Leprechaunism syndrome: genes and variants

Genes linked to Leprechaunism syndrome

• INSR: Insulin receptor

  Its activation by insulin coordinates glucose uptake, metabolism, growth, and gene expression through PI3K-AKT and MAPK pathways. Biallelic severe loss-of-function variants cause Donohue or Rabson-Mendenhall syndromes, while heterozygous variants can cause severe insulin resistance.

  14 disease-causing and 31 uncertain variants in INSR are linked to Leprechaunism syndrome.

Where Leprechaunism syndrome variants cluster

• INSR Extracellular (positions 28–758): 12 of 14 disease-causing changes, 1.6× more than its size predicts.

Known disease-causing variants in Leprechaunism syndrome

Which prediction tools work for Leprechaunism syndrome

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

• REVEL: 91 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)
• CATVariant: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 81 out of 100
• MetaLR: 81 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 78 out of 100
• phyloP: 61 out of 100

Same protein, different disease

• Rabson-Mendenhall syndrome is also caused by INSR variants; they fall mostly in different places as the Leprechaunism syndrome variants (8 disease-causing).
• Insulin-resistant diabetes mellitus AND acanthosis nigricans is also caused by INSR variants; they fall mostly in different places as the Leprechaunism syndrome variants (7 disease-causing).

Diseases related to Leprechaunism syndrome

• Monogenic diabetes, also linked to INSR
• Type 2 diabetes mellitus, also linked to INSR
• Diabetes mellitus, also linked to INSR
• Type 1 diabetes mellitus, also linked to INSR
• Rabson-Mendenhall syndrome, also linked to INSR
• Insulin-resistant diabetes mellitus AND acanthosis nigricans, also linked to INSR
• Hyperinsulinism due to INSR deficiency, also linked to INSR

Frequently asked questions

Which genes are linked to Leprechaunism syndrome?

In CATVariant, Leprechaunism syndrome is linked to 1 analyzed protein: INSR (Insulin receptor).

How many genetic variants are linked to Leprechaunism syndrome?

48 variants: 14 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 31 are of uncertain significance or have conflicting reports.

Which uncertain variants in Leprechaunism syndrome 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 Leprechaunism syndrome?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.81, based on 8 disease-causing and 14 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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