Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations

Daniz Kooshavar, David J. Amor, Kirsten Boggs, Naomi Baker, Christopher Barnett, Michelle G. de Silva, Samantha Edwards, Michael C. Fahey, Justine E. Marum, Penny Snell, Kiymet Bozaoglu, Kate Pope, Shekeeb S. Mohammad, Kate Riney, Rani Sachdev, Ingrid E. Scheffer, Sarah Schenscher, John Silberstein, Nicholas Smith, Melanie TomTyson L. Ware, Paul J. Lockhart, Richard J. Leventer

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

This study aimed to determine the diagnostic yield of singleton exome sequencing and subsequent research-based trio exome analysis in children with a spectrum of brain malformations seen commonly in clinical practice. We recruited children ≤ 18 years old with a brain malformation diagnosed by magnetic resonance imaging and consistent with an established list of known genetic causes. Patients were ascertained nationally from eight tertiary paediatric centres as part of the Australian Genomics Brain Malformation Flagship. Chromosome microarray was required for all children, and those with pathogenic copy number changes were excluded. Cytomegalovirus polymerase chain reaction on neonatal blood spots was performed on all children with polymicrogyria with positive patients excluded. Singleton exome sequencing was performed through a diagnostic laboratory and analysed using a clinical exome sequencing pipeline. Undiagnosed patients were followed up in a research setting, including reanalysis of the singleton exome data and subsequent trio exome sequencing. A total of 102 children were recruited. Ten malformation subtypes were identified with the commonest being polymicrogyria (36%), pontocerebellar hypoplasia (14%), periventricular nodular heterotopia (11%), tubulinopathy (10%), lissencephaly (10%) and cortical dysplasia (9%). The overall diagnostic yield for the clinical singleton exome sequencing was 36%, which increased to 43% after research follow-up. The main source of increased diagnostic yield was the reanalysis of the singleton exome data to include newly discovered gene–disease associations. One additional diagnosis was made by trio exome sequencing. The highest phenotype-based diagnostic yields were for cobblestone malformation, tubulinopathy and lissencephaly and the lowest for cortical dysplasia and polymicrogyria. Pathogenic variants were identified in 32 genes, with variants in 6/32 genes occurring in more than one patient. The most frequent genetic diagnosis was pathogenic variants in TUBA1A. This study shows that over 40% of patients with common brain malformations have a genetic aetiology identified by exome sequencing. Periodic reanalysis of exome data to include newly identified genes was of greater value in increasing diagnostic yield than the expansion to trio exome. This study highlights the genetic and phenotypic heterogeneity of brain malformations, the importance of a multidisciplinary approach to diagnosis and the large number of patients that remain without a genetic diagnosis despite clinical exome sequencing and research reanalysis.

Original languageEnglish
Article numberfcae056
Number of pages10
JournalBrain communications
Volume6
Issue number2
DOIs
Publication statusPublished - 28 Feb 2024

Fingerprint

Dive into the research topics of 'Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations'. Together they form a unique fingerprint.

Cite this