Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy

被引：50

作者：

Heyne, Henrike O. ^{[1
,2
,3
,4
]}

Artomov, Mykyta ^{[1
,2
,3
]}

Battke, Florian ^{[5
]}

Bianchini, Claudia ^{[6
]}

Smith, Douglas R. ^{[7
]}

Liebmann, Nora ^{[4
]}

Tadigotla, Vasisht ^{[7
]}

Stanley, Christine M. ^{[7
]}

Lal, Dennis ^{[1
,2
,3
,8
,9
]}

Rehm, Heidi ^{[10
]}

Lerche, Holger ^{[11
,12
]}

Daly, Mark J. ^{[1
,2
,3
]}

Helbig, Ingo ^{[13
]}

Biskup, Saskia ^{[5
]}

Weber, Yvonne G. ^{[11
,12
]}

Lemke, Johannes R. ^{[4
]}

机构：

[1] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[2] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[3] Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA 02142 USA

[4] Univ Leipzig, Med Ctr, Inst Human Genet, Leipzig, Germany

[5] Praxis Humangenet & CeGaT GmbH, Tubingen, Germany

[6] Univ Florence, Meyer Childrens Hosp, Pediat Neurol Neurogenet & Neurobiol, Unit & Labs, Florence, Italy

[7] Courtagen Life Sci Inc, Woburn, MA USA

[8] Cleveland Clin, Genom Med Inst, Cleveland, OH 44106 USA

[9] Cleveland Clin, Neurol Inst, Cleveland, OH 44106 USA

[10] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA

[11] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurol & Epileptol, Tubingen, Germany

[12] Univ Tubingen, Dept Neurosurg, Tubingen, Germany

[13] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA

来源：

GENETICS IN MEDICINE | 2019年 / 21卷 / 11期

关键词：

epilepsy; gene panel design; Mendelian genetics; clinical genetics; neurodevelopmental disorder; PROTEIN-TRUNCATING VARIANTS; DE-NOVO MUTATIONS; PRECISION MEDICINE; ASSOCIATION; GUIDELINES; DIAGNOSIS; TOOL;

D O I：

10.1038/s41436-019-0531-0

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Purpose: We aimed to gain insight into frequencies of genetic variants in genes implicated in neurodevelopmental disorder with epilepsy (NDD+E) by investigating large cohorts of patients in a diagnostic setting. Methods: We analyzed variants in NDD+E using epilepsy gene panel sequencing performed between 2013 and 2017 by two large diagnostic companies. We compared variant frequencies in 6994 panels with another 8588 recently published panels as well as exome-wide de novo variants in 1942 individuals with NDD+E and 10,937 controls. Results: Genes with highest frequencies of ultrarare variants in NDD+E comprised SCN1A, KCNQ2, SCN2A, CDKL5, SCN8A, and STXBP1, concordant with the two other epilepsy cohorts we investigated. In only 46% of the analyzed 262 dominant and Xlinked panel genes ultrarare variants in patients were reported. Among genes with contradictory evidence of association with epilepsy, CACNB4, CLCN2, EFHC1, GABRD, MAGI2, and SRPX2 showed equal frequencies in cases and controls. Conclusion: We show that improvement of panel design increased diagnostic yield over time, but panels still display genes with low or no diagnostic yield. With our data, we hope to improve current diagnostic NDD+E panel design and provide a resource of ultrarare variants in individuals with NDD+E to the community.

引用

页码：2496 / 2503

页数：8

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