Global transcriptome analysis is of growing importance in understanding how altered expression of genetic variants contributes to complex diseases such as cancer, diabetes, and heart disease. Analysis of genome-wide differential RNA expression provides researchers with greater insights into biological pathways and molecular mechanisms that regulate cell fate, development, and disease progression. A sequence-based approach is a very powerful tool for studying gene expression, having the advantage of querying known as well as previously unknown RNAs in a sample in a “hypothesis-neutral” discovery. This approach requires making cDNA copies of all RNA present in the sample, including sequencing them, mapping the sequences back to a reference genome, and deducing the structure using bioinformatic tools. At the CGEH we use our SOLiD5500xl pipeline to analyze novel transcripts, novel isoforms, alternative splice sites, rare transcripts and coding SNPs.