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 cell free DNA 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 bins outside the sequence of interest found to highly correlate with coverages of bins within the sequence of interest, 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 bins outside the sequence of interest as the subset of the training set, the identified training samples having a common systematic variability in normalized coverage, and (ii) obtaining the expected coverages from coverages in the bins of the subset; 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 cell free DNA 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 bins outside the sequence of interest found to highly correlate with coverages of bins within the sequence of interest, 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 bins outside the sequence of interest as the subset of the training set, the identified training samples having a common systematic variability in normalized coverage, and (ii) obtaining the expected coverages from coverages in the bins of the subset; and (e) evaluating a copy number of the sequence of interest in the test sample based on the adjusted coverages from (d). <EOS>