COMBINED SIZE- AND COUNT-BASED ANALYSIS OF MATERNAL PLASMA FOR DETECTION OF FETAL SUBCHROMOSOMAL ABERRATIONS

摘要

An aberration in a fetal genome can be identified by analyzing a sample of fetal and maternal DNA. Classifications of whether an aberration (amplification or deletion) exists in a subchromosomal region are determined using count-based and size-based methods. The count classification and the size classification can be used in combination to determine whether only the fetus or only the mother, or both, have the aberration in the subchromosomal region, thereby avoiding false positives when the mother has the aberration and the fetus does not.

主权项

1. A method of identifying a subchromosomal aberration in a fetal genome of a fetus by analyzing a biological sample from a female subject pregnant with the fetus, the biological sample including cell-free DNA molecules from the female subject and the fetus, the method comprising:
for each of a plurality of DNA molecules in the biological sample:
measuring a size of the DNA molecule;identifying a location of the DNA molecule in a reference genome; detecting, by a computer system, an aberration in the biological sample of a first subchromosomal region by:
determining a first amount of DNA molecules located in the first subchromosomal region;determining a second amount of DNA molecules located in a second region;computing a count parameter from the first amount and the second amount; andcomparing the count parameter to one or more count threshold to determine a count classification of a type of aberration existing in the biological sample for the first subchromosomal region; determining, by the computer system, a size classification for the first subchromosomal region by:
calculating a first statistical value of sizes of DNA molecules located in the first subchromosomal region;calculating a reference statistical value of sizes of DNA molecules located in a reference region;determining a separation value between the first statistical value and the reference statistical value; andcomparing the separation value to one or more size thresholds to obtain the size classification; and determining whether the fetus has the aberration in the first subchromosomal region based on the size classification and the count classification.