Haplotype analysis reveals a possible founder effect of SDHB gene mutation C166_170delCCTCA in Argentine patients.

DRA GABRIELA SANSO ; C. MATHO; DRA ANA VIEITES; DRA GLORIA LEVIN; DRA MARTA BARONTINI

Playa del Carmen

Congreso; XXIV Sociedad Latinoamericana de Endocrinología Pediátrica; 2014

Sociedad Latinoamericana de Endocrinologia Pediatrica

Haplotype analysis reveals a possible founder effect of SDHB gene mutation C166_170delCCTCA in Argentine patients. Introduction: paragangliomas are tumors arising from chromaffin extra-adrenal tissue. Familial paraganglioma associated with SDHB gene mutations (PGL 4) is an inherited syndrome with autosomal dominant inheritance, with incomplete penetrance and frequently malignant. Twenty four families with PGL 4 from different regions of Argentina were included in this study. Thirteen out of 24 families (55%) showed the C166_170delCCTCA deletion of SDHB gene. Have previously determined that the presence of this mutation in our population is significantly higher than in others (p<0.0001). These findings prompted us to evaluate by haplotype analysis if this specific mutation was inherited from a common ancestor, showing a founder effect and ruling out the hypothesis of an independent origin (hot spot). Patients: we studied 14 patients (9 unrelated) with C166_170delCCTCA deletion of SDHB gene with PGL4. Fourteen control individuals were also included in this study. Aim: to determine by haplotype analysis the presence of a common ancestor in the inheritance of the recurrent mutation C166_170delCCTCA due to a founder effect in a population Argentina. Methods: haplotype analysis of the polymorphic regions that are in linkage disequilibrium in the locus of SDHB (intron 2 to 6) was performed. The polymorphic regions studied were: rs 2235930, rs 2746467, rs 7550829, rs 10887990, rs 4920653. These five "tag SNP" were selected using Haploview Tagger software tool. Two additional microsatellites GATA29A05 and D1S2697 were included in the analysis. Genotype of the five Tag-SNP were determined through PCR and automatic sequencing or digestion with restriction enzymes. Microsatellites were amplified by PCR with one primer labeled with the fluorophore 6 -FAM. These labeled PCR products were separated by capillary electrophoresis according to their size, which was determined in each case using the Peak Scanner software. The PHASE program was used to calculate the frequency of haplotypes in the patients and in the control population. Results: haplotype distribution revealed the same haplotype 267 ACGTC 202 in all the SDHB c166_170delCCTCA mutation carriers and was not present in the control population of this study. These results are consistent with the low calculated theoretical frequency in CEU population (2.28 %) as well as the low frequency observed in the Spanish population (1.05 %). Conclusion: The presence of this rare haplotype 267 ACGTC 202 in all PGL4 patients analyzed with C166_170delCCTCA deletion of the SDHB gene support the hypothesis of the existence of a common ancestor for this mutation in our population, suggesting a founder effect.