{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:41:43Z","timestamp":1790692903960,"version":"4.1.0"},"reference-count":94,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,16]],"date-time":"2022-07-16T00:00:00Z","timestamp":1657929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Government of Canada through Genome Canada and the Ontario Genomics Institute"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms23147862","type":"journal-article","created":{"date-parts":[[2022,7,17]],"date-time":"2022-07-17T22:57:06Z","timestamp":1658098626000},"page":"7862","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["DNA Methylation Episignatures in Neurodevelopmental Disorders Associated with Large Structural Copy Number Variants: Clinical Implications"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7871-8982","authenticated-orcid":false,"given":"Kathleen","family":"Rooney","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada"},{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bekim","family":"Sadikovic","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada"},{"name":"Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1093\/brain\/awaa051","article-title":"A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants","volume":"143","author":"Symonds","year":"2020","journal-title":"Brain"},{"key":"ref_2","unstructured":"Institute of Medicine (US) Committee on Nervous System Disorders in Developing Countries (2001). Neurological, Psychiatric, and Developmental Disorders: Meeting the Challenge in the Developing World."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"65","DOI":"10.31887\/DCNS.2020.22.1\/macrocq","article-title":"Neurodevelopmental disorders\u2014The history and future of a diagnostic concept","volume":"22","author":"Crocq","year":"2020","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.tins.2020.05.004","article-title":"Neurodevelopmental Disorders: From Genetics to Functional Pathways","volume":"43","author":"Parenti","year":"2020","journal-title":"Trends Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1016\/S0140-6736(13)61132-0","article-title":"Risk factors for congenital anomaly in a multiethnic birth cohort: An analysis of the Born in Bradford study","volume":"382","author":"Sheridan","year":"2013","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.ajhg.2014.03.018","article-title":"Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders","volume":"94","author":"Pinto","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.ajhg.2010.04.006","article-title":"Consensus Statement: Chromosomal Microarray Is a First-Tier Clinical Diagnostic Test for Individuals with Developmental Disabilities or Congenital Anomalies","volume":"86","author":"Miller","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41431-018-0244-x","article-title":"European guidelines for constitutional cytogenomic analysis","volume":"27","author":"Silva","year":"2019","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1136\/jmg.2003.017731","article-title":"Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability\/mental retardation and dysmorphic features","volume":"41","author":"Redon","year":"2004","journal-title":"J. Med. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1086\/379977","article-title":"Array-Based Comparative Genomic Hybridization for the Genomewide Detection of Submicroscopic Chromosomal Abnormalities","volume":"73","author":"Vissers","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Haraksingh, R.R., Abyzov, A., and Urban, A.E. (2017). Comprehensive performance comparison of high-resolution array platforms for genome-wide Copy Number Variation (CNV) analysis in humans. BMC Genom., 18.","DOI":"10.1186\/s12864-017-3658-x"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1038\/ng.238","article-title":"Integrated detection and population-genetic analysis of SNPs and copy number variation","volume":"40","author":"McCarroll","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/nrg1767","article-title":"Structural variation in the human genome","volume":"7","author":"Feuk","year":"2006","journal-title":"Nat. Rev. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/pd.5422","article-title":"Are all chromosome microarrays the same? What clinicians need to know","volume":"39","author":"Levy","year":"2019","journal-title":"Prenat. Diagn."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"D\u2019Amours, G., Langlois, M., Mathonnet, G., Fetni, R., Nizard, S., Srour, M., Tihy, F., Phillips, M.S., Michaud, J.L., and Lemyre, E. (2014). SNP arrays: Comparing diagnostic yields for four platforms in children with developmental delay. BMC Med. Genom., 7.","DOI":"10.1186\/s12920-014-0070-0"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/cdev.12051","article-title":"Child Development and Structural Variation in the Human Genome","volume":"84","author":"Zhang","year":"2013","journal-title":"Child Dev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/ng1562","article-title":"Fine-scale structural variation of the human genome","volume":"37","author":"Tuzun","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/s00439-018-1910-3","article-title":"The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease","volume":"137","author":"Liu","year":"2018","journal-title":"Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Akhtar, M.S., Ashino, R., Oota, H., Ishida, H., Niimura, Y., Touhara, K., Melin, A.D., and Kawamura, S. (2022). Genetic variation of olfactory receptor gene family in a Japanese population. Anthr. Sci., 211024.","DOI":"10.1537\/ase.211024"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.neuron.2006.09.027","article-title":"Genomic Rearrangements and Gene Copy-Number Alterations as a Cause of Nervous System Disorders","volume":"52","author":"Lee","year":"2006","journal-title":"Neuron"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/ng.909","article-title":"A Copy Number Variation Morbidity Map of Developmental Delay","volume":"43","author":"Cooper","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1111\/cge.13906","article-title":"Smith-Magenis syndrome: Clinical and behavioral characteristics in a large retrospective cohort","volume":"99","author":"Jacquinet","year":"2021","journal-title":"Clin. