The Mutation Spectrum of Rare Variants in the Gene of Adenosine Triphosphate (ATP)-Binding Cassette Subfamily C Member 8 in Patients with a MODY Phenotype in Western Siberia

During differential diagnosis of diabetes mellitus, the greatest difficulties are encountered with young patients because various types of diabetes can manifest themselves in this age group (type 1, type 2, and monogenic types of diabetes mellitus, including maturity-onset diabetes of the young (MODY)). The MODY phenotype is associated with gene mutations leading to pancreatic-β-cell dysfunction. Using next-generation sequencing technology, targeted sequencing of coding regions and adjacent splicing sites of MODY-associated genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, KCNJ11, ABCC8, and APPL1) was carried out in 285 probands. Previously reported missense variants c.970G>A (p.Val324Met) and c.1562G>A (p.Arg521Gln) in the ABCC8 gene were found once each in different probands. Variant c.1562G>A (p.Arg521Gln) in ABCC8 was detected in a compound heterozygous state with a pathogenic variant of the HNF1A gene in a diabetes patient and his mother. Novel frameshift mutation c.4609_4610insC (p.His1537ProfsTer22) in this gene was found in one patient. All these variants were detected in available family members of the patients and cosegregated with diabetes mellitus. Thus, next-generation sequencing of MODY-associated genes is an important step in the diagnosis of rare MODY subtypes.