Table 1.
Clinical implications of some common and important causes of monogenic diabetes
| Gene | Inheritance/phenotypes | Disease mechanism/special features | Importance of genetic diagnosis |
|---|---|---|---|
| GCK | AD: GCK-MODY (common) | Reduced function of glucokinase enzyme raises set point for insulin secretion that is otherwise normal; high population prevalence of causal variants (∼1 in 1,000) | No treatment needed for most patients (except possibly during pregnancy) |
| AR: GCK-NDM (very rare) | |||
| HNF1A | AD: HNF1A-MODY (common) | LOF of β-cell transcription factor; glucosuria is common; risk for benign hepatic adenomas (rarely can become large and/or complicated) | Excellent glycemic control usually possible with low-dose oral sulfonylureas |
| HNF4A | AD: HNF4A-MODY (uncommon) | LOF of β-cell transcription factor; carriers may have history of large birth weights and/or hyperinsulinemic hypoglycemia | Often responsive to low-dose oral sulfonylureas |
| HNF1B | AD: HNF1B-MODY (uncommon) | LOF of pancreatic/renal transcription factor; renal cysts/genitourinary malformations (may be more penetrant than diabetes); hypomagnesemia; exocrine pancreatic insufficiency, altered liver function tests, hyperuricemia, developmental delay (as part of chromosome 17q deletion syndrome) | Optimal treatment for diabetes not well established; genetic diagnosis will inform monitoring and management of other features |
| ABCC8 | AD/AR: ABCC8-NDM (common) | Activating missense mutations in β-cell KATP channel SUR1 subunit impair glucose-stimulated insulin secretion; NDM may have a spectrum of neurodevelopmental dysfunction | Usually responds to high-dose oral sulfonylureas; genetic diagnosis facilitates monitoring/intervention for neurodevelopmental problems |
| ABCC8-MODY (rare) | |||
| KCNJ11 | AD: KCNJ11-NDM (common) | Activating missense mutations in β-cell KATP channel Kir6.2 subunit impair glucose-stimulated insulin secretion; NDM often have a spectrum of neurodevelopmental dysfunction | Usually responds to high-dose oral sulfonylureas; genetic diagnosis facilitates monitoring/intervention for neurodevelopmental problems |
| KCNJ11-MODY (rare) | |||
| 6q24 (imprinted locus) | Most common cause of transient NDM | Overexpression of maternally imprinted 6q24 genes causes impairment of β-cell development and function; after remission of NDM within first year of life, diabetes will often recur in adolescence or adulthood | Diabetes recurring later in life is often responsive to noninsulin therapies |
| INS | AD/AR: INS-NDM (common) | Missense mutations cause insulin protein misfolding and progressive β-cell death (other mechanisms occur more rarely) | Early intensive insulin treatment; future treatments may feasibly target molecular mechanism(s) |
| AD: INS-MODY (rare) |
AD, autosomal dominant; AR, autosomal recessive; Kir6.2, inward rectifier potassium channel 6.2; SUR, sulfonylurea receptor.