This work represents a team effort to bring genomic sequencing into a pediatric clinical setting. We have chosen to validate and study genomic sequencing for 5 groups of pediatric disorders that are genetically heterogeneous to the extent that gene by gene testing Is expensive and time consuming. We will study patients with 1) bilateral sensorineural hearing Impairment, Inherited retinal degenerations, nuclear encoded mitochondrial respiratory chain disorders, sudden cardiac arrest/sudden cardiac death and intellectual disability. Our studies will be Integrated across three projects (Clinical Genomic Studies;Sequencing, Analysis and Interpretation of Sequencing Data;and Ethical and Psychosocial Implications of Research) to develop the tools for identifying and consenting patients for study, carrying out and Interpreting the sequencing data and reporting back useful Information to the families of our patients. We will validate our ability to Identify clinically significant findings, as well as our ability to identify incidental findings and determine which o these will be useful to families. This unique study will allow us to work with families, scientist and ethicists up front, to determine how our patients should be counseled and educated before testing, what data should be provided back to Individual families, and what educational tools will help in understanding the Implications of the testing. In addition, the clinicians, diagnostic lab directors and scientists will develop the sequencing. Interpretative and bioinformatic tools necessary to accurately and thoughtfully extract the relevant data from our patient's genomes. We anticipate that at the end of this grant period. In concert with other centers carrying out similar work, genomic sequencing will be ready to be offered for diagnosis of pediatric disorders, with a clear view of the possible findings, and a plan for identification of clinically useful information.
Genetic disorders are highly prevalent in the pediatric population and contribution to a high percentage of morbidity and mortality, but diagnosis can be cumbersome and expensive. Genome sequencing offers the opportunity to carry out one test, with the ability to identify genetic causes of disease anywhere in the genome. This project promises to provide the tools to carry out and interpret genomic sequencing data.
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|Rohacek, Alex M; Bebee, Thomas W; Tilton, Richard K et al. (2017) ESRP1 Mutations Cause Hearing Loss due to Defects in Alternative Splicing that Disrupt Cochlear Development. Dev Cell 43:318-331.e5|
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|Abou Tayoun, Ahmad N; Krock, Bryan; Spinner, Nancy B (2016) Sequencing-based diagnostics for pediatric genetic diseases: progress and potential. Expert Rev Mol Diagn 16:987-99|
|Green, Robert C; Goddard, Katrina A B; Jarvik, Gail P et al. (2016) Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine. Am J Hum Genet 98:1051-1066|
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