Universität zu Köln

Niestroj, Lisa-Marie, Du, Juanjiangmeng, Nothnagel, Michael ORCID: 0000-0001-8305-7114, May, Patrick ORCID: 0000-0001-8698-3770, Palotie, Aarno, Daly, Mark J., Nuernberg, Peter, Bluemcke, Ingmar and Lal, Dennis (2018). Guideline-based and bioinformatic reassessment of lesion-associated gene and variant pathogenicity in focal human epilepsies. Epilepsia, 59 (11). S. 2145 - 2153. HOBOKEN: WILEY. ISSN 1528-1167

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Abstract

Objective Increasing availability of surgically resected brain tissue from patients with focal epilepsy and focal cortical dysplasia or low-grade glioneuronal tumors has fostered large-scale genetic examination. However, assessment of pathogenicity of germ line and somatic variants remains difficult. Here, we present a state-of-the-art evaluation of reported genes and variants associated with epileptic brain lesions. Methods Results We critically reevaluated the pathogenicity for all neuropathology-associated variants reported to date in the PubMed and ClinVar databases, including 101 neuropathology-associated missense variants encompassing 11 disease-related genes. We assessed gene variant tolerance and classified all identified missense variants according to guidelines from the American College of Medical Genetics and Genomics (ACMG). We further extended the bioinformatic variant prediction by introducing a novel gene-specific deleteriousness ranking for prediction scores. Application of ACMG guidelines and in silico gene variant tolerance analysis classified only seven of 11 genes to be likely disease-associated according to the reported disease mechanism, whereas 61 (60.4%) of 101 variants of those genes were classified as of uncertain significance, 37 (36.6%) as being likely pathogenic, and 3 (3%) as being pathogenic. Significance We concluded that the majority of neuropathology-associated variants reported to date do not have enough evidence to be classified as pathogenic. Interpretation of lesion-associated variants remains challenging, and application of current ACMG guidelines is recommended for interpretation and prediction.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Niestroj, Lisa-Marie UNSPECIFIED UNSPECIFIED UNSPECIFIED Du, Juanjiangmeng UNSPECIFIED UNSPECIFIED UNSPECIFIED Nothnagel, Michael UNSPECIFIED orcid.org/0000-0001-8305-7114 UNSPECIFIED May, Patrick UNSPECIFIED orcid.org/0000-0001-8698-3770 UNSPECIFIED Palotie, Aarno UNSPECIFIED UNSPECIFIED UNSPECIFIED Daly, Mark J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Bluemcke, Ingmar UNSPECIFIED UNSPECIFIED UNSPECIFIED Lal, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-166815
DOI:	10.1111/epi.14579
Journal or Publication Title:	Epilepsia
Volume:	59
Number:	11
Page Range:	S. 2145 - 2153
Date:	2018
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1528-1167
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INTERNATIONAL CONSENSUS CLASSIFICATION; PATHWAY MUTATIONS CAUSE; CORTICAL DYSPLASIA; SOMATIC MUTATIONS; DIAGNOSTIC METHODS; MAMMALIAN TARGET; MALFORMATIONS; STANDARDS; SPECTRUM Multiple languages Clinical Neurology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16681