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
Evidence for haploinsufficiency phenotype
PubMed ID Description
31206249 In 2019, Vidal, et al. used multiplex litigation-dependent probe amplification (MLPA) and qPCR on 14 individuals with Rett Syndrome. Analysis identified de novo deletions in the MECP2 gene in all 14 individuals. Five patients have deletions in the exon 4 and nine patients had deletions in exons 3 and 4.
10508514 In 1999, Amir, et al. used conformation sensitive gel electrophoresis on 29 individuals with Rett Syndrome. 2 individuals had de novo deletions (one frameshift and one nonsense) in the MECP2 gene and 27 individuals had missense variations.
16647997 In 2005, Bienvenu, et al. used PCR on 424 French individuals with clinically diagnosed Rett Syndrome. All 424 individuals had variations in the MECP2 gene with a total of 121 different variations identified including missense, nonsense, insertions and deletions.

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. PMID: 29428920 In 2018, Lallar et al. used Sanger sequencing on 11 individuals with classical Rett Syndrome and 1 individual with atypical Rett Syndrome. All 12 individuals contained variants of MECP2 including missense, nonsense, and deletions. 2 of the 12 individuals were large deletions and all of these variants are of unknown inheritance. PMID: 15000811 In 2003, Erlandson et al. used MLPA on 11 individuals with classical Rett Syndrome. 3 individuals had large deletions in MECP2. 2 individuals had exons 3 and 4 deleted and 1 individual had exons 1 and 2 deleted. All of these deletions are of unknown inheritance. PMID: 30081849 In 2018, Thahn et al. used Sanger sequencing of the MECP2 gene on 27 female individuals with Rett Syndrome. 20 individuals had variants of unknown inheritance in the MECP2 gene and of those 20, 12 had deletions (nonsense, frameshift, and deletions).

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:

To date, there have been no focal duplications of MECP2, therefore, the gene has a triplosensitivity score 0. However, duplications encompassing at least the genes MECP2 and IRAK1 have been associated with MECP2 duplication syndrome. Please see the related region curation Xq28 region (including MECP2) (ISCA-46304). 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.