Potential genomics to end the diagnostic odyssey in the NICU

Background: Congenital anomalies are a leading cause of infant morbidity and mortality. The vast majority of patients with congenital anomalies do not receive a clear genetic diagnosis. Over 22% of the population in the neonatal intensive care unit (NICU) of a ninety bed suburban children's hospital was suspected of having an underlying genetic disorder, had an appropriate genetic work-up, and 20% of this group received a clinical diagnosis.

Objectives: The focus of our study is to identify genetic and genomic factors that contribute to the root causes of congenital anomalies and evaluate the impact of genetic disease resulting in undiagnosed congenital anomalies.

Results: A subset of NICU families (n=70+) has enrolled in our study, 'Impact of Genetic Disorders' that requires a family trio (mother, father, and proband) to consent to Whole Genome Sequencing, RNA expression, methylation, and miRNA characterization. Clinical data are obtained from electronic health records as well as from parent input on nutrition, stress and environmental exposure. A variety of principal component, familial-based, pathway and genomic network analyses are utilized to identify the underlying genomic defect. Preliminary analyses of WGS data have already enabled us to identify the potential cause of previously undiagnosed disorders for several families enrolled in our study.

Conclusion: The application of WGS is expected to significantly enhance ability to understand the causes of congenital anomalies that result from complex genetic/genomic disease. Our study demonstrates the potential of WGS analysis to unequivocally end the diagnostic odyssey for patients with rare genetic disorders, and their families.