Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders

被引：198

作者：

Aref-Eshghi, Erfan ^{[1
]}

Kerkhof, Jennifer ^{[1
]}

Pedro, Victor P. ^{[2
]}

DI France, Groupe ^{[3
]}

Barat-Houari, Mouna ^{[4
]}

Ruiz-Pallares, Nathalie ^{[4
]}

Andrau, Jean-Christophe ^{[5
]}

Lacombe, Didier ^{[6
]}

Van-Gils, Julien ^{[6
]}

Fergelot, Patricia ^{[6
]}

Dubourg, Christele ^{[7
]}

Cormier-Daire, Valerie ^{[8
]}

Rondeau, Sophie ^{[8
]}

Lecoquierre, Francois ^{[9
]}

Saugier-Veber, Pascale ^{[9
]}

Nicolas, Gael ^{[9
]}

Lesca, Gaetan ^{[10
]}

Chatron, Nicolas ^{[10
]}

Sanlaville, Damien ^{[10
]}

Vitobello, Antonio ^{[11
,38
]}

Faivre, Laurence ^{[11
,39
]}

Thauvin-Robinet, Christel ^{[11
,39
]}

Laumonnier, Frederic ^{[12
,13
]}

Raynaud, Martine ^{[12
,13
]}

Alders, Marielle ^{[14
]}

Mannens, Marcel ^{[14
]}

Henneman, Peter ^{[14
]}

Hennekam, Raoul C. ^{[15
]}

Velasco, Guillaume ^{[16
]}

Francastel, Claire ^{[16
]}

Ulveling, Damien ^{[16
]}

Ciolfi, Andrea ^{[17
]}

Pizzi, Simone ^{[17
]}

Tartaglia, Marco ^{[17
]}

Heide, Solveig ^{[18
]}

Heron, Delphine ^{[18
]}

Mignot, Cyril ^{[18
]}

Keren, Boris ^{[18
]}

Whalen, Sandra ^{[19
]}

Afenjar, Alexandra ^{[19
]}

Bienvenu, Thierry ^{[20
]}

Campeau, Philippe M. ^{[21
]}

Rousseau, Justine ^{[21
]}

Levy, Michael A. ^{[1
,22
]}

Brick, Lauren ^{[23
]}

Kozenko, Mariya ^{[23
]}

Balci, Tugce B. ^{[24
,25
]}

Siu, Victoria Mok ^{[24
,25
]}

Stuart, Alan ^{[1
]}

Kadour, Mike ^{[26
,27
]}

机构：

[1] London Hlth Sci Ctr, Mol Diagnost Div, Mol Genet Lab, London, ON N6A 5W9, Canada

[2] Univ Western Ontario, Schulich Sch Med & Dent, London, ON N6A 5C1, Canada

[3] French Rare Dis Network Filiere AnDDI Rare France, Grp DI, Montpellier, France

[4] CHU Montpellier, Med Genet Dept Rare Dis & Personalized Med, Autoinflammatory & Rare Dis Unit, F-34090 Montpellier, France

[5] Univ Montpellier, IGMM, CNRS, UMR5535, F-34090 Montpellier, France

[6] Bordeaux Univ, CHU Bordeaux, Reference Ctr AD SOOR, Inserm U1211,Med Genet Dept,AnDDI Rare, F-33076 Bordeaux, France

[7] CHU Rennes, Serv Genet Mol & Genom, F-35000 Rennes, France

[8] Paris Descartes Univ, Necker Enfants Malad Hosp, Imagine Inst, Dept Med Genet,INSERM,UMR 1163, F-75015 Paris, France

[9] Univ Bourgogne Franche Comte, FHU TRANSLAD, Genet Dev Disorders, INSERM,UMR 1231,GAD, Dijon, France

[10] Univ Hosp Lyon, Dept Med Genet, F-69007 Lyon, France

[11] Univ Bourgogne Franche Comte, INSERM, Equipe GAD, UMR1231, Batiment B3, F-21000 Dijon, France

[12] Univ Tours, INSERM, iBrain, UMR 1253, F-37200 Tours, France

[13] CHU Tours, Serv Genet, F-37000 Tours, France

[14] Univ Amsterdam, Amsterdam Univ Med Ctr, Amsterdam Reprod & Dev Res Inst, Dept Clin Genet, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands

[15] Univ Amsterdam, Acad Med Ctr, Dept Pediat, NL-1012 WX Amsterdam, Netherlands

[16] Univ Paris, CNRS, Epigenet & Destin Cellulaire, F-75013 Paris, France

[17] IRCCS, Genet & Rare Dis Res Div, Osped Pediatr Bambino Gesu, I-00146 Rome, Italy

[18] Sorbonne Univ, Pitie Salpetriere Hosp, AP HP, Dept Genet,Referral Ctr Intellectual Disabil, F-75013 Paris, France

[19] Sorbonne Univ, Trousseau Hosp, AP HP, Unit Genet, F-75012 Paris, France

[20] Cochin Hosp, Dept Mol Genet, F-75014 Paris, France

[21] Univ Montreal, Dept Pediat, Montreal, PQ H3T 1J4, Canada

[22] Western Univ, Dept Pathol & Lab Med, London, ON N6A 3K7, Canada

[23] McMaster Univ, Dept Pediat, Genet Div, Hamilton, ON L8S 4K1, Canada

[24] Western Univ, Dept Pediat, Div Med Genet, London, ON N6A 3K7, Canada

[25] London Hlth Sci Ctr, Med Genet Program Southwestern Ontario, London, ON N6A 5W9, Canada

[26] London Hlth Sci Ctr, Dept Pathol & Lab Med, London, ON N6A 5W9, Canada

[27] St Josephs Hlth Care London, London, ON N6A 5W9, Canada

[28] Shinshu Univ Hosp, Ctr Med Genet, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan

[29] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, NL-6525 GA Nijmegen, Netherlands

[30] Donders Ctr Med Neurosci, NL-6525 GA Nijmegen, Netherlands

[31] Hunter Genet, Genet Learning Disabil Serv, Waratah, NSW 2298, Australia

[32] Univ Adelaide, Sch Med, Robinson Res Inst, Adelaide, SA 5005, Australia

[33] South Australian Hlth & Med Res Inst, Adelaide, SA 5005, Australia

[34] Childrens Hlth Res Inst, London, ON N6A 3K7, Canada

[35] Western Univ, Dept Biochem, London, ON N6A 3K7, Canada

[36] Greenwood Genet Ctr, Greenwood, SC 29646 USA

[37] Montpellier Univ, CHU Montpellier, Reference Ctr AD SOOR,Med Genet Dept Rare Dis & P, AnDDI RARE,Grp DI,Inserm U1183,Inst Regenerat Med, F-34090 Montpellier, France

[38] Dijon Univ Hosp, Unite Fonct Innovat Diagnost Genom Malad Rares, FHU TRANSLAD, F-21000 Dijon, France

[39] CHU Dijon, Ctr Reference Deficiences Intellectuelles Causes, F-21000 Dijon, France

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2020年 / 106卷 / 03期

关键词：

VARIANTS;

D O I：

10.1016/j.ajhg.2020.01.019

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.

引用

页码：356 / 370

页数：15

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