Low Prevalence of HNF1A Mutations After Molecular Screening of Multiple MODY Genes in 58 Italian Families Recruited in the Pediatric or Adult Diabetes Clinic From a Single Italian Hospital

Maturity-onset diabetes of the young (MODY; MIM# 606391) is a genetically and clinically heterogeneous form of diabetes, accounting for 1–2% of all diabetes cases (1). MODY is characterized by mild hyperglycemia or overt diabetes usually detected in three consecutive generations, with onset before the age of 25 years and absence of type 1 diabetes autoantibodies. Among the thirteen MODY genes identified, two subtypes, GCK-MODY and HNF1A-MODY, account for most of cases (1). The prevalence of GCK-MODY has been reported higher in Southern Europe (2), while HNF1A-MODY is the most common MODY subtype in Northern Europe (3). This difference might be attributable to the clinical setting in which genetic screening is performed, especially when pediatric and adult diabetes clinics are distinct entities. We addressed this issue by investigating MODY patients identified in the pediatric or in the adult diabetes clinics of the same research-based hospital in Southern Italy to obtain data from a homogeneous geographic and genetic background. We selected 58 probands of Italian ancestry fulfilling stringent MODY criteria: 1) blood glucose >100 mg/dL (confirmed), 2) no type 1 diabetes autoantibodies, and 3) three consecutive generations with hyperglycemia before age 25 years. Forty-three patients were recruited at the pediatric clinic (age 1–18 years) and 15 at the adult clinic (age >18 years). We screened by DNA sequencing six “classic” MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1) (1) in both groups and INS (MODY 10) and KCNJ11 (MODY 13) genes in the pediatric group.

In the pediatric group, we identified 29 GCK (67.4%), 6 HNF1A (14%), 2 HNF4A (4.6%), and 2 HNF1B (4.6%) mutations, with only 4 children (9.3%) remaining without a genetic diagnosis (MODY X). In the adult group, we detected 2 GCK (13.3%) (P < 0.001 vs. pediatric group), 3 HNF1A (20%), and 1 HNF4A (6.7%) mutations. Nine adult patients were classified as MODY X (60%, P < 0.001 vs. pediatric group) (Table 1).

We thus confirmed that GCK mutations represent the most common MODY defect in the pediatric setting, whereas they are rare in patients from the adult diabetes clinic. HNF1A mutations ranked second (14%) in the pediatric clinic but accounted for a similar proportion (20%) among adults. This result was in keeping with previous data (14%) obtained in a total of 42 Italian families with autosomal dominant diabetes recruited in Central (Tuscany, Sardinia) and Northern (Piedmont) Italy (4,5), and it was in sharp contrast with results obtained in Northern Europe (3). The major strength of our investigation is that the two groups of patients were recruited from the same geographic area and screened in the same laboratory. Conversely, we acknowledge that the small number of families in the adult group represents a study limitation. Thus, these results need to be replicated before one can firmly conclude that there is a “latitude” of MODY across Europe. In all, our study confirms that HNF1A mutations are much less prevalent in Italy compared with Northern Europe and that this does not depend on ascertainment bias.