Genetic and Clinical Characterization of Patients with HNF1B-Related MODY in Croatia

Abstract

Background: Mutation of the gene encoding Hepatocyte Nuclear transcription Factor-1 Beta (HNF1B) causes a rare monogenetic subtype of Maturity-Onset Diabetes of the Young (MODY). HNF1B-related MODY results in the dysfunction of multiple organ systems. However, genetic analysis enables personalized medicine for patients and families. Aims: To understand the clinical characteristics and explore the gene mutations in Croatian patients. Methods: This was a retrospective observational study of individuals (and their relatives) who were, due to the clinical suspicion of MODY, referred to the Department of Laboratory Diagnostics at the University Hospital Centre Zagreb for genetic testing. Results: A total of 118 participants, 56% females, were screened. Seven patients (three females) from five families were identified to have HNF1B-related MODY. The median age at diagnosis was 31 (11–45) years, the median c-peptide was 0.8 (0.55–1.39) nmol/L, the median HbA1c was 9.1 (5.7–18.4)%, and the median BMI was 22.9 kg/m2 (17–24.6). Patients had a variety of clinical manifestations; kidney disease was not as frequent as liver lesions, neuropsychiatric symptoms, hyperlipidemia, hyperuricemia, and hypomagnesemia. We identified two new pathogenic mutations (c.1006C > G protein p.His336Asp on exon 4 and c.1373T > G p protein Val458Gly on exon 7). Conclusions: In a study involving Croatian patients, new genetic (two previously unknown mutations) and clinical (diverse range of clinical presentations) aspects of HNF1B-related MODY were found.

The Phenotypic Variability Associated with Hepatocyte Nuclear Factor 1B Genetic Defects Poses Challenges in Both Diagnosis and Therapy

“…The p.His336Asp alteration (Patient 7) has been classified as a variant of uncertain significance (VUS) in the ClinVar database. However, in a recent cohort study from Croatia, this alteration was considered pathogenic, as it was segregated in several members of two families exhibiting MODY [11]. Similar findings were reported by a Turkish group [12].…”