Mariem Ben Rekaya1, Chokri Naouali2, Olfa Messaoud2, Meriem Jones3, Yosra Bouyacoub2, Majdi Nagara2, Tommaso Pippucci4, Haifa Jmel2, Mariem Chargui2, Manel Jerbi2, Mohamed Alibi2, Hamza Dallali2, Anu Bashamboo5, Kenneth McElreavey5, Giovanni Romeo4, Abdelhamid Barakat6, Mohamed Zghal7, Houda Yacoub-Youssef2, Sonia Abdelhak2. 1. Laboratory of Biomedical Genomics and Oncogenetics (LR11IPT05), Institut Pasteur de Tunis, Université Tunis El Manar, El Manar I, 2092 Tunis, Tunisia. Electronic address: mariem.benrekaya@pasteur.rns.tn. 2. Laboratory of Biomedical Genomics and Oncogenetics (LR11IPT05), Institut Pasteur de Tunis, Université Tunis El Manar, El Manar I, 2092 Tunis, Tunisia. 3. Laboratory of Biomedical Genomics and Oncogenetics (LR11IPT05), Institut Pasteur de Tunis, Université Tunis El Manar, El Manar I, 2092 Tunis, Tunisia; Dermatology Department, Hospital Charles Nicolle, 1006 Tunis, Tunisia. 4. Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. 5. Human Developmental Genetics, Institut Pasteur de Paris, France. 6. Laboratoire de génétique moléculaire humaine, département de recherche scientifique, Institut Pasteur, 20360 Casablanca, Morocco. 7. Dermatology Department, Hospital Charles Nicolle, 1006 Tunis, Tunisia.
Abstract
BACKGROUND: Skin cancers (SC) are complex diseases that develop from complex combinations of genetic and environmental risk factors. One of the most severe and rare genetic diseases predisposing to SC is the Xeroderma pigmentosum (XP) syndrome. OBJECTIVES: First, to identify the genetic etiology of XP and to better classify affected patients. Second, to provide early molecular diagnosis for pre-symptomatic patient and finally to offer genetic counseling for related individuals. METHODS: Whole Exome Sequencing (WES) and Run Of Homozygosity (ROH) were performed for two patients belonging to two different multiplex consanguineous families. The identified mutations were confirmed by Sanger sequencing and researched in ten Tunisian families including a total of 25 affected individuals previously suspected as having XP group V (XP-V) form. All patients had mild dermatological manifestations, absence of neurological abnormalities and late onset of skin tumors. RESULTS: Screening for functional variations showed the presence of the ERCC2 p.Arg683Gln in XP14KA-2 patient and a novel mutation, DDB2 p. (Lys381Argfs*2), in XP51-MAH-1 patient. Sanger sequencing and familial segregation showed that the ERCC2 mutation is present at a homozygous state in 10 affected patients belonging to 3 families. The second mutation in DDB2, is present at a homozygous state in 5 affected cases belonging to the same family. These two mutations are absent in the remaining 10 affected patients. The ERCC2 c.2048G > A mutation is present in a medium ROH region (class B) suggesting that it mostly arises from ancient relatedness within individuals. However, the c.1138delG DDB2 mutation is present in a large ROH region (class C) suggesting that it arises from recent relatedness. CONCLUSION: To our knowledge, this is the first study that identifies XP-D and XP-E complementation groups in Tunisia. These two groups are very rare and under-diagnosed in the world and were not reported in North Africa.
BACKGROUND:Skin cancers (SC) are complex diseases that develop from complex combinations of genetic and environmental risk factors. One of the most severe and rare genetic diseases predisposing to SC is the Xeroderma pigmentosum (XP) syndrome. OBJECTIVES: First, to identify the genetic etiology of XP and to better classify affected patients. Second, to provide early molecular diagnosis for pre-symptomatic patient and finally to offer genetic counseling for related individuals. METHODS: Whole Exome Sequencing (WES) and Run Of Homozygosity (ROH) were performed for two patients belonging to two different multiplex consanguineous families. The identified mutations were confirmed by Sanger sequencing and researched in ten Tunisian families including a total of 25 affected individuals previously suspected as having XP group V (XP-V) form. All patients had mild dermatological manifestations, absence of neurological abnormalities and late onset of skin tumors. RESULTS: Screening for functional variations showed the presence of the ERCC2p.Arg683Gln in XP14KA-2 patient and a novel mutation, DDB2 p. (Lys381Argfs*2), in XP51-MAH-1 patient. Sanger sequencing and familial segregation showed that the ERCC2 mutation is present at a homozygous state in 10 affected patients belonging to 3 families. The second mutation in DDB2, is present at a homozygous state in 5 affected cases belonging to the same family. These two mutations are absent in the remaining 10 affected patients. The ERCC2 c.2048G > A mutation is present in a medium ROH region (class B) suggesting that it mostly arises from ancient relatedness within individuals. However, the c.1138delGDDB2 mutation is present in a large ROH region (class C) suggesting that it arises from recent relatedness. CONCLUSION: To our knowledge, this is the first study that identifies XP-D and XP-E complementation groups in Tunisia. These two groups are very rare and under-diagnosed in the world and were not reported in North Africa.