Detecting fetal sub-chromosomal aneuploidies

A computer program product comprising a non-transitory machine readable medium storing program code that, when executed by one or more processors of a computer system, causes the computer system to implement a method for evaluation of copy number of a sequence of interest, said program code comprising code for:

• (a) receiving sequence reads obtained by sequencing DNA in a 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, wherein the sequence of interest is in a sub-chromosomal genomic region in which a copy number variation is associated with a genetic syndrome;
• (c) determining coverages of the test sequence tags for bins in the sequence of interest;
• (d) adjusting the coverages of the test sequence tags for the bins in the sequence of interest using expected coverages for the bins in the sequence of interest obtained from a subset of a training set of unaffected training samples, wherein training samples in the subset are more highly correlated with each other than training samples not in the subset are correlated with each other, and wherein the correlation is based on coverages in a plurality of bins outside of the sequence of interest;
• and
• (e) making a call of the copy number variation of the sequence of interest in the test sample based on the adjusted coverages from (d).

A system for evaluation of copy number of a sequence of interest related to a genetic syndrome using a test sample comprising nucleic acids, the system comprising:

• a sequencer for receiving nucleic acids from the test sample and providing nucleic acid sequence information from the test sample;
• logic designed or configured to execute or cause the following operations:
• (a) receiving sequence reads obtained by sequencing 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, wherein the sequence of interest is in a sub-chromosomal genomic region in which a copy number variation is associated with a genetic syndrome;
• (c) determining coverages of the test sequence tags for bins in the sequence of interest;
• (d) adjusting the coverages of the test sequence tags for the bins in the sequence of interest using expected coverages for the bins in the sequence of interest obtained from a subset of a training set of unaffected training samples, wherein training samples in the subset are more highly correlated with each other than training samples not in the subset are correlated with each other, and wherein the correlation is based on coverages in a plurality of bins outside of the sequence of interest;
• and
• (e) making a call of the copy number variation of the sequence of interest in the test sample based on the adjusted coverages from (d).