Levy Michael A, Relator Raissa, McConkey Haley, Pranckeviciene Erinija, Kerkhof Jennifer, Barat-Houari Mouna, Bargiacchi Sara, Biamino Elisa, Palomares Bralo María, Cappuccio Gerarda, Ciolfi Andrea, Clarke Angus, DuPont Barbara R, Elting Mariet W, Faivre Laurence, Fee Timothy, Ferilli Marco, Fletcher Robin S, Cherick Florian, Foroutan Aidin, Friez Michael J, Gervasini Cristina, Haghshenas Sadegheh, Hilton Benjamin A, Jenkins Zandra, Kaur Simranpreet, Lewis Suzanne, Louie Raymond J, Maitz Silvia, Milani Donatella, Morgan Angela T, Oegema Renske, Østergaard Elsebet, Pallares Nathalie R, Piccione Maria, Plomp Astrid S, Poulton Cathryn, Reilly Jack, Rius Rocio, Robertson Stephen, Rooney Kathleen, Rousseau Justine, Santen Gijs W E, Santos-Simarro Fernando, Schijns Josephine, Squeo Gabriella M, John Miya St, Thauvin-Robinet Christel, Traficante Giovanna, van der Sluijs Pleuntje J, Vergano Samantha A, Vos Niels, Walden Kellie K, Azmanov Dimitar, Balci Tugce B, Banka Siddharth, Gecz Jozef, Henneman Peter, Lee Jennifer A, Mannens Marcel M A M, Roscioli Tony, Siu Victoria, Amor David J, Baynam Gareth, Bend Eric G, Boycott Kym, Brunetti-Pierri Nicola, Campeau Philippe M, Campion Dominique, Christodoulou John, Dyment David, Esber Natacha, Fahrner Jill A, Fleming Mark D, Genevieve David, Heron Delphine, Husson Thomas, Kernohan Kristin D, McNeill Alisdair, Menke Leonie A, Merla Giuseppe, Prontera Paolo, Rockman-Greenberg Cheryl, Schwartz Charles, Skinner Steven A, Stevenson Roger E, Vincent Marie, Vitobello Antonio, Tartaglia Marco, Alders Marielle, Tedder Matthew L, Sadikovic Bekim
Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Ontario, Canada.
Autoinflammatory and Rare Diseases Unit, Medical Genetic Department for Rare Diseases and Personalized Medicine, CHU Montpellier, Montpellier, France.
Hum Mutat. 2022 Nov;43(11):1609-1628. doi: 10.1002/humu.24446. Epub 2022 Aug 21.
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.
越来越多的遗传综合征的特征是全基因组范围内的DNA甲基化谱破坏，即表观遗传特征。表观遗传特征是独特、高度敏感且特异的生物标志物，最近已应用于遗传综合征的临床诊断。表观遗传特征包含在更广泛的疾病特异性全基因组DNA甲基化变化中，这些变化在不同疾病之间可能有显著重叠。在本研究中，我们对与65种遗传综合征相关的疾病特异性和重叠的全基因组DNA甲基化变化进行了功能基因组评估，并与先前描述的表观遗传特征进行了比较。我们证明了疾病特异性和反复出现的全基因组差异甲基化探针（DMP）和区域（DMR）的存在。在所分析的大多数神经发育遗传综合征中，DMP和DMR的总体分布显示在基因启动子和CpG岛中大量富集，而在变异性更大的基因间区域中代表性不足。分析表明，DMP和DMR在与神经发育相关的基因途径和过程中显著富集，包括神经发生、突触信号传导和突触传递。本研究通过证明突变基因的功能与随之而来的基因组DNA甲基化谱之间的相关性，将DNA甲基化表观遗传特征的诊断效用扩展到遗传神经发育障碍分子病因学中的关键功能要素。
