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, wit...

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Published in:	Molecular genetics & genomic medicine Vol. 7; no. 12; pp. e962 - n/a
Main Authors:	Santana, Lucas S., Caetano, Lilian A., Costa‐Riquetto, Aline D., Franco, Pedro C., Dotto, Renata P., Reis, André F., Weinert, Letícia S., Silveiro, Sandra P., Vendramini, Marcio F., Prado, Flaviene A., Abrahão, Giovanna C. P., Almeida, Ana Gregória F. P., Tavares, Maria da G. Rodrigues, Gonçalves, Wagner Rodrigo B., Santomauro Junior, Augusto C., Halpern, Bruno, Jorge, Alexander A. L., Nery, Marcia, Teles, Milena G.
Format:	Journal Article
Language:	English
Published:	United States John Wiley & Sons, Inc 01-12-2019 John Wiley and Sons Inc Wiley
Subjects:	ACMG/AMP Adolescent Adult Autosomal dominant inheritance Basic Helix-Loop-Helix Transcription Factors - genetics Benign Beta2 protein Brazil Cohort Studies Data analysis Diabetes Diabetes mellitus Diabetes Mellitus, Type 2 - genetics Fasting Female Gene sequencing Genes Genetic analysis Genetic Predisposition to Disease Genetic screening Genetic Testing - methods Genomics Genotype & phenotype Heredity High-Throughput Nucleotide Sequencing - methods Homeodomain Proteins - genetics Humans Hyperglycemia Male Medical laboratories MODY MODY-X Mutation Original Peptides Phenotypes Sequence Analysis, DNA Studies Sulfonylurea Receptors - genetics targeted sequencing Trans-Activators - genetics Young Adult Brazil ACMG/AMP targeted sequencing MODY MODY-X
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Summary:	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. Maturity‐onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance and, to date, mutations in 11 genes have been frequently associated with this phenotype. We have conducted a NGS 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 and we were able to assign a genetic cause for 12.7% (13/102) of the probands, with three rare MODY subtypes were identified (PDX1/NEUROD1/ABCC8).
Bibliography:	Funding information Sao Paulo Research Foundation (FAPESP) grants #2013/19920‐2 and #2017/15365‐5 awarded to MGT, #2017/14703‐4 awarded to LSS, #2015/05123‐9 awarded to AFR, and #2013/02162‐8 awarded to Multiusuário SELA (School of Medicine, University of Sao Paulo—USP). National Council for Scientific and Technological Development (CNPq) grant #160044/2013‐8 awarded to RPD. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2324-9269 2324-9269
DOI:	10.1002/mgg3.962