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

Vasilyev, S. A.; Skryabin, N. A.; Кашеварова, А. А.; Tolmacheva, E. N.; Savchenko, R. R.; Vasilyeva, Oksana Yu.; Лопаткина, М. Е.; Zarubin, A. V.; Fishman, Veniamin; Belyaeva, E. O.; Filippova, Miroslava O.; Shorina, Asia R.; Maslennikov, Arkadiy B.; Shestovskikh, Olga L.; Gayner, Tatyana A.; Čulić, Viktor; Vulić, Robert; Nazarenko, L; Lebedev, I. N.

doi:10.1159/000514491

Cited by 9 publications

(8 citation statements)

References 33 publications

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“…IMMP2L might also regulate processes in the reproductive system. This hypothesis was confirmed by the identification of deletions of the IMMP2L gene in patients with primary infertility [ 49 ]. Unfortunately, regarding our cohort of pregnant women, we do not have information regarding their inability to conceive naturally, as this information is not mandatory.…”

Section: Discussionmentioning

confidence: 86%

Maternal Copy Number Imbalances in Non-Invasive Prenatal Testing: Do They Matter?

et al. 2022

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Non-invasive prenatal testing (NIPT) has become a routine practice in screening for common aneuploidies of chromosomes 21, 18, and 13 and gonosomes X and Y in fetuses worldwide since 2015 and has even expanded to include smaller subchromosomal events. In fact, the fetal fraction represents only a small proportion of cell-free DNA on a predominant background of maternal DNA. Unlike fetal findings that have to be confirmed using invasive testing, it has been well documented that NIPT provides information on maternal mosaicism, occult malignancies, and hidden health conditions due to copy number variations (CNVs) with diagnostic resolution. Although large duplications or deletions associated with certain medical conditions or syndromes are usually well recognized and easy to interpret, very little is known about small, relatively common copy number variations on the order of a few hundred kilobases and their potential impact on human health. We analyzed data from 6422 NIPT patient samples with a CNV detection resolution of 200 kb for the maternal genome and identified 942 distinct CNVs; 328 occurred repeatedly. We defined them as multiple occurring variants (MOVs). We scrutinized the most common ones, compared them with frequencies in the gnomAD SVs v2.1, dbVar, and DGV population databases, and analyzed them with an emphasis on genomic content and potential association with specific phenotypes.

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Section: Discussionmentioning

confidence: 86%

Maternal Copy Number Imbalances in Non-Invasive Prenatal Testing: Do They Matter?

et al. 2022

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“…In some cases, they can arise de novo during meiosis; however, the exact mechanism of the formation of CNVs is not yet fully understood. In mice and humans, it has been shown that CNVs can influence gene expression [Stranger et al, 2007;Henrichsen et al, 2009], which suggests that CNVs could mediate susceptibility to neuropsychiatric diseases through a dose-dependent mechanism or unmasking of recessive mutations, for example, in cases of deletions with CNVs on the second intact allele [Vorstman et al, 2013;Vasilyev et al, 2021].…”

Section: Discussionmentioning

confidence: 99%

Skewed X-Chromosome Inactivation as a Possible Marker of X-Linked CNV in Women with Pregnancy Loss

Fonova

Tolmacheva

Кашеварова

et al. 2022

Cytogenet Genome Res

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Skewed X-chromosome inactivation (sXCI) can be a marker of lethal genetic variants on the X chromosome in a woman since sXCI modifies the pathological phenotype. The aim of this study was to search for CNVs in women with miscarriages and sXCI. XCI was assayed using the classical method based on the amplification of highly polymorphic exon 1 of the androgen receptor (AR) gene. The XCI status was analysed in 313 women with pregnancy loss and in 87 spontaneously aborted embryos with 46,XX karyotype, as well as in control groups of 135 women without pregnancy loss and 64 embryos with 46,XX karyotype from induced abortions in women who terminated a normal pregnancy. The frequency of sXCI differed significantly between women with miscarriages and women without pregnancy losses (6.3% and 2.2%, respectively; p = 0.019). To exclude primary causes of sXCI, sequencing of the XIST and XACT genes was performed. The XIST and XACT gene sequencing revealed no known pathogenic variants that could lead to sXCI. Molecular karyotyping was performed using aCGH, followed by verification of X-linked CNVs by RT-PCR and MLPA. Microdeletions at Xp11.23 and Xq24 as well as gains of Xq28 were detected in women with sXCI and pregnancy loss.

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“…Vasilyev et al reported differential DNA methylation of intragenic CpG sites of the IMMP2L gene located in a critical region for the autism susceptibility locus on chromosome 7q (AUTS1). The authors suggest a partial compensation of IMMP2L gene haploinsufficiency in healthy CNV carriers by reducing the DNA methylation level (31).…”

Section: Known Genetic Background Of Cas Is Highly Heterogeneousmentioning

confidence: 95%

Case Report: Expressive Speech Disorder in a Family as a Hallmark of 7q31 Deletion Involving the FOXP2 Gene

Nagy

Kárteszi²,

Elmont³

et al. 2021

Front. Pediatr.

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Pathogenic variants of FOXP2 gene were identified first as a monogenic cause of childhood apraxia of speech (CAS), a complex disease that is associated with an impairment of the precision and consistency of movements underlying speech, due to deficits in speech motor planning and programming. FOXP2 variants are heterogenous; single nucleotide variants and small insertions/deletions, intragenic and large-scale deletions, as well as disruptions by structural chromosomal aberrations and uniparental disomy of chromosome 7 are the most common types of mutations. FOXP2-related speech and language disorders can be classified as “FOXP2-only,” wherein intragenic mutations result in haploinsufficiency of the FOXP2 gene, or “FOXP2-plus” generated by structural genomic variants (i.e., translocation, microdeletion, etc.) and having more likely developmental and behavioral disturbances adjacent to speech and language impairment. The additional phenotypes are usually related to the disruption/deletion of multiple genes neighboring FOXP2 in the affected chromosomal region. We report the clinical and genetic findings in a family with four affected individuals having expressive speech impairment as the dominant symptom and additional mild dysmorphic features in three. A 7.87 Mb interstitial deletion of the 7q31.1q31.31 region was revealed by whole genome diagnostic microarray analysis in the proband. The FOXP2 gene deletion was confirmed by multiplex ligation-dependent probe amplification (MLPA), and all family members were screened by this targeted method. The FOXP2 deletion was detected in the mother and two siblings of the proband using MLPA. Higher resolution microarray was performed in all the affected individuals to refine the extent and breakpoints of the 7q31 deletion and to exclude other pathogenic copy number variants. To the best of our knowledge, there are only two family-studies reported to date with interstitial 7q31 deletion and showing the core phenotype of FOXP2 haploinsufficiency. Our study may contribute to a better understanding of the behavioral phenotype of FOXP2 disruptions and aid in the identification of such patients. We illustrate the importance of a targeted MLPA analysis suitable for the detection of FOXP2 deletion in selected cases with a specific phenotype of expressive speech disorder. The “phenotype first” and targeted diagnostic strategy can improve the diagnostic yield of speech disorders in the routine clinical practice.

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

Cited by 9 publications

References 33 publications

Maternal Copy Number Imbalances in Non-Invasive Prenatal Testing: Do They Matter?

Maternal Copy Number Imbalances in Non-Invasive Prenatal Testing: Do They Matter?

Skewed X-Chromosome Inactivation as a Possible Marker of X-Linked CNV in Women with Pregnancy Loss

Case Report: Expressive Speech Disorder in a Family as a Hallmark of 7q31 Deletion Involving the FOXP2 Gene

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