Publications by authors named "Ekaterina N Tolmacheva"

9 Publications

  • Page 1 of 1

Differential DNA Methylation of the IMMP2L Gene in Families with Maternally Inherited 7q31.1 Microdeletions is Associated with Intellectual Disability and Developmental Delay.

Cytogenet Genome Res 2021 Apr 13:1-15. Epub 2021 Apr 13.

Research Institute of Medical Genetics, Tomsk National Research Medical Center, Tomsk, Russian Federation.

Most copy number variations (CNVs) in the human genome display incomplete penetrance with unknown underlying mechanisms. One such mechanism may be epigenetic modification, particularly DNA methylation. The IMMP2L gene is located in a critical region for autism susceptibility on chromosome 7q (AUTS1). The level of DNA methylation was assessed by bisulfite sequencing of 87 CpG sites in the IMMP2L gene in 3 families with maternally inherited 7q31.1 microdeletions affecting the IMMP2L gene alone. Bisulfite sequencing revealed comparable levels of DNA methylation in the probands, healthy siblings without microdeletions, and their fathers. In contrast, a reduced DNA methylation index and increased IMMP2L expression were observed in lymphocytes from the healthy mothers compared with the probands. A number of genes were upregulated in the healthy mothers compared to controls and downregulated in probands compared to mothers. These genes were enriched in components of the ribosome and electron transport chain, as well as oxidative phosphorylation and various degenerative conditions. Differential expression in probands and mothers with IMMP2L deletions relative to controls may be due to compensatory processes in healthy mothers with IMMP2L deletions and disturbances of these processes in probands with intellectual disability. The results suggest a possible partial compensation for IMMP2L gene haploinsufficiency in healthy mothers with the 7q31.1 microdeletion by reducing the DNA methylation level. Differential DNA methylation of intragenic CpG sites may affect the phenotypic manifestation of CNVs and explain the incomplete penetrance of chromosomal microdeletions.
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http://dx.doi.org/10.1159/000514491DOI Listing
April 2021

LINE-1 retrotransposon methylation in chorionic villi of first trimester miscarriages with aneuploidy.

J Assist Reprod Genet 2021 Jan 10;38(1):139-149. Epub 2020 Nov 10.

Research Institute of Medical Genetics, Tomsk National Research Medical Center, Nab. R. Ushaiki, 10, Tomsk, Russia.

Purpose: High frequency of aneuploidy in meiosis and cleavage stage coincides with waves of epigenetic genome reprogramming that may indicate a possible association between epigenetic mechanisms and aneuploidy occurrence. This study aimed to assess the methylation level of the long interspersed repeat element 1 (LINE-1) retrotransposon in chorionic villi of first trimester miscarriages with a normal karyotype and aneuploidy.

Methods: The methylation level was assessed at 19 LINE-1 promoter CpG sites in chorionic villi of 141 miscarriages with trisomy of chromosomes 2, 6, 8-10, 13-15, 16, 18, 20-22, and monosomy X using massive parallel sequencing.

Results: The LINE-1 methylation level was elevated statistically significant in chorionic villi of miscarriages with both trisomy (45.2 ± 4.3%) and monosomy X (46.9 ± 4.2%) compared with that in induced abortions (40.0 ± 2.4%) (p < 0.00001). The LINE-1 methylation levels were specific for miscarriages with different aneuploidies and significantly increased in miscarriages with trisomies 8, 14, and 18 and monosomy X (p < 0.05). The LINE-1 methylation level increased with gestational age both for group of miscarriages regardless of karyotype (R = 0.21, p = 0.012) and specifically for miscarriages with trisomy 16 (R = 0.48, p = 0.007). LINE-1 methylation decreased with maternal age in miscarriages with a normal karyotype (R = - 0.31, p = 0.029) and with trisomy 21 (R = - 0.64, p = 0.024) and increased with paternal age for miscarriages with trisomy 16 (R = 0.38, p = 0.048) and monosomy X (R = 0.73, p = 0.003).

Conclusion: Our results indicate that the pathogenic effects of aneuploidy in human embryogenesis can be supplemented with significant epigenetic changes in the repetitive sequences.
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http://dx.doi.org/10.1007/s10815-020-02003-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823001PMC
January 2021

Aneuploidy and DNA Methylation as Mirrored Features of Early Human Embryo Development.

Genes (Basel) 2020 09 17;11(9). Epub 2020 Sep 17.

Research Institute of Medical Genetics, Tomsk National Research Medical Center, 634050 Tomsk, Russia.

