Xq28 duplications including MECP2 in five females: Expanding the phenotype to severe mental retardation

Abstract

Duplications leading to functional disomy of chromosome Xq28, including MECP2 as the critical dosage-sensitive gene, are associated with a distinct clinical phenotype in males, characterized by severe mental retardation, infantile hypotonia, progressive neurologic impairment, recurrent infections, bladder dysfunction, and absent speech. Female patients with Xq duplications including MECP2 are rare. Only recently submicroscopic duplications of this region on Xq28 have been recognized in four females, and a triplication in a fifth, all in combination with random X-chromosome inactivation (XCI). Based on this small series, it was concluded that in females with MECP2 duplication and random XCI, the typical symptoms of affected boys are not present. We present clinical and molecular data on a series of five females with an Xq28 duplication including the MECP2 gene, both isolated and as the result of a translocation, and compare them with the previously reported cases of small duplications in females. The collected data indicate that the associated phenotype in females is distinct from males with similar duplications, but the clinical effects may be as severe as seen in males.

Fig. 1

Phenotypical characteristics of individuals with an Xq28 duplication including MECP2. a-c. patient 1, aged 1 year and 5 months (a), 3 years and 7 months (b) and 7 years (c). Note facial hypotonia, large mouth, and widely spaced teeth. d,e. patient 2, aged 2 years and 8 months (d) and 4 years and 6 months (e). f. Index patient in the described XLMR-family, his mother, patient 4 (g) and grandmother (h). Overall, patients show no common facial features, though patient 2 (c,d) and the index patient in the described XLMR-family (f) show almost identical prominent infraorbital fullness.

Fig. 2

Illustration of Xq duplication of the MECP2 region. a. FISH analysis in patient 1. The Xq duplication (RP11-333O06; red) is inserted in the long arm of chromosome 3 (black arrow), coinciding with the 3q duplication (RP11-67F24; green). Control probes: centromere chromosome 3 (a-sat 3, Cytocell; green) and centromere chromosome X (pBamX5; red). b. Array-CGH ratio profile in patient 3. Chromosome X array CGH ratio profile using DNA from the patient and a reference DNA from a normal female. On the left, the chromosome X ideogram. On the right, the log2 ratio of the chromosome X probes plotted as a function of chromosomal position. Each dot represents a single probe (oligo) spotted on the array. Oligos with a value of zero represent equal fluorescence intensity ratio between sample and reference. c. MLPA profiles showing an Xq duplication in family 4. Graphical representation of MLPA data (left panel, index patient; right panel, maternal grandmother), showing the bars of the duplicated Xq region in red (from SLC6A8 to OPN1MW including all MECP2 exons). In the index, peak valuesreach 1.50, suggesting a duplication as normal dose is normalized to 0.75. In the grandmother, peak values of the duplication (bars in red) reach 1.25, as normal dose corresponds to two X chromosomes.

Fig. 3

Pedigree of X-linked mental retardation family (previously published as pedigree E in Madrigal et al., 2007[30]). 49 y, age at last examination; d 15 y, died at the age of 15 years. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Schematic representation of part of the Xq28 region. The location of the duplications of our five patients and five previously reported females is depicted. Due to missing data, the patient described by Kirk et al. could not be included. Pattern codes: vertical stripes, insertion of Xq into an autosome; solid bar, unbalanced X-autosome translocation; horizontal stripes, familial intrachromosomal Xq duplication; dotted, de novo intrachromosomal duplication of Xq, diagonal stripes, de novo intrachromosomal triplication of Xq. Arrow, minimal critical region. Gene content of the region is shown from the UCSC Genome Browser version Human March 2006 (NCBI36/hg18).