10.5826/dpc.1401a50
Introduction: Xeroderma pigmentosum (XP), a rare inherited condition, hallmarked by extreme sensitivity to sun exposure resulting in multiple skin cancers and non-malignant skin alterations is attributed to homozygous inactivating pathogenic variants (PVs) in DNA repair genes, predominantly the XPC gene.
Objectives: Report a unique phenotypic expression of mutant XPC allele that may be compatible with a putative modifier role for MC1R polymorphism.
Methods: A family of 13 siblings, seven of whom were diagnosed with at least one cutaneous  melanoma (N = 53) and non-melanoma skin cancers (N = 9) was studied. Of seven melanoma-affected cases, five consented for genetic analysis. CDKN2A revealed no PV in any case and subsequent whole-exome sequencing (WES) identified a rare homozygous missense PV (c.919C&gt;T; p.Arg307Trp) in exon 8 of the XPC gene in all affected individuals. Notably, XPC PV carriers who co-harbored the p.I155T MC1R variant (N = 3) exhibited larger number of tumors, deeper Breslow indexes, higher rates of invasive melanomas and earlier age at diagnosis compared with non MC1R variant carriers (N = 2).
Conclusions: Familial malignant melanoma phenotype may, in fact, be an unusual clinical presentation of XPC, and MC1R may be a genetic modifier of penetrance and phenotype of mutant XPC alleles.
text/xml
2160-9381
3558
en
Luiz De Marco
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
modifier genes
 Familial Melanoma Phenotype With Xeroderma Pigmentosum Group C (XP-C) Genotype - The Putative Role of MC1R Polymorphism as Modifier
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2024-01-31
2023-05-31
2024-01-31
2024-02-21
e2024050
Dermatol Pract Concept
Introduction: Xeroderma pigmentosum (XP), a rare inherited condition, hallmarked by extreme sensitivity to sun exposure resulting in multiple skin cancers and non-malignant skin alterations is attributed to homozygous inactivating pathogenic variants (PVs) in DNA repair genes, predominantly the XPC gene.
Objectives: Report a unique phenotypic expression of mutant XPC allele that may be compatible with a putative modifier role for MC1R polymorphism.
Methods: A family of 13 siblings, seven of whom were diagnosed with at least one cutaneous  melanoma (N = 53) and non-melanoma skin cancers (N = 9) was studied. Of seven melanoma-affected cases, five consented for genetic analysis. CDKN2A revealed no PV in any case and subsequent whole-exome sequencing (WES) identified a rare homozygous missense PV (c.919C&gt;T; p.Arg307Trp) in exon 8 of the XPC gene in all affected individuals. Notably, XPC PV carriers who co-harbored the p.I155T MC1R variant (N = 3) exhibited larger number of tumors, deeper Breslow indexes, higher rates of invasive melanomas and earlier age at diagnosis compared with non MC1R variant carriers (N = 2).
Conclusions: Familial malignant melanoma phenotype may, in fact, be an unusual clinical presentation of XPC, and MC1R may be a genetic modifier of penetrance and phenotype of mutant XPC alleles.
Luiz De Marco
2024/01/31
10.5826/dpc.1401a50
e2024050
Departments of Surgery, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
2160-9381
modifier genes
en
e2024050
Jacobelli S, Soufir N, Lacapere JJ, et al. Xeroderma pigmentosum group C in a French Caucasian patient with multiple melanoma and unusual long-term survival. Br J Dermatol. 2008;159(4):968-973. DOI: 10.1111/j.1365-2133.2008.08791.x. PMID: 18717677.
 Familial Melanoma Phenotype With Xeroderma Pigmentosum Group C (XP-C) Genotype - The Putative Role of MC1R Polymorphism as Modifier
https://dpcj.org/index.php/dpc/article/download/3558/2425
    Familial Melanoma Phenotype With Xeroderma
     Pigmentosum Group C (XP-C) Genotype - The
   Putative Role of MC1R Polymorphism as Modifier
  Franciele Antonieta Bianchi Leidenz1, Flavia Vasques Bittencourt2, Williana Garcia Braga1,
    Elio Magno de Sá Araújo1, Carolina Cavalieri Gomes3, Vanessa de Fatima Bernardes3,
                              Eitan Friedman4, Luiz De Marco1


