The family-based characterisation of HNF1A-MODY

Background and aims: The view of the phenotype of HNF1A-MODY has largely been based on studies of individuals with either a pre-established diagnosis of MODY or features strongly suggestive of MODY, which poses a risk of neglecting phenotypic heterogeneity. To assess the timing of progression to diabetes, clinical features, and mortality among carriers of the most common MODY mutation in HNF1A, p.Gly292fs, we conducted a family-based comparative study in ten HNF1A-MODY families.
Materials and methods: From the families of the FINNMODY and Botnia studies, we examined 132 individuals with, and 123 without, the HNF1A mutation. Sampling included measurements of glucose, insulin, C-peptide (glucagon, FFA, and proinsulin for a subgroup) at fasting or during an OGTT, anthropometric measurements as well as mortality and morbidity data from national registries. Of 191 individuals with OGTT data, 106 participated in an OGTT more than once.
Results: Of 111 diabetic mutation carriers, the median age at diagnosis was 21 years (IQR: 17-34), whereas the median age of the 19 non-diabetic carriers at the most recent follow-up assessment was 27 years (IQR: 13-33, upper range: 63; two carriers lacked data for glucose values). The usability of the
Exeter MODY probability calculator was limited: 25 of 111 mutation carriers were older than 35 years at diagnosis, restricting the use of the calculator altogether. Of 86 carriers who developed diabetes by 35 years of age, the calculator failed to reach a threshold probability of 20% in 13 carriers. Thus, one-third of the diabetic carriers received either a false-negative probability score or no score at all. The BMI was 1.8 kg/m2 lower in carriers (adjusted BMI -1.4 kg/m2, adjusted weight -4.4 kg) than in non-carriers. Carriers and non-carriers showed no significant difference in birthweight (medians: 3.8 kg, 3.6 kg). Compared to non-carriers, carriers expectedly had an increased mortality rate during the follow-up (Cox HR 2.6, p=0.033; total N=204, 13 carriers and 12 non-carriers died).
Conclusion: HNF1A-MODY is more heterogeneous than previously reported; especially with respect to age at diagnosis of diabetes. Adult carriers are on average 4-5 kg leaner than non-carriers, despite no difference in birthweight.