Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders

被引：130

作者：

Sadikovic, Bekim ^{[1
,2
]}

Levi, Michael A. ^{[1
,2
]}

Kerkhof, Jennifer ^{[1
,2
]}

Aref-Eshghi, Erfan ^{[1
,2
]}

Schenkel, Laila ^{[1
,2
]}

Stuart, Alan ^{[1
,2
]}

McConkey, Haley ^{[1
,2
]}

Henneman, Peter ^{[3
]}

Venema, Andrea ^{[3
]}

Schwartz, Charles E. ^{[4
]}

Stevenson, Roger E. ^{[4
]}

Skinner, Steven A. ^{[4
]}

DuPont, Barbara R. ^{[4
]}

Fletcher, Robin S. ^{[4
]}

Balci, Tugce B. ^{[5
,6
]}

Siu, Victoria Mok ^{[5
,6
]}

Granadillo, Jorge L. ^{[7
]}

Masters, Jennefer ^{[1
,2
]}

Kadour, Mike ^{[1
,2
]}

Friez, Michael J. ^{[4
]}

van Haelst, Mieke M. ^{[3
]}

Mannens, Marcel M. A. M. ^{[3
]}

Louie, Raymond J. ^{[4
]}

Lee, Jennifer A. ^{[4
]}

Tedder, Matthew L. ^{[4
]}

Alders, Marielle ^{[3
]}

机构：

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

[2] Western Univ, Dept Pathol & Lab Med, London, ON, Canada

[3] Univ Amsterdam, Amsterdam Univ Med Ctr, Dept Clin Genet, Amsterdam Reprod & Dev Res Inst, Amsterdam, Netherlands

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

[5] Western Univ, Dept Pediat, Div Med Genet, London, ON, Canada

[6] London Hlth Sci Ctr, Med Genet Program Southwestern Ontario, London, ON, Canada

[7] Washington Univ, Sch Med, Dept Pediat, Div Genet & Genom Med, St Louis, MO 63110 USA

来源：

GENETICS IN MEDICINE | 2021年 / 23卷 / 06期

关键词：

SEQUENCE VARIANTS; VALIDATION; MICROARRAY; GUIDELINES; STANDARDS;

D O I：

10.1038/s41436-020-01096-4

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Purpose We describe the clinical implementation of genome-wide DNA methylation analysis in rare disorders across the EpiSign diagnostic laboratory network and the assessment of results and clinical impact in the first subjects tested. Methods We outline the logistics and data flow between an integrated network of clinical diagnostics laboratories in Europe, the United States, and Canada. We describe the clinical validation of EpiSign using 211 specimens and assess the test performance and diagnostic yield in the first 207 subjects tested involving two patient subgroups: the targeted cohort (subjects with previous ambiguous/inconclusive genetic findings including genetic variants of unknown clinical significance) and the screening cohort (subjects with clinical findings consistent with hereditary neurodevelopmental syndromes and no previous conclusive genetic findings). Results Among the 207 subjects tested, 57 (27.6%) were positive for a diagnostic episignature including 48/136 (35.3%) in the targeted cohort and 8/71 (11.3%) in the screening cohort, with 4/207 (1.9%) remaining inconclusive after EpiSign analysis. Conclusion This study describes the implementation of diagnostic clinical genomic DNA methylation testing in patients with rare disorders. It provides strong evidence of clinical utility of EpiSign analysis, including the ability to provide conclusive findings in the majority of subjects tested.

引用

页码：1065 / 1074

页数：10

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