Maturity-onset diabetes of the young: genes and variants

Genes linked to Maturity-onset diabetes of the young

• GCK: Hexokinase-4

  It sets the glucose threshold for insulin secretion in pancreatic beta cells and controls hepatic glucose phosphorylation after meals. Heterozygous loss-of-function variants cause GCK-MODY, stronger loss can cause neonatal diabetes, and activating variants can cause hyperinsulinemic hypoglycemia.

  68 disease-causing and 107 uncertain variants in GCK are linked to Maturity-onset diabetes of the young.

• HNF4A: Hepatocyte nuclear factor 4-alpha

  It coordinates transcription of genes involved in hepatic metabolism and pancreatic beta-cell function. Heterozygous pathogenic variants can cause maturity-onset diabetes of the young, often with fetal overgrowth and transient neonatal hyperinsulinemic hypoglycemia in affected families.

  9 disease-causing and 60 uncertain variants in HNF4A are linked to Maturity-onset diabetes of the young.

• KCNJ11: ATP-sensitive inward rectifier potassium channel 11

  Together with SUR1, its ATP-sensitive potassium conductance couples pancreatic beta-cell metabolism to membrane depolarization and insulin secretion. Activating variants cause neonatal diabetes, whereas loss-of-function variants can cause congenital hyperinsulinism.

  4 disease-causing and 80 uncertain variants in KCNJ11 are linked to Maturity-onset diabetes of the young.

• HNF1B: Hepatocyte nuclear factor 1-beta

  It controls developmental and metabolic gene programs in kidney, pancreas, liver, and genital tract. Haploinsufficiency or intragenic pathogenic variants cause a multisystem disorder often featuring renal cysts or malformations, maturity-onset diabetes of the young, hypomagnesemia, and genital abnormalities.

  4 disease-causing and 44 uncertain variants in HNF1B are linked to Maturity-onset diabetes of the young.

• PDX1: Pancreas/duodenum homeobox protein 1

  It directs pancreatic development and later maintains beta-cell identity and insulin transcription. Biallelic severe loss can cause pancreatic agenesis and neonatal diabetes, while heterozygous variants can cause maturity-onset diabetes of the young.

  4 disease-causing and 50 uncertain variants in PDX1 are linked to Maturity-onset diabetes of the young.

• INS: Insulin

  After processing to insulin, it lowers blood glucose by promoting cellular glucose uptake, glycogen and lipid synthesis, and suppression of hepatic glucose production. Pathogenic variants can cause neonatal diabetes, maturity-onset diabetes of the young, or hyperproinsulinemia depending on their effect on folding and secretion.

  3 disease-causing and 13 uncertain variants in INS are linked to Maturity-onset diabetes of the young.

• ABCC8: ATP-binding cassette sub-family C member 8

  It senses cellular nucleotide levels as the regulatory component of pancreatic beta-cell ATP-sensitive potassium channels and thereby couples glucose metabolism to insulin secretion. Loss-of-function variants cause congenital hyperinsulinism, whereas activating variants can cause neonatal diabetes.

  2 disease-causing and 106 uncertain variants in ABCC8 are linked to Maturity-onset diabetes of the young.

Where Maturity-onset diabetes of the young variants cluster

• HNF4A Nuclear receptor (positions 57–132): 3 of 9 disease-causing changes, 2.1× more than its size predicts.

Known disease-causing variants in Maturity-onset diabetes of the young

Showing 60 of 94.

Uncertain variants in Maturity-onset diabetes of the young that look disease-causing

Which prediction tools work for Maturity-onset diabetes of the young

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• MetaLR: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 91 out of 100
• CATVariant: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 84 out of 100
• AlphaMissense: 76 out of 100
• MutPred2: 67 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 66 out of 100

