the XP-related pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for XP are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Action for XP
Westfield, Cushnie, Nr Alford, Aberdeenshire, AB33 8LP
United Kingdom
Email: support@actionforxp.org
www.actionforxp.org
Enfants de la Lune
Siège de l’association
3 Rue Corneille 01200 Bellegarde sur Valserine
France
Phone: 04 57 05 13 61
Email: contact@enfantsdelalune.org
www.enfantsdelalune.org
Xeroderma Pigmentosum Society, Inc (XP Society)
437 Syndertown Road
Craryville NY 12521
Phone: 877-XPS-CURE (877-977-2873); 518-851-2612
Email: xps@xps.org
www.xps.org
XP Family Support Group
10259 Atlantis Drive
Elk Grove CA 95624
Phone: 916-628-3814
Email: contact@xpfamilysupport.org
www.xpfamilysupport.org
XP Freunde die Mondscheinkinder
Postfach 2124
48550 Steinfurt
Germany
Phone: 49 176 200 109 30
Email: info@xerodermapigmentosum.de
www.xerodermapigmentosum.de

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Xeroderma Pigmentosum: Genes and Databases

Table B.

OMIM Entries for Xeroderma Pigmentosum (View All in OMIM)

Molecular Pathogenesis

An intact DNA repair system that senses, excises, and repairs UV-induced dipyrimidine photoproducts and other forms of DNA damage is necessary to prevent replication errors and subsequent tumorigenesis (Figure 2) [DiGiovanna & Kraemer 2012].

Figure 2.

Nucleotide excision repair (NER) pathway Modified from DiGiovanna & Kraemer [2012]

Exposure to UV radiation from sunlight forms cyclobutane dimers or other photoproducts at adjacent pyrimidines, thereby distorting the DNA. Initial lesion recognition in non-transcribed DNA (global genome repair-GGR) is performed by DDB2-encoded protein [Clement et al 2010, Sugasawa 2010]. The XPC-encoded protein binding to the photoproducts is facilitated by the binding of the DDB2-encoded protein. The XPC-encoded protein is complexed with hHR23B and centrin [Sugasawa 2010].

DNA damage in transcribed genes (transcription coupled repair) is marked by stalled RNA polymerase. The CS (Cockayne syndrome)-encoded proteins (along with others) bind to the damage in the transcribed DNA strand.

ERCC2 is part of basal transcription factor TFIIH that is involved in regulation of the basal rate of transcription (RNA synthesis) of active genes, as well as in nucleotide excision repair (NER).

In both global genome repair and transcription-coupled repair, the XPA protein probably functions in conjunction with replication protein A and TFIIH – the basal transcription factor that is involved in regulation of the basal rate of transcription (RNA synthesis) of active genes, as well as in NER. The XPB/ERCC3 and XPD/ERCC2 proteins (helicases that are part of the TFIIH complex) partially unwind the DNA in the region of the damage, thereby exposing the lesion for further processing. The XPF/ERCC4 product, in a complex with ERCC1, makes a single-strand nick at the 5' side of the lesion, while the XPG/ERCC5 product makes a similar nick on the 3' side, resulting in the release of a region of approximately 30 nucleotides containing the damage. The resulting gap is filled by DNA polymerase using the other (undamaged) strand as a template in a process involving proliferating cell nuclear antigen. DNA ligase I seals the region, restoring the original undamaged sequence [van Steeg & Kraemer 1999, Bootsma et al 2002].

Individuals with the XP variant have a normal nucleotide excision pathway and a defect in POLH, encoding the DNA polymerase eta protein, which can replicate through UV-damaged DNA. Loss of polymerase eta function leads to replication by alternative error-prone polymerases.

Mechanism of disease causation. XP occurs via a loss-of-function mechanism of any of the NER or polymerase eta proteins.

Table 9.

