Method for precise genetic diagnosis

Abstract

Methods and apparatuses for selecting and arranging clinically relevant chromosomal loci allow an exemplary diagnostic array to simultaneously test for numerous genetic alterations that occur in many different parts of the human genome. Clinically irrelevant or ineffective loci are eliminated. One implementation increases reliability and accuracy by dividing the base-pair sequence of each chromosomal locus into segments and then assigning nucleic acid clones for comparative genomic hybridization to each different segment. The segments may overlap for increased resolution and control. Clones representing segments that are adjacent on a native chromosome are placed in non-adjacent target areas of the array to avoid interfering hybridization reactions. Arrangement motifs within an array may be redundantly repeated for high availability and increased reliability and accuracy of results. Techniques, hardware, software, logic engines, loci collections, and diagnostic arrays are described.

1 . A method for precision genetic diagnosis, comprising:
 selecting a locus associated with a genetic condition to be diagnosed;   representing at least part of a base-pair sequence of the locus as multiple base-pair segments;   selecting a reference base-pair sequence unrelated to the genetic condition;   assigning one of clones or oligomers to represent the multiple base-pair segments and the reference base-pair sequence;   arranging the clones or oligomers representing the multiple base-pair segments on a microarray for a comparative genomic hybridization (CGH) test; and   arranging the clones or oligomers representing the reference base-pair sequence on the microarray for a CGH test.   
   
   
       2 . The method of  claim 1 , further comprising comparing the CGH test of the reference base-pair sequence with the CGH test of the base-pair segments to determine a degree of genetic alteration of the locus for diagnosing the genetic condition. 
   
   
       3 . The method of  claim 1 , further comprising arranging the clones or oligomers in separate locations on the microarray to avoid hybridization influences. 
   
   
       4 . The method of  claim 1 , wherein the reference base-pair sequence occurs in proximity to the locus on a chromosome. 
   
   
       5 . The method of  claim 1 , wherein the reference base-pair sequence occurs adjacent to the locus on a chromosome. 
   
   
       6 . The method of  claim 5 , further comprising flanking the clones or oligomers representing the base-pair segments of the locus on the microarray with the clones or oligomer representing the reference base-pair sequence adjacent to the locus on the chromosome. 
   
   
       7 . A method for precision genetic diagnosis, comprising:
 selecting a chromosomal locus associated with a genetic condition to be diagnosed;   representing at least part of the base-pair sequence of the chromosomal locus in one or more target areas of a comparative genomic hybridization array; and   flanking one or more of the target areas with one or more reference target areas that include one or more reference base-pair sequences that are unaltered with respect to the genetic condition to be diagnosed; and   wherein a fluorescence signal from the reference base sequence is capable of being compared with a fluorescence signal from the one or more target areas representing the chromosomal locus.   
   
   
       8 . The method as recited in  claim 7 , wherein at least one of the reference base-pair sequences is contiguous with the chromosomal locus in vivo. 
   
   
       9 . A method, comprising:
 selecting a chromosomal locus associated with a genetic condition to be diagnosed;   representing at least part of the base-pair sequence of the chromosomal locus in one or more target areas of a comparative genomic hybridization array; and   representing, in target areas of the comparative genomic hybridization array, a chromosomal region in the vicinity of the chromosomal locus in vivo, wherein an extent of a base-pair sequence deletion associated with the chromosomal locus is capable of being determined from comparative genomic hybridization of the chromosomal region.   
   
   
       10 . The method of  claim 9 , wherein the chromosomal locus comprises one of 1p36.3, 1p12, 1q21, 1q44, 2p25.3, 2p11.2, 2q11.2, 2q37.3, 3p26.3, 3p11.2, 3q11.2, 3q29, 4p16.3, 4p12, 4q12, 4q35.2, 5p15.3, 5p12, 5q11.2, 5q35.3, 6p25.3, 6p11.2, 6q12, 6q27, 7p22.3, 7p11.2, 7q11.21, 7q36.3, 8p23.3, 8p11.2, 8q11.2, 8q24.3, 9p24.3, 9p11.2, 9q13, 9q34.3, 10p15.3, 10p11.21, 10q11.21, 10q26.3, 11p15.5, 11p11.2, 11q12, 11q25, 11p13.33, 12p11.21, 12q12, 12q24.33, 13q12.11, 13q34, 14q11.2, 14q32.33, 15q11.2, 15q26.3, 16p13.3, 16p11.2, 16q21.1, 16q24.3, 17p13.3, 17q11.2, 18p11.32, 18p11.21, 18q11.2, 18q23, 19p13.3, 19p12, 19q12, 19q13.43, 20p13, 20p11.21, 20q11.21, 20q13.33, 21q11.2, 21q22.3, 22q11.2, 22q13.3, Xp22.3, Xp11.22, Xq11.2, Xq28, YP11.3, Yp11.2, and YQ11.2; and
 wherein the respective chromosomal region is respectively in the vicinity of the corresponding chromosomal locus in vivo.