Megalencephaly-capillary malformation-polymicrogyria syndrome: genes and variants

Genes linked to Megalencephaly-capillary malformation-polymicrogyria syndrome

• 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.

  22 disease-causing and 4 uncertain variants in PIK3CA are linked to Megalencephaly-capillary malformation-polymicrogyria syndrome.

• RIT1: GTP-binding protein Rit1

  It transmits growth and stress signals through RAS-MAPK and related pathways and is important in cardiovascular and nervous-system development. Germline activating variants cause Noonan syndrome, often with a high frequency of hypertrophic cardiomyopathy.

  1 disease-causing and 0 uncertain variants in RIT1 are linked to Megalencephaly-capillary malformation-polymicrogyria syndrome.

Weakly linked (only a few uncertain records): AKT3 and PIK3R2.

Where Megalencephaly-capillary malformation-polymicrogyria syndrome variants cluster

• PIK3CA C2 PI3K-type (positions 330–487): 7 of 22 disease-causing changes, 2.1× more than its size predicts.

Known disease-causing variants in Megalencephaly-capillary malformation-polymicrogyria syndrome

Which prediction tools work for Megalencephaly-capillary malformation-polymicrogyria syndrome

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

• PolyPhen-2: 81 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 79 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 61 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 55 out of 100

Same protein, different disease

• PIK3CA related overgrowth syndrome is also caused by PIK3CA variants; they fall partly in the same places as the Megalencephaly-capillary malformation-polymicrogyria syndrome variants (30 disease-causing).
• Cowden syndrome is also caused by PIK3CA variants; they fall partly in the same places as the Megalencephaly-capillary malformation-polymicrogyria syndrome variants (23 disease-causing).
• Ovarian neoplasm is also caused by PIK3CA variants; they fall in the same places as the Megalencephaly-capillary malformation-polymicrogyria syndrome variants (5 disease-causing).
• PIK3CA constitutional syndrome is also caused by PIK3CA variants; they fall in the same places as the Megalencephaly-capillary malformation-polymicrogyria syndrome variants (4 disease-causing).
• Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes is also caused by PIK3CA variants; they fall in the same places as the Megalencephaly-capillary malformation-polymicrogyria syndrome variants (4 disease-causing).
• Noonan syndrome is also caused by RIT1 variants; they fall mostly in different places as the Megalencephaly-capillary malformation-polymicrogyria syndrome variants (22 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by RIT1 variants; they fall mostly in different places as the Megalencephaly-capillary malformation-polymicrogyria syndrome variants (9 disease-causing).
• RASopathy is also caused by RIT1 variants; they fall mostly in different places as the Megalencephaly-capillary malformation-polymicrogyria syndrome variants (5 disease-causing).

Diseases related to Megalencephaly-capillary malformation-polymicrogyria syndrome

• Noonan syndrome, also linked to PIK3CA and RIT1
• RASopathy, also linked to RIT1
• Cowden syndrome, also linked to PIK3CA
• Noonan syndrome and Noonan-related syndrome, also linked to RIT1
• Ovarian cancer, also linked to PIK3CA
• PIK3CA related overgrowth syndrome, also linked to PIK3CA
• Familial cancer of breast, 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
• Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, also linked to PIK3CA
• Non-small cell lung carcinoma, also linked to PIK3CA

Frequently asked questions

Which genes are linked to Megalencephaly-capillary malformation-polymicrogyria syndrome?

In CATVariant, Megalencephaly-capillary malformation-polymicrogyria syndrome is linked to 2 analyzed proteins: PIK3CA (Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform) and RIT1 (GTP-binding protein Rit1).

How many genetic variants are linked to Megalencephaly-capillary malformation-polymicrogyria syndrome?

45 variants: 23 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 4 are of uncertain significance or have conflicting reports.

Which uncertain variants in Megalencephaly-capillary malformation-polymicrogyria 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 Megalencephaly-capillary malformation-polymicrogyria syndrome?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.55, based on 18 disease-causing and 51 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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