Means and methods for non-invasive diagnosis of chromosomal aneuploidy

Abstract

The invention relates to a prenatal diagnostic method for the determination of a fetal chromosomal aneuploidy in a biological sample obtained from a pregnant woman, which method comprises enrichment and quantification of selected cell-free deoxyribonucleic acid sequences showing consensus nucleosome binding regions.

1 .- 14 . (canceled) 
     
     
         15 . A method for determining a chromosomal aberration in a biological sample obtained from an individual, wherein the biological sample includes nucleic acid molecules, the method comprising:
 (a) selecting for and isolating from the biological sample of an individual one or more target sequences of DNA molecules present in the biological sample, wherein the target sequences comprise DNA sequences leaving consensus nucleosome binding regions;   (b) amplifying the selected target sequences;   (c) sequencing the amplified selected target sequences and allotting them to the chromosomes of the genome and identifying the unique allotted target sequences;   (d) determining a first amount for each of one or more first chromosomes identified on the basis of the unique allotted target sequences originating from the one or more first chromosomes;   (e) determining a second amount for each of one or more second chromosomes identified on the basis of the unique allotted target sequences originating from the one or more second chromosomes; and   (f) determining based on the first and second amounts a chromosomal abberation.   
     
     
         16 . The method of  claim 15 , wherein step (f) further comprises:
 (i) determining a parameter from the first amount relative to the second amount;   (ii) comparing the parameter to a corresponding cut off control value; and   (iii) based upon the comparison in (ii), determining whether or not there is a difference allowing for the prediction of a chromosomal aberration in one or more of the first chromosomes.   
     
     
         17 . The method of  claim 15 , wherein the chromosomal aberration is indicative of a predisposition for cancer. 
     
     
         18 . The method of  claim 15 , wherein the individual is a human. 
     
     
         19 . The method of  claim 15 . wherein the biological sample comprises a cell suspected to be a cancer cell. 
     
     
         20 . A computer programme product which when executed on a computer or data processing device is capable of carrying out the following steps:
 (a) allotting amplified selected and isolated target sequences having consensus nucleosome binding regions from a biological sample of an individual to chromosomes of the genome and identifying unique allotted target sequences;   (b) determining a first amount for each of one or more first chromosomes identified on the basis of the unique allotted target sequences originating from the one or more first chromosomes; and   (c) determining a second amount for each of one or more second chromosomes identified on the basis of the unique allotted target sequences originating from the one or more second chromosomes; and   d) determining based on the first and second amounts a fetal chromosomal aneupoidy of one or more of the first chromosomes or a chromosomal aberration.   
     
     
         21 . The computer programme product of  claim 20 , wherein the determining in step (d) further comprises:
 (i) determining a parameter from the first amount relative to the second amount;   (ii) comparing the parameter to a corresponding cut off control value; and   (iii) based upon the comparison in (ii), determining whether or not there is a difference allowing for the prediction of a chromosomal aberration in one or more of the first chromosomes or determining whether or not there is a difference allowing for the prediction of a fetal chromosomal aneuploidy of one or more of the first chromosomes.   
     
     
         22 . A device for carrying out the method of  claim 15 , comprising:
 (a) an analyzing unit comprising a subunit capable of selecting for and isolating from the biological sample of an individual one or more target sequences of DNA molecules present in the biological sample, wherein the target sequences comprise DNA sequences having consensus nucleosome binding regions, a subunit for amplification of the target DNA molecules, and a subunit for sequencing of amplified target sequences; and   (b) an evaluation unit comprising a receiving subunit for the sequence data and a computer or data processing subunit executing a computer programme product, wherein the computer programme product which when executed on a computer or data processing device is capable of carrying out the following steps:
 (i) allotting amplified selected and isolated target sequences having consensus nucleosome binding regions from a biological sample of an individual to chromosomes of the genome and identifying unique allotted target sequences; 
 (ii) determining a first amount for each of one or more first chromosomes identified on the basis of the unique allotted target sequences originating from the one or more first chromosomes; and 
 (iii) determining a second amount for each of one or more second chromosomes identified on the basis of the unique allotted target sequences originating from the one or more second chromosomes; and 
 (iv) determining based on the first and second amount a fetal chromosomal aneupoidy of one or more of the first chromosomes or a chromosomal aberration.