Historical Tidbit: A cautionary genetics tidbit
Submitted by Walter L. Miller, MD
Whole exome sequencing (WES) aims to determine the sequence of all protein-coding segments (‘exons’) in genomic DNA. As this ‘exome’ comprises only ~2% of the whole genome, it is easier and cheaper than sequencing the whole genome. WES is increasingly used to identify mutations causing genetic disorders, but false-negative rates are high. Mice, like people, have genetic diseases. WES of mouse strains with defined Mendelian disorders identified the genetic cause in only 91/172 cases (Genome Res 2015; 25: 948–957). Various clinical studies yield ~37-47% (NEJM 380:25:2478-2480, 2019). Although WES is widely used to study DSD, it must be remembered that a positive WES result may (or may not) be informative, but a negative result is wholly uninformative. Caveat emptor.