Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions

Aref‐Eshghi, Erfan; Bend, Eric G.; Colaiacovo, Samantha; Caudle, Michelle; Chakrabarti, Rana; Napier, Melanie; Brick, Lauren; Brady, Lauren; Carere, Deanna Alexis; Levy, Michael A.; Kerkhof, Jennifer; Stuart, Alan; Saleh, Maha; Beaudet, Arthur L.; Li, Chumei; Kozenko, Maryia; Karp, Natalya; Prasad, Chitra; Siu, Victoria Mok; Tarnopolsky, Mark A.; Ainsworth, Peter; Lin, Hanxin; Rodenhiser, David I.; Krantz, Ian D.; Deardorff, Matthew A.; Schwartz, Charles E.; Sadiković, Bekim

doi:10.1016/j.ajhg.2019.03.008

Cited by 144 publications

(163 citation statements)

References 62 publications

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“…Here we replicated and expanded earlier findings [15][16][17] of DNA methylation changes in ADNP syndrome. The mechanisms leading to these methylation changes are still unknown.…”

supporting

confidence: 88%

Episignatures stratifying ADNP syndrome show modest correlation with phenotype

Breen

Garg

Tang

et al. 2020

Preprint

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ADNP syndrome, also known as Helsmoortel-van Der Aa syndrome, is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. ADNP syndrome is caused by mutations in the activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with ADNP syndrome, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with ADNP syndrome into two groups, based on the location of the mutations. Here, we conducted an independent study on 24 individuals with ADNP syndrome and replicated the existence of the two, mutation-dependent ADNP episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of ADNP syndrome. We found limited phenotypic differences between the two ADNP groups, and no evidence that individuals with more widespread methylation changes are more severely affected. Also, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with ADNP syndrome. Our data warrant caution in harnessing methylation signatures in ADNP syndrome as a tool for clinical stratification, at least with regards to behavioral phenotypes. Main textADNP syndrome, also known as Helsmoortel-van Der Aa syndrome, is an autosomal dominant neurodevelopmental disorder (NDD) caused by de novo mutations in the ADNP gene (MIM #615873) 1 . The syndrome was first described in 2014 by Helsmoortel and colleagues in ten individuals 1 . The clinical presentation included intellectual disability/developmental delay (ID/DD), autism spectrum disorder (ASD), facial dysmorphisms, hypotonia, and congenital heart defects (CHD) 1 . A recent study collating clinical information from medical records for 78 participants across 16 countries has further expanded the clinical spectrum and demonstrated high prevalence of CHD, visual problems, and gastrointestinal problems 2 .The ADNP gene encodes a multi-functional protein harboring nine zinc fingers 3 , a homeobox domain for the binding to the DNA 3 , a binding site for the heterochromatin protein 1 (HP1) 4 , and a nuclear localization sequence 3; 5 . In mouse embryonic stem (ES) cells, ADNP interacts with the chromatin remodeler CHD4 and the chromatin architectural protein HP1 to form a complex called ChAHP 6; 7 . The ChAHP complex binds to specific DNA regions and represses gene expression by locally rendering chromatin inaccessible 7 . Additionally, the ChAHP modulates the 3D chromatin architecture by antagonizing chromatin looping at CTCF sites 6 . Within the ChAHP, ADNP mediates the binding to specific DNA sites 6; 7 . The genes transcriptionally repressed by the ChAHP in ES cells control cell fate decisions 7 . In fact, Adnp null (Adnp -/-) ES cells undergo spontaneous differentiat...

