Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes: genes and variants

Genes linked to Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

• 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.

  12 disease-causing and 9 uncertain variants in MTOR are linked to Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.

• PIK3CA: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform

  Its p110-alpha catalytic activity generates PIP3 and activates AKT-dependent growth, survival, and metabolic signaling downstream of many receptors. Activating variants are frequent cancer drivers and, when present mosaically during development, can cause PIK3CA-related overgrowth spectrum.

  4 disease-causing and 2 uncertain variants in PIK3CA are linked to Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.

• PIK3R2: Phosphatidylinositol 3-kinase regulatory subunit beta

  1 disease-causing and 0 uncertain variants in PIK3R2 are linked to Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.

• AKT3: RAC-gamma serine/threonine-protein kinase

  It is especially important for growth and survival signaling in the developing brain. Activating mosaic or germline variants can cause megalencephaly and cortical malformation syndromes, while loss-of-function variants can be associated with microcephaly and neurodevelopmental impairment.

  1 disease-causing and 0 uncertain variants in AKT3 are linked to Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.

Where Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes variants cluster

• MTOR TPR 5 (positions 1474–1507): 3 of 12 disease-causing changes, 18.7× more than its size predicts.
• MTOR PI3K/PI4K catalytic (positions 2156–2469): 4 of 12 disease-causing changes, 2.7× more than its size predicts.

Known disease-causing variants in Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

Which prediction tools work for Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

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)
• SIFT: 52 out of 100

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 Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes variants (13 disease-causing).
• Isolated focal cortical dysplasia type II is also caused by MTOR variants; they fall mostly in different places as the Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes variants (9 disease-causing).
• CEBALID syndrome is also caused by MTOR variants; they fall mostly in different places as the Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes variants (6 disease-causing).
• PIK3CA related overgrowth syndrome is also caused by PIK3CA variants; they fall mostly in different places as the Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes variants (30 disease-causing).
• Cowden syndrome is also caused by PIK3CA variants; they fall mostly in different places as the Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes variants (23 disease-causing).
• Megalencephaly-capillary malformation-polymicrogyria syndrome is also caused by PIK3CA variants; they fall mostly in different places as the Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes variants (22 disease-causing).
• Ovarian neoplasm is also caused by PIK3CA variants; they fall partly in the same places as the Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes variants (5 disease-causing).
• PIK3CA constitutional syndrome is also caused by PIK3CA variants; they fall partly in the same places as the Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes variants (4 disease-causing).
• Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 is also caused by PIK3R2 variants; they fall mostly in different places as the Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes variants (6 disease-causing).
• Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 is also caused by AKT3 variants; they fall mostly in different places as the Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes variants (8 disease-causing).

Diseases related to Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

• Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, also linked to AKT3 and PIK3R2
• Noonan syndrome, also linked to PIK3CA
• Cowden syndrome, also linked to PIK3CA
• Ovarian cancer, also linked to PIK3CA
• PIK3CA related overgrowth syndrome, also linked to PIK3CA
• Familial cancer of breast, also linked to PIK3CA
• Megalencephaly-capillary malformation-polymicrogyria syndrome, also linked to PIK3CA
• Colorectal cancer, also linked to PIK3CA
• Gastric cancer, also linked to PIK3CA
• Malignant tumor of urinary bladder, also linked to PIK3CA
• Non-small cell lung carcinoma, also linked to PIK3CA
• Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, also linked to MTOR

Frequently asked questions

Which genes are linked to Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes?

In CATVariant, Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes is linked to 4 analyzed proteins: MTOR (Serine/threonine-protein kinase mTOR), PIK3CA (Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform), PIK3R2 (Phosphatidylinositol 3-kinase regulatory subunit beta) and AKT3 (RAC-gamma serine/threonine-protein kinase).

How many genetic variants are linked to Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes?

39 variants: 18 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 11 are of uncertain significance or have conflicting reports.

Which uncertain variants in Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes 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 Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.52, based on 8 disease-causing and 296 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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