A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY

Abstract

Aims/hypothesis Systematic studies on the phenotypic consequences of variants causal of HNF1A-MODY are rare. Our aim was to assess the phenotype of carriers of a single HNF1A variant and genetic and clinical factors affecting the clinical spectrum. Methods We conducted a family-based multigenerational study by comparing heterozygous carriers of the HNF1A p.(Gly292fs) variant with the non-carrier relatives irrespective of diabetes status. During more than two decades, 145 carriers and 131 non-carriers from 12 families participated in the study, and 208 underwent an OGTT at least once. We assessed the polygenic risk score for type 2 diabetes, age at onset of diabetes and measures of body composition, as well as plasma glucose, serum insulin, proinsulin, C-peptide, glucagon and NEFA response during the OGTT. Results Half of the carriers remained free of diabetes at 23 years, one-third at 33 years and 13% even at 50 years. The median age at diagnosis was 21 years (IQR 17–35). We could not identify clinical factors affecting the age at conversion; sex, BMI, insulin sensitivity or parental carrier status had no significant effect. However, for 1 SD unit increase of a polygenic risk score for type 2 diabetes, the predicted age at diagnosis decreased by 3.2 years. During the OGTT, the carriers had higher levels of plasma glucose and lower levels of serum insulin and C-peptide than the non-carriers. The carriers were also leaner than the non-carriers (by 5.0 kg, p=0.012, and by 2.1 kg/m2 units of BMI, p=2.2 × 10−4, using the first adult measurements) and, possibly as a result of insulin deficiency, demonstrated higher lipolytic activity (with medians of NEFA at fasting 621 vs 441 μmol/l, p=0.0039; at 120 min during an OGTT 117 vs 64 μmol/l, p=3.1 × 10−5). Conclusions/interpretation The most common causal variant of HNF1A-MODY, p.(Gly292fs), presents not only with hyperglycaemia and insulin deficiency, but also with increased lipolysis and markedly lower adult BMI. Serum insulin was more discriminative than C-peptide between carriers and non-carriers. A considerable proportion of carriers develop diabetes after young adulthood. Even among individuals with a monogenic form of diabetes, polygenic risk of diabetes modifies the age at onset of diabetes. Graphical abstract

Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts

“… 12 , 13 A recent study with a single pathogenic variant in HNF1A also found lower penetrance in extended family members supporting our results in the population cohort. 37 Our results showing reduced risk of disease in clinically unselected individuals have important clinical implications for the incidental finding of monogenic diabetes and a wide range of other monogenic disorders. Our data suggest that intensive close monitoring of the onset of diabetes may not be necessary for people with incidentally identified pathogenic variants in HNF1A and HNF4A due to a substantially lower risk of diabetes.…”

“…These suggest that the inherent risk of diabetes with pathogenic variants is constant irrespective of the setting and that the variation in the observed absolute risk of diabetes is due to varying proportions of non-variant factors (environmental or/and genetic modifiers). 11 , 37 These results also suggest that these factors are proportionally more in family members and less in the UK Biobank participants. Further studies across different settings are needed to identify genetic or non-genetic modifiers.…”

Achievements, prospects and challenges in precision care for monogenic insulin-deficient and insulin-resistant diabetes

“…Indeed, a high genome-wide burden of common risk alleles from genome-wide association studies (GWAS) confers a risk of diseases including diabetes that approaches the risk of single pathogenic Mendelian mutations [40]. Moreover, the penetrance of diabetes in those with HNF1A mutations is significantly influenced by polygenic type 2 diabetes risk score [41,42]. Interactions among rarer alleles are also likely, but adequately powered studies to identify genetic modifiers agnostically in rare disease are notoriously challenging or impossible for all but the least rare disease-causing mutations.…”

Identification of monogenic variants in more than ten per cent of children without type 1 diabetes-related autoantibodies at diagnosis in the Finnish Pediatric Diabetes Register

“…The sequencing and the mixed-meal tolerance test (MMTT) in an individual with a pathogenic variant in the KCNJ11 gene were performed in collaboration with the FINNMODY study [ 14 ], which identified and characterised individuals with a suspected or established diagnosis of monogenic diabetes in Finland from 2014 onwards ( www.botnia-study.org/finnmody ). The results of the MMTT were compared with 45 control individuals without diabetes from the Botnia Study described previously [ 15 ].…”