To Exome, or Not to Exome – That Is the Question

shutterstock_146497481_v2Dr. J. Lawrence Merritt, II discusses the implications of Whole Exome Sequencing.

Exome sequencing today is growing, quickly. We are finding ways to use this technology to do things we could only really dream of 10 years ago. While you can’t just sequence your DNA completely at level equivalent of a certified clinical laboratory just on your own (yet) – it is coming soon whether we want it to or not.

I had the privilege of getting to know a young boy a number of years ago. He came to see me because he was beginning to lose developmental milestones and had chronic anemia. His hematologist sent him to evaluate for a mitochondrial disorder known as Pearson syndrome. Soon his ability to swallow became encumbered. We did many “standard” biochemical genetic screening testing including lactate, pyruvate, urine organic acids, plasma acylcarnitines, plasma amino acids, uric acid, coenzyme Q10 levels, ammonia, and mitochondrial testing for the common point mutations and deletion that cause Pearson. Everything was normal. His MRI and MR spectroscopy was non-diagnostic. We watched his muscle tone worsen, his respiratory condition slowly worsened as he developed aspiration pneumonia and then required a gastrostomy tube to maintain his nutrition. If you picked a subspecialist, he saw them.

So we then applied for insurance preauthorization for Whole Exome Sequencing (WES). Insurance typically takes a few weeks, and this took longer, months. Then the family had to be schedule to see the genetic counselor to discuss the consent form for WES and then DNA samples from the patient and both parents were sent.

Results took another 4 months and reported a variant in the gene SLC52A2 that has been reported to cause a disorder known as Brown-Vialetto-Van Laere syndrome (BVVL). This is a disorder resulting from the disruption of riboflavin transport that leads to a neuronopathy specifically affecting the pontobulbar region of the brainstem. Plasma acylcarnitine profile will often be abnormal. This affects breathing, speaking, and limb movement. Individuals may have sensorineural hearing loss and then if untreated may have progressive disease with spasticity, ataxia, hyperreflexia, ultimately leading to respiratory insufficiency and death. Treatment involves high dose riboflavin supplementation at 10 to 50 mg/kg/day and has resulted in improvements in neuronopathy and the acylcarnitine profile. My patient responded riboflavin with improvements in his neurological awareness and anemia, but unfortunately passed away from his disease 6 months later.

So the question arises – and the family of course is asking this because of the impact on their child – how can we improve the process for performing whole exome sequencing so these rare diseases can be treated earlier – and hopefully provide improved health for affected children? This is certainly a very complex question. The presence of variants and mutations within a patient may show there are multiple diseases present – some with more grave implications. These implications will not just affect the patient, but as well their parents. Variants will be found that show the parents are at risk for breast cancer, Huntington’s disease, or Alzheimer’s disease. Where do the moral and ethical obligations of the geneticist stop? And of course this will not just stop with subspecialists, but eventually more primary care providers will have “to exome, or not to exome”.

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