Genetic Disease Diagnostics with NGS

A couple of recent papers demonstrate a significant opportunity for the use of NextGen Sequencing in the diagnosis of genetic disease. Dennis Lo et al, at The Chinese University of Hong Kong, have published results for a NGS fetal genetic diagnostic test based on recovery of fragments of fetal DNA from the mother's blood plasma. Preliminary results show that complete coverage of the fetal diploid genome is possible [Science Translational Medicine] at a resolution that allows for differentiation of heterozygous vs. homozygous mutations in disease genes; and also that aneuploidy, such as trisomy 21 can be detected with high specificity and sensitivity [British Medical Journal]. The key benefit of this approach is that it can be done non-invasively from simple blood draw from the mother, so it avoids the relatively high incidence of pregnancy complications created by amniocentesis or chorionic villus sampling procedures.

Meanwhile, the lab of Stephen Kingsmore at the US National Center for Genome Resources reported results of a targeted sequencing carrier screen for a total of 448 severe (rare) recessive genetic diseases [Science Translational Medicine]. This work is particularly significant because the screen is designed to work in multiplex, allowing for a potential total cost per patient of below $500 (less than $1 per disease screened). While each gene is rare in isolation, the combined screen shows an average of 2.8 mutations per individual tested in the proof-of-concept phase of the study.

Taken together, these advances suggest that routine clinical applications of NGS will soon be practical, attractive, and economically feasible for large numbers of healthy people (pregnant women and marriage minded couples). This is great news for NGS equipment vendors, and also suggests a software engineering opportunity for the development of much more robust bioinformatics pipelines for processing this data and including it in electronic medical records. At the same time, I am worried that the lab folks may be progressing much more rapidly than the thinking in the ELSI community. What kind of databases will be created when every pregnancy and every marriage license is associated with gigabyte files of deep sequencing data? This issue is all the more problematic because disease carrier testing and Down syndrome screening are already so widely accepted. Changing prenatal tests to use sequencing in order to reduce complications in pregnancy, and adding pre-conception tests for diseases that were previously thought to be too rare to merit widespread screening are non-controversial medical advances. The downside might come from the unintentional discovery of other genetic information, the availability to law enforcement and other organizations of large files of genetic information on every person, etc.