The Genetic Architecture of Diabetes in Pregnancy: Implications for Clinical Practice

The genetic architecture of diabetes mellitus in general and in pregnancy is complex, owing to the multiple types of diabetes that comprise both complex/polygenic forms and monogenic (largely caused by a mutation in a single gene) forms such as maturity-onset diabetes of the young (MODY). Type 1 diabetes (T1D) and type 2 diabetes (T2D) have complex genetic etiologies, with over 40 and 90 genes/loci, respectively, implicated that interact with environmental/lifestyle factors. The genetic etiology of gestational diabetes mellitus has largely been found to overlap that of T2D. Genetic testing for complex forms of diabetes is not currently useful clinically, but genetic testing for monogenic forms, particularly MODY, has important utility for determining treatment, managing risk in family members, and pregnancy management. In particular, diagnosing MODY2, caused by GCK mutations, indicates that insulin should not be used, including during pregnancy, with the possible exception of an unaffected pregnancy during the third trimester to prevent macrosomia. A relatively simple method for identifying women with MODY2 has been piloted. MODY1, caused by HNF4A mutations, can paradoxically cause neonatal hyperinsulinemic hypoglycemia and macrosomia, indicating that detecting these cases is also clinically important. Diagnosing all MODY types provides opportunities for diagnosing other family members.