Familial hyperinsulinism: genes and variants

Genes linked to Familial hyperinsulinism

• 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.

  20 disease-causing and 3 uncertain variants in ABCC8 are linked to Familial hyperinsulinism.

• 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 4 uncertain variants in KCNJ11 are linked to Familial hyperinsulinism.

• 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.

  1 disease-causing and 0 uncertain variants in GCK are linked to Familial hyperinsulinism.

Weakly linked (only a few uncertain records): HNF4A.

Where Familial hyperinsulinism variants cluster

• ABCC8 ABC transporter 2 (positions 1344–1578): 9 of 20 disease-causing changes, 3.0× more than its size predicts.

Known disease-causing variants in Familial hyperinsulinism

Uncertain variants in Familial hyperinsulinism that look disease-causing

Which prediction tools work for Familial hyperinsulinism

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

• CADD: 97 out of 100
• REVEL: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 86 out of 100
• phyloP: 82 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 Familial hyperinsulinism variants (31 disease-causing).
• Type 2 diabetes mellitus is also caused by ABCC8 variants; they fall mostly in different places as the Familial hyperinsulinism variants (27 disease-causing).
• Hereditary hyperinsulinism is also caused by ABCC8 variants; they fall mostly in different places as the Familial hyperinsulinism variants (22 disease-causing).
• Diabetes mellitus, transient neonatal, 2 is also caused by ABCC8 variants; they fall mostly in different places as the Familial hyperinsulinism variants (19 disease-causing).
• Diabetes mellitus, permanent neonatal 3 is also caused by ABCC8 variants; they fall mostly in different places as the Familial hyperinsulinism variants (17 disease-causing).
• Neonatal diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Familial hyperinsulinism variants (8 disease-causing).
• Diabetes mellitus, permanent neonatal 3 is also caused by KCNJ11 variants; they fall mostly in different places as the Familial hyperinsulinism variants (7 disease-causing).
• Hyperinsulinemic hypoglycemia, familial, 1 is also caused by KCNJ11 variants; they fall partly in the same places as the Familial hyperinsulinism variants (7 disease-causing).
• Diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Familial hyperinsulinism variants (6 disease-causing).
• Permanent neonatal diabetes mellitus is also caused by KCNJ11 variants; they fall partly in the same places as the Familial hyperinsulinism variants (6 disease-causing).
• Monogenic diabetes is also caused by GCK variants; they fall mostly in different places as the Familial hyperinsulinism variants (235 disease-causing).
• Maturity-onset diabetes of the young is also caused by GCK variants; they fall mostly in different places as the Familial hyperinsulinism variants (68 disease-causing).
• Hyperinsulinemic hypoglycemia, familial, 1 is also caused by GCK variants; they fall mostly in different places as the Familial hyperinsulinism variants (7 disease-causing).
• Permanent neonatal diabetes mellitus is also caused by GCK variants; they fall mostly in different places as the Familial hyperinsulinism variants (4 disease-causing).

Diseases related to Familial hyperinsulinism

• Monogenic diabetes, also linked to ABCC8, GCK and KCNJ11
• Maturity-onset diabetes of the young, also linked to ABCC8, GCK and KCNJ11
• Type 2 diabetes mellitus, also linked to ABCC8, GCK and KCNJ11
• Hyperinsulinemic hypoglycemia, familial, 1, also linked to ABCC8, GCK and KCNJ11
• Permanent neonatal diabetes mellitus, also linked to ABCC8, GCK and KCNJ11
• Diabetes mellitus, permanent neonatal 3, also linked to ABCC8 and KCNJ11
• Neonatal diabetes mellitus, also linked to ABCC8 and KCNJ11
• Diabetes mellitus, transient neonatal, 2, also linked to ABCC8 and KCNJ11
• Diabetes mellitus, 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 Familial hyperinsulinism?

In CATVariant, Familial hyperinsulinism is linked to 3 analyzed proteins: ABCC8 (ATP-binding cassette sub-family C member 8), KCNJ11 (ATP-sensitive inward rectifier potassium channel 11) and GCK (Hexokinase-4).

How many genetic variants are linked to Familial hyperinsulinism?

36 variants: 27 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 9 are of uncertain significance or have conflicting reports.

Which uncertain variants in Familial hyperinsulinism look disease-causing?

2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example KCNJ11 R136H and KCNJ11 R301C. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Familial hyperinsulinism?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.97, based on 22 disease-causing and 30 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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