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.

Introduction

Duplications leading to functional disomy of chromosome Xq28 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 (see [1] and [2] for reviews). This combination of features is known as the Xq28 microduplication syndrome or Lubs syndrome and was first described by Pai et al. and Lubs et al.[3], [4], followed by many others. The reported Xq28 duplications vary in size and location, however the majority are intrachromosomal duplications ranging from 0.3 to 2.3 Mb. Alternatively, duplications may be the result of another mechanism, such as rearrangements between Xq and Xp, or between Xq and the Y chromosome [5]. The methyl-CpG binding protein (MECP2) gene on Xq28 is proposed to be the critical dosage-sensitive gene responsible for the severe phenotypes observed in patients with this duplication. In males, over 140 cases of Xq28 duplications including MECP2 have been described to date [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24].

Female patients with an Xq28 duplication are rare. In families with X-linked pedigrees, female carriers of an Xq duplication are usually asymptomatic, due to skewed X-chromosome inactivation (XCI) pattern with preferential inactivation of the rearranged chromosome. Until recently, only three symptomatic females had been reported with large, cytogenetically visible Xq28 duplications (summarized in [21]). Clinically, these females presented with severe developmental delay and other features similar to those observed in affected males. In all cases the duplication was the result of an unbalanced X-autosome translocation, explaining the absence of skewing of the aberrant X-chromosome and the effect on the phenotype. After introduction of array CGH analysis, smaller, submicroscopic duplications of this region on Xq28 have been detected in four females, all in combination with random XCI [25], [26], [27]. The patient with a MECP2 duplication described by Ariani et al. [28] should not be included in this series, as the patient turned out to have a 47,XXX karyotype (F. Ariani, personal communication). 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 [26]. Instead, the clinical signs in female patients consist of unspecific mild to moderate mental retardation, combined with variable symptoms (autistic features, recurrent infections in early childhood, constipation, and late-onset neurological features). Recently, a girl with a de novo complex X-chromosomal rearrangement was described, with a triplication of a fragment containing MECP2. She was severely mentally retarded and had seizures, but no other symptoms as seen in boys with a duplication [29].

Here we present clinical and molecular data on a series of five females with an Xq28 duplication including the MECP2 gene and these are compared with the previously reported cases of small duplications in females. In patient 1, a MECP2 duplication was the result of a rare insertion duplication of a small segment of Xq28 into an autosome. Patients 2 and 3 are functionally disomic for region Xq28 due to an unbalanced X-autosome translocation. The fourth patient is a mildly affected obligate carrier from an X-linked mental retardation (XLMR) family. We detected a familial, intrachromosomal Xq duplication including MECP2 in her, but unlike previously reported carrier females in X-linked families, she showed random X-inactivation. Patient 5 carries a small intrachromosomal de novo duplication of Xq28, including MECP2. In contrast to the previously reported series of affected females, our series includes a female patient with the typical symptoms of affected boys, therefore expanding the phenotypic spectrum of small Xq28 duplications including MECP2 in females.