A method, implemented at a computer system that includes one or more processors and system memory, for evaluation of copy number of a sequence of interest in a test sample comprising nucleic acids of one or more genomes, wherein the sequence of interest is in a sub-chromosomal genomic region where a copy number variation is associated with a genetic syndrome, the method comprising: (a) receiving sequence reads obtained by sequencing nucleic acids in the test sample; (b) aligning the sequence reads of the test sample to a reference genome comprising the sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins; (c) determining a coverage of the test sequence tags for bins in the reference genome including the sequence of interest; (d) adjusting the coverages of the test sequence tags in the bins in the reference genome including the sequence of interest by employing expected coverages obtained from a subset of a training set of unaffected training samples sequenced and aligned in substantially the same manner as the test sample, wherein the expected coverages were obtained using coverages of a group of bins outside the sequence of interest, and wherein the group of bins outside the sequence of interest were identified by: determining correlations between the coverage in each bin under consideration within the sequence of interest and coverages in a plurality of bins outside the sequence of interest comprising the group of bins outside the sequence of interest, and selecting highly correlated bins in the plurality of bins to form the group of bins, and wherein the expected coverages were obtained by (i) identifying training samples among the training set that correlate to one another in their coverages in the group of bins outside the sequence of interest as the subset of the training set, and (ii) obtaining the expected coverages from coverages in the bins of the identified subset of the training set; and (e) evaluating a copy number of the sequence of interest in the test sample based on the adjusted coverages from (d). (a) receiving sequence reads obtained by sequencing nucleic acids in the test sample; (b) aligning the sequence reads of the test sample to a reference genome comprising the sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins; (c) determining a coverage of the test sequence tags for bins in the reference genome including the sequence of interest; (d) adjusting the coverages of the test sequence tags in the bins in the reference genome including the sequence of interest by employing expected coverages obtained from a subset of a training set of unaffected training samples sequenced and aligned in substantially the same manner as the test sample, wherein the expected coverages were obtained using coverages of a group of bins outside the sequence of interest, and wherein the group of bins outside the sequence of interest were identified by: determining correlations between the coverage in each bin under consideration within the sequence of interest and coverages in a plurality of bins outside the sequence of interest comprising the group of bins outside the sequence of interest, and selecting highly correlated bins in the plurality of bins to form the group of bins, and wherein the expected coverages were obtained by (i) identifying training samples among the training set that correlate to one another in their coverages in the group of bins outside the sequence of interest as the subset of the training set, and (ii) obtaining the expected coverages from coverages in the bins of the identified subset of the training set; and (e) evaluating a copy number of the sequence of interest in the test sample based on the adjusted coverages from (d). <EOS>