Analýza inaktivace chromozomu X u dětí s neurovývojovými onemocněními s X-vázanými chromozomovými abnormalitami


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Title in English X-inactivation analysis in paediatric patients with X-linked chromosomal abnormalities


Year of publication 2022
Type Appeared in Conference without Proceedings
MU Faculty or unit

Faculty of Science

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Description X-inactivation (XCI) represents an epigenetic mechanism of gene dosage compensation between mammalian sexes. In human it is commonly a random process which begins in early embryogenesis. Skewed XCI is observed in female carriers of X-linked chromosomal abnormalities or sequence variants, which may result in associated abnormal phenotypes. In our study we observed XCI status in females with X-linked sequence variants and CNVs and we discussed it in the relationship with the manifestation of X-linked neurodevelopmental disorders (NDDs). XCI status was studied using methylation-sensitive restriction digestion and amplification of polymorphic X-linked markers (STRs) in AR, CNKSR2, RP2, PCSK1N genes. STR markers are located in the close proximity of target sequences of restriction digestion. Our study included 58 individuals. XCI analysis was performed in 29 females with X-linked clinically relevant variants, and linkage analysis was performed in their unaffected relatives. The first part of the study was focused on the optimalization and introduction of XCI methodology. Then, XCi status was assessed in 86% of females (25/29). Random XCI was identified in 62% of females (18/29). Skewed XCI was assessed in 6.9% of females (2/29) and extremely skewed XCI in 17.2% (5/29). Skewed and extremely skewed XCI was proved in 67% of carriers of large X-chromosome rearrangements, conversely, random XCI was identified in 83% of carriers of X-linked CNVs. Linkage analyses in relatives suggested a protective impact of skewed XCI in asymptomatic carriers of causative X-linked variants, and its role on the manifestation of NDDs. XCI analyses contribute to the specification of genotype-phenotype correlation and improve the prediction of the clinical manifestation of X-linked chromosomal abnormalities in patients with NDDs. Supported by projects of Faculty of Science MU MUNI/A/1522/2020, MUNI/A/1325/2021, and Ministry of Health of the Czech Republic, grant nr. NU20-07-00145. All rights reserved.
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