ClinGen Dosage Sensitivity Curation Page

Xq28 region (includes MECP2)

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

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.

Evidence for Triplosenstive Phenotype

Evidence for triplosensitivity phenotype
PubMed ID Description
32043567 Pascual-Alonso et al. (2020) used array CGH and PCR on 21 patients (2 girls, 19 boys) with delayed speech and language development, intellectual disability, and neonatal hypotonia. All 21 patients had detected duplications including MECP2 and IRAK1 and 5 were inherited de novo. The duplication was maternally inherited in the other 16 patients, with 14 mothers being asymptomatic.
29618507 Miguet et al. (2018) used PCR, MLPA, or array CGH on 59 French individuals with MECP2 duplication syndrome. All 59 individuals had duplications including the genes MECP2 and IRAK1, but many participants had larger duplications involving many genes. 6 individuals had de novo deletions.
22679399 Van Esch (2012) reviewed several papers that included over 110 reported patients with MECP2 duplication syndrome and varying duplications in the region. All of these duplications included MECP2 and IRAK1.
29141583 Li et al. (2017) used aCGH, MLPA and FISH analysis on a 4-generation Chinese family with neurodevelopmental disorders. Four male patients and four female patients were found to have a 550 kb duplication on the Xq28 region that included 24 genes.

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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.