Abstract
BackgroundRett 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.ResultsUsing 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.ConclusionsOur 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.
Highlights
Rett syndrome (RTT) is an X-linked neurodevelopmental disease affecting predominantly females caused by molecular and clinical aspects of Xq28 (MECP2) mutations
We have only found studies describing whole genome analysis of RTT females by array comparative genomic hybridization (CGH), which was performed for testing whether copy number variants (CNVs) are able to modulate the phenotype in mutation-positive RTT cases [9,10]
We decided to share our data on the evaluation of MEPC2-mutation negative females from Russian RTT cohort addressed by BAC and oligonucleotide array CGH with bioinformatic analysis
Summary
Rett syndrome (RTT) is an X-linked neurodevelopmental disease affecting predominantly females caused by MECP2 mutations. It has been shown that Xq28 microdeletions can affect MECP2 leading to RTT-like phenotype [7,8] Since these submicroscopic genome variations were commonly detected in children with presumably idiopathic intellectual disability, autism, epilepsy and/or congenital anomalies [7], it is probable that submicroscopic Xq28 deletions are not rare and can be associated with RTT. In this context, one can suggest Xq28 deletions spanning the MECP2 gene to be a potential cause of the disease in affected females without mutations detectable by Sanger sequencing. We decided to share our data on the evaluation of MEPC2-mutation negative females from Russian RTT cohort addressed by BAC and oligonucleotide array CGH with bioinformatic analysis
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