Xeroderma Pigmentosum: Notable Pathogenic Variants by Gene

Chapter Notes

Author Notes

NIH Study 99-C-0099. Examination of Clinical and Laboratory Abnormalities in Patients with Defective DNA Repair: Xeroderma Pigmentosum, Cockayne Syndrome, or Trichothiodystrophy is actively recruiting new patients for a study in Bethesda, MD. Click here for more information.

Acknowledgements

This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and National Human Genome Research Institute.

We wish to thank the many patients and families throughout the world who have participated in the XP protocols at the National Institutes of Health, National Cancer Institute.

Author History

John J DiGiovanna, MD (2011-present)
Kenneth H Kraemer, MD (2003-present)
Deborah Tamura, RN (2022-present)
Daniel J Wattendorf, MD; National Institutes of Health (2003-2008)

Revision History

24 March 2022 (ha) Comprehensive update posted live
29 September 2016 (ma) Comprehensive update posted live
13 February 2014 (me) Comprehensive update posted live
14 February 2013 (cd) Revision: changes in testing available for POLH, ERCC3, XPA, XPC, and DDB2
1 November 2012 (cd) Revision: testing for ERCC4 mutations available clinically; Figure 2 added
15 March 2012 (cd) Revision: sequence analysis available clinically for ERCC1 and ERCC3 and no longer available for DDB2
4 August 2011 (me) Comprehensive update posted live
22 April 2008 (me) Comprehensive update posted live
14 May 2007 (cd) Revision: sequence analysis clinically available for XPA and XPC
1 June 2006 (cd) Revision: confirmation of XPA and XPC mutations identified in a research lab clinically available
15 September 2005 (me) Comprehensive update posted live
24 February 2004 (kk) Revision: Molecular Genetics
1 October 2003 (kk) Revision: clinical testing no longer available
20 June 2003 (me) Review posted live
28 April 2003 (kk) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview "Xeroderma Pigmentosum" is in the public domain in the United States of America.

References

Published Guidelines / Consensus Statements

Moriwaki S, Kanda F, Hayashi M, Yamashita D, Sakai Y, Nishigori C, et al. Xeroderma pigmentosum clinical practice guidelines. J Dermatol. 2017;44:1087–96. [PubMed: 28771907]
Tamura D, Kraemer KH, DiGiovanna JJ. Xeroderma pigmentosum. In: Lebwohl MG, Heymann WR, Berth-Jones J, Coulson I, eds. Treatment of Skin Disease: Comprehensive Therapeutic Strategies. 4 ed. London, UK: Elsevier; 2014.

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Sethi M, Lehmann AR, Fawcett H, Stefanini M, Jaspers N, Mullard K, Turner S, Robson A, McGibbon D, Sarkany R, Fassihi H. Patients with xeroderma pigmentosum complementation groups C, E and V do not have abnormal sunburn reactions. Br J Dermatol. 2013;169:1279–87. [PubMed: 23889214]
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Publication Details

Author Information and Affiliations

Kenneth H Kraemer, MD

Laboratory of Cancer Biology and Genetics Center for Cancer Research National Cancer Institute Bethesda, Maryland

Email: vog.hin@kremeark

John J DiGiovanna, MD

Laboratory of Cancer Biology and Genetics Center for Cancer Research National Cancer Institute Bethesda, Maryland

Email: vog.hin.liam@avoigidj

Deborah Tamura, RN

Laboratory of Cancer Biology and Genetics Center for Cancer Research National Cancer Institute Bethesda, Maryland

Email: vog.hin.liam@darumat

Publication History

Initial Posting: June 20, 2003; Last Update: March 24, 2022.