1 Departments of Surgery, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
2 Departments of Medicine, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
3 Departments of Pathology, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
4 The Preventive Personalized Medicine Center, Assuta Medical Center and the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel



Key words: Xeroderma Pigmentosum, Familial melanoma, XPC, MC1R, modifier genes
Citation: Leidenz FA, Bittencourt FV, Braga WG, et al. Familial Melanoma Phenotype With Xeroderma Pigmentosum Group C (XP-C)
Genotype - The Putative Role of MC1R Polymorphism as Modifier. Dermatol Pract Concept. 2024;14(1):e2024050. DOI: https://doi.
org/10.5826/dpc.1401a50
Accepted: September 27, 2023; Published: January 2024
Copyright: ©2024 Leidenz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: This work was partially funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq# 302291/2019-9),
CAPES and Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG# CDS-RED-00019-16). The sponsors had no role in the design
or conduct of this research.
Competing interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding author: L. De Marco, Department of Surgery, School of Medicine, Universidade Federal de Minas Gerais, Av Alfredo Balena
190, Belo Horizonte 30130-100, Brazil; e-mail: Ldemarco@ufmg.br.



  ABSTRACT             Introduction: Xeroderma pigmentosum (XP), a rare inherited condition, hallmarked by extreme sen-
                       sitivity to sun exposure resulting in multiple skin cancers and non-malignant skin alterations is at-
                       tributed to homozygous inactivating pathogenic variants (PVs) in DNA repair genes, predominantly
                       the XPC gene.
                       Objectives: Report a unique phenotypic expression of mutant XPC allele that may be compatible
                       with a putative modifier role for MC1R polymorphism.
                       Methods: A family of 13 siblings, seven of whom were diagnosed with at least one cutaneous melano-
                       ma (N = 53) and non-melanoma skin cancers (N = 9) was studied. Of seven melanoma-affected cases,
                       five consented for genetic analysis. CDKN2A revealed no PV in any case and subsequent whole-exome
                       sequencing (WES) identified a rare homozygous missense PV (c.919C>T; p.Arg307Trp) in exon 8 of
                       the XPC gene in all affected individuals. Notably, XPC PV carriers who co-harbored the p.I155T
                       MC1R variant (N = 3) exhibited larger number of tumors, deeper Breslow indexes, higher rates of
                       invasive melanomas and earlier age at diagnosis compared with non MC1R variant carriers (N = 2).
                       Conclusions: Familial malignant melanoma phenotype may, in fact, be an unusual clinical presen-
                       tation of XPC, and MC1R may be a genetic modifier of penetrance and phenotype of mutant XPC
                       alleles.



