Researchers at Children’s Mercy Hospitals and Clinics in Kansas City reported the first use of whole genome information for diagnosing critically ill infants. As reported in Science Translational Medicine, the team describes STAT-Seq, a whole genome sequencing approach – from blood sample to returning results to a physician – in about 50 hours. Currently, testing even a single gene takes six weeks or more.
Monogenic diseases are frequent causes of neonatal morbidity and mortality, and disease presentations are often undifferentiated at birth. More than 3500 monogenic diseases have been characterized, but clinical testing is available for only some of them and many feature clinical and genetic heterogeneity. Hence, an immense unmet need exists for improved molecular diagnosis in infants.
Because disease progression is extremely rapid, albeit heterogeneous, in newborns, molecular diagnoses must occur quickly to be relevant for clinical decision-making. We describe 50-hour differential diagnosis of genetic disorders by whole-genome sequencing (WGS) that features automated bioinformatic analysis and is intended to be a prototype for use in neonatal intensive care units. Retrospective 50-hour WGS identified known molecular diagnoses in two children. Prospective WGS disclosed potential molecular diagnosis of a severe GJB2-related skin disease in one neonate; BRAT1-related lethal neonatal rigidity and multifocal seizure syndrome in another infant; identified BCL9L as a novel, recessive visceral heterotaxy gene (HTX6) in a pedigree; and ruled out known candidate genes in one infant. Sequencing of parents or affected siblings expedited the identification of disease genes in prospective cases. Thus, rapid WGS can potentially broaden and foreshorten differential diagnosis, resulting in fewer empirical treatments and faster progression to genetic and prognostic counseling.
Speed of diagnosis is most critical in acute care situations, as in a neonatal intensive care unit (NICU), where medical decision-making is made in hours not weeks. Using STAT-Seq, with consent from parents, the investigators diagnosed acutely ill infants from the hospital’s NICU. By casting a broad net over the entire set of about 3,500 genetic diseases, STAT-Seq demonstrates for the first time the potential for genome sequencing to influence therapeutic decisions in the immediate needs of NICU patients.
“Up to one third of babies admitted to a NICU in the U.S. have genetic diseases,” said Stephen Kingsmore, M.B. Ch.B., D.Sc., FRCPath, Director of the Center for Pediatric Genomic Medicine at Children’s Mercy. “By obtaining an interpreted genome in about two days, physicians can make practical use of diagnostic results to tailor treatments to individual infants and children.”
Genetic diseases affect about three percent of children and account for 15 percent of childhood hospitalizations. Treatments are currently available for more than 500 genetic diseases. In about 70 of these, such as infantile Pompe disease and Krabbe disease, initiation of therapy in newborns can help prevent disabilities and life-threatening illnesses.
STAT-Seq uses software that translates physician-entered clinical features in individual patients into a comprehensive set of relevant diseases. Developed at Children’s Mercy, this software substantially automates identification of the DNA variations that can explain the child’s condition. The team uses Illumina’s HiSeq 2500 system, which sequences an entire genome at high coverage in about 25 hours.
Although further research is needed, STAT-Seq also has the potential to offer cost-saving benefits. “By shortening the time-to-diagnosis, we may markedly reduce the number of other tests performed and reduce delays to a diagnosis,” said Kingsmore. “Reaching an accurate diagnosis quickly can help to shorten hospitalization and reduce costs and stress for families.”
C. J. Saunders, N. A. Miller, S. E. Soden, D. L. Dinwiddie, A. Noll, N. A. Alnadi, N. Andraws, M. L. Patterson, L. A. Krivohlavek, J. Fellis, S. Humphray, P. Saffrey, Z. Kingsbury, J. C. Weir, J. Betley, R. J. Grocock, E. H. Margulies, E. G. Farrow, M. Artman, N. P. Safina, J. E. Petrikin, K. P. Hall, S. F. Kingsmore, Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units. Sci. Transl. Med. 4, 154ra135 (2012) DOI: 10.1126/scitranslmed.3004041.
Source: Children’s Mercy Hospitals and Clinics, Kansas City, Mo