The candidate is fully trained in pediatrics, medical genetics, and child neurology, and this K08 will allow protected time for the consolidation of skills and establishment of his career as an independent researcher in neurogenetics. The candidate's immediate career goals are to integrate phenotyping, molecular genetics, and computer science skills, and establish a research lab the bridges between next-generation genomic sequencing technologies and bioinformatics. Long term career goals are to further the understanding of the key neurodevelopmental disorders affecting large numbers of children in the United States -- epilepsy, autism, and intellectual disability. Inclusive in these goals are th identification of targets for new disease therapies. Environment The proposed work will be performed at the Seattle Children's Research Institute (SCRI), and whole genome sequencing will be completed at the University Of Washington (UW). UW has a longstanding commitment to excellence in medical research, including world-class resources in the Department of Genome Sciences. Research The proposed project addresses infantile spasms - a significant cause of neurologic morbidity in the pediatric population, and for which new therapies are much needed. We believe the best new therapies will arise when underlying mechanisms of pathogenesis are understood. In this proposal we expand on evidence from our group and others that abnormalities of ventral forebrain development and synapse function account for ISS pathogenesis, by designing experiments that integrate cutting-edge genomics with novel bioinformatics approaches. We expect to improve the clinical classification of the disorders presenting with infantile spasms with a new technique of quantitative phenotyping. We expect to identify several new genetic causes of infantile spasms, and to connect those genes to pathways of pathogenesis that can be acted upon in the future development of disease-specific therapies. Finally, we will deploy a publicly available web-based tool that will help in the diagnosis, counseling, and future therapy selection for these disorders.
Infantile spasms are a severe epilepsy disorder affecting 1 in every 2000-4000 live births, and can be associated with neurologic sequelae such as intractable epilepsy and autism that are a significant burden on public health. Understanding the biological causes of infantile spasms should identify new treatment targets.
|Cushion, Thomas D; Paciorkowski, Alex R; Pilz, Daniela T et al. (2014) De novo mutations in the beta-tubulin gene TUBB2A cause simplified gyral patterning and infantile-onset epilepsy. Am J Hum Genet 94:634-41|
|Seltzer, Laurie E; Paciorkowski, Alex R (2014) Genetic disorders associated with postnatal microcephaly. Am J Med Genet C Semin Med Genet 166C:140-55|
|Paciorkowski, Alex R; Weisenberg, Judy; Kelley, Joshua B et al. (2014) Autosomal recessive mutations in nuclear transport factor KPNA7 are associated with infantile spasms and cerebellar malformation. Eur J Hum Genet 22:587-93|
|Seltzer, Laurie E; Ma, Mandy; Ahmed, Sohnee et al. (2014) Epilepsy and outcome in FOXG1-related disorders. Epilepsia 55:1292-300|
|Ghoneim, Dalia H; Myers, Jason R; Tuttle, Emily et al. (2014) Comparison of insertion/deletion calling algorithms on human next-generation sequencing data. BMC Res Notes 7:864|
|Mirzaa, Ghayda M; Millen, Kathleen J; Barkovich, A James et al. (2014) The Developmental Brain Disorders Database (DBDB): a curated neurogenetics knowledge base with clinical and research applications. Am J Med Genet A 164A:1503-11|
|Mirzaa, Ghayda M; Vitre, Benjamin; Carpenter, Gillian et al. (2014) Mutations in CENPE define a novel kinetochore-centromeric mechanism for microcephalic primordial dwarfism. Hum Genet 133:1023-39|
|Paciorkowski, Alex R; Keppler-Noreuil, Kim; Robinson, Luther et al. (2013) Deletion 16p13.11 uncovers NDE1 mutations on the non-deleted homolog and extends the spectrum of severe microcephaly to include fetal brain disruption. Am J Med Genet A 161A:1523-30|