Original Article | Dermatol Pract Concept. 2024;14(1):e2024050                                                                              1
Introduction                                                            a mutant MC1R allele seemingly affected the clinical mela-
                                                                        noma phenotype.
Xeroderma Pigmentosum (XP) is a rare autosomal recessive
disorder whose estimated rates of 2.3/1,000,000 in Western
countries clinically hallmarked by multitude of skin anoma-
                                                                        Methods
lies [1]: hyperpigmentation, premature skin aging, cutaneous            The proband (Figure 1), individual II.11, was referred in
(and ocular) photosensitivity, and an increased risk for de-            2000 at age 28, after a diagnosis of melanoma and a history
veloping a host of skin tumors [2]. Genetically, XP is asso-            of death of his older brother from metastatic melanoma of
ciated with homozygous pathogenic variants (PVs) in seven               the lower lip at age 38. Since then, a total of 24 melanomas
nucleotide excision repair pathway genes: XPA, ERCC3,                   have been confirmed in the proband. These melanomas were
XPC, ERCC2, DDB2, ERCC4, ERCC5 and one clinical vari-                   mostly located in the head (N = 19) and neck (N = 2) regions,
ant (XPV, Xeroderma Pigmentosum Variant) attributed to a                including the scalp (Figure 2), and upper trunk (N = 3). The
mutated POLH gene [2].                                                  majority (19/24) were in situ, three were thin melanomas
    The most commonly mutated gene underlying XP in                     (Breslow 0.45 mm, 0.47 mm and 0.9 mm), one was 1.4 mm,
Caucasians is XPC group C (MIM #278720) [3]. The clin-                  and one was 2.0 mm. Physical examination revealed brown
ical phenotype in XP due to mutant XPC alleles dependent                hair and brown eyes, Fitzpatrick phototype III, sun damage
on sun exposure and the mutational background, hence on                 on exposed areas with some pigmented changes, such as
the geographical origin [4]. The incidence of skin cancers is           solar lentigines. Throughout 20 years of follow-up, he also
1,000 times higher in XP patients compared with average                 presented two basal cell carcinomas (BCC) and one baso-­
risk population and a major contributor to the substantially            squamous carcinoma of the head and neck. History of un-
decreased life expectancy in XP cases, around 30 years [5].             protected excessive sun exposure was reported. Dermoscopy
These patients have an estimated 10,000-fold increased risk             of pigmented lesions did not show any specific patterns. All
of non-melanoma skin cancer, a 2,000-fold increased risk of             consenting siblings (12) were examined, and five of these sib-
melanoma under the age of 20 [1] and the first skin lesions             lings were diagnosed with melanoma, (a total of 7/13 mela-
may appear as early as eight years of age [5].                          noma affected siblings). Of melanoma patients, the majority
    Familial melanoma syndrome (FMS) is a term used to                  had multiple atypical nevi (three had more than 20, one had
describe the presence of two or more cases of cutaneous mel-            fewer than 10 and one had none), all have a relevant his-
anoma in first- or second-degree relatives [6]. An alternative          tory of unprotected sun exposure throughout life. They did
classification [7] refers to these cases as Melanoma dominant           not get sunburned easily and did not have a recollection of
syndrome when melanoma is the first or the predominant                  many blistering despite having a long history of excessive un-
clinical manifestation in a family.                                     protected sun exposure. Most of them have freckles or solar
                                                                        melanosis, confirming the sun-damaged skin. Clinical char-
Objectives                                                              acteristics of affected individuals are shown in Table 1. All
                                                                        melanoma cases reported a history of significant sun expo-
Here we report a family with cutaneous melanomas with                   sure, Fitzpatrick type III, and solar lentigines in sun exposed
a seemingly autosomal dominant inheritance pattern with-                areas. At the time of reporting, five of the six living affected
out clear clinical characteristics of XP, where a homozygous            siblings have had multiple primary melanomas, varying from
XPC inactivating PV co-segregated with the phenotype, and               three to 24 tumors per person. Age range at first melanoma




Figure 1. Pedigree of proband (II.11) family. Individuals affected by cutaneous melanoma are represented in black-filled shapes, while white
shapes represent individuals without history of melanoma.



2                                                                            Original Article | Dermatol Pract Concept. 2024;14(1):e2024050
Figure 2. Clinical images of affected individuals. (A) Note skin photoaging and solar lentigines on sun exposed areas of the proband with a
large scar from a previous removed melanoma and a new melanoma on the left side of the scar. (B) Melanoma on the scalp in the proband,
in a relatively sun protected area. (C) Two melanomas on the forehead of individual II.8. (D) One melanoma in the left cervical region of
individual II.13 on exposed area showing solar lentigines, surrounded by pigmentary changes.



                                 Table 1 Familial melanoma and their characteristics
  Affected       Age of first     Number of            Tumor(s)           Breslow          Sun          Total nevus        Other skin
 individuals     melanoma         melanomas         localization(s)      thickness       exposure       body count          cancers
 II.4            45               3                Head (3)            All in situ      Excessive       <20              None
                                                                                        unprotected
 II.7            33               11               Head (3), neck      All in situ      Excessive       20-100           Two BCC
                                                   (1), limbs (2)                       unprotected
                                                   and upper
                                                   trunk (5)
 II.8            35               7                Head (3), neck      0.24mm and Excessive             20-100           Three BCC
                                                   (2), and chest      6 in situ  unprotected
                                                   (2)
 II.10           48               1                Head (scalp)        in situ          Excessive       20-100           None
                                                                                        unprotected
 II.11           28               24               Head (19),      0.45mm;              Excessive       >100             Two BCC, one
                                                   neck (2), and   0.47mm;              unprotected                      basosquamous
                                                   upper trunk (3) 0.9mm;                                                carcinoma
                                                                   1.4mm;
                                                                   2.0mm and
                                                                   19 in situ
 II.13           22               7                Head (3), neck      0.23mm;          Excessive       >100             One BCC
                                                   (3) and upper       0.36 mm;         unprotected
                                                   trunk (1)           2.3 mm and
                                                                       4 in situ



