Isolated focal cortical dysplasia type II: genes and variants

Genes linked to Isolated focal cortical dysplasia type II

• MTOR: Serine/threonine-protein kinase mTOR

  It integrates nutrient, energy, oxygen, and growth-factor signals to control protein synthesis, autophagy, metabolism, and cell growth. Activating germline or mosaic variants can cause developmental brain overgrowth and epilepsy, while persistent pathway activation is common in cancer.

  9 disease-causing and 16 uncertain variants in MTOR are linked to Isolated focal cortical dysplasia type II.

• TSC2: Tuberin

  Together with TSC1, it inactivates RHEB and restrains mTORC1 when growth conditions are unfavorable. Loss-of-function variants cause tuberous sclerosis complex with hamartomas and tumors affecting the brain, kidneys, skin, heart, lungs, and other organs.

  2 disease-causing and 169 uncertain variants in TSC2 are linked to Isolated focal cortical dysplasia type II.

• RHEB: GTP-binding protein Rheb

  Its GTP-bound form directly activates mTORC1 in response to growth and nutrient signals and is normally restrained by the TSC1-TSC2 complex. Activating variants can cause neurodevelopmental overgrowth and epilepsy phenotypes through excessive mTOR signaling.

  1 disease-causing and 0 uncertain variants in RHEB are linked to Isolated focal cortical dysplasia type II.

• TSC1: Hamartin

  Together with TSC2, it restrains RHEB and mTORC1 signaling, preventing inappropriate cell growth when nutrients or growth signals are limited. Loss-of-function variants cause tuberous sclerosis complex with hamartomas and tumors in the brain, kidney, skin, heart, lungs, and other organs.

  0 disease-causing and 219 uncertain variants in TSC1 are linked to Isolated focal cortical dysplasia type II.

Weakly linked (only a few uncertain records): NTHL1.

Where Isolated focal cortical dysplasia type II variants cluster

• MTOR TPR 4 (positions 1443–1473): 4 of 9 disease-causing changes, 36.5× more than its size predicts.

Known disease-causing variants in Isolated focal cortical dysplasia type II

Which prediction tools work for Isolated focal cortical dysplasia type II

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

• PolyPhen-2: 78 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome is also caused by MTOR variants; they fall mostly in different places as the Isolated focal cortical dysplasia type II variants (13 disease-causing).
• Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes is also caused by MTOR variants; they fall mostly in different places as the Isolated focal cortical dysplasia type II variants (12 disease-causing).
• CEBALID syndrome is also caused by MTOR variants; they fall mostly in different places as the Isolated focal cortical dysplasia type II variants (6 disease-causing).
• Tuberous sclerosis is also caused by TSC2 variants; they fall mostly in different places as the Isolated focal cortical dysplasia type II variants (57 disease-causing).
• Ovarian cancer is also caused by TSC2 variants; they fall mostly in different places as the Isolated focal cortical dysplasia type II variants (4 disease-causing).

Diseases related to Isolated focal cortical dysplasia type II

• Tuberous sclerosis, also linked to TSC1 and TSC2
• Ovarian cancer, also linked to TSC1 and TSC2
• Tuberous sclerosis syndrome, also linked to TSC1 and TSC2
• Lymphangiomyomatosis, also linked to TSC1 and TSC2
• Familial adenomatous polyposis, also linked to TSC2
• Malignant tumor of urinary bladder, also linked to TSC1
• Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, also linked to MTOR
• Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, also linked to MTOR
• Hepatocellular carcinoma, also linked to TSC2
• CEBALID syndrome, also linked to MTOR

Frequently asked questions

Which genes are linked to Isolated focal cortical dysplasia type II?

In CATVariant, Isolated focal cortical dysplasia type II is linked to 4 analyzed proteins: MTOR (Serine/threonine-protein kinase mTOR), TSC2 (Tuberin), RHEB (GTP-binding protein Rheb) and TSC1 (Hamartin).

How many genetic variants are linked to Isolated focal cortical dysplasia type II?

448 variants: 12 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 405 are of uncertain significance or have conflicting reports.

Which uncertain variants in Isolated focal cortical dysplasia type II look disease-causing?

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

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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