title: Noninvasive prenatal diagnosis of duchenne muscular dystrophy: comprehensive genetic diagnosis in carrier, proband, and fetus.
abstract: BACKGROUND
  Noninvasive prenatal diagnosis of monogenic disorders using maternal plasma and targeted massively parallel sequencing is being investigated actively. We previously demonstrated that comprehensive genetic diagnosis of a Duchenne muscular dystrophy (DMD) patient is feasible using a single targeted sequencing platform. Here we demonstrate the applicability of this approach to carrier detection and noninvasive prenatal diagnosis.
  
  
  METHODS
  Custom solution-based target enrichment was designed to cover the entire dystrophin (DMD) gene region. Targeted massively parallel sequencing was performed using genomic DNA from 4 mother and proband pairs to test whether carrier status could be detected reliably. Maternal plasma DNA at varying gestational weeks was collected from the same families and sequenced using the same targeted platform to predict the inheritance of the DMD mutation by their fetus. Overrepresentation of an inherited allele was determined by comparing the allele fraction of 2 phased haplotypes after examining and correcting for the recombination event.
  
  
  RESULTS
  The carrier status of deletion/duplication and point mutations was detected reliably through using a single targeted massively parallel sequencing platform. Whether the fetus had inherited the DMD mutation was predicted correctly in all 4 families as early as 6 weeks and 5 days of gestation. In one of these, detection of the recombination event and reconstruction of the phased haplotype produced a correct diagnosis.
  
  
  CONCLUSIONS
  Noninvasive prenatal diagnosis of DMD is feasible using a single targeted massively parallel sequencing platform with tiling design.
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Korea; Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Korea;
authors.forename: Seong-Keun
authors.initials: SK
authors.lastname: Yoo
authors.affiliation: Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea; Institute of Reproductive Medicine and Population, Medical Research Center, Seoul National University, Seoul, Korea;
authors.forename: Byung Chan
authors.initials: BC
authors.lastname: Lim
authors.affiliation: Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea;
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Byeun
authors.affiliation: Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea;
authors.forename: Hee
authors.initials: H
authors.lastname: Hwang
authors.affiliation: Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea;
authors.forename: Ki Joong
authors.initials: KJ
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea;
authors.forename: Yong Seung
authors.initials: YS
authors.lastname: Hwang
authors.affiliation: Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea;
authors.forename: JoonHo
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea;
authors.forename: Joong Shin
authors.initials: JS
authors.lastname: Park
authors.affiliation: Bioinformatics Technology Lab, Healthcare Group, Future Technology R&D Division, SK Telecom, Sungnam, Korea;
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Bioinformatics Technology Lab, Healthcare Group, Future Technology R&D Division, SK Telecom, Sungnam, Korea;
authors.forename: Junghyun
authors.initials: J
authors.lastname: Namkung
authors.affiliation: Bioinformatics Technology Lab, Healthcare Group, Future Technology R&D Division, SK Telecom, Sungnam, Korea;
authors.forename: Jungsun
authors.initials: J
authors.lastname: Park
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Korea;
authors.forename: Seungbok
authors.initials: S
authors.lastname: Lee
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Korea; Macrogen, Seoul, Korea;
authors.forename: Jong-Yeon
authors.initials: JY
authors.lastname: Shin
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Korea; Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Korea; Macrogen, Seoul, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea; Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jeong-Sun
authors.initials: JS
authors.lastname: Seo
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea; Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea. jongil@snu.ac.kr chaeped1@snu.ac.kr.
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea; Institute of Reproductive Medicine and Population, Medical Research Center, Seoul National University, Seoul, Korea; jongil@snu.ac.kr chaeped1@snu.ac.kr.
authors.forename: Jong Hee
authors.initials: JH
authors.lastname: Chae
mesh_terms: D004247:DNA / Q000097:blood; D016189:Dystrophin / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening / Q000379:methods*; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D020388:Muscular Dystrophy, Duchenne / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods*; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D016189:Dystrophin; D004247:DNA