A Comprehensive Analysis of Hungarian MODY Patients—Part I: Gene Panel Sequencing Reveals Pathogenic Mutations in HNF1A, HNF1B, HNF4A, ABCC8 and INS Genes

Abstract

Maturity-onset diabetes of the young (MODY) has about a dozen known causal genes to date, the most common ones being HNF1A, HNF4A, HNF1B and GCK. The phenotype of this clinically and genetically heterogeneous form of diabetes depends on the gene in which the patient has the mutation. We have tested 450 Hungarian index patients with suspected MODY diagnosis with Sanger sequencing and next-generation sequencing and found a roughly 30% positivity rate. More than 70% of disease-causing mutations were found in the GCK gene, about 20% in the HNF1A gene and less than 10% in other MODY-causing genes. We found 8 pathogenic and 9 likely pathogenic mutations in the HNF1A gene in a total of 48 patients and family members. In the case of HNF1A-MODY, the recommended first-line treatment is low dose sulfonylurea but according to our data, the majority of our patients had been on unnecessary insulin therapy at the time of requesting their genetic testing. Our data highlights the importance of genetic testing in the diagnosis of MODY and the establishment of the MODY subtype in order to choose the most appropriate treatment.

Severe nephrotic syndrome and early end-stage diabetic kidney disease in ABCC8-MODY12: A case report

“…Pathogenic or likely pathogenic variants in ABCC8 are present in about 15% of individuals with neonatal diabetes and in some 2% of patients with MODY-monogenic diabetes ( De Franco et al, 2015 ; Gaál et al, 2021 ; Rafique et al, 2021 ). With regard to diabetic kidney disease, microalbuminuria was indeed observed in some patients with ABCC8 -MODY12.…”

Genetikai vizsgálati módszerek fejlődése egy emberöltő alatt és jelentőségük az endokrinológiában • Evolution of Genetic Methods in the Past Decades and Their Relevance in Endocrinology

“…Elsősorban azokban a betegségekben indokolt az NGS használata, ahol több gén érintettsége is felmerül. Különösen fontos ez az endokrinológiában a nemi mirigyek alulműködésének azon genetikailag meghatározott formáiban, ahol a gond az ezeket szabályozó agyi központokban (elsősorban a hipotalamuszban) található (hipogonadotróp hipogonadizmus) (Butz et al, 2021), a cukorbetegség ritka formáiban (Gaál et al, 2021) és e cikkgyűjtemény egy másik cikkében bemutatott feokromocitóma/paraganglióma (Perge-Igaz, 996-1004. ) genetikai hátterének vizsgálatában (Sarkadi et al, 2021).…”

The role of hepatocyte nuclear factor 4α (HNF4α) in tumorigenesis

“…Another vital role of HNF4α is the regulation of metabolic homeostasis. Most HNF4α-related diseases have abnormal insulin secretion such as occurrence of diabetes mellitus (including Type I and Type II diabetes mellitus), while the underlying molecular mechanism remains elusive ( 6 , 7 ). It has been shown that HNF4α interacts with Circadian Locomoter Output Cycles Protein Kaput (CLOCK)/BMAL1 to regulate a series of metabolic genes involved in lipid, glucose and amino acid homeostasis.…”