Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood

Levy, Michael A.; Beck, David B.; Metcalfe, Kay; Douzgou, Sofia; Sithambaram, Sivagamy; Cottrell, Trudie; Ansar, Muhammad; Kerkhof, Jennifer; Mignot, Cyril; Nouguès, Marie‐Christine; Keren, Boris; Moore, Hannah W.; Oegema, Renske; Giltay, Jacques C.; Simon, Marleen; Jaarsveld, Richard H. van; Bos, Jessica; Haelst, Mieke M. van; Motazacker, Mahdi M.; Boon, Elles M. J.; Santen, Gijs W.E.; Ruivenkamp, Claudia; Alders, Mariëlle; Luperchio, Teresa Romeo; Boukas, Leandros; Ramsey, Keri; Narayanan, Vinodh; Schaefer, Gerald; Bonasio, Roberto; Doheny, Kimberly F.; Stevenson, Roger E.; Banka, Siddharth; Sadiković, Bekim; Fahrner, Jill A.

doi:10.1038/s41525-021-00256-y

Cited by 16 publications

(16 citation statements)

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“…We have previously described the development of 56 distinct diagnostic episignatures encompassing 65 neurodevelopmental syndromes caused by pathogenic variants in 61 genes, and their use as highly sensitive and specific diagnostic biomarkers (Aref‐Eshghi, Bend, et al, 2018; Aref‐Eshghi, E., Rodenhiser, 2018; Aref‐Eshghi et al, 2017, 2020; Bend et al, 2019; Ciolfi et al, 2020, 2021; Haghshenas et al, 2021; Hood et al, 2016; Kerkhof et al, 2021; Krzyzewska et al, 2019; Levy et al, 2021, 2022; Radio et al, 2021; Rooney et al, 2021; Sadikovic et al, 2021; Schenkel et al, 2017, 2018, 2021). In these studies, we demonstrated that a monogenic syndrome may have more than one episignature depending on the location and/or functional consequence of the underlying genetic variant within the gene.…”

Section: Introductionmentioning

confidence: 99%

Functional correlation of genome‐wide DNA methylation profiles in genetic neurodevelopmental disorders

et al. 2022

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An expanding range of genetic syndromes are characterized by genome‐wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive, and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder‐specific genome‐wide DNA methylation changes, which can share significant overlap among different conditions. In this study, we performed functional genomic assessment and comparison of disorder‐specific and overlapping genome‐wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder‐specific and recurring genome‐wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under‐representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders.

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Section: Introductionmentioning

confidence: 99%

Functional correlation of genome‐wide DNA methylation profiles in genetic neurodevelopmental disorders

et al. 2022

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“…Unfortunately, none SHFLD3 locus modifier was discovered so far. Considering the current state of the art, we could suspect the presence of epigenetic changes, i.e., methylation profile changes or histone modifications that have been visualized in some Mendelian disorders recently [20][21][22][23]. Unfortunately, we were unable to broaden our research and perform studies to reveal modifying factors/additional genomic or epigenetic changes, whose presence might have explained the asymptomatic 17p13.3 duplication carriers' occurrence (F1.& F2.3) or phenotypic variability observed in affected male individuals (F1.2, F2.1, F2.2).…”

Section: Discussionmentioning

confidence: 99%

SHFLD3 phenotypes caused by 17p13.3 triplication/ duplication encompassing Fingerin (BHLHA9) invariably

