Genetic Testing for Malformations of Cortical Development: A Clinical Diagnostic Study

• Published in: Neurology. Genetics Vol. 8; no. 5; p. e200032
• Main Authors: Straka, Barbora, Hermanovska, Barbora, Krskova, Lenka, Zamecnik, Josef, Vlckova, Marketa, Balascakova, Miroslava, Tesner, Pavel, Jezdik, Petr, Tichy, Michal, Kyncl, Martin, Musilova, Alena, Lassuthova, Petra, Marusic, Petr, Krsek, Pavel
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer 01.10.2022
• ISSN: 2376-7839; 2376-7839
• DOI: 10.1212/NXG.0000000000200032

Malformations of cortical development (MCD), though individually rare, constitute a significant burden of disease. The diagnostic yield of next-generation sequencing (NGS) in these patients varies across studies and methods, and novel genes and variants continue to emerge. Patients (n = 123) with a definite radiologic or histopathologic diagnosis of MCD, with or without epilepsy were included in this study. They underwent NGS-based targeted gene panel (TGP) testing, whole-exome sequencing (WES), or WES-based virtual panel testing. Selected patients who underwent epilepsy surgery (n = 69) also had somatic gene testing of brain tissue-derived DNA. We analyzed predictors of positive germline genetic finding and diagnostic yield of respective methods. Pathogenic or likely pathogenic germline genetic variants were detected in 21% of patients (26/123). In the surgical subgroup (69/123), we performed somatic sequencing in 40% of cases (28/69) and detected causal variants in 18% (5/28). Diagnostic yield did not differ between TGP, WES-based virtual gene panel, and open WES ( = 0.69). Diagnosis of focal cortical dysplasia type 2A, epilepsy, and intellectual disability were associated with positive results of germline testing. We report previously unpublished variants in 16/26 patients and 4 cases of MCD with likely pathogenic variants in non-MCD genes. In this study, we are reporting genetic findings of a large cohort of MCD patients with epilepsy or potentially epileptogenic MCD. We determine predictors of successful ascertainment of a genetic diagnosis in real-life setting and report novel, likely pathogenic variants in MCD and non-MCD genes alike.