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NLM Citation

Kraemer KH, DiGiovanna JJ, Tamura D. Xeroderma Pigmentosum. 2003 Jun 20 [Updated 2022 Mar 24]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

Gene ^1, 2	Familiar Clinical Disease (Complementation Group) Name	Proportion of XP Attributed to Pathogenic Variants in Gene ³	Proportion of Pathogenic Variants ⁴ Detectable by Method
Gene ^1, 2	Familiar Clinical Disease (Complementation Group) Name		Sequence analysis ⁵	Gene-targeted deletion/duplication analysis ⁶
DDB2	XP-E	1%	19/19 ⁷	Unknown ⁸
ERCC1	ERCC1	<0.5%	2/2 ^7, 9
ERCC2	XP-D	15%	>99% ⁷
ERCC3	XP-B	0.5%	8/8 ^7, 10
ERCC4	XP-F	2%	>99% ⁷	Rare
ERCC5	XP-G	1%	>99% ⁷	Unknown ⁸
POLH	XP VARIANT (XP-V)	23.5%	85% ^7, 11	15% ^7, 11
XPA	XP-A	30%	100% ⁷	Unknown ⁸
XPC	XP-C	27%	100% ⁷	Unknown ⁸

Feature	% of Persons w/Feature	Comment
Acute sunburn reaction w/minimal UV exposure	60%
Freckle-like lesions on sun-exposed skin	100%
Xerosis & poikiloderma on sun-exposed skin	100%	Extent of xerosis & poikiloderma is dependent on amount of sun/UV exposure.
Ocular abnormalities	90%	Limited to anterior, UV-exposed portion of eyes & lids
Progressive neurologic abnormalities	25%	Primarily in those w/pathogenic variants in ERCC2, ERCC3, ERCC4, ERCC5, or XPA
Cutaneous neoplasia	65%	Frequency & extent of neoplastic lesions is dependent on amount of sun/UV exposure.
Other neoplasias	10- to 20-fold increase	Internal neoplasms incl brain & CNS tumors, hematologic malignancies, breast cancer, tumors of female reproductive tract, papillary thyroid cancer, kidney cancer, & cancer in smokers have been reported.

Gene	XP w/o Neurologic Abnormalities	XP w/Mild Neurologic Abnormalities	XP w/Severe Neurologic Abnormalities
DDB2	●
ERCC1			●
ERCC2	●	●	●
ERCC3		●
ERCC4	●		● ¹
ERCC5	●		●
POLH	●
XPA		●	●
XPC	●

Gene(s)	Allelic Disorder	Clinical Characteristics
ERCC1 ERCC2 ERCC5	Cerebrooculofacioskeletal syndrome ¹ (OMIM PS214150)	See Differential Diagnosis.
ERCC2 ERCC3	Trichothiodystrophy ¹ (OMIM PS601675)	See Differential Diagnosis.
ERCC4	Fanconi anemia	Heterogeneous condition characterized by physical abnormalities, bone marrow failure, & ↑ risk for malignancy

Gene(s)	Disorder ¹	Clinical Features / Comment
ERCC1 ¹ ERCC2 ¹ ERCC5 ¹ ERCC6 ²	Cerebrooculofacioskeletal syndrome (COFS; OMIM PS214150)	Progressive neurologic disorder marked by microcephaly w/intracranial calcifications, growth failure, ocular findings (microcornea, cataracts, optic atrophy) & congenital joint contractures. Photosensitivity may occur w/concurrent cellular phenotype of UV sensitivity.
ERCC2 ¹ ERCC3 ¹ GTF2H5 GTF2E2 ³ MPLKIP ⁴	Trichothiodystrophy (TTD; OMIM PS601675)	Variable phenotype incl photosensitivity, ichthyosis, brittle hair w/"tiger tail" appearance under polarizing microscopy, intellectual impairment, short stature, microcephaly, dysmyelination of brain, & characteristic facial features of protruding ears & micrognathia. 20-fold ↑ risk of death before age 10 yrs, primarily from infections. Frequency of pregnancy complications & neonatal abnormalities is ↑ in ERCC2-related TTD but not in mothers w/XP w/different pathogenic variants in ERCC2. ⁵
ERCC2 ¹ ERCC3 ¹ ERCC4 ¹ ERCC5 ^1, 6, 7	XP / Cockayne syndrome (CS) complex	Assoc w/facial freckling & early skin cancers typical of XP & some features of CS (e.g., ID, spasticity, short stature, hypogonadism) but not skeletal dysplasia. Unlike XP, in which neuronal degeneration predominates, retinal pigmentary changes, calcification of basal ganglia, & dysmyelination typical of CS are observed in XP/CS.
ERCC2 ¹	COFS/TTD ⁸	Combined features of COFS & TTD. Hair may be short, brittle, & will demonstrate "tiger tail" banding under polarizing microscopy.
	CS/TTD complex ⁸	Combined features of CS & TTD. Hair may be short, brittle, & will demonstrate "tiger tail" banding under polarizing microscopy.
	XP/TTD complex ⁹	Phenotypic features of TTD w/clinical & cellular phenotype of XP. Unlike most people w/TTD, those w/XP/TTD may experience ↑ frequency of skin cancers.
ERCC6 ERCC8	Cockayne syndrome	CS type I (classic form): normal prenatal growth w/onset of growth & developmental abnormalities in 1st 2 yrs. When disease fully manifests, height, weight, & head circumference are far below 5th %ile. Progressive impairment of vision, hearing & CNS/PNS function → severe disability. Death typically in 1^st-2nd decade. As in XP, cells from those w/CS are hypersensitive to killing by UV, but CS cells have normal post-UV UDS. CS cells also have delayed recovery of RNA synthesis after UV exposure, reflecting their deficiency in transcription-coupled NER.
ERCC6 ¹⁰ ERCC8 ¹⁰ UVSSA ¹⁰	UV-sensitive syndrome	Mild photosensitivity w/o pigmentary abnormalities or apparent defects in CNS. Cells from affected persons have same transcription defects as those in persons w/CS.

