Genetic Testing for Malformations of Cortical Development: A Clinical Diagnostic Study
Barbora Straka1, Barbora Hermanovska1, Lenka Krskova1
1Department of Paediatric Neurology (B.S., B.H., A.M., P.L., P.K.), Second Faculty of Medicine, Charles University and Motol University Hospital; Department of Pathology and Molecular Medicine (L.K., J.Z.), Second Faculty of Medicine, Charles University and Motol University Hospital; Department of Biology and Medical Genetics (M.V., M.B., P.T.), Second Faculty of Medicine, Charles University and Motol University Hospital; Faculty of Electrical Engineering (P.J.), Department of Circuit Theory, Czech Technical University in Prague; Department of Neurosurgery (M.T.), Second Faculty of Medicine, Charles University and Motol University Hospital; Department of Radiology (M.K.), Second Faculty of Medicine, Charles University and Motol University Hospital; and Department of Neurology (P.M.), Second Faculty of Medicine, Charles University and Motol University Hospital, Czech Republic.
Background And Objectives:
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.
Methods:
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.
Results:
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 (p = 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 We report previously unpublished variants in 16/26 patients and 4 cases of MCD with likely pathogenic variants in non-MCD genes.
Discussion:
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.
