Abstract
Duplications of the Xq28 region are the most frequent chromosomal aberrations observed in patients with intellectual disability (ID), especially in males. These duplications occur by variable mechanisms, including interstitial duplications mediated by segmental duplications in this region and terminal duplications (functional disomy) derived from translocation with other chromosomes. The most commonly duplicated region includes methyl CpG-binding protein 2 gene (MECP2), which has a minimal duplicated size of 0.2 Mb. Patients with MECP2 duplications show severe ID, intractable seizures and recurrent infections. Duplications in the telomeric neighboring regions, which include GDP dissociation inhibitor 1 gene (GDI1) and ras-associated protein RAB39B gene (RAB39B), are independently associated with ID, and many segmental duplications located in this region could mediate these frequently observed interstitial duplications. In addition, large duplications, including MECP2 and GDI1, induce hypoplasia of the corpus callosum. Abnormalities observed in the white matter, revealed by brain magnetic resonance imaging, are a common finding in patients with MECP2 duplications. As primary sequence analysis cannot be used to determine the region responsible for chromosomal duplication syndrome, finding this region relies on the collection of genotype–phenotype data from patients.
Highlights
Widespread application of chromosomal microarray testing has identified many new, contiguous gene syndromes.[1]
methyl CpG-binding protein 2 gene (MECP2) duplication syndrome is associated with the X-linked recessive trait and skewed X-chromosome inactivation (XCI) in female carriers, which suggests condition was first recognized as Lubs-type X-linked mental retardation syndrome (MIM #300260),[22] and its genetic etiology was identified as chromosomal duplications in the MECP2 region.[17,23]
The GDP dissociation inhibitor 1 gene (GDI1; MIM #300104) is located on the telomeric neighboring region of the shortest region overlapped of MECP2 duplication syndrome (Figure 1) and was identified as a gene responsible for intellectual disability (ID) because it was mutated in male patients.[29]
Summary
Widespread application of chromosomal microarray testing has identified many new, contiguous gene syndromes.[1]. MECP2 duplication syndrome is associated with the X-linked recessive trait and skewed XCI in female carriers, which suggests condition was first recognized as Lubs-type X-linked mental retardation syndrome (MIM #300260),[22] and its genetic etiology was identified as chromosomal duplications in the MECP2 region.[17,23] Varying sizes of the MECP2 duplications (0.2–4.0 Mb) have been identified.[24,25,26] Overlapping duplications narrowed down the shortest region overlapped in which MECP2 and that overexpression of neighboring genes in the duplicated region, rather than MECP2 itself, may induce negative selection in the early embryo, leading to a preferential XCI.[28] Alternatively, embryonic damage may be more severe in cases of MECP2 duplication compared with MECP2 nucleotide changes, this remains controversial.
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