Graduate Research Degree Awarded - Daniz Kooshavar
Congratulations to Daniz Kooshavar - Graduate Research Degree Awarded May 2024.
Degree: PhD
Supervisors: Prof Paul Lockhart (primary), Prof. Richard J Leventer, Prof. David J Amor, Dr. Kiymet Bozaolglu
Advisory Committee: Prof. Ed Stanley (Chair) and Dr. Peter Houweling
Thesis Title: Understanding the genetic basis of malformations of brain development
Thesis Summary:
Background
Malformations of brain development (MBD) are relatively common disorders causing epilepsy, cerebral palsy, and developmental delay. The most common ones, accounting for >50% of cases, are polymicrogyria, periventricular nodular heterotopia and focal cortical dysplasia. Greater than 1500 Australian children per year are born with a malformation of brain development and tens of thousands of living Australians are affected. Genetic causes are thought to underlie the majority of brain malformations. Yet, a precise genetic diagnosis is only achieved in ~40% of individuals, suggesting that additional genes for MBD remain to be identified. A genetic diagnosis provides essential information for prognosis, accurate genetic counselling, and diagnostic/prenatal testing. In addition, the analyses of individuals with MBD can give us a greater understanding of brain function and development, enable genomic medicine and translate to specific therapeutics (precision medicine). The development of next-generation sequencing (NGS) tools has resulted in a significant increase in our understanding of the genetic basis of MBD and increased the diagnostic yield to ~40% for this collection of conditions. The overarching hypothesis of this thesis is that the application of research testing would improve diagnostic yield in MBD and provide an opportunity to identify additional causal genes and pathways underlying this heterogenous collection of disorders.
Methods
Children ≤18 years with a spectrum of brain malformation were recruited nationally from nine tertiary paediatric centres as part of the Australian Genomics Brain Malformation Flagship. Those with pathogenic copy number changes on microarray were excluded as were those with polymicrogyria and a positive cytomegalovirus PCR on neonatal blood spots. Singleton exome sequencing was analysed using a clinical exome sequencing pipeline. Undiagnosed patients were studied in a research setting, including a reanalysis of exome data and trio exome. Results 102 children with ten malformation subtypes were identified including polymicrogyria (36%), pontocerebellar hypoplasia (14%), periventricular nodular heterotopia (11%), tubulinopathy (10%), lissencephaly (10%) and cortical dysplasia (9%). The diagnostic yield for singleton exome sequencing was 36%, increasing to 43% after research. Research reanalysis of singleton exome data was the main reason for the 7% increased diagnostic yield. One additional diagnosis was made possible solely by trio exome. Pathogenic variants were identified in 32 genes, with variants in 6/32 genesoccurring in more than one patient. The most frequent genetic diagnosis were pathogenic variants in TUBA1A.
Conclusions
Over 40% of patients with common brain malformations had a genetic aetiology identified by exome sequencing. Periodic reanalysis of data to include newly identified genes was of greater diagnostic value than expansion to trio. 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 remaining without a genetic diagnosis despite clinical exome sequencing and research reanalysis.
Date awarded: May 2024
