Targeted sequencing identifies novel variants in common and rare MODY genes

Background: Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. To date, mutations in 11 genes have been frequently associated with this phenotype. In Brazil, few cohorts have been screened for MODY, all using a candidate gene approach, with a high prevalence of undiagnosed cases (MODY-X). Methods: We conducted a next-generation sequencing target panel (tNGS) study to investigate, for the first time, a Brazilian cohort of MODY patients with a negative prior genetic analysis. One hundred and two patients were selected, of which 26 had an initial clinical suspicion of MODY-GCK and 76 were non-GCK MODY. Results: After excluding all benign and likely benign variants and variants of uncertain significance, we were able to assign a genetic cause for 12.7% (13/102) of the probands. Three rare MODY subtypes were identified (PDX1/NEUROD1/ABCC8), and eight variants had not been previously described/mapped in genomic databases. Important clinical findings were evidenced in some cases after genetic diagnosis, such as MODY-PDX1/HNF1B. Conclusion: A multiloci genetic approach allowed the identification of rare MODY subtypes, reducing the large percentage of MODY-X in Brazilian cases and contributing to a better clinical, therapeutic, and prognostic characterization of these rare phenotypes

Analysis of polymorphisms ALA55VAL and exon 8 insertion/delection of UCP-2 gene and their relations with severe obesity

As proteínas desacopladoras ("Uncoupling Proteins" - UCP) sao transportadores da membrana mitocondrial interna que dissipam o gradiente de prótons, liberando a energia estocada na forma de calor. Um dos subtipos desta proteína, a UCP-2, é largamente expressa no tecido adiposo branco em humanos, estando implicada no balanço energético em indivíduos adultos. Sendo a obesidade decorrente de um desbalanço entre o consumo calórico e o gasto energético, as UCPs tem sido investigadas como genes candidatos para a regulaçao do peso corporal. No presente estudo, investigamos associaçoes entre os polimorfismos Ala55Val no exon 4 e Inserçao / Deleçao de 45 pares de base no exon 8 do gene Ida UCP-2 com indicadores de obesidade e resistência à insulina. Foram selecionados 100 indivíduos portadores de obesidade severa (I.M.C. ? 40 kg/m2) e 70 indivíduos com I.M.C. entre 18 e 25 kg/m2, comparáveis em relaçao a idade e sexo Verificamos que a distribuiçao genotípica dos dois polimorfismos foi semelhante entre os indivíduos portadores de obesidade e os com peso adequado. Em relaçao ao polimorfismo Ala55Val no exon 4, os portadores de obesidade e carreadores do alelo Val apresentaram maiores níveis de pressao arterial sistólica (150 ñ 13,5 mmHg vs 140 ñ 19,3 mmHg; p= 0,024) quando comparados àqueles com genótipo Ala/Ala. Porém, em relaçao a outras variáveis antropométricas e metabólicas pesquisadas, nao encontramos associaçao com os polimorfismos. Em conclusao, na populaçao estudada, as variantes Ala55Val no exon 4 e Inserçao / Deleçao no exon 8 do gene da UCP-2 nao sao fatores contribuintes para a obesidade severa ou outras anormalidades metabólicas. Porém, é possível que a variante do exon 4 do gene da UCP-2 possa contribuir para a elevaçao de pressao arterial sistólica entre os portadores de obesidade.BV UNIFESP: Teses e dissertaçõe

Targeted sequencing identifies novel variants in common and rare MODY genes

Background: Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. To date, mutations in 11 genes have been frequently associated with this phenotype. In Brazil, few cohorts have been screened for MODY, all using a candidate gene approach, with a high prevalence of undiagnosed cases (MODY-X). Methods: We conducted a next-generation sequencing target panel (tNGS) study to investigate, for the first time, a Brazilian cohort of MODY patients with a negative prior genetic analysis. One hundred and two patients were selected, of which 26 had an initial clinical suspicion of MODY-GCK and 76 were non-GCK MODY. Results: After excluding all benign and likely benign variants and variants of uncertain significance, we were able to assign a genetic cause for 12.7% (13/102) of the probands. Three rare MODY subtypes were identified (PDX1/NEUROD1/ABCC8), and eight variants had not been previously described/mapped in genomic databases. Important clinical findings were evidenced in some cases after genetic diagnosis, such as MODY-PDX1/HNF1B. Conclusion: A multiloci genetic approach allowed the identification of rare MODY subtypes, reducing the large percentage of MODY-X in Brazilian cases and contributing to a better clinical, therapeutic, and prognostic characterization of these rare phenotypes

Targeted sequencing identifies novel variants in common and rare MODY genes

Background: Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. To date, mutations in 11 genes have been frequently associated with this phenotype. In Brazil, few cohorts have been screened for MODY, all using a candidate gene approach, with a high prevalence of undiagnosed cases (MODY-X). Methods: We conducted a next-generation sequencing target panel (tNGS) study to investigate, for the first time, a Brazilian cohort of MODY patients with a negative prior genetic analysis. One hundred and two patients were selected, of which 26 had an initial clinical suspicion of MODY-GCK and 76 were non-GCK MODY. Results: After excluding all benign and likely benign variants and variants of uncertain significance, we were able to assign a genetic cause for 12.7% (13/102) of the probands. Three rare MODY subtypes were identified (PDX1/NEUROD1/ABCC8), and eight variants had not been previously described/mapped in genomic databases. Important clinical findings were evidenced in some cases after genetic diagnosis, such as MODY-PDX1/HNF1B. Conclusion: A multiloci genetic approach allowed the identification of rare MODY subtypes, reducing the large percentage of MODY-X in Brazilian cases and contributing to a better clinical, therapeutic, and prognostic characterization of these rare phenotypes