DNA Methylation Episignatures in Neurodevelopmental Disorders Associated with Large Structural Copy Number Variants: Clinical Implications

Rooney, Kathleen; Sadiković, Bekim

doi:10.3390/ijms23147862

Cited by 13 publications

(6 citation statements)

References 92 publications

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“…Interestingly, the 9q34.3 duplication DNA methylation profile is not “mirroring” or overlapping the KS episignature, as has been demonstrated for some reciprocal microdeletion/microduplication syndromes 18 . It is possible that the difference in cellular effects of the overexpression vs. loss results in different DNA methylation changes.…”

Section: Discussionmentioning

confidence: 89%

“…Interestingly, the 9q34.3 duplication DNA methylation profile is not "mirroring" or overlapping the KS episignature, as has been demonstrated for some reciprocal microdeletion/microduplication syndromes. 18 It is possible that the difference in cellular effects of the overexpression vs. loss results in different DNA methylation changes. It is also possible that the profile identified among the 9q34.3 microduplication cases results from overexpression of several genes or another gene (e.g., ZMYND19), as has been shown for…”

Section: Discussionmentioning

confidence: 99%

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Refining the 9q34.3 microduplication syndrome reveals mild neurodevelopmental features associated with a distinct global DNA methylation profile

Rots,

Rooney,

Relator

et al. 2024

Clinical Genetics

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Precise regulation of gene expression is important for correct neurodevelopment. 9q34.3 deletions affecting the EHMT1 gene result in a syndromic neurodevelopmental disorder named Kleefstra syndrome. In contrast, duplications of the 9q34.3 locus encompassing EHMT1 have been suggested to cause developmental disorders, but only limited information has been available. We have identified 15 individuals from 10 unrelated families, with 9q34.3 duplications <1.5 Mb in size, encompassing EHMT1 entirely. Clinical features included mild developmental delay, mild intellectual disability or learning problems, autism spectrum disorder, and behavior problems. The individuals did not consistently display dysmorphic features, congenital anomalies, or growth abnormalities. DNA methylation analysis revealed a weak DNAm profile for the cases with 9q34.3 duplication encompassing EHMT1, which could segregate the majority of the affected cases from controls. This study shows that individuals with 9q34.3 duplications including EHMT1 gene present with mild non‐syndromic neurodevelopmental disorders and DNA methylation changes different from Kleefstra syndrome.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Refining the 9q34.3 microduplication syndrome reveals mild neurodevelopmental features associated with a distinct global DNA methylation profile

Rots,

Rooney,

Relator

et al. 2024

Clinical Genetics

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“…Genome‐wide DNA methylation patterns may provide additional evidence for variant classification in genes affected by chromatin remodeling or epigenetic reprogramming (Aref‐Eshghi et al, 2019 ; Sadikovic et al, 2021 ; Rooney & Sadikovic, 2022 ). EpiSign analysis was particularly important for reclassification as it provided an independent functional link between an atypical ARID1B missense variant and a cluster of ARID1B episignatures.…”

Section: Discussionmentioning

confidence: 99%

Integration of EpiSign, facial phenotyping, and likelihood ratio interpretation of clinical abnormalities in the re‐classification of an ARID1B missense variant

Forwood,

Ashton,

Zhu

et al. 2023

American J of Med Genetics Pt C

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Heterozygous ARID1B variants result in Coffin–Siris syndrome. Features may include hypoplastic nails, slow growth, characteristic facial features, hypotonia, hypertrichosis, and sparse scalp hair. Most reported cases are due to ARID1B loss of function variants. We report a boy with developmental delay, feeding difficulties, aspiration, recurrent respiratory infections, slow growth, and hypotonia without a clinical diagnosis, where a previously unreported ARID1B missense variant was classified as a variant of uncertain significance. The pathogenicity of this variant was refined through combined methodologies including genome‐wide methylation signature analysis (EpiSign), Machine Learning (ML) facial phenotyping, and LIRICAL. Trio exome sequencing and EpiSign were performed. ML facial phenotyping compared facial images using FaceMatch and GestaltMatcher to syndrome‐specific libraries to prioritize the trio exome bioinformatic pipeline gene list output. Phenotype‐driven variant prioritization was performed with LIRICAL. A de novo heterozygous missense variant, ARID1B p.(Tyr1268His), was reported as a variant of uncertain significance. The ACMG classification was refined to likely pathogenic by a supportive methylation signature, ML facial phenotyping, and prioritization through LIRICAL. The ARID1B genotype–phenotype has been expanded through an extended analysis of missense variation through genome‐wide methylation signatures, ML facial phenotyping, and likelihood‐ratio gene prioritization.

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“…Gross deletions at the exon level represent the most common type of mutation (~80%). The genotypic background of these neuropsychiatric disorders is highly heterogeneous; expression and the resulting phenotype may be influenced by environmental or even epigenetic factors through different methylation patterns [ 48 ]. IMMP2L might also regulate processes in the reproductive system.…”

Section: Discussionmentioning

confidence: 99%

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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DNA Methylation Episignatures in Neurodevelopmental Disorders Associated with Large Structural Copy Number Variants: Clinical Implications

Cited by 13 publications

References 92 publications

Refining the 9q34.3 microduplication syndrome reveals mild neurodevelopmental features associated with a distinct global DNA methylation profile

Refining the 9q34.3 microduplication syndrome reveals mild neurodevelopmental features associated with a distinct global DNA methylation profile

Integration of EpiSign, facial phenotyping, and likelihood ratio interpretation of clinical abnormalities in the re‐classification of an ARID1B missense variant

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

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