Probabilistic method for detecting copy number variation in a fetal genome using maternal plasma sequencing

Motivation: The past several years have seen the development of methodologies to identify genomic variation within a fetus through the non-invasive sequencing of maternal blood plasma. These methods are based on the observation that maternal plasma contains a fraction of DNA (typically 5-15%) originating from the fetus, and such methodologies have already been used for the detection of whole-chromosom events (aneuploidies), and to a more limited extent for smaller (typically several megabases long) copy number variants (CNVs). Results: Here we present a probabilistic method for non-invasive analysis of de novo CNVs in fetal genome based on maternal plasma sequencing. Our novel method combines three types of information within a unified Hidden Markov Model: the imbalance of allelic ratios at SNP positions, the use of parental genotypes to phase nearby SNPs and depth of coverage to better differentiate between various types of CNVs and improve precision. Our simulation results, based on in silico introduction of novel CNVs into plasma samples with 13% fetal DNA concentration, demonstrate a sensitivity of 90% for CNVs 4400 kb (with 13 calls in an unaffected genome), and 40% for 50- 400 kb CNVs (with 108 calls in an unaffected genome).