Abstract
BackgroundDuplications of MECP2 gene in males cause a syndrome characterized by distinctive clinical features, including severe to profound mental retardation, infantile hypotonia, mild dysmorphic features, poor speech development, autistic features, seizures, progressive spasticity and recurrent infections. Patients with complex chromosome rearrangements, leading to Xq28 duplication, share most of the clinical features of individuals with tandem duplications, in particular neurologic problems, suggesting a major pathogenetic role of MECP2 overexpression.ResultsWe performed cytogenetic and molecular cytogenetic studies in a previously described family with affected males showing congenital ataxia, late-onset progressive myoclonic encephalopathy and selective macular degeneration. Microsatellite, FISH and array-CGH analyses identified a recombinant X chromosome with a deletion of the PAR1 region, encompassing SHOX, replaced by a duplicated segment of the Xq28 terminal portion, including MECP2.ConclusionsOur report describes the identification of the actual genetic cause underlying a severe syndrome that previous preliminary analyses erroneously associated to a terminal Xp22.33 region. In the present family as well as in previously reported patients with similar rearrangements, the observed neurologic phenotype is ascribable to MECP2 duplication, with an undefined contribution of the other involved genes. Maculopathy, presented by affected males reported here, could be a novel clinical feature associated to Xq28 disomy due to recombinant X chromosomes, but at present the underlying pathogenetic mechanism is unknown and this potential clinical correlation should be confirmed through the collection of additional patients.
Highlights
Large duplications of the X chromosome long arm are rare, usually involve the distal Xq27-qter region, and cause a severe phenotype in males, while most carrier females are phenotypically normal, as a consequence of a skewed inactivation of the abnormal chromosome [1, 2]
Fluorescence In Situ Hybridization (FISH) and array-Comparative genomic hybridization (CGH) analyses FISH analysis with XpYp subtelomere specific probes confirmed the microdeletion in the tip of chromosome X short arm (Fig. 2a) in all studied samples (III1, III3, III7, III10, IV2 and IV15)
As the loss of pseudoautosomal region 1 (PAR1) did not explain the neurologic phenotype observed in males, the DNA of carrier female IV2 was analysed by array-CGH to evaluate the presence of additional cryptic imbalances involving different genomic regions
Summary
Large duplications of the X chromosome long arm are rare, usually involve the distal Xq27-qter region, and cause a severe phenotype in males, while most carrier females are phenotypically normal, as a consequence of a skewed inactivation of the abnormal chromosome [1, 2]. The majority of MECP2 duplications are intrachromosomal and represent non-recurrent events, probably mediated by fork stalling and template switching (FoSTeS) mechanism; more rarely, they can arise from complex rearrangements, resulting in the translocation of the duplicated segment to the short arm of the X chromosome, to an autosome or to the Y chromosome [4,5,6]. In 1992, Bertini et al described a family with a severe Xlinked phenotype characterized by congenital ataxia with generalized hypotonia, psychomotor retardation, lateonset progressive myoclonic encephalopathy, selective macular degeneration and recurrent bronchopulmonary infections. Duplications of MECP2 gene in males cause a syndrome characterized by distinctive clinical features, including severe to profound mental retardation, infantile hypotonia, mild dysmorphic features, poor speech development, autistic features, seizures, progressive spasticity and recurrent infections. Patients with complex chromosome rearrangements, leading to Xq28 duplication, share most of the clinical features of individuals with tandem duplications, in particular neurologic problems, suggesting a major pathogenetic role of MECP2 overexpression
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