title: Noninvasive detection of fetal subchromosome abnormalities via deep sequencing of maternal plasma.
abstract: The purpose of this study was to determine the deep sequencing and analytic conditions needed to detect fetal subchromosome abnormalities across the genome from a maternal blood sample. Cell-free (cf) DNA was isolated from the plasma of 11 pregnant women carrying fetuses with subchromosomal duplications and deletions, translocations, mosaicism, and trisomy 20 diagnosed by metaphase karyotype. Massively parallel sequencing (MPS) was performed with 25-mer tags at approximately 10(9) tags per sample and mapped to reference human genome assembly hg19. Tags were counted and normalized to fixed genome bin sizes of 1 Mb or 100 kb to detect statistically distinct copy-number changes compared to the reference. All seven cases of microdeletions, duplications, translocations, and the trisomy 20 were detected blindly by MPS, including a microdeletion as small as 300 kb. In two of these cases in which the metaphase karyotype showed additional material of unknown origin, MPS identified both the translocation breakpoint and the chromosomal origin of the additional material. In the four mosaic cases, the subchromosomal abnormality was not demonstrated by MPS. This work shows that in nonmosaic cases, it is possible to obtain a fetal molecular karyotype by MPS of maternal plasma cfDNA that is equivalent to a chromosome microarray and in some cases is better than a metaphase karyotype. This approach combines the advantage of enhanced fetal genomic resolution with the improved safety of a noninvasive maternal blood test.
authors: Verinata Health, Inc., Redwood City, CA 94063, USA.
authors: Anupama
authors: A
authors: Srinivasan
authors: Diana W
authors: DW
authors: Bianchi
authors: Hui
authors: H
authors: Huang
authors: Amy J
authors: AJ
authors: Sehnert
authors: Richard P
authors: RP
authors: Rava
mesh_terms: D000782:Aneuploidy; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D058674:Chromosome Duplication / Q000235:genetics; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D004247:DNA / Q000097:blood*; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D005333:Fetus / Q000378:metabolism*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007621:Karyotyping; D008297:Male; D009030:Mosaicism; D011247:Pregnancy; D014178:Translocation, Genetic
chemical_list: D004247:DNA