Abstract
Background: Monogenic diabetes of the young, better known as MODY (Maturity Onset Diabetes of the Young) corresponds to 1-2% of all cases of diabetes mellitus, representing a significant number of cases, since it is subtype of a highly prevalent disease in Brazil and worldwide. MODY is characterized by defects of insulin secretion, autosomal dominant mode of inheritance, early-onset hyperglycemia (usually before 25 years old) and negative beta cell antibodies. Patients with MODY show great clinical and genetic heterogeneity and are often misdiagnosed as type 1 or type 2 diabetes. Diagnosis of MODY has great therapeutic and prognostic relevance; however, confirmation can only be done by molecular genetic testing. Given the difficulty of performing routine genetic testing (especially high cost), most patients with MODY are not diagnosed. To date, several mutations in 13 different genes have been implicated in MODY. Up to 80% of cases with MODY phenotype show mutations in those genes. Usually, molecular diagnosis is done by traditional sequencing of a specific gene associated with a MODY subtype, according to the patient's phenotype. Next-generation sequencing seems a cost-effective genetic analysis in patients with clinical diagnosis of MODY, and also enables the identification of novel genes associated with this disease. Objectives: To develop and to validate a new method for molecular genetic diagnosis of MODY using next-generation sequencing (NGS) platform. Correlate the molecular findings to the clinical characteristics of patients with MODY phenotype. Patients and Methods: We will study 60 cases with MODY phenotype. We will perform simultaneous sequencing of the coding regions and introns of 13 genes associated with MODY (MiSeq, Illumina, Inc.). In cases with no identified mutation, we will perform exome sequencing of 32 genes previously related to other forms of monogenic diabetes. Inclusion of candidate genes may allow the identification of novel genes associated with MODY. NGS results will be validated by Sanger sequencing and/or Multiplex Ligation-dependent Probe Amplification (MLPA). Identified mutations will be correlated with phenotype. Novel mutations will be validated in normal non-diabetic population and if required will be submitted to functional studies. (AU)
Scientific publications
(7)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
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CAETANO, LILIAN A.;
COSTA-RIQUETTO, ALINE D.;
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DOTTO, RENATA P.;
REIS, ANDRE F.;
WEINERT, LETICIA S.;
SILVEIRO, SANDRA P.;
VENDRAMINI, MARCIO F.;
DO PRADO, FLAVIENE A.;
ABRAHAO, GIOVANNA C. P.;
DE ALMEIDA, ANA GREGORIA F. P.;
RODRIGUES TAVARES, MARIA DA G.;
GONCALVES, WAGNER RODRIGO B.;
SANTOMAURO JUNIOR, AUGUSTO C.;
HALPERN, BRUNO;
JORGE, ALEXANDER A. L.;
NERY, MARCIA;
TELES, MILENA G.
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FLOH, F. O.;
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