diagnosis was 22-45 years of age. Neither visceral metastasis          0472.0.203.240-11). Prior to enrolment, written informed
nor lymph node disease have been reported in any of the                consent was obtained from all patients.
six affected siblings, and no adjuvant therapies were given.               Sanger sequencing for the CDKN2A gene, the most com-
Interestingly, no relevant ophthalmologic condition has been           mon high penetrance melanoma susceptibility gene, was ini-
diagnosed in the affected family members. The siblings were            tially performed. Subsequently, peripheral blood DNA from
born to consanguineous (second-degree cousins) phenotyp-               individual II.11 was submitted to Whole-Exome Sequencing
ically healthy parents; the father died at age 58 without any          (WES). The VCF file was analyzed using Mendel, MD soft-
history of skin cancer. The mother is still alive (age 86), in         ware (http://mendel.medicina.ufmg.br) [8] as well as by In-
good health and never had any skin cancer. Occupational ex-            genuity® Variant AnalysisTM software (www.ingenuity.com/
posure to sun was suggested by the fact that they were mostly          variants). Captured sequences were aligned with the human
farm laborers. Figure 2 demonstrates some of their clinical            reference genome GRCh37 and a sequence of filters applied.
features. This study was approved by the Institutional Re-             A flow chart is shown in Figure 3. Given the autosomal re-
view Board of Universidade Federal de Minas Gerais (CAAE               cessive inheritance pattern in the studied family we focused



Original Article | Dermatol Pract Concept. 2024;14(1):e2024050                                                                           3
                 Figure 3. Flowchart of variant analyses.


on homozygous variants. All seemingly candidate variants          homozygous variants only, it was narrowed down to eight
were confirmed by Sanger sequencing and co- segregation           genes, of whom XPC was the strongest candidate.
was subsequently carried out in all consenting cases (N = 15)        Sequencing of XPC demonstrated that the clinically un-
using Sanger sequencing.                                          affected mother carried the heterozygous XPC variant p.Ar-
    To further assess the putative clinical significance of the   g307Trp (c.919C>T) in exon 8. All five affected individuals
detected XPC sequence variant and the possibility of residual     studied were homozygous (T/T) for this sequence variant.
protein function, we performed immunohistochemical anal-             Another     known      pathogenic      variant    (c.464T>C;
ysis using XPC antibody (D-10: sc-74410, Santa Cruz Bio-          p.Ile155Thr) was detected in the MC1R gene (NM_002386.4)
technology) both on melanoma tissue from the proband and          by WES. Three (II.7, II. 11 and II.13) of the five affected
on normal mucosal tissue from the same individual mucosa          melanoma cases who carried the XPC homozygous variant
(serving as control).                                             harbored this heterozygous PV. These three co-carriers (XPC
                                                                  and MC1R) carriers displayed significantly worse disease

Results                                                           phenotype compared with the two non-co-carriers: higher
                                                                  number of melanomas per person (14 versus 5), earlier age
CDKN2A gene genotyping yielded no PVs. WES showed                 of melanoma diagnosis (average 27.6 years versus 40 years)
46,452 variants and, after a series of filtering, exclusion       and thicker melanomas (three invasive in co-carriers ver-
of variants in our control exomes bank and selection of           sus noninvasive melanomas in non-co-carriers, with mean



4                                                                     Original Article | Dermatol Pract Concept. 2024;14(1):e2024050
Figure 4. Immunohistochemistry assay. (A) Melanoma tissue from proband stained with H&E. (B) Melanoma tissue from proband very
lightly stained by the XPC antibody, suggesting there is no significant expression of this protein in this tissue. The dark color is mostly due to
melanin. (C) XPC antibody in a control tissue (mucosa) showing high positivity, therefore, significant quantity of XPC protein in this normal
tissue. (D) the same melanoma tissue from proband highly colored by a control anti-tubulin antibody, showing that this tissue is indeed viable.


