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. 2019 Dec;7(12):e962.
doi: 10.1002/mgg3.962. Epub 2019 Oct 8.

Targeted sequencing identifies novel variants in common and rare MODY genes

Lucas S de Santana  1 , Lilian A Caetano  1   2 , Aline D Costa-Riquetto  1   2 , Pedro C Franco  1   2 , Renata P Dotto  3 , André F Reis  3 , Letícia S Weinert  4 , Sandra P Silveiro  4 , Marcio F Vendramini  5 , Flaviene A do Prado  6 , Giovanna C P Abrahão  7 , Ana Gregória F P de Almeida  8 , Maria da G Rodrigues Tavares  9 , Wagner Rodrigo B Gonçalves  10 , Augusto C Santomauro Junior  11 , Bruno Halpern  12 , Alexander A L Jorge  1 , Marcia Nery  2 , Milena G Teles  1   2
Affiliations

Targeted sequencing identifies novel variants in common and rare MODY genes

Lucas S de Santana et al. Mol Genet Genomic Med. 2019 Dec.

Abstract

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.

Keywords: ACMG/AMP; MODY; MODY-X; targeted sequencing.

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Conflict of interest statement

Nothing to Disclose—authors LSS, LAC, ADCR, PCF, RPD, AFR, LSW, SPS, MFV, FAP, GCPA, AGFPA, MGRT, WRBG, ACSJ, BH, AALJ, MN, MGT.

Figures

Figure 1
Figure 1
Flowchart of the study cohort selection. To select candidates for tNGS, we performed an initial genetic screening in 198 probands for 3 MODY subtypes, namely, GCK, HNF1A, and HNF1B. This candidate gene approach has been guided using clinical laboratory characteristics specific to each phenotype. Only 1 gene was investigated per patient, using Sanger sequencing (GCK OR HNF1A) OR MLPA (HNF1B). The cohort described in the current study is composed of patients who did not present any candidate variant in this initial approach (GCK, HNF1A, HNF1B) and were selected for tNGS. *Minimum inclusion criteria: Available in Supplemental Material ‐ Cohort Selection and Data Analysis; ¥ Number of patients presenting pathogenic / likely pathogenic variants
Figure 2
Figure 2
Pedigrees of screened MODY families with pathogenic/likely pathogenic/uncertain significance variants (A ‐ Common MODY genes, B ‐ Rare MODY genes). Square: male; Circle: female; Grey filled symbol: patient with prediabetes; Black filled symbol: patient with diabetes; Empty symbol: patient without diabetes nor prediabetes; Green filled symbol: renal cysts; Red filled symbol: pancreatic malformation; Blue filled symbol: low fecal elastase (LFE); Yellow filled symbol: LDL elevation; WT: wild‐type allele; MT: altered allele; ?/?: patient not genotyped
See this image and copyright information in PMC

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