Prenatal Diagnosis by Whole Exome Sequencing in Fetuses with Ultrasound Abnormalities

Whole-exome sequencing (WES) has been used as a standard of care for postnatal diagnosis in the clinical setting in the past few years for children and adults with undiagnosed disease. Many rare disorders have been diagnosed through WES, which is less expensive than the traditional serial genetic testing where patients had previously spent years on an uninformative diagnostic odyssey. Seeking a diagnosis often entails enduring time consuming, and sometimes invasive procedures which may be associated with medical risks that are stressful for families and impose a heavy burden on the health-care system. However, the use of WES is considered impractical in the prenatal and neonatal testing period because of the technical and computational challenges of performing genomic sequencing from small amounts of genetic material, and the need for faster turnaround time (TAT) than the current 6-8 weeks TAT provided by most clinical labs offering postnatal testing. With the rapidly evolving methods of sequence analysis, there are clinical challenges such as the constantly increasing number of genes being identified which are not yet fully phenotypically characterized, especially when ascertained prenatally or neonatally before all the clinical features may be evident. Despite these challenges, there are many clinical benefits to acquiring genomic information in the prenatal and neonatal period. These include superior prognostic information which allows for prenatal planning of mode of delivery and hospital for delivery and optimized neonatal management. We have developed a clinical WES assay using small amounts of DNA with a TAT of 10 days for use in the prenatal or neonatal setting. This test is used to detect small nucleotide variants and indels in fetuses and neonates with structural abnormalities.