Genome stability is an integral feature of all living organisms. Aneuploidy is the most common cause of fetal death in humans. The timing of bursts in increased aneuploidy frequency coincides with the waves of global epigenetic reprogramming in mammals. During gametogenesis and early embryogenesis, parental genomes undergo two waves of DNA methylation reprogramming. Failure of these processes can critically affect genome stability, including chromosome segregation during cell division. Abnormal methylation due to errors in the reprogramming process can potentially lead to aneuploidy. On the other hand, the presence of an entire additional chromosome, or chromosome loss, can affect the global genome methylation level. The associations of these two phenomena are well studied in the context of carcinogenesis, but here, we consider the relationship of DNA methylation and aneuploidy in early human and mammalian ontogenesis. In this review, we link these two phenomena and highlight the critical ontogenesis periods and genome regions that play a significant role in human reproduction and in the formation of pathological phenotypes in newborns with chromosomal aneuploidy.
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http://dx.doi.org/10.3390/genes11091084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564410PMC
September 2020

Delineation of Clinical Manifestations of the Inherited Xq24 Microdeletion Segregating with sXCI in Mothers: Two Novel Cases with Distinct Phenotypes Ranging from UBE2A Deficiency Syndrome to Recurrent Pregnancy Loss.

Cytogenet Genome Res 2020 30;160(5):245-254. Epub 2020 May 30.

Chromosomal microdeletion syndromes present with a wide spectrum of clinical phenotypes that depend on the size and gene content of the affected region. In a healthy carrier, epigenetic mechanisms may compensate for the same microdeletion, which may segregate through several generations without any clinical symptoms until the epigenetic modifications no longer function. We report 2 novel cases of Xq24 microdeletions inherited from mothers with extremely skewed X-chromosome inactivation (sXCI). The first case is a boy presenting with X-linked mental retardation, Nascimento type, due to a 168-kb Xq24 microdeletion involving 5 genes (CXorf56, UBE2A, NKRF, SEPT6, and MIR766) inherited from a healthy mother and grandmother with sXCI. In the second family, the presence of a 239-kb Xq24 microdeletion involving 3 additional genes (SLC25A43, SLC25A5-AS1, and SLC25A5) was detected in a woman with sXCI and a history of recurrent pregnancy loss with a maternal family history without reproductive wastages or products of conception. These cases provide evidence that women with an Xq24 microdeletion and sXCI may be at risk for having a child with intellectual disability or for experiencing a pregnancy loss due to the ontogenetic pleiotropy of a chromosomal microdeletion and its incomplete penetrance modified by sXCI.
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http://dx.doi.org/10.1159/000508050DOI Listing
September 2020

A mosaic intragenic microduplication of LAMA1 and a constitutional 18p11.32 microduplication in a patient with keratosis pilaris and intellectual disability.

Am J Med Genet A 2018 11 23;176(11):2395-2403. Epub 2018 Sep 23.

Laboratory of Cytogenetics, Research Institute of Medical Genetics, Tomsk NRMC, Tomsk, Russia.

The application of array-based comparative genomic hybridization and next-generation sequencing has identified many chromosomal microdeletions and microduplications in patients with different pathological phenotypes. Different copy number variations are described within the short arm of chromosome 18 in patients with skin diseases. In particular, full or partial monosomy 18p has also been associated with keratosis pilaris. Here, for the first time, we report a young male patient with intellectual disability, diabetes mellitus (type I), and keratosis pilaris, who exhibited a de novo 45-kb microduplication of exons 4-22 of LAMA1, located at 18p11.31, and a 432-kb 18p11.32 microduplication of paternal origin containing the genes METTL4, NDC80, and CBX3P2 and exons 1-15 of the SMCHD1 gene. The microduplication of LAMA1 was identified in skin fibroblasts but not in lymphocytes, whereas the larger microduplication was present in both tissues. We propose LAMA1 as a novel candidate gene for keratosis pilaris. Although inherited from a healthy father, the 18p11.32 microduplication, which included relevant genes, could also contribute to phenotype manifestation.
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http://dx.doi.org/10.1002/ajmg.a.40478DOI Listing
November 2018

Compound phenotype in a girl with r(22), concomitant microdeletion 22q13.32-q13.33 and mosaic monosomy 22.

Mol Cytogenet 2018 27;11:26. Epub 2018 Apr 27.

1Research Institute of Medical Genetics, Tomsk NRMC, Tomsk, Russia.

Background: Ring chromosome instability may influence a patient's phenotype and challenge its interpretation.

Results: Here, we report a 4-year-old girl with a compound phenotype. Cytogenetic analysis revealed her karyotype to be 46,XX,r(22). aCGH identified a 180 kb 22q13.32 duplication, a 2.024 Mb subtelomeric 22q13.32-q13.33 deletion, which is associated with Phelan-McDermid syndrome, and a maternal single gene 382-kb deletion of uncertain clinical significance located in the region of the 3q13.31 deletion syndrome. All chromosomal aberrations were confirmed by real-time PCR in lymphocytes and detected in skin fibroblasts. The deletions were also found in the buccal epithelium. According to FISH analysis, 8% and 24% of the patient's lymphocytes and skin fibroblasts, respectively, had monosomy 22.