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“…Here we replicated and expanded earlier findings [15][16][17] of DNA methylation changes in ADNP syndrome. The mechanisms leading to these methylation changes are still unknown.…”

supporting

confidence: 88%

Episignatures stratifying ADNP syndrome show modest correlation with phenotype

Breen

Garg

Tang

et al. 2020

Preprint

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“…Additional minor signs were present in single individuals. These samples were compared with a reference cohort of controls from a pool of healthy individuals in the London Health Sciences EpiSign Knowledge Database [17]. A larger set of controls used to assess the specificity of the classification model was compiled from three large databases of general population samples with various age and ethnicity (GSE42861, GSE87571, and GSE99863) [18][19][20].…”

Section: Patients and Cohortsmentioning

confidence: 99%

Frameshift mutations at the C-terminus of HIST1H1E result in a specific DNA hypomethylation signature

et al. 2020

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Background: We previously associated HIST1H1E mutations causing Rahman syndrome with a specific genomewide methylation pattern. Results: Methylome analysis from peripheral blood samples of six affected subjects led us to identify a specific hypomethylated profile. This "episignature" was enriched for genes involved in neuronal system development and function. A computational classifier yielded full sensitivity and specificity in detecting subjects with Rahman syndrome. Applying this model to a cohort of undiagnosed probands allowed us to reach diagnosis in one subject. Conclusions: We demonstrate an epigenetic signature in subjects with Rahman syndrome that can be used to reach molecular diagnosis.

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“…Amongst all epigenetic alterations in cancer, aberrant DNA hypermethylation is more studied than aberrant hypomethylation, and diagnostic tests being developed also tend to look for hypermethylated regions rather than hypomethylated ones. 62 The reason for the focus on hypermethylation instead of hypomethylation is technical. Methylation assays produce a signal for methylated DNA, and a lack of signal signifies a lack of methylated DNA due to either hypomethylation of the DNA present or due to absence of the targeted DNA in the assay.…”

Section: Epigenetic Biomarkers In Cancermentioning

confidence: 99%

<p>The Current Understanding Of Asbestos-Induced Epigenetic Changes Associated With Lung Cancer</p>

Cheng¹,

Rath²,

Linton³

et al. 2020

LCTT

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Asbestos is a naturally occurring mineral consisting of extremely fine fibres that can become trapped in the lungs after inhalation. Occupational and environmental exposures to asbestos are linked to development of lung cancer and malignant mesothelioma, a cancer of the lining surrounding the lung. This review discusses the factors that are making asbestos-induced lung cancer a continuing problem, including the extensive historic use of asbestos and decades long latency between exposure and disease development. Genomic mutations of DNA nucleotides and gene rearrangements driving lung cancer are well-studied, with biomarkers and targeted therapies already in clinical use for some of these mutations. The genes involved in these mutation biomarkers and targeted therapies are also involved in epigenetic mechanisms and are discussed in this review as it is hoped that identification of epigenetic aberrations in these genes will enable the same gene biomarkers and targeted therapies to be used. Currently, understanding of how asbestos fibres trapped in the lungs leads to epigenetic changes and lung cancer is incomplete. It has been shown that oxidoreduction reactions on fibre surfaces generate reactive oxygen species (ROS) which in turn damage DNA, leading to genetic and epigenetic alterations that reduce the activity of tumour suppressor genes. Epigenetic DNA methylation changes associated with lung cancer are summarised in this review, and some of these changes will be due to asbestos exposure. So far, little research has been carried out to separate the asbestos driven epigenetic changes from those due to non-asbestos causes of lung cancer. Asbestos-associated lung cancers exhibit less methylation variability than lung cancers in general, and in a large proportion of samples variability has been found to be restricted to promoter regions. Epigenetic aberrations in cancer are proving to be promising biomarkers for diagnosing cancers. It is hoped that further understanding of epigenetic changes in lung cancer can result in useful asbestos-associated lung cancer biomarkers to guide treatment. Research is ongoing into the detection of lung cancer epigenetic alterations using non-invasive samples of blood and sputum. These efforts hold the promise of non-invasive cancer diagnosis in the future. Efforts to reverse epigenetic aberrations in lung cancer by epigenetic therapies are ongoing but have not yet yielded success.

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Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions

Cited by 144 publications

References 62 publications

Episignatures stratifying ADNP syndrome show modest correlation with phenotype

Episignatures stratifying ADNP syndrome show modest correlation with phenotype

Frameshift mutations at the C-terminus of HIST1H1E result in a specific DNA hypomethylation signature

<p>The Current Understanding Of Asbestos-Induced Epigenetic Changes Associated With Lung Cancer</p>

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