title: Noninvasive detection of a balanced fetal translocation from maternal plasma.
abstract: BACKGROUND
  Massively parallel sequencing of circulating cell free (ccf) DNA from maternal plasma has been demonstrated to be a powerful method for the detection of fetal copy number variations (CNVs). Although the detection of CNVs has been described by multiple independent groups, genomic aberrations resulting in copy number-neutral events including balanced translocations have proven to be more challenging to detect noninvasively from ccf DNA.
  
  
  METHODS
  Data modeling was initially performed to evaluate multiple methods, ultimately leveraging the short length of ccf DNA and paired-end sequencing to construct read-specific mapping characteristics. After testing in a model system, we evaluated the methods on ccf DNA isolated from the plasma of a donor known to be carrying a fetus with a balanced translocation [t(8;11)]. Sequencing was performed with Illumina sequencing technology.
  
  
  RESULTS
  Our methodology identified the known translocation (P = 1.21 × 10(-8)) and discounted the likelihood of others, enabling the base specific identification of the rearrangement positions. In total, 402 unique sequencing reads spanned the putative breakpoints, of which 76 contained the structural rearrangement. In addition, 38 of the chimeric reads were mapped to each of the resulting derivative chromosomes, supporting the presence of a reciprocal translocation. Finally, we identified a 6-bp deletion present within der(8) that was absent from the der(11) reciprocal rearrangement.
  
  
  CONCLUSIONS
  We have developed an algorithm to detect balanced rearrangements and applied our methodology to demonstrate the first proof-of-principle study on the noninvasive detection of a fetal-specific balanced translocation by sequencing ccf DNA from maternal plasma.
authors.affiliation: Sequenom Laboratories, San Diego, CA;
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Jensen
authors.affiliation: Sequenom Laboratories, San Diego, CA;
authors.forename: Sung K
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Sequenom Inc., San Diego, CA.
authors.forename: Dirk
authors.initials: D
authors.lastname: van den Boom
authors.affiliation: Sequenom Laboratories, San Diego, CA;
authors.forename: Cosmin
authors.initials: C
authors.lastname: Deciu
authors.affiliation: Sequenom Inc., San Diego, CA. mehrich@sequenom.com.
authors.forename: Mathias
authors.initials: M
authors.lastname: Ehrich
mesh_terms: D000328:Adult; D000465:Algorithms; D001483:Base Sequence; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D003198:Computer Simulation; D004247:DNA / Q000097:blood* / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005333:Fetus / Q000378:metabolism*; D005865:Gestational Age; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods*; D017422:Sequence Analysis, DNA / Q000379:methods; D014178:Translocation, Genetic
chemical_list: D004247:DNA