Guideline-based and bioinformatic reassessment of lesion-associated gene and variant pathogenicity in focal human epilepsies

Show full item record



Permalink

http://hdl.handle.net/10138/260973

Citation

Niestroj , L-M , Du , J , Nothnagel , M , May , P , Palotie , A , Daly , M J , Nürnberg , P , Blümcke , I & Lal , D 2018 , ' Guideline-based and bioinformatic reassessment of lesion-associated gene and variant pathogenicity in focal human epilepsies ' , Epilepsia , vol. 59 , no. 11 , pp. 2145-2152 . https://doi.org/10.1111/epi.14579

Title: Guideline-based and bioinformatic reassessment of lesion-associated gene and variant pathogenicity in focal human epilepsies
Author: Niestroj, Lisa-Marie; Du, Juanjiangmeng; Nothnagel, Michael; May, Patrick; Palotie, Aarno; Daly, Mark J.; Nürnberg, Peter; Blümcke, Ingmar; Lal, Dennis
Contributor: University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, The Broad Institute of MIT and Harvard
Date: 2018-11
Language: eng
Number of pages: 8
Belongs to series: Epilepsia
ISSN: 0013-9580
URI: http://hdl.handle.net/10138/260973
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.
Subject: focal cortical dysplasia
focal epilepsies
gene pathogenicity
low-grade epilepsy-associated tumors
variant pathogenicity
INTERNATIONAL CONSENSUS CLASSIFICATION
PATHWAY MUTATIONS CAUSE
CORTICAL DYSPLASIA
SOMATIC MUTATIONS
DIAGNOSTIC METHODS
MAMMALIAN TARGET
MALFORMATIONS
STANDARDS
SPECTRUM
3112 Neurosciences
3124 Neurology and psychiatry
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
Niestroj_et_al_2018_Epilepsia.pdf 657.1Kb PDF View/Open
Niestroj_et_al_2018_Epilepsia.pdf 653.9Kb PDF View/Open

This item appears in the following Collection(s)

Show full item record