System/Concern	Evaluation	Comment
Photosensitivity & accelerated photoaging	Baseline exam of skin (incl all sun-exposed as well as sun-shielded areas)	Look for evidence of sunlight-induced damage incl pigmentary changes, precancerous lesions, & skin cancers.
	Examine scalp using hair dryer (on a cool setting) to blow hair aside.
	Exam of lip & adjacent tip of tongue	Check for signs of sun damage, incl actinic cheilitis (type of actinic keratosis or leukoplakia occurring on lips) & prominent telangiectasia, which may precede development of cancer in these areas.
	Baseline clinical color photographs of entire skin surface w/close-ups (incl ruler) of individual lesions	To facilitate follow up & detection of early skin cancers
Sun-induced damage to eyes & degenerative changes to lens (cataract) & retina	Examine lids & anterior UV-exposed portions of globe as well as retina.	Look for evidence of sun-induced damage incl ectropion, entropion, inflammatory masses (pterygia, pinguecula), clouding of cornea, cataracts, & cancer of lids, conjunctiva, or cornea. Eversion of lids may be necessary to detect cancers of mucosal surface. Dilated eye exam looking for retinal changes
	Schirmer test to detect dry eyes	This test involves measurement of extent of absorption of tears into filter paper placed under eyelids for a few minutes.
Progressive neurologic abnormalities	Baseline developmental assessment in children & assess for need for educational support. Neurologic eval w/baseline neurocognitive testing if neurologic problems are detected Measurement of head circumference to determine if microcephaly is present. Deep tendon reflex testing MRI of brain & NCVs, if other neurologic problems are detected Baseline audiometry eval to screen for sensorineural hearing loss
Thyroid abnormalities	Palpation of thyroid &/or thyroid ultrasound assessing for presence of thyroid nodules	Thyroid ultrasound is more sensitive in identifying presence of thyroid nodules. TI-RADS score provides descriptors for suspicion levels of nodules.
Genetic counseling	By genetics professionals ¹	To inform affected persons & families re nature, MOI, & implications of XP to facilitate medical & personal decision making
Family support & resources	Assess need for: Community or online resources incl XP support groups; Social work involvement for parental support; Home nursing referral.

