Macrocephaly-autism syndrome: genes and variants

Genes linked to Macrocephaly-autism syndrome

• PTEN: Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN

  A lipid and protein phosphatase that removes phosphate groups from signaling molecules, especially PIP3. By opposing the PI3K-AKT pathway, it limits cell growth and survival signals, and PTEN variants are associated with Cowden syndrome and multiple cancers.

  13 disease-causing and 18 uncertain variants in PTEN are linked to Macrocephaly-autism syndrome.

Where Macrocephaly-autism syndrome variants cluster

• PTEN Phosphatase tensin-type (positions 14–185): 10 of 13 disease-causing changes, 1.8× more than its size predicts.

Known disease-causing variants in Macrocephaly-autism syndrome

Which prediction tools work for Macrocephaly-autism syndrome

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

• CATVariant: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 100 out of 100
• ESM1b (LLR): 100 out of 100
• SIFT: 100 out of 100
• DMS / MaveDB: 66 out of 100

Same protein, different disease

• PTEN hamartoma tumor syndrome is also caused by PTEN variants; they fall partly in the same places as the Macrocephaly-autism syndrome variants (147 disease-causing).
• Cowden syndrome is also caused by PTEN variants; they fall partly in the same places as the Macrocephaly-autism syndrome variants (41 disease-causing).
• Glioma susceptibility 1 is also caused by PTEN variants; they fall partly in the same places as the Macrocephaly-autism syndrome variants (5 disease-causing).

Diseases related to Macrocephaly-autism syndrome

• PTEN hamartoma tumor syndrome, also linked to PTEN
• Cowden syndrome, also linked to PTEN
• Familial cancer of breast, also linked to PTEN
• Glioma susceptibility 1, also linked to PTEN
• Familial meningioma, also linked to PTEN
• Prostate cancer, also linked to PTEN
• Endometrial carcinoma, also linked to PTEN
• Thyroid cancer, nonmedullary, 2, also linked to PTEN
• Melanoma, also linked to PTEN
• Familial prostate cancer, also linked to PTEN

Frequently asked questions

Which genes are linked to Macrocephaly-autism syndrome?

In CATVariant, Macrocephaly-autism syndrome is linked to 1 analyzed protein: PTEN (Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN).

How many genetic variants are linked to Macrocephaly-autism syndrome?

36 variants: 13 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 18 are of uncertain significance or have conflicting reports.

Which uncertain variants in Macrocephaly-autism 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 Macrocephaly-autism syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 1.00, based on 13 disease-causing and 8 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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