The combination of two monogenic diseases, congenital lamellar ichthyosis and type 2 MODY diabetes mellitus

Objective — the research was aimed at studying clinical and molecular genetic characteristics of the most common subtypes of MODY (1—3) detected by NGS. Material and methods. The study included 312 patients (162 boys and 150 girls) aged 3 months to 25 years with suspected MODY. Inclusion criteria were as follows: carbohydrate metabolism disorders of varying severity, negative titer of ICA, IA2, and GAD autoantibodies, preserved secretion of endogenous insulin. NGS technique was used for molecular genetic studies. Custom DNA Panel was used for the multiplex PCR and sequencing using the Ion Ampliseq technique. Custom Diabetes Panel included 28 genes (13 MODY candidates genes and other diabetes-associated genes). Non-synonymous mutations that were not previously described were rated as «probably pathogenic» if they had minor allele frequency of <0.1% and «pathogenic» when assessed against the ANNOVAR database. Results. Mutations in MODY candidate genes were detected in 178 (57.1%) probands. Of these, 99 mutations in GCK99 gene were found in 129 (41.4%) probands and 77 relatives, 20 mutations in HNF1A gene were found in 19 (6.1%) probands and 14 relatives, 8 mutations in HNF4A gene — in 9 (2.9%) probands and 3 relatives. All detected mutations were heterozygous. MODY1 subtype was not previously described in the Russian Federation. Conclusions. The Russian population is dominated by MODY2 subtype. Only MODY2 is characterized by typical clinical presentation. NGS is a highly effective method in the diagnosis of MODY.

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