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/S0168-9525(01)02492-1","article-title":"Recent duplication, domain accretion and the dynamic mutation of the human genome","volume":"17","author":"Eichler","year":"2001","journal-title":"Trends Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1146\/annurev.genom.7.080505.115618","article-title":"Structural Variation of the Human Genome","volume":"7","author":"Sharp","year":"2006","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/j.ajhg.2011.09.009","article-title":"Frequency of Nonallelic Homologous Recombination Is Correlated with Length of Homology: Evidence that Ectopic Synapsis Precedes Ectopic Crossing-Over","volume":"89","author":"Liu","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/s41431-020-00707-7","article-title":"Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents","volume":"29","author":"Lavrichenko","year":"2021","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1136\/jmg.2004.027755","article-title":"Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome","volume":"42","author":"Douglas","year":"2005","journal-title":"J. Med. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e198","DOI":"10.3928\/19382359-20180419-01","article-title":"An Update on Common Chromosome Microdeletion and Microduplication Syndromes","volume":"47","author":"Goldenberg","year":"2018","journal-title":"Pediatr. Ann."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1038\/ejhg.2009.154","article-title":"High-resolution SNP arrays in mental retardation diagnostics: How much do we gain?","volume":"18","author":"Bernardini","year":"2010","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1056\/NEJMoa1206524","article-title":"Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability","volume":"367","author":"Willemsen","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1111\/j.1528-1167.2012.03516.x","article-title":"Targeted next generation sequencing as a diagnostic tool in epileptic disorders","volume":"53","author":"Lemke","year":"2012","journal-title":"Epilepsia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1038\/gim.2017.247","article-title":"Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature","volume":"20","author":"Schwarze","year":"2018","journal-title":"Genet. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1002\/humu.22332","article-title":"Targeted Next-Generation Sequencing can Replace Sanger Sequencing in Clinical Diagnostics","volume":"34","author":"Johansson","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/s41390-020-01151-5","article-title":"The influence of social determinants of health on the genetic diagnostic odyssey: Who remains undiagnosed, why, and to what effect?","volume":"89","author":"Fraiman","year":"2021","journal-title":"Pediatr. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/s41436-020-00975-0","article-title":"(Un)standardized testing: The diagnostic odyssey of children with rare genetic disorders in Alberta, Canada","volume":"23","author":"McInnes","year":"2021","journal-title":"Genet. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1111\/cge.12732","article-title":"Diagnostic odyssey in severe neurodevelopmental disorders: Toward clinical whole-exome sequencing as a first-line diagnostic test","volume":"89","author":"Thevenon","year":"2016","journal-title":"Clin. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/j.jmoldx.2016.06.005","article-title":"Clinical Validation of Fragile X Syndrome Screening by DNA Methylation Array","volume":"18","author":"Schenkel","year":"2016","journal-title":"J. Mol. Diagn."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1002\/ajmg.a.32261","article-title":"Mosaic FMR1 Deletion Causes Fragile X Syndrome and Can Lead to Molecular Misdiagnosis","volume":"146A","author":"Coffee","year":"2008","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.ejpn.2014.12.014","article-title":"The diagnostic pathway in complex paediatric neurology: A cost analysis","volume":"19","author":"Schieving","year":"2015","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1038\/s41436-021-01110-3","article-title":"Systematic assessment of outcomes following a genetic diagnosis identified through a large-scale research study into developmental disorders","volume":"23","author":"Copeland","year":"2021","journal-title":"Genet. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1038\/s41431-020-0644-6","article-title":"Who ever heard of 16p11.2 deletion syndrome? Parents\u2019 perspectives on a susceptibility copy number variation syndrome","volume":"28","author":"Kleinendorst","year":"2020","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"526779","DOI":"10.3389\/fped.2021.526779","article-title":"Genetic Testing in Neurodevelopmental Disorders","volume":"9","author":"Savatt","year":"2021","journal-title":"Front. Pediatr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"100075","DOI":"10.1016\/j.xhgg.2021.100075","article-title":"Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders","volume":"3","author":"Levy","year":"2021","journal-title":"Hum. Genet. Genom. Adv."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.ajhg.2020.01.019","article-title":"Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders","volume":"106","author":"Kerkhof","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1038\/s41436-020-01096-4","article-title":"Clinical epigenomics: Genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders","volume":"23","author":"Sadikovic","year":"2021","journal-title":"Genet. