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Hum Mutat. 2018 Nov;39(11):1476-1484. doi: 10.1002/humu.23632.

The ClinGen Epilepsy Gene Curation Expert Panel-Bridging the divide between clinical domain knowledge and formal gene curation criteria.

Author information

1
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
2
Department of Neuropediatrics, Christian-Albrechts-University of Kiel, Kiel, Germany.
3
Autism & Developmental Medicine Institute, Geisinger Health System, Lewisburg, Pennsylvania, USA.
4
Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe University, Frankfurt am Main, Frankfurt, Germany.
5
Department of Neurology, Epilepsy Center Hessen, Philipps University, Marburg, Marburg, Germany.
6
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
7
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
8
Department of Pathology and Laboratory Medicine, Western University Molecular Genetic Laboratory, London Health Sciences, London, Ontario, Canada.
9
Division of Child Neurology, Columbia University Medical Center, New York, New York, USA.
10
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
11
Quest Diagnostics, Athena Diagnostics, Marlborough, Massachusetts, USA.
12
Departments of Pediatrics and Neurology, University of California, San Francisco, California, USA.
13
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.
14
Department of Pediatrics, University of Washington, Seattle, Washington, USA.
15
Department of Pediatrics and Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.
16
Department of Neurology, University of Virginia, Charlottesville, Virginia, USA.
17
GeneDx, Gaithersburg, Maryland, USA.
18
Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
19
Pediatric Neurology and Muscular Diseases Unit, DINOGMI-Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, "G. Gaslini" Institute, University of Genoa, Genova, Italy.
20
Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.
21
Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts, USA.
22
Division of Genetic Medicine, University of Washington, Seattle, Washington, USA.

Abstract

The field of epilepsy genetics is advancing rapidly and epilepsy is emerging as a frequent indication for diagnostic genetic testing. Within the larger ClinGen framework, the ClinGen Epilepsy Gene Curation Expert Panel is tasked with connecting two increasingly separate fields: the domain of traditional clinical epileptology, with its own established language and classification criteria, and the rapidly evolving area of diagnostic genetic testing that adheres to formal criteria for gene and variant curation. We identify critical components unique to the epilepsy gene curation effort, including: (a) precise phenotype definitions within existing disease and phenotype ontologies; (b) consideration of when epilepsy should be curated as a distinct disease entity; (c) strategies for gene selection; and (d) emerging rules for evaluating functional models for seizure disorders. Given that de novo variants play a prominent role in many of the epilepsies, sufficient genetic evidence is often awarded early in the curation process. Therefore, the emphasis of gene curation is frequently shifted toward an iterative precuration process to better capture phenotypic associations. We demonstrate that within the spectrum of neurodevelopmental disorders, gene curation for epilepsy-associated genes is feasible and suggest epilepsy-specific conventions, laying the groundwork for a curation process of all major epilepsy-associated genes.

KEYWORDS:

ClinGen/Clinical Genome Resource; clinical validity; epilepsy; epileptic encephalopathy; gene-disease association

PMID:
30311377
DOI:
10.1002/humu.23632

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