The advent of next-generation sequencing technologies has revolutionized the 
study of genetic variation in the human genome. Whole-genome sequencing 
currently represents the most comprehensive strategy for variant detection 
genome-wide but is costly for large sample sizes, and variants detected in 
noncoding regions remain largely uninterpretable. By contrast, whole-exome 
sequencing has been widely applied in the identification of germline mutations 
underlying Mendelian disorders, somatic mutations in various cancers and de novo 
mutations in neurodevelopmental disorders. Since whole-exome sequencing focuses 
upon the entire set of exons in the genome (the exome), it requires additional 
exome-enrichment steps compared with whole-genome sequencing. Although the 
availability of multiple commercial exome-enrichment kits has made whole-exome 
sequencing technically feasible, it has also added to the overall cost. This has 
led to the emergence of transcriptome (or RNA) sequencing as a potential 
alternative approach to variant detection within protein coding regions, since 
the transcriptome of a given tissue represents a quasi-complete set of 
transcribed genes (mRNAs) and other noncoding RNAs. A further advantage of this 
approach is that it bypasses the need for exome enrichment. Here we discuss the 
relative merits and limitations of these approaches as they are applied in the 
context of variant detection within gene coding regions.