Table 1.

Summary of actionable genes with related diabetes phenotype and actionability.

Gene	Mutation	Phenotype	Disease Mechanism	Additional Complication	Birth Weight	Actionability
ABCC8/ KCNJ11	Heterozygous and Homozygous GOF	Neonatal diabetes MODY Adult-onset diabetes	KATP channel permanently open, K+ efflux/membrane hyperpolarization/defective insulin secretion	Neurodevelopment dysfunction	Normal, as long as maternal hyperglycemia is properly treated Low, when only the fetus is mutated	High dose of sulphonylureas (also in pregnancy, as long as the fetus is mutated; otherwise, insulin should be given)
GCK	Heterozygous LOF Homozygous/Compound heterozygous LOF	GCK-MODY (moderate fasting hyperglycemia from birth, low risk of chronic complication) Neonatal diabetes	Increased glucose sensor threshold (glucose stimulated insulin secretion begins at higher glucose level)	None	Normal, as long as maternal hyperglycemia is properly treated Low, when only the fetus is mutated	No treatment needed (except during pregnancy when insulin is the treatment of choice)
HNF1A	Heterozygous and Homozygous LOF	HNF1A-MODY (fasting glycemia increase with age, normoglycemic glycosuria, liver adenomatosis)	Reduced HNF1A expression, reduced β-cell mass, blunted glycolysis and ATP production and eventually defective insulin secretion	Retinopathy, nephropathy and neuropathy are common. Ketoacidosis can develop	Normal, as long as maternal hyperglycemia is properly treated	Low dose of sulphonylureas also in pregnancy for the first two trimesters (when both the mother and the fetus are mutated)
HNF4A	Heterozygous LOF	HNF4-MODY (fasting glycemia increase with age, liver dysfunction)	Reduced HNF1A expression, reduced β-cell mass, blunted glycolysis and ATP production and eventually defective insulin secretion	Reduced triglycerides and lipoprotein serum concentration	Normal, as long as maternal hyperglycemia is properly treated
HNF1B	Heterozygous LOF	HNF1B-MODY (high fasting glycemia, ketoacidosis)	Reduced HNF1B expression, pancreatic hypoplasia, blunted glycolysis and ATP production and eventually defective insulin secretion	Kidney cysts and urinary tract abnormalities, atrophic pancreas, genital abnormalities, hyperuricemia, gout	Normal, as long as maternal hyperglycemia is properly treated Low, when only the fetus is mutated	Systemic screening for renal cysts, exocrine pancreatic function and genital abnormalities (especially in females)
PPARG	Heterozygous LOF	Severe insulin resistance	Defective adipocyte differentiation due to PPARG haploinsufficiency or dominant negative LOF mutation	Familial partial lipodystrophy type 3 (early-onset diabetes, hypertension, severe insulin resistance and dyslipidemia, hepatic steatosis)	No clear data are available	Thiazolidinediones
GATA4	Heterozygous LOF or complete gene deletion	Neonatal diabetes	Dysfunctional transcriptional activity, and altered embryonic organ development	Congenital heart malformation, pancreatic agenesis or hypoplasia	Low	Evaluation and follow up of congenital heart malformation and pancreatic agenesis/hypoplasia
GATA6	Heterozygous LOF	Neonatal diabetes Adult-onset diabetes	Dysfunctional transcriptional activity, and altered embryonic organ development	Congenital biliary tract anomalies, gut developmental disorders, neurocognitive abnormalities, additional endocrine abnormalities	Low

GOF: gain of function. LOF: loss of function.