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. 2020 Nov 12;43(12):3117–3128. doi: 10.2337/dci20-0065

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.