Conclusions: We believe that a combination of 22q13.32-q13.33 deletion and monosomy 22 in a portion of cells can better define the clinical phenotype of the patient. Importantly, the presence of monosomic cells indicates ring chromosome instability, which may favor karyotype correction that is significant for the development of chromosomal therapy protocols.
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http://dx.doi.org/10.1186/s13039-018-0375-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923029PMC
April 2018

Comparative Cytogenetic Analysis of Spontaneous Abortions in Recurrent and Sporadic Pregnancy Losses.

Biomed Hub 2016 Jan-Apr;1(1):1-11. Epub 2016 Apr 27.

Laboratory of Cytogenetics, Institute of Medical Genetics, Siberian State Medical University, Tomsk, Russia.

Background: The majority of miscarriages are sporadic; however, 1-5% of couples experience recurrent pregnancy loss (RPL). Approximately 50-60% of miscarriages result from chromosomal abnormalities. Currently, there are conflicting reports regarding the rates of chromosomal abnormalities between recurrent and sporadic pregnancy losses.

Methods: A retrospective comparative cytogenetic analysis of 442 RPL and 466 sporadic abortions (SA) was performed. Maternal age and medical background were evaluated, and chromosomal abnormality rates were compared between groups.

Results: The frequency of embryos with abnormal karyotypes was significantly higher in SA compared to RPL (56.7 and 46.6%, respectively), and abortions from women under 30 years of age were the main contributor to this difference. An age-dependent increase in the abnormal karyotype rate was observed in two groups of women - those with SA [53.0 and 70.1% for younger and older (≥35-year-old) mothers, respectively] and those with idiopathic RPL without any concomitant reproductive pathology (46.5 and 78.4% for younger and older mothers) - but not in the group of women with RPL associated with concomitant reproductive pathology. The incidence of recurrent abnormal karyotypes in subsequent miscarriages was significantly higher than random probability (odds ratio = 22.75).

Conclusion: Our findings highlight the variability in the risk of aneuploidy in recurrent abortion.
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http://dx.doi.org/10.1159/000446099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945958PMC
April 2016

Single gene microdeletions and microduplication of 3p26.3 in three unrelated families: CNTN6 as a new candidate gene for intellectual disability.

Mol Cytogenet 2014 31;7(1):97. Epub 2014 Dec 31.

Laboratory of Cytogenetics, Institute of Medical Genetics, 10 Nab. Ushaiki, 634050 Tomsk, Russia ; Department of Medical Genetics, Siberian State Medical University, Tomsk, Russia.

Background: Detection of submicroscopic chromosomal alterations in patients with a idiopathic intellectual disability (ID) allows significant improvement in delineation of the regions of the genome that are associated with brain development and function. However, these chromosomal regions usually contain several protein-coding genes and regulatory elements, complicating the understanding of genotype-phenotype correlations. We report two siblings with ID and an unrelated patient with atypical autism who had 3p26.3 microdeletions and one intellectually disabled patient with a 3p26.3 microduplication encompassing only the CNTN6 gene.

Results: Two 295.1-kb microdeletions and one 766.1-kb microduplication of 3p26.3 involving a single gene, CNTN6, were identified with an Agilent 60K array. Another 271.9-kb microdeletion of 3p26.3 was detected using an Affymetrix CytoScan HD chromosome microarray platform. The CHL1 and CNTN4 genes, although adjacent to the CNTN6 gene, were not affected in either of these patients.

Conclusions: The protein encoded by CNTN6 is a member of the immunoglobulin superfamily and functions as a cell adhesion molecule that is involved in the formation of axon connections in the developing nervous system. Our results indicate that CNTN6 may be a candidate gene for ID.
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http://dx.doi.org/10.1186/s13039-014-0097-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299808PMC
January 2015

Array CGH analysis of a cohort of Russian patients with intellectual disability.

Gene 2014 Feb 27;536(1):145-50. Epub 2013 Nov 27.

Institute of Medical Genetics, Tomsk, Russia.

The use of array comparative genomic hybridization (array CGH) as a diagnostic tool in molecular genetics has facilitated the identification of many new microdeletion/microduplication syndromes (MMSs). Furthermore, this method has allowed for the identification of copy number variations (CNVs) whose pathogenic role has yet to be uncovered. Here, we report on our application of array CGH for the identification of pathogenic CNVs in 79 Russian children with intellectual disability (ID). Twenty-six pathogenic or likely pathogenic changes in copy number were detected in 22 patients (28%): 8 CNVs corresponded to known MMSs, and 17 were not associated with previously described syndromes. In this report, we describe our findings and comment on genes potentially associated with ID that are located within the CNV regions.
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http://dx.doi.org/10.1016/j.gene.2013.11.029DOI Listing
February 2014