title: Non-Invasive Prenatal Diagnosis of Lethal Skeletal Dysplasia by Targeted Capture Sequencing of Maternal Plasma.
abstract: BACKGROUND
  Since the discovery of cell-free foetal DNA in the plasma of pregnant women, many non-invasive prenatal testing assays have been developed. In the area of skeletal dysplasia diagnosis, some PCR-based non-invasive prenatal testing assays have been developed to facilitate the ultrasound diagnosis of skeletal dysplasias that are caused by de novo mutations. However, skeletal dysplasias are a group of heterogeneous genetic diseases, the PCR-based method is hard to detect multiple gene or loci simultaneously, and the diagnosis rate is highly dependent on the accuracy of the ultrasound diagnosis. In this study, we investigated the feasibility of using targeted capture sequencing to detect foetal de novo pathogenic mutations responsible for skeletal dysplasia.
  
  
  RESULTS
  Three families whose foetuses were affected by skeletal dysplasia and two control families whose foetuses were affected by other single gene diseases were included in this study. Sixteen genes related to some common lethal skeletal dysplasias were selected for analysis, and probes were designed to capture the coding regions of these genes. Targeted capture sequencing was performed on the maternal plasma DNA, the maternal genomic DNA, and the paternal genomic DNA. The de novo pathogenic variants in the plasma DNA data were identified using a bioinformatical process developed for low frequency mutation detection and a strict variant interpretation strategy. The causal variants could be specifically identified in the plasma, and the results were identical to those obtained by sequencing amniotic fluid samples. Furthermore, a mean of 97% foetal specific alleles, which are alleles that are not shared by maternal genomic DNA and amniotic fluid DNA, were identified successfully in plasma samples.
  
  
  CONCLUSIONS
  Our study shows that capture sequencing of maternal plasma DNA can be used to non-invasive detection of de novo pathogenic variants. This method has the potential to be used to facilitate the prenatal diagnosis of skeletal dysplasia.
authors.affiliation: Department of Perinatal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Dan
authors.affiliation: Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.|Tianjin Translational Genomics Centre, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.|BGI-Shenzhen, Shenzhen, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.|Tianjin Translational Genomics Centre, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.|BGI-Shenzhen, Shenzhen, China.
authors.forename: Yaoshen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.|Tianjin Translational Genomics Centre, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.|BGI-Shenzhen, Shenzhen, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.affiliation: Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.|Tianjin Translational Genomics Centre, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.|BGI-Shenzhen, Shenzhen, China.
authors.forename: Changxin
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Perinatal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
authors.forename: Song
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Perinatal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Perinatal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.affiliation: Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.|Tianjin Translational Genomics Centre, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.|BGI-Shenzhen, Shenzhen, China.
authors.lastname: Asan
authors.affiliation: Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.|Tianjin Translational Genomics Centre, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.|BGI-Shenzhen, Shenzhen, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.|Tianjin Translational Genomics Centre, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.|BGI-Shenzhen, Shenzhen, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Perinatal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Deng
authors.affiliation: Department of Perinatal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Su
authors.affiliation: Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.|Tianjin Translational Genomics Centre, BGI-Tianjin, BGI-Shenzhen, Tianjin, China.|BGI-Shenzhen, Shenzhen, China.|Guangzhou Key Laboratory of Cancer Trans-Omics Research (GZ2012, NO348), BGI-Guangzhou, BGI-Shenzhen, Guangzhou, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yi
mesh_terms: D000483:Alleles; D000653:Amniotic Fluid / Q000737:chemistry; D001848:Bone Diseases, Developmental / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D002474:Cell-Free System; D019465:Craniofacial Abnormalities / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D004247:DNA / Q000097:blood* / Q000737:chemistry; D005260:Female; D005333:Fetus; D006801:Humans; D009154:Mutation; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011296:Prenatal Diagnosis; D017422:Sequence Analysis, DNA
chemical_list: D004247:DNA