Manifestation/Concern	Treatment	Considerations/Other
Premalignant lesions (e.g., actinic keratoses)	Freezing w/liquid nitrogen
Larger areas of sun- damaged skin	Field treatments such as topical 5-fluorouracil or imiquimod preparations ¹
Larger areas of sun- damaged skin	Rarely, therapeutic dermatome shaving or dermabrasion is used to remove more damaged superficial epidermal layers.	This procedure permits repopulation by relatively UV-shielded cells from follicles & glands.
Cutaneous neoplasms	Treatment as in persons w/o XP	Involves electrodesiccation/curettage, surgical excision, or Mohs micrographic surgery
Recurrent skin cancers (or skin cancers in locations at high risk for recurrence)	Best treated w/Mohs micrographic surgery	Because multiple surgical procedures are often needed, removal of non-cancerous skin should be minimized. Severe cases have been treated by excision of large portions of facial surface & grafting w/sun-protected skin.
Active development of large numbers of new tumors	Oral isotretinoin or acitretin can be effective in preventing new neoplasms in persons w/multiple skin cancers after removal of existing cancers. ²	Some persons may respond to lower doses of isotretinoin or acitretin w/less toxicity. Toxicity incl hepatic, hyperlipidemic, & teratogenic effects; calcification of ligaments & tendons; premature closure of epiphyses.
Metastatic melanoma & invasive squamous cell carcinoma	Systemic chemotherapy w/anti-PD1, anti-PDL-1, & BRAF inhibitors ³	Monitor for systemic autoimmune adverse events.
Hematologic malignancies	Standard chemotherapy	Bone marrow transplant has not been successful in XP.
Internal malignancies (e.g., brain, lung)	Standard therapy When x-radiation therapy is indicated, an initial small dose is advisable to test for clinical hypersensitivity.	Most persons w/XP are not abnormally sensitive to therapeutic x-rays & have responded normally to full-dose therapeutic x-radiation for treatment of inoperable neoplasms. ⁴ However, cultured cells from a few persons w/XP were found to be hypersensitive to x-radiation. ⁵
Thyroid nodules	Biopsy of suspicious nodules	Thyroidectomy if cancer is identified
Neoplasms of eyelids, conjunctiva, & cornea	Surgical treatment Topical 5-fluorouracil 1% Topical interferon beta 1b
Corneal injury assoc w/eyelid abnormality	Methylcellulose eye drops or soft contact lenses to keep cornea moist & protect against mechanical trauma
Severe keratitis w/corneal opacity	Corneal transplantation	Immunosuppression necessary to prevent transplant rejection may ↑ risk for skin cancer.
Hearing loss	Use of hearing aids Cochlear implants	See also Deafness and Hereditary Hearing Loss Overview.
Premature menopause	Hormone replacement therapy	Persons w/XP may be at ↑ risk for osteoporosis & cardiovascular disease due to premature menopause.

System/Concern	Evaluation	Frequency
Skin	Exam by physician	Every 3-12 mos depending on severity of skin disease
Skin	Exam by affected person or caregivers to look for abnormal pigmented lesions or appearance of basal cell or squamous cell carcinoma (requires instruction in recognition of cutaneous neoplasms)	Whenever caregivers have opportunity to view affected child’s skin; at least 1x/wk
Eyes	Exam for signs of UV exposure & damage	At least every 6 mos depending on severity of ocular UV exposure & damage
Neurologic	Routine neurologic exam for progressive neurologic abnormalities that are present in minority of persons w/XP & may not be detected in young children	Every 12 mos for symptomatic patients unless there is new onset of neurologic abnormalities
Hearing	Audiograms	Every 6-12 mos
Female reproductive system	Laboratory assessment for premature ovarian insufficiency ¹	Every 12 mos beginning at age 18 yrs

