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J Clin Endocrinol Metab. 2014 Jun;99(6):E1022-30. doi: 10.1210/jc.2014-1118. Epub 2014 Feb 28.

Noninvasive prenatal diagnosis of congenital adrenal hyperplasia using cell-free fetal DNA in maternal plasma.

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Departments of Pediatrics and Medicine (M.I.N., T.Y., C.P., A.K., M.Y., S.-M.K., L.S., M.Z.), Mt Sinai School of Medicine, New York, New York 10029; Centre for Research into Circulating Fetal Nucleic Acids (Y.K.T., P.J., K.C.A.C., G.J.W.L., R.W.K.C., Y.M.D.L.), Li Ka Shing Institute of Health Sciences, Hong Kong; and Department of Chemical Pathology (Y.K.T., P.J., K.C.A.C., G.J.W.L., R.W.K.C., Y.M.D.L.), The Chinese University of Hong Kong, Hong Kong SAR, China.



Congenital adrenal hyperplasia (CAH) is an autosomal recessive condition that arises from mutations in CYP21A2 gene, which encodes for the steroidogenic enzyme 21-hydroxylase. To prevent genital ambiguity in affected female fetuses, prenatal treatment with dexamethasone must begin on or before gestational week 9. Currently used chorionic villus sampling and amniocentesis provide genetic results at approximately 14 weeks of gestation at the earliest. This means that mothers who want to undergo prenatal dexamethasone treatment will be unnecessarily treating seven of eight fetuses (males and three of four unaffected females), emphasizing the desirability of earlier genetic diagnosis in utero.


The objective of the study was to develop a noninvasive method for early prenatal diagnosis of fetuses at risk for CAH.


Fourteen families, each with a proband affected by phenotypically classical CAH, were recruited.


Cell-free fetal DNA was obtained from 3.6 mL of maternal plasma. Using hybridization probes designed to capture a 6-Mb region flanking CYP21A2, targeted massively parallel sequencing (MPS) was performed to analyze genomic DNA samples from parents and proband to determine parental haplotypes. Plasma DNA from pregnant mothers also underwent targeted MPS to deduce fetal inheritance of parental haplotypes.


In all 14 families, the fetal CAH status was correctly deduced by targeted MPS of DNA in maternal plasma, as early as 5 weeks 6 days of gestation.


MPS on 3.6 mL plasma from pregnant mothers could potentially provide the diagnosis of CAH, noninvasively, before the ninth week of gestation. Only affected female fetuses will thus be treated. Our strategy represents a generic approach for noninvasive prenatal testing for an array of autosomal recessive disorders.

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