Breslow thickness of 0.17 mm in carriers, versus 0.017 mm                  a family with atypical XP presentation age in the proband.
in non-carriers). Our data shows that the median number                    Late onset of tumors and late diagnosis of XP are uncommon
of non-melanoma skin cancer (NMSC) per person among                        but there are a few previously reported cases with distinct
MC1R wild-type XP-C individuals was 1.5 (three BCC in                      phenotypes [10,11]. To our knowledge, there are two reports
two subjects). In contrast, among carriers of the I155T vari-              of XPC-related XP phenotype being diagnosed in late adult-
ant, the median number of NMSC was 2.0, with six tumors                    hood: an 83-year-old French woman with multiple melano-
occurring in three individuals.                                            mas whose unusual long-term survival was attributed to a
    The XPC c.919C>T;p.Arg307Trp variant is predicted to                   lower UV-radiation exposure and regular clinical follow-up
be pathogenic by several different bioinformatics tools: dis-              and a 42-year-old Caucasian man with multiple melanomas
ease causing by MutationTaster (http://www.mutationtaster                  and a missense PV in the XPC gene that still retained some
.org/), probably damaging by PolyPhen-2 with a score of                    XPC protein function and, seemingly contributing to late XP
1.0 (http://genetics.bwh.harvard.edu/pph2/) and deleteri-                  diagnosis [4,11].
ous by the Protein Variation Effect Analyzer (PROVEAN,                         XP typically leads to a shortened life span, with cancer
http://provean.jcvi.org/index.php), with a score of –6.872.                related death usually occurring at 30-40 years of age [12]. In
The pathogenicity of the c.919C>T;p.Arg307Trp sequence                     the case described herein all but one patient are alive aged
variant is also inferred by its rarity (prevalence in GnomAD               41-62 years, at the time of reporting (Figure 1). The less se-
(https://gnomad.broadinstitute.org/) 0.00002422 with none                  vere phenotype and the less pronounced effect on early age
reported in Brazilian databanks (https://abraom.ib.usp.br/).               mortality in this family suggests that the XPC mutated pro-
Variant classification according to 2015 ACMG guidelines                   tein is still capable of exerting some residual activity and re-
is PM2 (moderate evidence of pathogenicity) and with addi-                 pair DNA damage, as previously suggested [4].
tional supporting evidence of pathogenicity (PP1).                             Being a recessive condition, it is expected that around
    Immunohistochemistry analysis demonstrated no XPC                      25% of the offspring would be affected. In this family, seven
staining in the melanoma tissue compared with normal non                   of the 13 siblings are affected (53.8%), with an extraordi-
cancer surrounding dermal tissue, as is predicted by func-                 nary higher number of melanomas (N = 43) compared with
tional studies [9] (Figure 4).                                             non-melanoma skin cancers (n= 9), an unusual tumor distri-
                                                                           bution to the one usually seen in XP patients – carcinomas

Conclusions                                                                are five times more common than melanomas [1]. Additional
                                                                           clinically unique features in this family that have led to XP
XP is usually diagnosed in childhood heralded by the pres-                 not even being considered as a possible diagnosis prior to
ence of typical skin lesions [5]. The current study describes              genetic analysis, were the fact that melanomas were not only



