Birth defects are common causes of infant mortality, represent frustrating and costly challenges for families, physicians, and society, and are frequently inherited. Infants and children with birth defects are often subjected to duplicative, sequential, and invasive diagnostic testing without establishment of clinically actionable diagnoses, prognoses, or therapeutic options. Recent advances in genetic diagnosis have improved diagnostic success to ~25%. To address the urgent need for discovery of the missing heritability in infants with birth defects, the hypothesis that a comprehensive, integrated whole genome/transcriptome sequencing platform will improve diagnostic success from 25% to 40% will be tested with the following specific aims.
- Compare diagnostic success of 2 different state of the art gene decoding strategies, exome sequencing and whole genome sequencing
- Integrate a new approach, transcriptome signatures in affected tissues, to improve diagnostic success
- ·Use these tools to develop a pipeline for discovery of clinically actionable genetic causes of birth defects
This award will accelerate application of state of the art precision medicine strategies to infants with birth defects, improve diagnostic success, and define genome-directed disease categorization, prognosis, therapeutic strategies, and future genetic risk.