AUTHOR=Chikhaoui Asma , Elouej Sahar , Nabouli Imen , Jones Meriem , Lagarde Arnaud , Ben Rekaya Meriem , Messaoud Olfa , Hamdi Yosr , Zghal Mohamed , Delague Valerie , Levy Nicolas , De Sandre-Giovannoli Annachiara , Abdelhak Sonia , Yacoub-Youssef Houda 

TITLE=Identification of a ERCC5 c.2333T>C (L778P) Variant in Two Tunisian Siblings With Mild Xeroderma Pigmentosum Phenotype

JOURNAL=Frontiers in Genetics

VOLUME=Volume 10 - 2019

YEAR=2019

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2019.00111

DOI=10.3389/fgene.2019.00111

ISSN=1664-8021

ABSTRACT=Background 
Xeroderma Pigmentosum (XP) is a rare autosomal recessive disorder in DNA repair system (NER), characterized by severe sunburns, development of freckles, premature skin ageing and susceptibility to develop cancers at an average age of 8 years. XP is an example of accelerated photo-ageing. It is genetically and clinically heterogeneous. Eight groups are described in the world. In Tunisia, 5 groups were already identified. 
In this work, we investigated the genetic etiology in a particular family with an atypical mild XP phenotype. 
Methods 
Blood samples were collected from two affected siblings after written informed consent. As all known mutations in Tunisia have been explored using Sanger sequencing without success, we carried out mutational analysis through targeted panel gene sequencing using the Agilent HaloPlex target enrichment system.
Results
We identified, for the first time, the XP-G complementation group in Tunisia and in North Africa. The patients were carriers of an homozygous T to C transition at the nucleotide position c.2333 causing the leucine to proline amino acid change at position 778 (p.Leu778Pro) of the ERCC5 gene, resulting in an XP-G phenotype. The same variation was previously reported at the heterozygous state in a patient’s cell line, in Europe, for which no clinical data were available and was suggested to confer an XP/CS phenotype on the basis of functional tests.
Conclusion 
Thanks to multiple efforts made in Tunisia for early diagnosis of XP patients and disease prevention via prenatal diagnosis and genetic counselling, new under-diagnosed phenotypes are emerging, such as these siblings, who have photosensitivity, no cancers yet, but early skin photo-aging. This makes targeted gene sequencing essential for the diagnosis of mild XP phenotypes to prevent cancer onset at more advanced ages.