Original Article | Dermatol Pract Concept. 2024;14(1):e2024050                                                                                  5
diagnosed in chronically sun exposed areas, such as scalp of               3. Ali MZ, Blatterer J, Khan MA, et al. Identification of a novel
hairy individuals, lack of typical XP-associated skin changes                 protein truncating mutation p.Asp98* in XPC associated with
                                                                              xeroderma pigmentosum in a consanguineous Pakistani fam-
such as actinic keratosis, atrophy, telangiectasias and marked
                                                                              ily. Mol Genet Genomic Med. 2020;8(2):e1060. DOI: 10.1002
skin photoaging.
                                                                              /mgg3.1060. PMID: 31923348. PMCID: PMC7005610.
    In the present study, having both the XPC homozygous                   4. Meneses M, Chavez-Bourgeois M, Badenas C, et al. Atypical
variant and a variant MC1R allele (p.I155T) may have dele-                    Clinical Presentation of Xeroderma Pigmentosum in a Patient
teriously affected the phenotype, with those harboring both                   Harboring a Novel Missense Mutation in the XPC Gene: The
variants exhibiting seemingly a more aggressive clinical and                  Importance of Clinical Suspicion. Dermatology. 2015;231(3):
                                                                              217-221. DOI: 10.1159/000433527. PMID: 26278556.
pathological phenotype. Few studies reported the effect of
                                                                           5. Ribeiro MG, Zunta GL, Santos JS, Moraes AM, Lima CSP,
co-harbouring MC1R alleles in genetically proven XP cases.
                                                                              Ortega MM. Clinical features related to xeroderma pigmento-
A previous study of 17 Nepalese XP patients suggested that                    sum in a Brazilian patient diagnosed at advanced age. Appl Clin
the p.R163Q MC1R variant in XPC patients was associated                       Genet. 2018;11:89-92. DOI: 10.2147/TACG.S155083. PMID:
with younger age at first carcinoma and more numerous cu-                     30127633. PMCID: PMC6089094.
taneous carcinomas, although this latter difference was not                6. Sá BCS, Moredo LF, Gomes EE, Araújo ESS, Duprat JP.
                                                                              Hereditary melanoma: a five-year study of Brazilian patients in
statistically significant [1]. Additionally, it has been specu-
                                                                              a cancer referral center - phenotypic characteristics of probands
lated that the coexistence of XPC mutation with another
                                                                              and pathological features of primary tumors. An Bras Dermatol.
MC1R variant (p.V60L) was associated with multiple pri-                       2018;93(3):337-340. DOI: 10.1590/abd1806-4841.20186201.
mary melanoma phenotype in a single French patient who                        PMID: 29924249. PMCID: PMC6001076.
had 10 melanomas and six BCC before being diagnosed with                   7. Abdo JF, Sharma A, Sharma R. Role of Heredity in Mela-
XP [12]. Although the putative modifier effect on MC1R                        noma Susceptibility: A Primer for the Practicing Surgeon.
                                                                                Surg Clin North Am. 2020;100(1):13-28. DOI: 10.1016/j.suc
variant on the phenotype of the homozygous deleterious
                                                                                .2019.09.006. PMID: 31753108.
variant in the XPC gene is intriguing, it remains currently
                                                                           8.   G C C L Cardenas R, D Linhares N, L Ferreira R, Pena SDJ.
speculative at best and awaits further functional studies and/                  Mendel,MD: A user-friendly open-source web tool for analyz-
or additional families displaying similar effect.                               ing WES and WGS in the diagnosis of patients with Mendelian
    In conclusion, a familial melanoma phenotype with                           disorders. PLoS Comput Biol. 2017;13(6):e1005520. DOI:
a presumed autosomal recessive inheritance pattern was                          10.1371/journal.pcbi.1005520. PMID: 28594829. PMCID:
                                                                                PMC5464533.
shown to be atypical in a genetically proven XP. The role, if
                                                                           9.   Budden T, Davey RJ, Vilain RE, et al. Repair of UVB-induced
any, of MC1R alleles in modifying the clinical tumor pheno-
                                                                                DNA damage is reduced in melanoma due to low XPC and
type in XPC mutation carriers is suggested. Validation and                      global genome repair. Oncotarget. 2016;7(38):60940-60953.
extension of these preliminary observations are needed.                         DOI: 10.18632/oncotarget.10902. PMID: 27487145. PMCID:
    Ethics statement: This study was approved by the Insti-                     PMC5308628.
tutional Review Board of Universidade Federal de Minas                    10.   Fassihi H, Sethi M, Fawcett H, et al. Deep phenotyping of 89
                                                                                xeroderma pigmentosum patients reveals unexpected hetero-
Gerais (CAAE 0472.0.203.240-11). Prior to enrolment,
                                                                                geneity dependent on the precise molecular defect. Proc Natl
written informed consent was obtained from all patients.
                                                                                Acad Sci U S A. 2016 1;113(9):E1236- E1245. DOI: 10.1073
                                                                                /pnas.1519444113. PMID: 26884178. PMCID: PMC4780618.

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6                                                                               Original Article | Dermatol Pract Concept. 2024;14(1):e2024050
