Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders.
Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders.
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DOI：
10.1016/j.xhgg.2021.100075
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发表时间：
2022-01-13
期刊：
影响因子：
--
通讯作者：
Sadikovic B
中科院分区：
文献类型：
--
作者：
Levy MA;McConkey H;Kerkhof J;Barat-Houari M;Bargiacchi S;Biamino E;Bralo MP;Cappuccio G;Ciolfi A;Clarke A;DuPont BR;Elting MW;Faivre L;Fee T;Fletcher RS;Cherik F;Foroutan A;Friez MJ;Gervasini C;Haghshenas S;Hilton BA;Jenkins Z;Kaur S;Lewis S;Louie RJ;Maitz S;Milani D;Morgan AT;Oegema R;Østergaard E;Pallares NR;Piccione M;Pizzi S;Plomp AS;Poulton C;Reilly J;Relator R;Rius R;Robertson S;Rooney K;Rousseau J;Santen GWE;Santos-Simarro F;Schijns J;Squeo GM;St John M;Thauvin-Robinet C;Traficante G;van der Sluijs PJ;Vergano SA;Vos N;Walden KK;Azmanov D;Balci T;Banka S;Gecz J;Henneman P;Lee JA;Mannens MMAM;Roscioli T;Siu V;Amor DJ;Baynam G;Bend EG;Boycott K;Brunetti-Pierri N;Campeau PM;Christodoulou J;Dyment D;Esber N;Fahrner JA;Fleming MD;Genevieve D;Kerrnohan KD;McNeill A;Menke LA;Merla G;Prontera P;Rockman-Greenberg C;Schwartz C;Skinner SA;Stevenson RE;Vitobello A;Tartaglia M;Alders M;Tedder ML;Sadikovic B
重叠的临床表型和不断扩大的广度和复杂性的基因组协会是一个日益增长的挑战，在诊断和临床管理的孟德尔疾病。基因组变异的功能后果和临床影响可能涉及独特的、疾病特异性的基因组DNA甲基化表观特征。在这项研究中，我们描述了19种新的episignatures疾病，并将这些发现与38种先前建立的episignatures进行比较，共57种episignatures与65种遗传综合征相关。我们展示了从蛋白质复合物，基因，亚基因，蛋白质结构域，甚至单核苷酸水平的孟德尔episignatures的分辨率和特异性增加。我们展示了多类建模的力量，以开发高度准确和疾病特异性的诊断分类器。这项研究显著扩大了具有可检测的DNA甲基化表观特征的疾病的数量和谱，通过解决未解决的病例和重新分类未知临床意义的变体来提高临床诊断能力，并进一步深入了解孟德尔疾病的分子病因学。
Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.
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DOI：
10.1007/978-3-319-67144-4_20
发表时间：
2017-01-01
期刊：
RARE DISEASES EPIDEMIOLOGY: UPDATE AND OVERVIEW, 2ND EDITION
影响因子：
--
作者：
Cutillo, Christine M.;Austin, Christopher P.;Groft, Stephen C.
通讯作者：
Groft, Stephen C.
影响因子：
9.8
作者：
Choufani, Sanaa;Gibson, William T.;Weksberg, Rosanna
通讯作者：
Weksberg, Rosanna
影响因子：
9.8
作者：
Aref-Eshghi, Erfan;Kerkhof, Jennifer;Sadikovic, Bekim
通讯作者：
Sadikovic, Bekim
影响因子：
5.7
作者：
Ciolfi, Andrea;Aref-Eshghi, Erfan;Tartaglia, Marco
通讯作者：
Tartaglia, Marco
影响因子：
3.7
作者：
Aref-Eshghi, Erfan;Schenkel, Laila C.;Sadikovic, Bekim
通讯作者：
Sadikovic, Bekim