Severe neonatal-onset encephalopathy with microcephaly: genes and variants

Genes linked to Severe neonatal-onset encephalopathy with microcephaly

• MECP2: Methyl-CpG-binding protein 2

  It interprets DNA methylation and organizes transcriptional and chromatin states that are especially important in mature neurons. Loss-of-function variants cause Rett syndrome, whereas increased dosage causes MECP2 duplication syndrome.

  29 disease-causing and 176 uncertain variants in MECP2 are linked to Severe neonatal-onset encephalopathy with microcephaly.

Where Severe neonatal-onset encephalopathy with microcephaly variants cluster

• MECP2 MBD (positions 90–162): 15 of 29 disease-causing changes, 3.4× more than its size predicts.
• MECP2 Interaction with TBL1XR1 (positions 285–309): 8 of 29 disease-causing changes, 5.4× more than its size predicts.

Known disease-causing variants in Severe neonatal-onset encephalopathy with microcephaly

Which prediction tools work for Severe neonatal-onset encephalopathy with microcephaly

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

• CATVariant: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 94 out of 100
• MetaLR: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 85 out of 100
• PolyPhen-2: 83 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 72 out of 100

Same protein, different disease

• Rett syndrome is also caused by MECP2 variants; they fall partly in the same places as the Severe neonatal-onset encephalopathy with microcephaly variants (88 disease-causing).
• X-linked intellectual disability-psychosis-macroorchidism syndrome is also caused by MECP2 variants; they fall in the same places as the Severe neonatal-onset encephalopathy with microcephaly variants (4 disease-causing).

Diseases related to Severe neonatal-onset encephalopathy with microcephaly

• Rett syndrome, also linked to MECP2
• Angelman syndrome, also linked to MECP2
• Autism, also linked to MECP2
• Focal epilepsy, also linked to MECP2
• X-linked intellectual disability-psychosis-macroorchidism syndrome, also linked to MECP2
• Syndromic X-linked intellectual disability Lubs type, also linked to MECP2

Frequently asked questions

Which genes are linked to Severe neonatal-onset encephalopathy with microcephaly?

In CATVariant, Severe neonatal-onset encephalopathy with microcephaly is linked to 1 analyzed protein: MECP2 (Methyl-CpG-binding protein 2).

How many genetic variants are linked to Severe neonatal-onset encephalopathy with microcephaly?

297 variants: 29 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 176 are of uncertain significance or have conflicting reports.

Which uncertain variants in Severe neonatal-onset encephalopathy with microcephaly 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 Severe neonatal-onset encephalopathy with microcephaly?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 23 disease-causing and 168 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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