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13148-020-00990-7","article-title":"DNA methylation epi-signature is associated with two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome","volume":"13","author":"Schenkel","year":"2021","journal-title":"Clin. Epigenetics"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1101\/gad.1787609","article-title":"An operational definition of epigenetics","volume":"23","author":"Berger","year":"2009","journal-title":"Genes Dev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1534\/genetics.114.173492","article-title":"What Do You Mean, \u201cEpigenetic\u201d?","volume":"199","author":"Deans","year":"2015","journal-title":"Genetics"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/hdy.2010.54","article-title":"Epigenetics and gene expression","volume":"105","author":"Gibney","year":"2010","journal-title":"Heredity"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"a019133","DOI":"10.1101\/cshperspect.a019133","article-title":"DNA Methylation in Mammals","volume":"6","author":"Li","year":"2014","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_51","unstructured":"Kundu, T.K. (2013). The Role of DNA Methylation and Histone Modifications in Transcriptional Regulation in Humans. Epigenetics: Development and Disease, Springer."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/nrg3230","article-title":"Functions of DNA methylation: Islands, start sites, gene bodies and beyond","volume":"13","author":"Jones","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1080\/15592294.2017.1381807","article-title":"The defining DNA methylation signature of Kabuki syndrome enables functional assessment of genetic variants of unknown clinical significance","volume":"12","author":"Schenkel","year":"2017","journal-title":"Epigenetics"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s13148-018-0453-8","article-title":"Peripheral blood epi-signature of Claes-Jensen syndrome enables sensitive and specific identification of patients and healthy carriers with pathogenic mutations in KDM5C","volume":"10","author":"Schenkel","year":"2018","journal-title":"Clin. Epigenetics"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s13148-016-0254-x","article-title":"Identification of a methylation profile for DNMT1-associated autosomal dominant cerebellar ataxia, deafness, and narcolepsy","volume":"8","author":"Kernohan","year":"2016","journal-title":"Clin. Epigenetics"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1212\/WNL.0b013e318284076d","article-title":"DNMT1 mutation hot spot causes varied phenotypes of HSAN1 with dementia and hearing loss Background: Mutations in DNA methyltransferase 1 (DNMT1) have been identified in 2 autosomal","volume":"80","author":"Klein","year":"2013","journal-title":"Neurology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/ng.830","article-title":"Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss","volume":"43","author":"Klein","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/ng.2917","article-title":"Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability","volume":"46","author":"Seal","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1093\/hmg\/ddm341","article-title":"DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function","volume":"17","author":"Jin","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41525-021-00256-y","article-title":"Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood","volume":"6","author":"Levy","year":"2021","journal-title":"NPJ Genom. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.ajhg.2019.12.007","article-title":"Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency","volume":"106","author":"Beck","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"38803","DOI":"10.1038\/srep38803","article-title":"The defining DNA methylation signature of Floating-Harbor Syndrome","volume":"6","author":"Hood","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s13072-017-0118-4","article-title":"Identification of epigenetic signature associated with alpha thalassemia\/mental retardation X-linked syndrome","volume":"10","author":"Schenkel","year":"2017","journal-title":"Epigenet. Chromatin"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4885","DOI":"10.1038\/s41467-018-07193-y","article-title":"BAFopathies\u2019 DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin\u2013Siris and Nicolaides\u2013Baraitser syndromes","volume":"9","author":"Bend","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"5121","DOI":"10.1093\/hmg\/ddt366","article-title":"A comprehensive molecular study on Coffin\u2013Siris and Nicolaides\u2013Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling","volume":"22","author":"Wieczorek","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1038\/s41436-020-0898-y","article-title":"De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides\u2013Baraitser syndrome","volume":"22","author":"Cappuccio","year":"2020","journal-title":"Genet. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13148-019-0658-5","article-title":"Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome","volume":"11","author":"Bend","year":"2019","journal-title":"Clin. Epigenet."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.ajhg.2020.07.003","article-title":"Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype","volume":"107","author":"Breen","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1159\/000508050","article-title":"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","volume":"160","author":"Tolmacheva","year":"2020","journal-title":"Cytogenet. Genome Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1038\/s41467-018-03895-5","article-title":"Functional crosstalk between histone H2B ubiquitylation and H2A modifications and variants","volume":"9","author":"Wojcik","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1111\/j.1365-2249.2012.04621.x","article-title":"X chromosome gene methylation in peripheral lymphocytes from monozygotic twins discordant for scleroderma","volume":"169","author":"Selmi","year":"2012","journal-title":"Clin. Exp. