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Genotypic characterization of Brazilian xeroderma pigmentosum patients and search for founder effects

Grant number: 18/05216-5
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): April 01, 2018
Effective date (End): October 31, 2019
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Carlos Frederico Martins Menck
Grantee:Ligia Pereira Castro
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:14/15982-6 - Consequences of repair deficiencies in damaged genome, AP.TEM
Associated scholarship(s):18/24923-4 - Search for founder effects and cellular characterization of cells from brazilian patients with the DNA repair-deficient Xeroderma Pigmentosum disease, BE.EP.PD


Deficiencies in nucleotide excision repair lead to human disorders where patients display photosensitivity and/or neurological problems, such as xeroderma pigmentosum (XP), cockayne syndrome (CS) and trichothiodystrophy (TTD). Case reports and genotypic descriptions of patients have been published worldwide, mainly in North America, Europe, Africa and Japan. The follow up of these patients for decades and the study with these cells led to the understanding of what is currently known about the molecular pathways and genetic defects involved in the phenotypes of these syndromes. In Brazil, a few case-reports describe some patients with these phenotypes, and genetic and molecular characterizations are scarce. With the possibility to identify mutations directly by Next Generation Sequencing (NGS) technique, we initiated a project to diagnose the mutations involved in these NER syndromes, mainly XP. Thus, up to now, we identified mutations for 39 Brazilian patients, including 17 XP-V patients from Faina, an isolated community at Goiás (Munford, Castro et al., 2016). Many of these mutations are novel and include 26 at XPV, six at XPC, two at XPA and four at XPE gene, and one TTD mutated at XPD gene. We propose to continue this project to identify the molecular mutation of other XP patients in Brazil, in order to constitute an extensive patient cohort of patients and define the distribution of affected genes for XP in this country. Moreover, we observed a high frequency of patients from different states with the same mutation, as well as patients with mutations already reported from abroad. Therefore, we also plan to investigate the origins of these mutations and ancestries by the analysis of haplotypes with SNP-array assays. Particularly interesting, the two different POLH mutations from Faina, GO, were already identified in Europe; and one XPC mutation also found at Comorian Islands, close to Mozambique, from where slaves were trade to Brazil in the XIX century. Thus, with international established collaborations, we plan to identify part of the genetic history of our population and human migration carrying these mutations.

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