<i>MECP2</i> Duplications in Symptomatic Females

Antonio‐Arce, Victoria San; Fenollar-Cortés, María; Ionescu, Raluca Oancea; DeSantos-Moreno, Teresa; Gallego-Merlo, J.; Câmara, Francisco; Pérez, M.

doi:10.1177/2329048x16630673

Cited by 11 publications

(6 citation statements)

References 20 publications

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“…In future studies, however, it will be important to determine whether females with MDS have a different developmental trajectory and disease progression so as to better develop personalized interventions. Some prior studies suggest that females with MDS are as severely affected as their male counterparts (San Antonio‐Arce et al, 2016), while others suggest that they could possibly have a milder disease course (Scott Schwoerer et al, 2014) possibly accounted for by differences in X‐inactivation skewing.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic features in MECP2 duplication syndrome: Effects of age

Peters

Marsh

et al. 2020

American J of Med Genetics Pt A

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Background: MECP2 Duplication syndrome (MDS) is a rare X-linked genomic disorder that is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. Although phenotypic features in MDS have been described, there is a limited understanding of the range of severity of these features, and how they evolve with age. Methods:The cross-sectional results of N = 69 participants (ages 6 months-33 years) enrolled in a natural history study of MDS are presented. Clinical severity was assessed using a clinician-report measure as well as a parent-report measure. Data was also gathered related to the top 3 concerns of parents as selected from the most salient symptoms related to MDS. The Child Health Questionnaire was also utilized to obtain parental reports of each child's quality of life to establish disease burden.Results: The results of linear regression from the clinician-reported measure show that overall clinical severity scores, motor dysfunction, and functional skills are significantly worse with increasing age. Top concerns rated by parents included lack of effective communication, abnormal walking/balance issues, constipation, and seizures. Higher levels of clinical severity were also related to lower physical health quality of life scores as reported by parents. Conclusions:The data suggest that increasing levels of clinical severity are noted with older age, and this is primarily attributable to motor dysfunction, and functional skills. The results provide an important foundation for creating an MDS-specific severity scale highlighting the most important domains to target for treatment trials and will help clinicians and researchers define clinically meaningful changes.

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Section: Discussionmentioning

confidence: 99%

Phenotypic features in MECP2 duplication syndrome: Effects of age

Peters

Marsh

et al. 2020

American J of Med Genetics Pt A

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Section: Discussionmentioning

confidence: 92%

“…Any instances of this that have been reported to date were of female patients with the MECP2 duplication syndrome. The duplicated segment was confirmed by FISH to have been inserted into the autosome (case of chromosomes 10 28 and 21 29 ), and these duplicated segments could thereby escape X‐inactivation. Prior reports of the MECP2 duplication syndrome arising due to insertional translocation within an X chromosome, as in case 2 in our present study, are very limited 30 .…”

Section: Discussionmentioning

confidence: 92%

Clinical application of long‐read nanopore sequencing in a preimplantation genetic testing pre‐clinical workup to identify the junction for complex Xq chromosome rearrangement‐related disease

et al. 2023

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Objective: Xq chromosome duplication with complex rearrangements is generally acknowledged to be associated with neurodevelopmental disorders, such as Pelizaeus-Merzbacher disease (PMD) and MECP2 duplication syndrome. For couples who required a PGT-M (pre-implantation genetic testing for monogenic disease) for these disorders, junction-specific PCR is useful to directly detect pathogenic variants. Therefore, pre-clinical workup for PGT-M requires the identification of the junction of duplicated segments in PMD and MECP2 duplication syndrome, which is generally difficult. Methods:In this report, we used nanopore long-read sequencing targeting the X chromosome using an adaptive sampling method to identify breakpoint junctions in disease-causing triplications.Results: By long-read sequencing, we successfully identified breakpoint junctions in one PMD case with PLP1 triplication and in another MECP2 triplication case in a single sequencing run. Surprisingly, the duplicated region involving MECP2 was inserted 45 Mb proximal to the original position. This inserted region was confirmed by FISH analysis. With the help of precise mapping of the pathogenic variant, we successfully re-established STR haplotyping for PGT-M and avoided any potential misinterpretation of the pathogenic allele due to recombination. Conclusion:Long-read sequencing with adaptive sampling in a PGT-M pre-clinical workup is a beneficial method for identifying junctions of chromosomal complex structural rearrangements. Key pointsWhat's already known about this topic? � For couples who required a PGT-M (pre-implantation genetic testing for monogenic disease) for diseases with complex chromosomal structural rearrangements, junction-specific PCR is useful to directly detect pathogenic variants. Therefore, pre-clinical workup for 304 -

