The patient in this example has been previously diagnosed with a Medium-chain acyl-coenzyme A dehydrogenase deficiency, through phenotype characterization which was confirmed with molecular diagnosis (PCR) at a reference lab to be homozygous for the mutation rs77931234. The diagnosis was made when he was young, and his disease has been well managed. Around puberty new symptoms began to appear which are not normally associated with the known disease phenotype. The patient and family has tried a variety of medications with mixed results often resulting in reappearance of symptoms following six months or so of stability. A battery of both metabolite and genetic tests have been run with no clear diagnosis, but metabolite values are often outside of normal ranges. The family has been on a classic "diagnostic odyssey" with no clear explanation.
Fortunately for this family are patients at a regional medical center in a large metropolitan area and have been referred to the Individualized Medicine Clinic. After being seen in the clinic, and returning for a follow up the family is presented with 4 options for genome scale testing in an attempt to find possible genetic causes for the additional symptoms:
1 - Participation in a clinical trial offering full exome analysis for the patient and the parents at no cost
2 - Run a full genome for the patient only and try to get costs covered by insurance(4-6 months)
3 - Run a full genome on the patient and pay out of pocket ($5-$10k)
4 - Use a direct to consumer service and perform analysis of the raw results
The family unsure of which option is best, has sent an email describing the situation and asking for advice on what they should do.
My recommendation will be colored by my experience as a bioinformatician working in a genome center who has had experience with research protocols, clinical genotyping, WGS and WES analysis. I would strongly recommend the family go with option 1 "clinical trial offering full exome to the family", for the following reasons.
While we are quickly approaching a future of genome enabled medical care, with deep understanding of how the genome works and changes affect health, we have not reached that point. This is the primary problem with options 2 and 3. These options both have the additional problem of "who owns the data", if the patient pays for it and how would a sequencing center deliver this information for interpretation? If the insurance pays for it, do they have a right to dig through the data and adjust your rates based on the findings? Sending a hard drive to a patient (or a clinician) who is unfamiliar with the standard file formats or tools used to evaluate data is not a real solution. The additional complication of a genome returning on the order of 4-5 million variants or more, makes manual interpretation impossible. Additionally as wgs tools advance and becomes more common a deeper understanding of the genome will emerge, however we currently rely on the data compiled in the previous century which focused heavily on gene, and pathway analysis and how single variants would impact this system, making most of the variants associated with pathogenic conditions contained inside of the gene sequence itself, leaving much of the intergenic sequence regions dark and unexplored, and variation in these regions poorly characterized. Option 4 (direct to consumer) while possibly cheaper, means you have to find an informatician and possibly contract them to do the analysis, and then follow up with finding a clinician to return some interpretation of the variants found. The problem is compounded by the variety of vendors, price and quality of data produced. 23andME is actually a very reliable data producer, unfortunately interpretation of results for medical care is hamstrung by the FDA's recent threats against the company. Those companies that provide wgs or wes as a service require careful evaluation as many cut costs (and corners) by providing a lower threshold of data returned (say 10x coverage instead of the industry accepted 25-40x for wgs) reducing the confidence of calls in complex gene regions.
Many of these problems are solved by option 1, the clinical exom trial. First it limits data analysis to gene exons which is where most of our variant knowledge exists meaning that variants found through this tool will have likely been seen and characterized in a publicly available database such as OMIM, dbsnp, or Exome variant server ect. The recommendation of exome trio analysis is also part of the presentation. Having the parents sequenced in parallel with the child allows for the removal of the variants which were inherited from two unaffected a parents leaving those that are likely the source if the disease is genetic in origin. While trio analysis also has a long way to go for the detection of hetrerozygous gene drop out, it remains one of the most powerful tools in genetic analysis. As part of a clinical study implies that there will be other sequencing runs done and having the data be part of a well quality controlled pool and workflow is just as important as the trio analysis.
While I would love to recommend that everybody get a wgs analysis done, for a single patient trying to make sense of the complex and rapidly changing world of genetic analysis the current state of the art would suggest exome analysis as the most reasonable method with the greatest clinical application.
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