Targeted sequencing identifies novel variants in common and rare MODY genes

Abstract

BackgroundMaturity‐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).MethodsWe 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.ResultsAfter 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.ConclusionA 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.

Genetic variants of ABCC8 and phenotypic features in Chinese early onset diabetes

“…2 In another East Asian study conducted in a Korean cohort with clinical suspicion of MODY, one (1/109, 0.9%) patient with ABCC8-MODY was identified. 33 Our findings were similar to the previous studies in diabetic populations despite different recruitment criteria for genetic test and ethnicity background.…”

Maturity Onset Diabetes of the Young—New Approaches for Disease Modelling

“…The MODY subtypes described above account for more than 99% of all MODY cases. With the increase in next-generation sequencing (NGS) capabilities, other rarer MODY cases have been reported [ 105 , 106 ]. The current knowledge for possible molecular pathophysiology in rarer forms of MODY were extensively summarised elsewhere [ 107 , 108 , 109 ].…”

GAD‐65 antibodies in a case of HNF1A‐Maturity‐Onset Diabetes of the Young: Double diabetes?

“…Because HNF‐1α is very important for the β‐cell functional differentiation and growth as well as its ability to synthesize and release insulin, mutations in this transcription factor lead to defective insulin secretion 12 . However, it often takes a long time before overt diabetes is diagnosed, as mutations in HNF‐1α compensatory downregulate the expression of SGLT‐2 in the kidneys 4 . This causes a lowered kidney threshold with increased glucosuria, which lowers glycemia.…”

“…Also the patient's daughter is heterozygous for the pathogenic mutation HNF1A:c.872dupC,p. Gly292ARgfs*25, which is the same mutation the father carries 4 …”

“…According to the current diagnostic criteria, MODY is characterized by the absence of autoantibodies to β‐cell antigens 2‐4 . If you are antibody positive, it follows you cannot have MODY.…”