Diagnostic Utility of Exome Sequencing in Malformations of Brain Development

Abstract

Background: Malformations of brain development (MBDs) are a broad spectrum of congenital anomalies resulting from disturbance of early brain development. MBDs are the major cause of neurodevelopmental delay, cerebral palsy, and epilepsy. Genetic causes underlie the majority of MBDs; however, the diagnostic utility of genomic testing applied to a wide range of MBDs ascertained through routine clinical practise is unknown. Aim: This study aimed to determine the genetic diagnostic yield currently achievable for MBDs utilizing exome sequencing (ES) in the Australian Genomics MBD flagship cohort. Methods: Affected children were selected through stringent inclusion criteria regarding age, imaging phenotype, and prior genetic testing. We performed singleton clinical ES on the probands. If the result was negative in the clinical setting, we followed up with a research re-analysis of the singleton data. For the individuals who remained unsolved, we performed ES on the parents, followed by a trio analysis. Results: 102 patients were recruited, and ten types of MBDs were ascertained. The diagnostic yield was 35.3% using clinical singleton ES, which improved to 42.16% with the research follow-up. The yield varied between different MBDs, with tubulinopathy and lissencephaly having the highest diagnostic rates and polymicrogyria and focal cortical dysplasia having the lowest. Conclusion: This study demonstrated the high utility of ES as a reliable method for investigating the genetics of MBDs. Nevertheless, the utility of trio analysis appears to outweigh singleton ES regarding the expended resources, time, and energy. Ultimately, a genetic diagnosis would end the diagnostic odyssey and improve prognostic and reproductive counseling for affected individuals.