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

Abstract

Summary 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 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. Results 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.

Clinical sequencing yield in epilepsy, autism spectrum disorder, and intellectual disability: A systematic review and meta‐analysis

“…We found an upward trend for the number of genes with pathogenic variants being reported (Figure in the Supplement). However, not all genetic variants identified in a diagnostic test are pathogenic 10,22 . Interpretation guidelines have been developed by the community, leading to the implementation of the ACMG guidelines in 2015.…”

Clinical sequencing yield in epilepsy, autism spectrum disorder, and intellectual disability A systematic review and meta-analysis

“…However, not all genetic variants identified in a diagnostic test are pathogenic. 10,18 Interpretation guidelines have been developed by the community, leading to the implementation of the (ACMG) guidelines in 2015. We examined whether investigators applied the guidelines in NDD sequencing studies.…”

Retrospective analysis and reclassification of DYSF variants in a large French series of dysferlinopathy patients

“…Largescale studies of this type can be undertaken by any group without need to access patient-related information. 13,14 In comparison, patient-based variant reclassification takes into account patient and family related data, such as segregation and phenotypic data, in addition to the updated variant frequency and literature information. This reclassification has to be done by the same group that published the original cohort, thus making this type of study more difficult to perform and less frequent.…”