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.ajhg.2019.03.008","article-title":"Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions","volume":"104","author":"Bend","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1101\/gr.125187.111","article-title":"Age-associated DNA methylation in pediatric populations","volume":"22","author":"Alisch","year":"2012","journal-title":"Genome Res."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Houseman, E.A., Accomando, W.P., Koestler, D.C., Christensen, B.C., Marsit, C.J., Nelson, H.H., Wiencke, J.K., and Kelsey, K.T. (2012). DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinform., 13.","DOI":"10.1186\/1471-2105-13-86"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1093\/ije\/dyr238","article-title":"Bump hunting to identify differentially methylated regions in epigenetic epidemiology studies","volume":"41","author":"Jaffe","year":"2012","journal-title":"Int. J. Epidemiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/j.jmoldx.2017.07.002","article-title":"Clinical Validation of a Genome-Wide DNA Methylation Assay for Molecular Diagnosis of Imprinting Disorders","volume":"19","author":"Schenkel","year":"2017","journal-title":"J. Mol. Diagn."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.ajhg.2017.12.008","article-title":"Genomic DNA Methylation Signatures Enable Concurrent Diagnosis and Clinical Genetic Variant Classification in Neurodevelopmental Syndromes","volume":"102","author":"Rodenhiser","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1186\/s13148-019-0749-3","article-title":"A genome-wide DNA methylation signature for SETD1B-related syndrome","volume":"11","author":"Krzyzewska","year":"2019","journal-title":"Clin. Epigenet."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s13229-018-0205-9","article-title":"Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations","volume":"9","author":"Siper","year":"2018","journal-title":"Mol. Autism"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/gim.2013.144","article-title":"22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan\u2013McDermid syndrome","volume":"16","author":"Sarasua","year":"2014","journal-title":"Genet. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1038\/ejhg.2008.107","article-title":"Interstitial 22q13 deletions: Genes other than SHANK3 have major effects on cognitive and language development","volume":"16","author":"Wilson","year":"2008","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1101\/gr.229102","article-title":"The Human Genome Browser at UCSC","volume":"12","author":"Kent","year":"2002","journal-title":"Genome Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.ajhg.2015.05.019","article-title":"Symmetrical Dose-Dependent DNA-Methylation Profiles in Children with Deletion or Duplication of 7q11.23","volume":"97","author":"Strong","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s13148-019-0684-3","article-title":"Functional DNA methylation signatures for autism spectrum disorder genomic risk loci: 16p11.2 deletions and CHD8 variants","volume":"11","author":"Siu","year":"2019","journal-title":"Clin. Epigenetics"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Rooney, K., Levy, M.A., Haghshenas, S., Kerkhof, J., Rogaia, D., Tedesco, M.G., Imperatore, V., Mencarelli, A., Squeo, G.M., and Di Venere, E. (2021). Identification of a DNA Methylation Episignature in the 22q11.2 Deletion Syndrome. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168611"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Van Gils, J., Magdinier, F., Fergelot, P., and Lacombe, D. (2021). Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder. Genes, 12.","DOI":"10.3390\/genes12070968"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"10207","DOI":"10.1038\/ncomms10207","article-title":"NSD1 mutations generate a genome-wide DNA methylation signature","volume":"6","author":"Choufani","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.molcel.2017.11.019","article-title":"A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene","volume":"68","author":"Singh","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1089\/cmb.2018.0143","article-title":"Measuring DNA Copy Number Variation Using High-Density Methylation Microarrays","volume":"26","author":"Cho","year":"2019","journal-title":"J. Comput. Biol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"R30","DOI":"10.1186\/gb-2014-15-2-r30","article-title":"Using high-density DNA methylation arrays to profile copy number alterations","volume":"15","author":"Feber","year":"2014","journal-title":"Genome Biol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3982","DOI":"10.1093\/bioinformatics\/btx513","article-title":"ChAMP: Updated methylation analysis pipeline for Illumina BeadChips","volume":"33","author":"Tian","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1093\/bioinformatics\/btt684","article-title":"ChAMP: 450k Chip Analysis Methylation Pipeline","volume":"30","author":"Morris","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_93","unstructured":"Papillon-Cavanagh, S., Fortin, J.-P., and De Jay, N. (2022, May 15). CopyNumber 450k: An R Package for CNV Inference Using Illumina 450k DNA Methylation Assay. Available online: http:\/\/rdrr.io\/github\/spapillon\/CopyNumber450k\/."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.1002\/ajmg.a.62754","article-title":"Genome-wide DNA methylation profiling confirms a case of low-level mosaic Kabuki syndrome 1","volume":"188","author":"Montano","year":"2022","journal-title":"Am. J. Med. Genet. 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