Bukowska‐Olech

Sowińska‐Seidler

Wierzba

et al. 2022

Orphanet J Rare Dis

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Background Split-hand/ foot malformation with long bone deficiency 3 (SHFLD3) is an extremely rare condition associated with duplications located on 17p13.3, which invariably encompasses the BHLHA9 gene. The disease inherits with variable expressivity and significant incomplete penetrance as high as 50%. Results We have detected 17p13.3 locus one-allele triplication in a male proband from family 1 (F1.1), and duplication in a male proband from family 2 (F2.1) applying array comparative genomic hybridization (array CGH). The rearrangements mapped to the following chromosomal regions–arr[GRCh38] 17p13.3(960254–1291856)×4 in F1.1 and arr[GRCh38] 17p13.3(1227482–1302716)×3 in F2.1. The targeted quantitative PCR revealed that the 17p13.3 locus was also duplicated in the second affected member from family 2 (F2.2; brother of F2.1). In the next step, we performed segregation studies using quantitative PCR and revealed that F1.1 inherited the triplication from his healthy father—F1.2, whereas the locus was unremarkable in the mother of F2.1 & F2.2 and the healthy son of F2.1. However, the duplication was present in a healthy daughter of F2.2, an asymptomatic carrier. The breakpoint analysis allowed to define the exact size and span of the duplicated region in Family 2, i.e., 78,948 bp chr17:1225063–1304010 (HG38). Interestingly, all symptomatic carriers from both families presented with variable SHFLD3 phenotype. The involvement of secondary modifying locus could not be excluded, however, the Sanger sequencing screening of BHLHA9 entire coding sequence was unremarkable for both families. Conclusions We have shed light on the one-allele CNV triplication occurrence that should be considered when a higher probe (over duplication range) signal is noted. Second, all SHFLD3 patients were accurately described regarding infrequent limb phenotypes, which were highly variable even when familial. Of note, all symptomatic individuals were males. SHFLD3 still remains a mysterious ultra-rare disease and our findings do not answer crucial questions regarding the disease low penetrance, variable expression and heterogeneity. However, we have presented some clinical and molecular aspects that may be helpful in daily diagnostic routine, both dysmorphological and molecular assessment, of patients affected with SHFLD3.

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“…Mutations in DNMT3B , which cause immunodeficiency, centromere instability and facial anomalies (ICF) syndrome, also result in genomic defects in DNAm [ 59 ]. We recently demonstrated a genome-wide DNA hypermethylation episignature in a DNA demethylation gene Tet methylcytosine dioxygenase 3 ( TET3 ), an “eraser” gene that opposes the writer function of DNMT1 [ 60 ]. Mutations in the highly conserved catalytic domain of TET3 cause Beck–Fahrner syndrome (BEFAHRS).…”

Section: The Role Of Epigenetics In Ndds and Subsequent Episignature ...mentioning

confidence: 99%

“…Inheritance patterns of BEFAHRS vary and include autosomal dominant or recessive forms [ 61 ]. Through episignature mapping, we were able to differentiate between affected individuals with mono- and bi-allelic mutations [ 60 ].…”

Section: The Role Of Epigenetics In Ndds and Subsequent Episignature ...mentioning

confidence: 99%

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

Rooney

Sadiković

2022

IJMS

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Large structural chromosomal deletions and duplications, referred to as copy number variants (CNVs), play a role in the pathogenesis of neurodevelopmental disorders (NDDs) through effects on gene dosage. This review focuses on our current understanding of genomic disorders that arise from large structural chromosome rearrangements in patients with NDDs, as well as difficulties in overlap of clinical presentation and molecular diagnosis. We discuss the implications of epigenetics, specifically DNA methylation (DNAm), in NDDs and genomic disorders, and consider the implications and clinical impact of copy number and genomic DNAm testing in patients with suspected genetic NDDs. We summarize evidence of global methylation episignatures in CNV-associated disorders that can be used in the diagnostic pathway and may provide insights into the molecular pathogenesis of genomic disorders. Finally, we discuss the potential for combining CNV and DNAm assessment into a single diagnostic assay.

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Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood

Cited by 16 publications

References 40 publications

Functional correlation of genome‐wide DNA methylation profiles in genetic neurodevelopmental disorders

Functional correlation of genome‐wide DNA methylation profiles in genetic neurodevelopmental disorders

SHFLD3 phenotypes caused by 17p13.3 triplication/ duplication encompassing Fingerin (BHLHA9) invariably

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

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