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. 2013 Nov 27;6(1):53.
doi: 10.1186/1755-8166-6-53.

Xq28 (MECP2) microdeletions are common in mutation-negative females with Rett syndrome and cause mild subtypes of the disease

Ivan Y Iourov  1 , Svetlana G Vorsanova, Victoria Y Voinova, Oxana S Kurinnaia, Maria A Zelenova, Irina A Demidova, Yuri B Yurov
Affiliations

Xq28 (MECP2) microdeletions are common in mutation-negative females with Rett syndrome and cause mild subtypes of the disease

Ivan Y Iourov et al. Mol Cytogenet. .

Abstract

Background: Rett syndrome (RTT) is an X-linked neurodevelopmental disease affecting predominantly females caused by MECP2 mutations. Although RTT is classically considered a monogenic disease, a stable proportion of patients, who do not exhibit MECP2 sequence variations, does exist. Here, we have attempted at uncovering genetic causes underlying the disorder in mutation-negative cases by whole genome analysis using array comparative genomic hybridization (CGH) and a bioinformatic approach.

Results: Using BAC and oligonucleotide array CGH, 39 patients from RTT Russian cohort (in total, 354 RTT patients), who did not bear intragenic MECP2 mutations, were studied. Among the individuals studied, 12 patients were those with classic RTT and 27 were those with atypical RTT. We have detected five 99.4 kb deletions in chromosome Xq28 affecting MECP2 associated with mild manifestations of classic RTT and five deletions encompassing MECP2 spanning 502.428 kb (three cases), 539.545 kb (one case) and 877.444 kb (one case) associated with mild atypical RTT. A case has demonstrated somatic mosaicism. Regardless of RTT type and deletion size, all the cases exhibited mild phenotypes.

Conclusions: Our data indicate for the first time that no fewer than 25% of RTT cases without detectable MECP2 mutations are caused by Xq28 microdeletions. Furthermore, Xq28 (MECP2) deletions are likely to cause mild subtypes of the disease, which can manifest as both classical and atypical RTT.

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Figures

Figure 1
Figure 1
Flow chart illustrating the diagnostic workup for genetic evaluation in Russian RTT cohort.
Figure 2
Figure 2
Schematic overview of detected Xq28 deletions depicted using UCSC Genome Browser (Human Feb. 2009 (GRCh37/hg19) Assembly) (see also Table1for details).
Figure 3
Figure 3
FISH demonstrating mosaic MECP2 deletion. (A) interphase FISH: two signals correspond to two MECP2 copies in a nucleus without deletion and a single signal is observed in a nucleus lacking one MECP2 copy; (B) percentages of abnormal cells detected by array CGH and FISH.
See this image and copyright information in PMC

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