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US 20120053062A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0053062 A1 BROOKS (43) Pub. Date: Mar. 1, 2012 (54) DEFINING DAGNOSTIC AND Publication Classification THERAPEUTIC TARGETS OF CONSERVED FREE FLOATING FETAL DNA IN MATERNAL (51) Int. Cl. CIRCULATING BLOOD C40B 20/00 (2006.01) G06F 7/30 (2006.01) (75) Inventor: Andrew BROOKS, New York, NY C40B 40/06 (2006.01) (US) (73) Assignee: Bio Dx, Inc., San Diego, CA (US) (52) U.S. Cl. ......... 506/2:506/16; 707/758; 707/E17.014 (21) Appl. No.: 13/216,992 (22) Filed: Aug. 24, 2011 (57) ABSTRACT Related U.S. Application Data The present invention provides methods and materials useful (60) Provisional application No. 61/376,637, filed on Aug. for detecting cell free fetal DNA as well as markers for fetal 24, 2010. conditions by using biological samples of a maternal host. US 2012/0053062 A1 Mar. 1, 2012 DEFINING DAGNOSTIC AND 0009. In one embodiment, the conserved genomic seg THERAPEUTIC TARGETS OF CONSERVED ment is a genomic segment provided in Table 1. In one FREE FLOATING FETAL DNA IN MATERNAL embodiment, the conserved genomic segment includes any CIRCULATING BLOOD probe identified in Table 1. In another embodiment, the con served genomic segment includes any geneidentified in Table CROSS REFERENCE TO RELATED 1. In yet another embodiment, the conserved genomic seg APPLICATIONS ment is a fragment of a gene identified in Table 1, e.g., a fragment associated with any genotype marker of a gene 0001. This application claims priority to U.S. Provisional identified in Table 1. In still another embodiment, the con Application No. 61/376,637 filed, Aug. 24, 2010, which is served genomic segment is any gene identifiable by the probe incorporated by reference herein in its entirety. or associated with the probe identified in Table 1. 0010. In one embodiment, the method comprises detect FIELD OF THE INVENTION ing the genotypes of at least two, at least three, at least four, at 0002 The present invention provides for detecting and least five, at least six, at least seven, at least eight, at least nine, characterizing fetal genetic material, e.g., fetal DNA in at least ten, at least 20, at least 50, at least 100, at least 150, at maternal samples, e.g., maternal blood as well as identifica least 200, at least 250, at least 500, at least 600, at least 700, tion of fetal conditions based on non-invasive prenatal test or at least 800 conserved genomic segments provided in Table 1ng. 1 in a biological sample of a maternal host and comparing the genotypes to the corresponding maternal genotypes to deter BACKGROUND OF THE INVENTION mine the presence of fetal DNA based on one or more differ ences between the genotype of the sample and the genotype of 0003. The challenges associated with DNA diagnostics the maternal host. from free floating fetal DNA are many. Issues associated with 0011. In one embodiment, the genotype of a conserved the amount of DNA, enrichment of fetal specific DNA, genomic segment comprises the profile of any one or more nucleic acid purity and understanding the specific fetal DNA genetic makeup suitable for distinguishing one genome from sequence that is conserved across pregnancies and Subjects another genome. For example, the genotype of a conserved are among the largest hurdles. Currently there is no satisfac genomic segment can comprise the profile of single nucle tory methodology for determining the presence offetal DNA otide polymorphism (SNP), restriction fragment length poly prior to diagnostic testing which adversely affects the ability moprhism (RFLP), short tandem repeats (STR), DNA to report consistent and reliable data. There is also lack of sequence, or any combination thereof. In one embodiment, sufficient characterization of free floating fetal DNA that can the genotype of a conserved genomic segment comprises the be used to identify specific sequences (in addition to disease profile of SNP. In yet another embodiment, the genotype of targets) that can be used to obtain a high rate of Success in one or more conserved genomic segments comprises the pro assay development across pregnancies. file of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 0004 Sequence and mutation specific assay development 35, 40, 50, 60, 70, 80, 90, or 100 SNPs in one or more is currently difficult to carry out given the variability associ conserved genomic segments. ated with prenatal nucleic acid analysis from maternal whole 0012. In one embodiment, the biological sample of a blood. maternal host includes any processed or unprocessed, Solid, 0005. As such, there remains a need in the art for methods semi-solid, or liquid biological sample, e.g., blood, urine, and approaches of detecting fetal DNA and related fetal con saliva, mucosal samples (such as samples from uterus or ditions. vagina, etc.). For example, the biological sample of a mater 0006. The