Genetic and clinical characteristics of patients with HNF1A gene variations from the German-Austrian DPV database

OBJECTIVE: To determine prevalence, genetic and phenotype characteristics of patients with hepatocyte nuclear factor-1alpha (HNF1A) variants in the Diabetes Patienten Verlaufsdokumenation (DPV) multicentre database and to examine the influence of HNF1A mutation type, or location on clinical phenotypes. PATIENTS AND METHODS: Seventy-one DPV patients were labelled as HNF1A-MODY (MODY3). Forty-four patients carried HNF1A mutations, while 27 patients were found to have HNF1A polymorphisms only. Associations between mutation type/position and age at disease onset, HbAlc, body mass index (BMI), diagnosis, family history and treatment modality were analysed using non-parametric statistics (Wilcoxon test). RESULTS: Patients with HNF1A mutations were 36% male, aged 14.1+/-5.8 years at diagnosis, and slightly overweight (BMI-SDS: +0.8+/-1.1). Treatment was lifestyle intervention (20.5%), insulin (35.3%), oral anti-diabetic (OAD, 43%) and both insulin+OAD (15.9%). More patients with missense mutations (60%) than patients with nonsense mutations/frameshift (23.8%) did not use insulin (P=0.03). No differences were found with regard to mutation types, isoform or domain. We identified several previously undescribed mutations in the cohort including c.-158insGGGTTGG in the promoter region, G31X, E41X, Q130X, L162P, R245I, A269P, S355X, Q398X, Q473X, Q495X, E508X, P588fs-insGCCA and P588fs-delAC. Patients carrying HNF1A polymorphisms were significantly younger at diagnosis than patients with HNF1A mutations (10.9+/-4.2 vs 14.19+/-5.8 years; P=0.027), and all carried I27L, S487N and A98V (n=3). CONCLUSION: HNF1A-MODY is the second most frequent MODY diagnosis registered in the DPV database, and previously undescribed HNF1A mutations account for about one-third of HNF1A-MODY cases. Patients with HNF1A polymorphisms documented as HNF1A-MODY were misclassified. They may have autoantibody-negative type 1B or type 2 diabetes or may have other MODY types

HLA-typing, clinical, and immunological characterization of youth with type 2 diabetes mellitus phenotype from the German/Austrian DPV database.

AIM: To characterize the clinical and immunological features of HLA-typed youth with pediatric onset of type 2 diabetes mellitus (T2DM). METHOD: One hundred and seven patients with clinically diagnosed T2DM (aged ≤20 yr at diagnosis) were examined. DNA and serum, obtained after a median diabetes duration of 2.2 (Q1-Q3: 0.8-4.6) yr, were used for centralized HLA-typing and autoantibody (GADA, IA-2A, ZnT8A) measurements. RESULTS: 64.6% of patients were female and median age at diagnosis was 13.8 (Q1-Q3: 11.6-15.4) yr. Patients were obese [median body mass index-standard deviation score (BMI-SDS): 2.6 (2.0-3.1)], 88.0% had a family history of diabetes and 40.2% a migration background. Islet autoantibodies were detected in 16 (15.0%), among which 7 (6.5%) had multiple islet autoantibodies. Autoantibody positive patients had poorer metabolic control than autoantibody negative patients [glycosylated hemoglobin A1c (HbA1c): 8.1 (6.9-10.1) % vs. 6.6 (5.9-8.0) %; p = 0.033], while patients with HLA-DR genetic risk had higher BMI-SDS than those with HLA-DRXX [2.6 (2.4-3.7) vs. 2.4 (1.7-2.9); p = 0.007]. Metabolic syndrome (61.7%), microalbuminuria (13.4%), and retinopathy (3.9%) were diagnosed. Therapies used were lifestyle only (35.5%), oral anti-diabetics (OAD) only (43.3 %), insulin +  OAD (15.9%) and insulin only (5.6%). Patients with β-cell autoimmunity or HLA-DR genetic risk more frequently used insulin than confirmed T2DM patients (50.0 vs. 22.0%; p = 0.037) and less often had diabetic relatives (61.1 vs. 86.0%; p = 0.030). CONCLUSION: T2DM was confirmed in about 90% of patients while about 10% with β-cell autoimmunity or HLA-DR genetic risk likely had either T1.5DM or 'double diabetes' or an unknown diabetes type