Clinical and molecular genetic characteristics of MODY cases with digenic and oligogenic inheritance as defined by targeted next-generation sequencing

Abstract

The diagnosis of MODY should be verified by molecular genetic analysis. Recently the introduction of next-generation sequencing, allowing simultaneous analysis of several candidate genes, greatly facilitates the diagnosis of monogenic diseases including MODY. In addition, the simultaneous analysis of several candidate genes allows to identify cases with digenic and oligogenic inheritance. In this work we present the first description of MODY cases with digenic and oligogenic inheritance in our country.Aim — to characterize MODY cases with digenic and oligogenic inheritance as defined by targeted next-generation sequencing.Material and methods. 256 subjects (age range, 0.3—25 yrs; males, n=149, females, n=107) were included in the study. The patients fulfilled the following MODY criteria: diabetes or intermediate hyperglycemia, absence of β-cell autoimmunity (ICA, GAD, IA2, IAA antibodies), preserved C-peptide secretion. Molecular genetic analysis was performed by next-generation sequencing using custom Ion Ampliseq gene panel and PGM semiconductor sequencer (Ion Torrent). All mutations were confirmed by Sanger sequencing.Results. 10 patients (8 probands, 1 sibling and 1 parent) showed digenic inheritance of MODY: 3 patients with combination of mutations in 2 candidate genes of MODY, 7 — in a candidate genes of MODY and another gene, associated with diabetes mellitus. In 1 case (sibling) showed oligogenic inheritance (mutations in GCK, HNF4A and INSR genes). Seven of the identified mutations were not previously described.Conclusion. Next-generation sequencing is useful in identifying of MODY cases with digenic and oligogenic inheritance, which is extremely important with potentially modifying effect on the phenotype.

Genome Editing Human Pluripotent Stem Cells to Model β-Cell Disease and Unmask Novel Genetic Modifiers

“…epistasis, oligogenic inheritance) dedicated to understanding the effect of one gene/allele on the phenotypic expression of a second gene/allele ( 154 , 155 ). In the case of diabetes, there is a growing body of evidence that some subtypes may be the result of oligogenic inheritance, wherein the underlying etiology of the disorder is primarily genetic, but still requires the synergistic action of several genetic modifiers at disparate disease-linked loci ( 156 , 170 , 171 ). In this continuum between classical Mendelian and complex traits, possible protein coding disease modifiers include allelic heterogeneity that results from mutations within disease-linked loci, the activity of modifier genes that regulate others with important roles in glucose homeostasis, and the presence/absence of single nucleotide polymorphisms (SNPs) that are either necessary or sufficient to change the presence, penetrance, expressivity/heritability, or rate of progression of a disease.…”