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Case Reports
. 2021 May 31:12:650639.
doi: 10.3389/fgene.2021.650639. eCollection 2021.

Case Report: Identification of Novel Variants in ERCC4 and DDB2 Genes in Two Tunisian Patients With Atypical Xeroderma Pigmentosum Phenotype

Imen Nabouli  1 , Asma Chikhaoui  1 , Houcemeddine Othman  2 , Sahar Elouej  1   3 , Meriem Jones  1   4 , Arnaud Lagarde  3 , Meriem Ben Rekaya  1 , Olfa Messaoud  1 , Mohamed Zghal  4 , Valerie Delague  3 , Nicolas Levy  3   5 , Annachiara De Sandre-Giovannoli  3   6 , Sonia Abdelhak  1 , Houda Yacoub-Youssef  1
Affiliations
Case Reports

Case Report: Identification of Novel Variants in ERCC4 and DDB2 Genes in Two Tunisian Patients With Atypical Xeroderma Pigmentosum Phenotype

Imen Nabouli et al. Front Genet. .

Abstract

Xeroderma Pigmentosum (XP) is a rare genetic disorder affecting the nucleotide excision repair system (NER). It is characterized by an extreme sensitivity to sunlight that induces cutaneous disorders such as severe sunburn, freckling and cancers. In Tunisia, six complementation groups have been already identified. However, the genetic etiology remains unknown for several patients. In this study, we investigated clinical characteristics and genetic defects in two families with atypical phenotypes originating from the central region in Tunisia. Clinical investigation revealed mild cutaneous features in two patients who develop multiple skin cancers at later ages, with no neurological disorders. Targeted gene sequencing revealed that they carried novel variants. A homozygous variation in the ERCC4 gene c.1762G>T, p.V588F, detected in patient XP21. As for patient XP134, he carried two homozygous mutations in the DDB2 gene c.613T>C, p.C205R and c.618C>A, p.S206R. Structural modeling of the protein predicted the identified ERCC4 variant to mildly affect protein stability without affecting its functional domains. As for the case of DDB2 double mutant, the second variation seems to cause a mild effect on the protein structure unlike the first variation which does not seem to have an effect on it. This study contributes to further characterize the mutation spectrum of XP in Tunisian families. Targeted gene sequencing accelerated the identification of rare unexpected genetic defects for diagnostic testing and genetic counseling.

Keywords: DDB2 gene; ERCC4/XPF; NER defects; skin cancer; xeroderma pigmentosum.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Pedigrees and clinical images describing two XP affected family members (XP21 and XP134) (A,B). Filled symbols represent affected individuals, open symbols represent unaffected individuals, gray symbols are for suspected individuals, the studied pro-band is indicated with an arrow.
Figure 2
Figure 2
Molecular findings: (A) Electropherogram showing the variation in ERCC4 gene in exon 8 (c.1762 G>T p.V588F) at a homozygous state in the patient XP21. (B) Electropherogram showing double variation in DDB2 gene (c.613 T>C p.C205R and c.618 C>A p.S206R) in exon 5 in XP134 patient. (C) Structures of the XPF protein and F588 XPF mutant suggesting a mild distortion in helix domain. (D) DNA DDB2 protein interaction for muted DDB2 protein suggestion that R206 affect this process.
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