title: Noninvasive prenatal diagnosis in a fetus at risk for methylmalonic acidemia.
abstract: OBJECTIVE
  Prenatal diagnosis of fetal Mendelian disorders can benefit from noninvasive approaches using fetal cell-free DNA in maternal plasma. Detecting metabolic disorders before birth can result in immediate treatment postpartum in order to optimize outcome.
  
  
  METHODS
  We developed a mathematical model and an experimental methodology to analyze the case of a fetus with a 25% risk of inheriting two known mutations in MUT that cause methylmalonic acidemia. To accomplish this, we measured allelic counts at the mutation sites and the fetal fraction from high minor-allele-frequency single-nucleotide polymorphism positions.
  
  
  RESULTS
  By counting linked alleles, the test was able to distinguish 11 positive markers from the negative controls and thereby determine whether or not the mutations carried by the parents were inherited by the fetus. For a homozygous fetus, the Z-score of the mutation site was 5.97, whereas the median Z-score of all the linked alleles was 4.56 when all negative (heterozygous) controls had a Z-score <2.5.
  
  
  CONCLUSIONS
  The application of this methodology for diagnosing methylmalonic acidemia shows that this is a cost-effective and noninvasive approach to diagnosing known mutations related to Mendelian disorders in the fetus.
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California, USA.
authors.forename: Winston
authors.initials: W
authors.lastname: Koh
authors.affiliation: 1] Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California, USA [2] Center for Fetal and Maternal Health, Lucile Packard Children's Hospital, Stanford, California, USA.
authors.forename: Yair J
authors.initials: YJ
authors.lastname: Blumenfeld
authors.affiliation: 1] Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California, USA [2] Center for Fetal and Maternal Health, Lucile Packard Children's Hospital, Stanford, California, USA.
authors.forename: Yasser Y
authors.initials: YY
authors.lastname: El-Sayed
authors.affiliation: 1] Center for Fetal and Maternal Health, Lucile Packard Children's Hospital, Stanford, California, USA [2] Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Louanne
authors.initials: L
authors.lastname: Hudgins
authors.affiliation: 1] Center for Fetal and Maternal Health, Lucile Packard Children's Hospital, Stanford, California, USA [2] Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Hintz
authors.affiliation: 1] Department of Bioengineering, Stanford University, Stanford, California, USA [2] Department of Applied Physics, Stanford University, Stanford, California, USA [3] Howard Hughes Medical Institute, Stanford University, Stanford, California, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Quake
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics*; D004247:DNA / Q000097:blood / Q000235:genetics*; D005260:Female; D005333:Fetus / Q000378:metabolism*; D005787:Gene Frequency; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008765:Methylmalonyl-CoA Mutase / Q000235:genetics*; D008962:Models, Theoretical; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods*
chemical_list: D004247:DNA; D008765:Methylmalonyl-CoA Mutase