High Prevalence and Common Forms of Maturity-Onset Diabetes of the Young in Greenland.

Abstract

Objectives: Population studies have identified common genetic variants contributing substantially to the burden of diabetes in Greenland. However, handling of suspected monogenic diabetes in diabetes clinics in Greenland has not been described. We aimed to describe the referral rate, prevalence, and genetic causes of clinically identified monogenic diabetes in Greenland.

Methods: All diabetes patients in Greenland referred for genetic testing due to suspected monogenic diabetes between 2014-2022 were tallied. Targeted short read sequencing and Sanger sequencing of probands and their family members were used to screen for potentially deleterious variants in the Maturity-Onset Diabetes of the Young (MODY) genes GCK, HNF1A, HNF1B, and HNF4A. Clinical data were extracted from the electronic medical records and whole genome sequencing was performed for families with potentially deleterious variants for genetic ancestry analysis.

Results: Over the study period, 58 probands were referred for genetic testing, equivalent to 0.1% of the population. Five variants were identified: GCK p.F133L, GCK p.D205E, HNF1A c.1108G>T, HNF1B p.Q182*, HNF4A -178A>G. These variants were found in 11 probands and 19 family members, equivalent to a population prevalence of monogenic diabetes of 0.05%. Local ancestry analysis revealed that all the variants were found exclusively in Inuit haplotypes, despite all individuals being admixed with both Inuit and European genetic ancestry.

Conclusions: We show that the rate of referral and prevalence of monogenic diabetes is substantially higher in Greenland than in other populations and that both rare and more common population-specific variants of Inuit genetic ancestry contribute to the high prevalence.