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.
Next-generation sequencing (NGS) identified genetic variants in 21% of patients with malformations of cortical development (MCD). Focal cortical dysplasia type 2A, epilepsy, and intellectual disability predicted positive germline genetic findings.
Area of Science:
- Neurogenetics
- Developmental Neuroscience
- Genomic Medicine
Background:
- Malformations of cortical development (MCD) are rare but significant causes of neurological disease.
- The diagnostic yield of genetic testing for MCD varies, with ongoing discovery of new genes and variants.
Purpose of the Study:
- To evaluate the diagnostic yield of next-generation sequencing (NGS) methods in a large cohort of patients with malformations of cortical development (MCD).
- To identify predictors of successful genetic diagnosis in patients with MCD, including those with epilepsy.
- To report novel genetic variants associated with MCD.
Main Methods:
- A cohort of 123 patients with diagnosed MCD underwent targeted gene panel (TGP) testing, whole-exome sequencing (WES), or WES-based virtual panel testing.
- Somatic gene testing of brain tissue DNA was performed in a subgroup of patients who underwent epilepsy surgery.
- Analysis focused on predictors of positive germline genetic findings and the diagnostic yield of different NGS methods.
Main Results:
- Pathogenic or likely pathogenic germline variants were detected in 21% (26/123) of patients.
- In the surgical subgroup, somatic sequencing identified causal variants in 18% (5/28) of cases.
- Diagnostic yield was similar across TGP, WES-based virtual panels, and open WES. Focal cortical dysplasia type 2A, epilepsy, and intellectual disability were associated with positive germline results.
- Novel variants were reported in 16/26 patients, including variants in non-MCD genes.
Conclusions:
- NGS provides a significant diagnostic yield for patients with MCD, particularly when epilepsy and specific cortical malformations are present.
- Germline genetic testing is effective in identifying causative variants in a substantial proportion of MCD patients.
- The study highlights the genetic heterogeneity of MCD and the potential for variants in non-MCD genes to contribute to the phenotype.
