Advanced Whole-Genome Sequencing and Analysis of Fetal Genomes from Amniotic Fluid

Clin Chem. 2018 Apr;64(4):715-725. doi: 10.1373/clinchem.2017.281220. Epub 2018 Mar 15.


Background: Amniocentesis is a common procedure, the primary purpose of which is to collect cells from the fetus to allow testing for abnormal chromosomes, altered chromosomal copy number, or a small number of genes that have small single- to multibase defects. Here we demonstrate the feasibility of generating an accurate whole-genome sequence of a fetus from either the cellular or cell-free DNA (cfDNA) of an amniotic sample.

Methods: cfDNA and DNA isolated from the cell pellet of 31 amniocenteses were sequenced to approximately 50× genome coverage by use of the Complete Genomics nanoarray platform. In a subset of the samples, long fragment read libraries were generated from DNA isolated from cells and sequenced to approximately 100× genome coverage.

Results: Concordance of variant calls between the 2 DNA sources and with parental libraries was >96%. Two fetal genomes were found to harbor potentially detrimental variants in chromodomain helicase DNA binding protein 8 (CHD8) and LDL receptor-related protein 1 (LRP1), variations of which have been associated with autism spectrum disorder and keratosis pilaris atrophicans, respectively. We also discovered drug sensitivities and carrier information of fetuses for a variety of diseases.

Conclusions: We were able to elucidate the complete genome sequence of 31 fetuses from amniotic fluid and demonstrate that the cfDNA or DNA from the cell pellet can be analyzed with little difference in quality. We believe that current technologies could analyze this material in a highly accurate and complete manner and that analyses like these should be considered for addition to current amniocentesis procedures.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics
  • Adult
  • Amniocentesis
  • Amniotic Fluid / metabolism*
  • Autism Spectrum Disorder / genetics
  • Cohort Studies
  • DNA Copy Number Variations
  • Darier Disease / genetics
  • Eyebrows / abnormalities
  • Feasibility Studies
  • Female
  • Fetus / metabolism*
  • Genetic Predisposition to Disease
  • Genome, Human*
  • Humans
  • Male
  • Mutation
  • Whole Genome Sequencing*

Supplementary concepts

  • Burnett Schwartz Berberian syndrome