Permanent neonatal diabetes mellitus: genes and variants

Genes linked to Permanent neonatal diabetes mellitus

• 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.

  7 disease-causing and 14 uncertain variants in ABCC8 are linked to Permanent neonatal diabetes mellitus.

• 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.

  6 disease-causing and 10 uncertain variants in KCNJ11 are linked to Permanent neonatal diabetes mellitus.

• 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.

  4 disease-causing and 15 uncertain variants in GCK are linked to Permanent neonatal diabetes mellitus.

• 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.

  0 disease-causing and 1 uncertain variants in INS are linked to Permanent neonatal diabetes mellitus.

Weakly linked (only a few uncertain records): KMT2D.

Where Permanent neonatal diabetes mellitus variants cluster

• ABCC8 ABC transporter 2 (positions 1344–1578): 3 of 7 disease-causing changes, 2.9× more than its size predicts.

Known disease-causing variants in Permanent neonatal diabetes mellitus

Which prediction tools work for Permanent neonatal diabetes mellitus

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

• REVEL: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 94 out of 100
• MutPred2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 83 out of 100
• phyloP: 81 out of 100
• SIFT: 73 out of 100

Same protein, different disease

• Hyperinsulinemic hypoglycemia, familial, 1 is also caused by ABCC8 variants; they fall mostly in different places as the Permanent neonatal diabetes mellitus variants (31 disease-causing).
• Type 2 diabetes mellitus is also caused by ABCC8 variants; they fall mostly in different places as the Permanent neonatal diabetes mellitus variants (27 disease-causing).
• Hereditary hyperinsulinism is also caused by ABCC8 variants; they fall mostly in different places as the Permanent neonatal diabetes mellitus variants (22 disease-causing).
• Familial hyperinsulinism is also caused by ABCC8 variants; they fall mostly in different places as the Permanent neonatal diabetes mellitus variants (20 disease-causing).
• Diabetes mellitus, transient neonatal, 2 is also caused by ABCC8 variants; they fall mostly in different places as the Permanent neonatal diabetes mellitus variants (19 disease-causing).
• Neonatal diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Permanent neonatal diabetes mellitus variants (8 disease-causing).
• Diabetes mellitus, permanent neonatal 3 is also caused by KCNJ11 variants; they fall mostly in different places as the Permanent neonatal diabetes mellitus variants (7 disease-causing).
• Hyperinsulinemic hypoglycemia, familial, 1 is also caused by KCNJ11 variants; they fall mostly in different places as the Permanent neonatal diabetes mellitus variants (7 disease-causing).
• Diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Permanent neonatal diabetes mellitus variants (6 disease-causing).
• Type 2 diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Permanent neonatal diabetes mellitus variants (6 disease-causing).
• Monogenic diabetes is also caused by GCK variants; they fall mostly in different places as the Permanent neonatal diabetes mellitus variants (235 disease-causing).
• Maturity-onset diabetes of the young is also caused by GCK variants; they fall mostly in different places as the Permanent neonatal diabetes mellitus variants (68 disease-causing).
• Hyperinsulinemic hypoglycemia, familial, 1 is also caused by GCK variants; they fall mostly in different places as the Permanent neonatal diabetes mellitus variants (7 disease-causing).

Diseases related to Permanent neonatal diabetes mellitus

• Monogenic diabetes, also linked to ABCC8, GCK, INS and KCNJ11
• Maturity-onset diabetes of the young, also linked to ABCC8, GCK, INS and KCNJ11
• Type 2 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
• Diabetes mellitus, also linked to ABCC8, INS and KCNJ11
• 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
• Hereditary hyperinsulinism, also linked to ABCC8

Frequently asked questions

Which genes are linked to Permanent neonatal diabetes mellitus?

In CATVariant, Permanent neonatal diabetes mellitus is linked to 4 analyzed proteins: ABCC8 (ATP-binding cassette sub-family C member 8), KCNJ11 (ATP-sensitive inward rectifier potassium channel 11), GCK (Hexokinase-4) and INS (Insulin).

How many genetic variants are linked to Permanent neonatal diabetes mellitus?

69 variants: 17 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 41 are of uncertain significance or have conflicting reports.

Which uncertain variants in Permanent neonatal diabetes mellitus look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Permanent neonatal diabetes mellitus?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 11 disease-causing and 870 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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