Same protein, different disease

• Monogenic diabetes is also caused by GCK variants; they fall partly in the same places as the Maturity-onset diabetes of the young variants (235 disease-causing).
• Hyperinsulinemic hypoglycemia, familial, 1 is also caused by GCK variants; they fall in the same places as the Maturity-onset diabetes of the young variants (7 disease-causing).
• Monogenic diabetes is also caused by HNF4A variants; they fall mostly in different places as the Maturity-onset diabetes of the young variants (50 disease-causing).
• Renal cysts and diabetes syndrome is also caused by HNF1B variants; they fall mostly in different places as the Maturity-onset diabetes of the young variants (71 disease-causing).
• Nonpapillary renal cell carcinoma is also caused by HNF1B variants; they fall mostly in different places as the Maturity-onset diabetes of the young variants (4 disease-causing).
• Type 2 diabetes mellitus is also caused by HNF1B variants; they fall mostly in different places as the Maturity-onset diabetes of the young variants (4 disease-causing).
• Neonatal diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Maturity-onset diabetes of the young variants (8 disease-causing).
• Diabetes mellitus, permanent neonatal 3 is also caused by KCNJ11 variants; they fall mostly in different places as the Maturity-onset diabetes of the young variants (7 disease-causing).
• Hyperinsulinemic hypoglycemia, familial, 1 is also caused by KCNJ11 variants; they fall mostly in different places as the Maturity-onset diabetes of the young variants (7 disease-causing).
• Diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Maturity-onset diabetes of the young variants (6 disease-causing).
• Familial hyperinsulinism is also caused by KCNJ11 variants; they fall mostly in different places as the Maturity-onset diabetes of the young variants (6 disease-causing).
• Diabetes mellitus, permanent neonatal 3 is also caused by INS variants; they fall mostly in different places as the Maturity-onset diabetes of the young variants (11 disease-causing).
• Neonatal diabetes mellitus is also caused by INS variants; they fall mostly in different places as the Maturity-onset diabetes of the young variants (11 disease-causing).
• Type 1 diabetes mellitus is also caused by INS variants; they fall mostly in different places as the Maturity-onset diabetes of the young variants (8 disease-causing).
• Hyperproinsulinemia is also caused by INS variants; they fall mostly in different places as the Maturity-onset diabetes of the young variants (6 disease-causing).

Diseases related to Maturity-onset diabetes of the young

• Monogenic diabetes, also linked to ABCC8, GCK, HNF1B, HNF4A and 3 more
• Type 2 diabetes mellitus, also linked to ABCC8, GCK, HNF1B, HNF4A and 3 more
• Diabetes mellitus, also linked to ABCC8, HNF1B, HNF4A, INS and 2 more
• Permanent neonatal diabetes mellitus, also linked to ABCC8, GCK, INS and KCNJ11
• Hyperinsulinemic hypoglycemia, familial, 1, also linked to ABCC8, GCK and KCNJ11
• Diabetes mellitus, permanent neonatal 3, also linked to ABCC8, INS and KCNJ11
• Neonatal diabetes mellitus, also linked to ABCC8, INS and KCNJ11
• Familial hyperinsulinism, also linked to ABCC8, GCK and KCNJ11
• Renal cysts and diabetes syndrome, also linked to HNF1B and HNF4A
• Diabetes mellitus, transient neonatal, 2, also linked to ABCC8 and KCNJ11
• Atrial septal defect, also linked to ABCC8
• Pulmonary arterial hypertension, also linked to ABCC8

Frequently asked questions

Which genes are linked to Maturity-onset diabetes of the young?

In CATVariant, Maturity-onset diabetes of the young is linked to 7 analyzed proteins: GCK (Hexokinase-4), HNF4A (Hepatocyte nuclear factor 4-alpha), KCNJ11 (ATP-sensitive inward rectifier potassium channel 11), HNF1B (Hepatocyte nuclear factor 1-beta), PDX1 (Pancreas/duodenum homeobox protein 1), INS (Insulin) and 1 more.

How many genetic variants are linked to Maturity-onset diabetes of the young?

594 variants: 94 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 460 are of uncertain significance or have conflicting reports.

Which uncertain variants in Maturity-onset diabetes of the young look disease-causing?

13 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example GCK M41V, GCK I293T, GCK F330V, GCK E70Q and GCK L185R. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Maturity-onset diabetes of the young?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.91, based on 35 disease-causing and 36 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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