AM KOPPS¹, J MEIENBERG¹, R BRUGGMANN², K OEXLE¹, G MATYAS<sup>1

1</sup>Center for Cardiovascular Genetics and Gene Diagnostics, Foundation for People with Rare Diseases, Schlieren-Zurich, Switzerland, ²Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Berne, Berne, Switzerland

Current clinical next-generation sequencing makes use of gene panels and exome analysis, both of which involve selective capturing of target regions. However, capturing has limitations in sufficiently covering coding exons, especially GC-rich regions. We compared whole exome sequencing (WES, SureSelect Human All Exon v5+UTR) with the most recent PCR-free whole genome sequencing (WGS, Illumina TruSeq) for five female samples. We assessed the proportion of completely and sufficiently covered (³13×) RefSeq coding exons. Thereby we analyzed (i) the entire exome and subsets of clinically relevant exons, i.e. (ii) genes recommended by the American College of Medical Genetics or (iii) exons with mutations recorded in the Human Gene Mutation Database. PCR-free WGS appears to be insensitive to GC content and is thus able to provide hitherto unprecedented complete coverage of the coding region of the genome. Although the average read depth was less than half (65× in WGS vs. 154× in WES), the proportion of completely and sufficiently covered coding exons was significantly higher in PCR-free WGS for all analyzed set of exons. The advantage of WGS does not only include the potential of identifying non-coding pathogenic variation but, in view of its more homogenous and complete exomic coverage, WGS is the better WES, thereby outweighing the higher costs. Thus, from a clinical/technical point of view capturing is no longer necessary for the most comprehensive genomic testing of Mendelian disorders.