title: Clinical validation of a noninvasive prenatal test for genomewide detection of fetal copy number variants.
abstract: BACKGROUND
  Current cell-free DNA assessment of fetal chromosomes does not analyze and report on all chromosomes. Hence, a significant proportion of fetal chromosomal abnormalities are not detectable by current noninvasive methods. Here we report the clinical validation of a novel noninvasive prenatal test (NIPT) designed to detect genomewide gains and losses of chromosomal material ≥7 Mb and losses associated with specific deletions <7 Mb.
  
  
  OBJECTIVE
  The objective of this study is to provide a clinical validation of the sensitivity and specificity of a novel NIPT for detection of genomewide abnormalities.
  
  
  METHODS
  This retrospective, blinded study included maternal plasma collected from 1222 study subjects with pregnancies at increased risk for fetal chromosomal abnormalities that were assessed for trisomy 21 (T21), trisomy 18 (T18), trisomy 13 (T13), sex chromosome aneuploidies (SCAs), fetal sex, genomewide copy number variants (CNVs) ≥7 Mb, and select deletions <7 Mb. Performance was assessed by comparing test results with findings from G-band karyotyping, microarray data, or high coverage sequencing.
  
  
  RESULTS
  Clinical sensitivity within this study was determined to be 100% for T21 (95% confidence interval [CI], 94.6-100%), T18 (95% CI, 84.4-100%), T13 (95% CI, 74.7-100%), and SCAs (95% CI, 84-100%), and 97.7% for genomewide CNVs (95% CI, 86.2-99.9%). Clinical specificity within this study was determined to be 100% for T21 (95% CI, 99.6-100%), T18 (95% CI, 99.6-100%), and T13 (95% CI, 99.6-100%), and 99.9% for SCAs and CNVs (95% CI, 99.4-100% for both). Fetal sex classification had an accuracy of 99.6% (95% CI, 98.9-99.8%).
  
  
  CONCLUSIONS
  This study has demonstrated that genomewide NIPT for fetal chromosomal abnormalities can provide high resolution, sensitive, and specific detection of a wide range of subchromosomal and whole chromosomal abnormalities that were previously only detectable by invasive karyotype analysis. In some instances, this NIPT also provided additional clarification about the origin of genetic material that had not been identified by invasive karyotype analysis.
authors.affiliation: Sequenom Laboratories, San Diego, CA.
authors.forename: Roy B
authors.initials: RB
authors.lastname: Lefkowitz
authors.affiliation: Sequenom Laboratories, San Diego, CA.
authors.forename: John A
authors.initials: JA
authors.lastname: Tynan
authors.affiliation: Sequenom Laboratories, San Diego, CA.
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.affiliation: Sequenom Laboratories, San Diego, CA.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Sequenom Laboratories, San Diego, CA.
authors.forename: Amin R
authors.initials: AR
authors.lastname: Mazloom
authors.affiliation: Sequenom Laboratories, San Diego, CA.
authors.forename: Eyad
authors.initials: E
authors.lastname: Almasri
authors.affiliation: Sequenom Laboratories, San Diego, CA.
authors.forename: Grant
authors.initials: G
authors.lastname: Hogg
authors.affiliation: Sequenom Laboratories, San Diego, CA.
authors.forename: Vach
authors.initials: V
authors.lastname: Angkachatchai
authors.affiliation: Sequenom Laboratories, San Diego, CA.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Sequenom Inc, San Diego, CA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Grosu
authors.affiliation: Sequenom Inc, San Diego, CA.
authors.forename: Graham
authors.initials: G
authors.lastname: McLennan
authors.affiliation: Sequenom Inc, San Diego, CA. Electronic address: mehrich@sequenom.com.
authors.forename: Mathias
authors.initials: M
authors.lastname: Ehrich
mesh_terms: D000293:Adolescent; D000328:Adult; D002869:Chromosome Aberrations; D025063:Chromosome Disorders / Q000175:diagnosis* / Q000000981:diagnostic imaging; D056915:DNA Copy Number Variations; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007621:Karyotyping; D008423:Maternal Age; D008875:Middle Aged; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods*; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D055815:Young Adult
keywords: cell-free DNA; chromosomal copy number variant; genomewide; microdeletions; noninvasive prenatal testing; subchromosomal copy number variant