Rett syndrome: genes and variants

Genes linked to Rett syndrome

• 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.

  88 disease-causing and 80 uncertain variants in MECP2 are linked to Rett syndrome.

• FOXG1: Forkhead box protein G1

  It controls forebrain progenitor proliferation, neuronal differentiation, and cortical patterning during embryonic development. Haploinsufficiency or dysregulating variants cause FOXG1 syndrome, characterized by severe developmental impairment, absent or limited speech, abnormal movements, and frequent epilepsy.

  5 disease-causing and 2 uncertain variants in FOXG1 are linked to Rett syndrome.

• CDKL5: Cyclin-dependent kinase-like 5

  It phosphorylates neuronal substrates involved in synapse development, cytoskeletal organization, and signaling during early brain maturation. Loss-of-function variants cause CDKL5 deficiency disorder with very early epilepsy and severe developmental impairment.

  0 disease-causing and 0 uncertain variants in CDKL5 are linked to Rett syndrome.

Where Rett syndrome variants cluster

• MECP2 MBD (positions 90–162): 55 of 88 disease-causing changes, 4.2× more than its size predicts.
• MECP2 Interaction with TBL1XR1 (positions 285–309): 18 of 88 disease-causing changes, 4.0× more than its size predicts.
• FOXG1 Fork-head (positions 181–275): 5 of 5 disease-causing changes, 5.2× more than its size predicts.

Known disease-causing variants in Rett syndrome

Showing 60 of 93.

Uncertain variants in Rett syndrome that look disease-causing

Which prediction tools work for Rett syndrome

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

• MetaLR: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 95 out of 100
• EVE: 92 out of 100
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 79 out of 100

Same protein, different disease

• Severe neonatal-onset encephalopathy with microcephaly is also caused by MECP2 variants; they fall in the same places as the Rett syndrome variants (29 disease-causing).
• FOXG1 disorder is also caused by FOXG1 variants; they fall partly in the same places as the Rett syndrome variants (70 disease-causing).

Diseases related to Rett syndrome

• Angelman syndrome, also linked to CDKL5 and MECP2
• Autism, also linked to CDKL5 and MECP2
• FOXG1 disorder, also linked to FOXG1
• Angelman syndrome-like, also linked to CDKL5
• CDKL5 disorder, also linked to CDKL5
• Severe neonatal-onset encephalopathy with microcephaly, also linked to MECP2
• Microcephaly, also linked to FOXG1
• Focal epilepsy, also linked to MECP2
• Infantile spasms, also linked to CDKL5
• 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 Rett syndrome?

In CATVariant, Rett syndrome is linked to 3 analyzed proteins: MECP2 (Methyl-CpG-binding protein 2), FOXG1 (Forkhead box protein G1) and CDKL5 (Cyclin-dependent kinase-like 5).

How many genetic variants are linked to Rett syndrome?

310 variants: 93 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 82 are of uncertain significance or have conflicting reports.

Which uncertain variants in Rett syndrome look disease-causing?

5 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example FOXG1 N232Y, MECP2 L100R, MECP2 V122A, MECP2 D97E and MECP2 R115C. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Rett syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.95, based on 83 disease-causing and 206 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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