Genomic medicine gap: the questionable alleles in everyone's genome
Genomic medicine is revealing a big gap in medical knowledge. Whole genome data reveals each person has about 400-500 sequence variants creating missense or indel in the coding regions of their genome. With estimates as high as 25% of the genes in the human genome being involved in disease biology, any one individual harbors about 100 codon-changing issues in their important “disease” genes. Surprisingly, frameshifting indels account for 6.7% of these variant lesions. (PMC5282828). As a result, a significant number of questionable alleles are part of the background of anyone’s personal genome. How does the physician and clinical geneticist make sense of this noise in the system when trying to determine:
Is the gene mutation seen in my patient Benign or Pathogenic?
Phenotype Profiling in Animal Models
CRISPR technology now allows us to insert the same mutations seen in disease genes into the same homologous gene present in animal models (PMID:28677007). This allows one to fully characterize the phenotypic effect of a disease mutant allele in a well controlled system. Traditionally, this has been done in mice models, but is highly expensive. Knudra Transgenics in partnership with NemaMetrix is developing a platform for robust production and analysis of clinical variants. The homologous mutation is installed in an animal model and the effect on physiology is measured. Two powerful models that can be manipulated easily in fluidics paradigms are C. elegans and zebrafish. When a clinical variant is installed in fish, the researcher can examine if the phenotypic effect is conserved with man. Although the worm does not have the same physiological similarity as fish, the installation of clinical variant in the worm frequently has functional consequence if the gene mutation installed is truly pathogenic. The result is a multi-animal system for discovery of disease biology. Because both animal models thrive in liquid formats, It becomes easy to rapidly screen compounds for therapeutic effects. Microfluidics systems have recently be introduced by NemaMetrix (ScreenChip) to enable rapid and quantitative measure of phenotype in C. elegans. By combining the ScreenChip system with the fast production of transgenics at Knudra, researchers can now access to a rapid phenotyping system detecting the presences of pathogenicity in clinical variants of uncertain significance. Mutation-specific animal models can be made and tested in a few weeks, instead of the years it takes with traditional animal models. The capacity for fast assessment may allow decisions on treatment options to be made in a time frame where a positive impact can be quite high. Ultimately a faster decision on how to devise a treatment will enable care providers to improve patent outcome and save lives.