Duplication of the MECP2 Region Is a Frequent Cause of Severe Mental Retardation and Progressive Neurological Symptoms in Males

Abstract

Loss-of-function mutations of the MECP2 gene at Xq28 are associated with Rett syndrome in females and with syndromic and nonsyndromic forms of mental retardation (MR) in males. By array comparative genomic hybridization (array-CGH), we identified a small duplication at Xq28 in a large family with a severe form of MR associated with progressive spasticity. Screening by real-time quantitation of 17 additional patients with MR who have similar phenotypes revealed three more duplications. The duplications in the four patients vary in size from 0.4 to 0.8 Mb and harbor several genes, which, for each duplication, include the MR-related L1CAM and MECP2 genes. The proximal breakpoints are located within a 250-kb region centromeric of L1CAM, whereas the distal breakpoints are located in a 300-kb interval telomeric of MECP2. The precise size and location of each duplication is different in the four patients. The duplications segregate with the disease in the families, and asymptomatic carrier females show complete skewing of X inactivation. Comparison of the clinical features in these patients and in a previously reported patient enables refinement of the genotype-phenotype correlation and strongly suggests that increased dosage of MECP2 results in the MR phenotype. Our findings demonstrate that, in humans, not only impaired or abolished gene function but also increased MeCP2 dosage causes a distinct phenotype. Moreover, duplication of the MECP2 region occurs frequently in male patients with a severe form of MR, which justifies quantitative screening of MECP2 in this group of patients.

Copy-number variations on the X chromosome in Japanese patients with mental retardation detected by array-based comparative genomic hybridization analysis

“…The patients manifested several common phenotypes such as severe MR, muscular hypotonia, absence of speech and recurrent respiratory infections as reported. [15][16][17][18][19] Mapping at dup(X)(q28) of our three families indicated that the smallest region of overlap contained thirteen genes including L1CAM and MECP2 (Supplementary Figure S4a), suggesting that these genes contribute to their …”

Implications of gene copy-number variation in health and diseases

“…MECP2, X-linked methyl-CpG-binding protein 2 gene at Xq28 is also found to be associated with the developmental delay, MR and fatal infantile encephalopathy in males, and recently it has been reported that low copy number of MECP2 gene confers a clinical phenotype, resulting in MR or developmental delay and altered neurological symptoms (particularly seizures) phenotypes in males. [21][22][23][24] Needless to say, this is perhaps one of the most complex phenotype and the clear picture will emerge when all possible loci and their interactions are well defined.…”

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

“…In contrast to phenotypically well-defined genomic duplications of MECP2 in males (OMIM 300260) and of FOXG1, [25][26][27][28][29][30] the clinical consequences of increased dosage of CDKL5 are poorly understood. Thus far, only larger-sized (8-21 Mb) Xp22 duplications involving CDKL5 have been described, [31][32][33][34] making phenotypic contribution of CDKL5 duplication challenging to dissect.…”