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Genet Med. 2019 May 6. doi: 10.1038/s41436-019-0531-0. [Epub ahead of print]

Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy.

Author information

1
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. hheyne@broadinstitute.org.
2
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. hheyne@broadinstitute.org.
3
Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. hheyne@broadinstitute.org.
4
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany. hheyne@broadinstitute.org.
5
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
6
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
7
Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
8
Praxis für Humangenetik and CeGaT GmbH, Tuebingen, Germany.
9
Pediatric Neurology, Neurogenetics and Neurobiology, Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
10
Courtagen Life Sciences Inc., Woburn, MA, USA.
11
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
12
Cleveland Clinic Genomic Medicine Institute and Neurological Institute, Cleveland, OH, USA.
13
Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
14
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, and Department of Neurosurgery, University of Tuebingen, Tuebingen, Germany.
15
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
16
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany. johannes.lemke@medizin.uni-leipzig.de.

Abstract

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 X-linked 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.

KEYWORDS:

Mendelian genetics; clinical genetics, neurodevelopmental disorder; epilepsy; gene panel design

PMID:
31056551
DOI:
10.1038/s41436-019-0531-0

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