Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability

Abstract

Objective: Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient group is important for daily clinical care. We assessed the diagnostic yield of whole exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy. Methods: One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient ≤ 85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. WES analysis was performed in two steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so-called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines. Results: In 58 patients, the diagnostic WES analysis reported one or more variant(s).In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 of 25 patients (40%) with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future. Significance: This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield. K E Y W O R D S genetic diagnosis, learning disability, next generation sequencing, seizures

Redefining the Etiologic Landscape of Cerebellar Malformations

“…The molecular diagnostic rate in our discovery cohort (36%) is similar to those for childhood epilepsy (25%), ID (28%), and autism (28%). [27][28][29] However, after removing the 33 individuals with any prenatal risk factor, the diagnostic yield in our cohort rises to 33 of 67 (49%). If we then partition our cohort by cerebellar malformation, the diagnostic yield is 72% (26 of 36) in CBLH and 23% (7 of 31) in DWM.…”

Whole‐exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late

“…newborns and children, [3][4][5][6] while less attention has been paid to adult DEE patients who never underwent next generation genetic tests. [7][8][9] This population of undiagnosed adult patients represents the socalled "lost generation," 10 who had to experience the frustration of "diagnostic odysseys" characterized by inconclusive gene-by-gene tests along decades, prior to the advent of NGS techniques.…”

Identification and Analysis of Genetic Epilepsy and Epileptic Encephalopathies in the Outpatient Practice of Epilepsy Specialists

“…12 Discussing the leadership in the use of sequencing on the diagnostic panel is most likely associated with economic feasibility, which is shown in many Russian publications.11 But changes in the ratio of diagnostic efficiency / cost of fullexomic sequencing taking place in the world will probably lead this method to leading positions in Russia in the future too. 13 The lack of confirmation of the mutation and its origin according to Sanger (inherited from parents / de novo) is also mainly due to the economic aspect. However, this fact indicates the possibility of errors in the interpretation of the clinical significance of the detected mutations by epileptologists, since in most patients it was carried out only by the similarity of the clinical picture.…”