Gene	Chromosome Locus	Protein	Locus-Specific Databases	HGMD	ClinVar
DDB2	11p11.2	DNA damage-binding protein 2	DDB2 database	DDB2	DDB2
ERCC1	19q13.32	DNA excision repair protein ERCC-1	ERCC1 database	ERCC1	ERCC1
ERCC2	19q13.32	General transcription and DNA repair factor IIH helicase subunit XPD	ERCC2 @ LOVD	ERCC2	ERCC2
ERCC3	2q14.3	General transcription and DNA repair factor IIH helicase subunit XPB	ERCC3 database	ERCC3	ERCC3
ERCC4	16p13.12	DNA repair endonuclease XPF	ERCC4 database	ERCC4	ERCC4
ERCC5	13q33.1	DNA excision repair protein ERCC-5	ERCC5 database	ERCC5	ERCC5
POLH	6p21.1	DNA polymerase eta	POLH database	POLH	POLH
XPA	9q22.33	DNA repair protein complementing XP-A cells	XPA database	XPA	XPA
XPC	3p25.1	DNA repair protein complementing XP-C cells	XPC database	XPC	XPC

126340	ERCC EXCISION REPAIR 2, TFIIH CORE COMPLEX HELICASE SUBUNIT; ERCC2
126380	ERCC EXCISION REPAIR 1, ENDONUCLEASE NONCATALYTIC SUBUNIT; ERCC1
133510	ERCC EXCISION REPAIR 3, TFIIH CORE COMPLEX HELICASE SUBUNIT; ERCC3
133520	ERCC EXCISION REPAIR 4, ENDONUCLEASE CATALYTIC SUBUNIT; ERCC4
133530	ERCC EXCISION REPAIR 5, ENDONUCLEASE; ERCC5
278700	XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A; XPA
278720	XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP C; XPC
278730	XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D; XPD
278740	XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP E
278750	XERODERMA PIGMENTOSUM, VARIANT TYPE; XPV
278760	XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP F; XPF
278780	XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP G; XPG
600811	DNA DAMAGE-BINDING PROTEIN 2; DDB2
603968	POLYMERASE, DNA, ETA; POLH
610651	XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP B; XPB
611153	XPA, DNA DAMAGE RECOGNITION AND REPAIR FACTOR; XPA
613208	XPC COMPLEX SUBUNIT, DNA DAMAGE RECOGNITION AND REPAIR FACTOR; XPC

Gene ¹	Reference Sequences	DNA Nucleotide Change	Predicted Protein Change	Comment [Reference]
ERCC2	NM_000400.4 NP_000391.1	c.2047C>T	p.Arg683Trp	Suspected founder variant in Iraqi Jewish population [Falik-Zaccai et al 2012]
POLH	NM_006502.3	c.490G>T ²	--	Accounts for 33% of POLH pathogenic variants in Japanese persons [Masaki et al 2008]
	NM_006502.3 NP_006493.1	c.725C>G	p.Ser242Ter	Accounts for 11% of POLH pathogenic variants in Japanese persons [Masaki et al 2008]
	NM_006502.3	c.764+1G>A	--	Founder variant in Basque region / northern Spain & central Brazil [Calmels et al 2016, Munford et al 2017]
	NM_006502.3 NP_006493.1	c.916G>T	p.Glu306Ter	Accounts for 20% of POLH pathogenic variants in Japanese persons [Masaki et al 2008]
		c.1075-2567_1244+1188del3925 (del incl. exon 10)	p.Asn359ValfsTer32	Founder variant in Tunisia / North Africa [Ben Rekaya et al 2014]
		c.1664delA (1661delA ³)	p.Asn555ThrfsTer30	Accounts for 22% of POLH pathogenic variants in Japanese persons [Masaki et al 2008]
XPA	NM_000380.4 NP_000371.1	c.335_338delTTATinsCATAAGAAA	p.Phe112SerfsTer2	Founder variant in India [Tamhankar et al 2015]
	NM_000380.4	c.390-1G>C	--	Founder variant in Japan w/carrier frequency of 1% [Hirai et al 2006]
	NM_000380.4 NP_000371.1	c.682C>T	p.Arg228Ter	Founder variant in Tunisia [Messaoud et al 2010]
XPC	NM_004628.5 NP_004619.3	c.1643_1644delTG	p.Val548AlafsTer25	Founder variant in North Africa (Algeria, Morocco, & Tunisia) [Soufir et al 2010, Hadj-Rabia et al 2013, Jerbi et al 2016]