title: Noninvasive prenatal diagnosis of congenital adrenal hyperplasia using cell-free fetal DNA in maternal plasma.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  The objective of the study was to develop a noninvasive method for early prenatal diagnosis of fetuses at risk for CAH.
  
  
  METHODS
  Fourteen families, each with a proband affected by phenotypically classical CAH, were recruited.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Maria I
authors.initials: MI
authors.lastname: New
authors.forename: Yu K
authors.initials: YK
authors.lastname: Tong
authors.forename: Tony
authors.initials: T
authors.lastname: Yuen
authors.forename: Peiyong
authors.initials: P
authors.lastname: Jiang
authors.forename: Christian
authors.initials: C
authors.lastname: Pina
authors.forename: K C Allen
authors.initials: KC
authors.lastname: Chan
authors.forename: Ahmed
authors.initials: A
authors.lastname: Khattab
authors.forename: Gary J W
authors.initials: GJ
authors.lastname: Liao
authors.forename: Mabel
authors.initials: M
authors.lastname: Yau
authors.forename: Se-Min
authors.initials: SM
authors.lastname: Kim
authors.forename: Rossa W K
authors.initials: RW
authors.lastname: Chiu
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Mone
authors.initials: M
authors.lastname: Zaidi
authors.forename: Y M Dennis
authors.initials: YM
authors.lastname: Lo
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000175:diagnosis*; D001483:Base Sequence; D002474:Cell-Free System / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000097:blood*; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005333:Fetus / Q000378:metabolism*; D006801:Humans; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy / Q000097:blood; D011296:Prenatal Diagnosis / Q000379:methods*; D013255:Steroid 21-Hydroxylase / Q000235:genetics
chemical_list: D004247:DNA; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase