HOW USEFUL ARE GENOMIC APPROACHES TO SOLVING MYSTERY GENETIC DISEASES?
Thus far, for the vast majority of mystery genetic diseases, exome and whole genome sequencing has been successful in identifying the likely disease- causing mutations in about 25%–30% of cases. Furthermore, when the causative mutation is identified, only in a handful of these cases has the information been valuable for optimizing treatment. Often whole genome sequencing or exome sequencing generates a short list of possible disease- causing mutations; narrowing the list further requires additional tests and experiments. There have been, however, a few spectacular successes.
The case of Nicholas Volker offers one early example in which genome sequencing played an important role in the diagnosis and treatment of an unsolved disease. Nicholas was healthy until age two years, when he suffered a cut that would not heal. His condition dramatically worsened, and he frequently developed sepsis (infection of the blood) from many serious wounds, for which over one hundred surgeries were required. He had his colon removed, could not eat or drink, and required total parenteral nutrition (i.e., all his nutrition was administered intravenously). By sequencing his genome, doctors deduced that he had a mutation in the XIAP gene, which is associated with immune function. He received a cord blood transplant from an anonymous donor, made a remarkable recovery, and is now doing well at age six years.
Another successful case is that of the non-identical (fraternal) Beery twins (Figure 1). They were born as “floppy” babies, had seizures and delayed motor skills, and were diagnosed with cerebral palsy. Upon receiving a new diagnosis of Segawa’s dystonia, the children were treated with dopamine, which improved their health but did not completely alleviate their symptoms; indeed, their health slowly deteriorated. Finally, upon the sequencing of their genomes many years later, a mutation in both copies of the SPR gene was discovered in each of the two children. The SPR gene is involved in producing both dopamine and serotonin. This finding suggested that in addition to dopamine, serotonin supplementation might be beneficial. Administration of a serotonin precursor to the children along with dopamine significantly improved the health of each child so that they are now symptom-free. Thus, similar to the case of Nicholas Volker, in the case of the Beery twins genome sequencing provided important information that was used for effective treatment and significant health benefits.
Figure 1. The Beery twins at high school graduation (2015). Using genome sequencing, the twins were found to have a mutation in the SPR gene (right). This led to successful treatment with dopamine and a serotonin precursor (5-hydroxytryptophan). Picture courtesy of Retta Beery.
Unfortunately, in contrast with these examples, finding the disease-causing mutation does not lead to effective treatments in the vast majority of cases. Nonetheless, in nearly every one of the cases in which a disease-causing mutation is found, the information is still valuable to patients and their families. Finding a scientific explanation typically brings considerable relief to patients and families and provides some peace of mind. For some individuals and families, the information is helpful for planning future pregnancies. Some individuals elect to use in vitro fertilization (IVF) and genetic testing to select embryos that lack the disease-causing mutations. Embryos generated by IVF can be screened by isolating a few cells from early embryos, amplifying the DNA regions of interest from those cells, and performing DNA sequencing. Embryos lacking the disease-causing genetic mutations (or carrying at least one normal copy of the affected gene in the case of recessive mutations) are chosen for implantation. Thus, although the original genomic information may not directly benefit the person affected, it can be useful in family planning. Finally, in some cases the identification of the disease-causing mutation might be helpful in predicting the possible course of the individual’s disease and their long-term prognosis.