DNA sequencing of maternal plasma to detect Down syndrome: An international clinical validation study

Glenn E. Palomaki, Edward M. Kloza, Geralyn M. Lambert-Messerlian, James E. Haddow, Louis M. Neveux, Mathias Ehrich, Dirk van den Boom, Allan T. Bombard, Cosmin Deciu, Wayne W. Grody, Stanley F. Nelson, Jacob A. Canick
2011 Genetics in Medicine  
Purpose: Prenatal screening for Down syndrome has improved, but the number of resulting invasive diagnostic procedures remains problem-atic. Measurement of circulating cell-free DNA in maternal plasma might offer improvement. Methods: A blinded, nested case-control study was designed within a cohort of 4664 pregnancies at high risk for Down syndrome. Fetal karyotyping was compared with an internally validated, laboratory-developed test based on next-generation sequenc-ing in 212 Down syndrome
more » ... 212 Down syndrome and 1484 matched euploid pregnancies. None had been previously tested. Primary testing occurred at a CLIA-certified commercial laboratory, with cross validation by a CLIA-certified university laboratory. Results: Down syndrome detection rate was 98.6% (209/212), the false-positive rate was 0.20% (3/1471), and the testing failed in 13 pregnancies (0.8%); all were euploid. Before unblinding, the primary testing laboratory also reported multiple alter-native interpretations. Adjusting chromosome 21 counts for guanine cytosine base content had the largest impact on improving performance. Conclusion: When applied to high-risk pregnancies, measuring mater-nal plasma DNA detects nearly all cases of Down syndrome at a very low false-positive rate. This method can substantially reduce the need for invasive diagnostic procedures and attendant procedure-related fetal losses. Although implementation issues need to be addressed, the evidence supports introducing this testing on a clinical basis. Genet Med 2011:XX(XX):000 -000.
doi:10.1097/gim.0b013e3182368a0e pmid:22005709 fatcat:q7y2uo5gybb7rldtjb3qa45nby