ClinGen Dosage Sensitivity Curation Page

MECP2

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
  • Haploinsufficiency Phenotype: RETT SYNDROME; RTT

Haploinsufficiency phenotype comments:

Intragenic and whole-gene deletions of MECP2 typically result in Rett syndrome or atypical Rett syndrome in females and severe neonatal encephalopathy in males. Other sequence level changes have also been reported in individuals with X-linked intellectual disability (PPM-X syndrome), Angelman syndrome-like features, and autism. See Gene Review: http://www.ncbi.nlm.nih.gov/books/NBK1497.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity phenotype comment:

Duplications encompassing the entire MECP2 gene are associated with MECP2 duplication syndrome. While the size of duplications in patients varies, the smallest region of overlap includes only the MECP2 and IRAK1 genes, and pathogenicity is believed to be due to the increased dosage of MECP2. Patients with MECP2 triplications have also been reported with more severe phenotypes. See Gene Review: http://www.ncbi.nlm.nih.gov/books/NBK1284/.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.