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“…Six of these genes encode proteins that form part of a network, according to the results of text mining and co-expression arrays (STRING DB, https://version-11-5.string-db.org/cgi/network?networkId=bWgRg6ih0nDV). Deletions or duplications in many of these genes have been reported to cause different impairments and diseases [93][94][95][96][97][98][99] , with autism featuring prominently among these clinical manifestations. Right next to this DMR (chrX:152,989,492-152,990,345 in GRCh37), the boysonly analysis revealed another significant DMR (chrX:153,046,451-153,046,767 in GRCh37) co-located with a promoter (ensembl ID: ENSR00002105690, see Fig.…”

Section: Dmrs Co-located With Genes Involved In Key Developmental Pro...mentioning

confidence: 99%

The X-factor in ART: does the use of Assisted Reproductive Technologies influence DNA methylation on the X chromosome?

Romanowska

Nustad

Page

et al. 2022

Preprint

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Background: Assisted reproductive technologies (ART) may perturb DNA methylation (DNAm) in early embryonic development. Although a handful of epigenome-wide association studies of ART have been published, none have investigated CpGs on the X chromosome. To bridge this knowledge gap, we leveraged one of the largest collections of mother-father-newborn trios of ART and non-ART (natural) conceptions to date to investigate DNAm differences on the X chromosome. Materials and Methods: The discovery cohort consisted of 982 ART and 963 non-ART trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa). The replication cohort consisted of 149 ART and 58 non-ART neonates from the Australian "Clinical review of the Health of adults conceived following Assisted Reproductive Technologies" (CHART) study. The Illumina EPIC array was used to measure DNA methylation (DNAm) in both datasets. In the MoBa cohort, we performed a set of X-chromosome-wide association studies ("XWASs" hereafter) to search for sex-specific DNAm differences between ART and non-ART newborns. We tested several models to investigate the influence of various confounders, including parental DNAm. We also searched for differentially methylated regions (DMRs) and regions of co-methylation flanking the most significant CpGs. For replication purposes, we ran an analogous model to our main model on the CHART dataset. Results and conclusions: In the MoBa cohort, we found more differentially methylated CpGs and DMRs in girls than boys. Most of the associations persisted even after controlling for parental DNAm and other confounders. Many of the significant CpGs and DMRs were in gene-promoter regions, and several of the genes linked to these CpGs are expressed in tissues relevant for both ART and sex (testis, placenta, and fallopian tube). We found no support for parental infertility as an explanation for the observed associations in the newborns. The most significant CpG in the boys-only analysis was in UBE2DNL, which is expressed in testes but with unknown function. The most significant CpGs in the girls-only analysis were in EIF2S3 and AMOT. These three loci also displayed differential DNAm in the CHART cohort. Overall, genes that co-localized with the significant CpGs and DMRs are implicated in several key biological processes (e.g., neurodevelopment) and disorders (e.g., intellectual disability and autism. These connections are particularly compelling in light of previous findings indicating that neurodevelopmental outcomes differ in ART-conceived children compared to naturally-conceived.

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MECP2 Duplications in Symptomatic Females

Cited by 11 publications

References 20 publications

Phenotypic features in MECP2 duplication syndrome: Effects of age

Phenotypic features in MECP2 duplication syndrome: Effects of age

Clinical application of long‐read nanopore sequencing in a preimplantation genetic testing pre‐clinical workup to identify the junction for complex Xq chromosome rearrangement‐related disease

The X-factor in ART: does the use of Assisted Reproductive Technologies influence DNA methylation on the X chromosome?

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