present invention describes a technological nal host can be a sample of whole blood, partially lysed whole approach for detecting and characterizing fetal genetic mate blood, plasma, partially processed whole blood. In one rial in maternal samples. In addition, the present invention embodiment, the biological sample of a maternal host is a provides methods and related materials for identifying fetal sample of cell free DNA or free floating DNA from the whole conditions based on fetal genetic materials in maternal samples. blood of the maternal host. 0013. In one embodiment, the biological sample of a maternal host is enriched for fetal DNA. In one embodiment, SUMMARY OF THE INVENTION the biological sample of a maternal host is enriched for fetal 0007. The present invention is based, in part, on the dis DNA by DNA size fractionation. In one embodiment the covery that certain fetal genetic materials are conserved in fraction of DNA containing fetal DNA is characterized by maternal biological samples, e.g., maternal blood. Accord having a size of about less than 500 base pairs, or about 50 to ingly the present invention provides methods and materials about 500 base pairs or about 50 to about 400 base pairs, or useful for detecting fetal genetic material as well as for iden about 50 to about 300 base pairs, or about 50 to about 200 base tification of fetal conditions. pairs, or about 50 to about 100 base pairs. 0008. In one aspect, the present invention provides a 0014. In one embodiment, the genotype of at least one method for detecting the presence of fetal DNA in a biologi conserved genomic segment in a biological sample of a cal sample of a maternal host. In one embodiment, the method maternal host that has been enriched for fetal DNA is deter comprises identifying the genotype of at least one conserved mined and compared to a maternal genotype for the same genomic segment in a biological sample of a maternal host conserved genomic segments in a maternal cell sample. In and comparing the genotype to the corresponding maternal one embodiment, the maternal biological sample enriched for genotype to determine the presence of fetal DNA based on fetal DNA is a whole blood sample. In a further embodiment, one or more differences between the genotype of the sample the maternal cell sample is derived from a maternal whole and the genotype of the maternal host. blood sample, e.g., prior to pregnancy. US 2012/0053062 A1 Mar. 1, 2012 0015. In another aspect, the invention provides for a 0021. In one embodiment, the genetic maker is associated method of detecting the presence or absence of a genetic with an aneuploidy. In one embodiment, the aneuploidy is a condition in a fetus comprising detecting the presence or trisomy. In a further embodiment, the genetic marker associ absence of a genetic marker in a biological sample obtained ated with a trisomy is within one or more of the chromosomal from the maternal host of a fetus. In one embodiment, the locations selected from the group consisting of X21.2-Xp21. genetic marker is within a chromosomal location conserved 1, 17q11.2-17q11.2, 3p26-3p25, 5q13-5q13, 16q24.3-16cq24. in cell free fetal DNA in the biological sample of the maternal 3, 1q24.2-1q23 and/or 11cq22-11q23. In one embodiment, the host. In one embodiment, the chromosomal location is genetic marker associated with a trisomy is within a chromo selected from the chromosomal locations listed in Table 2. In somal location of chromosome 13, 14, 15, 16, 18, 21, 22, Xor one embodiment, the presence or absence of the genetic Y. In another embodiment, the genetic marker includes a marker indicates the presence or absence of the genetic con panel of genetic markers from a chromosomal location of dition in the fetus. chromosome 13, 14, 15, 16, 18, 21, 22, X, Y, or any combi 0016. In one embodiment, the biological sample of a nation thereof. In yet another embodiment, the generic maternal host includes any processed or unprocessed, Solid, marker includes a panel of genetic markers from one or more semi-solid, or liquid biological sample, e.g., blood, urine, chromosomal locations of X21.2-Xp21. 1, 17q11.2-17q11.2, saliva, mucosal samples (such as samples from uterus or 3p26-3p25, 5q13-5q13, 16q24.3-16c24.3, 1q24.2-1q23. vagina, etc.). For example, the biological sample of a mater 11q22-11q23 or any combination thereof. nal host can be a sample of whole blood, partially lysed whole 0022. In one aspect, the current invention provides a blood, plasma, partially processed whole blood. In one method for selecting a genetic marker for determining a embodiment, the biological sample of a maternal host is a genetic condition of a fetus in a biological sample of a mater sample of cell free DNA or free floating DNA from the whole nal host of the fetus by identifying a group of genetic markers blood of the maternal host.
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