Stories from the Front Lines Precision Medicine in Practice

By Nephi Walton, MD MS FACMG FAMIA

There was an air of excitement as I ended a conference call where we officially completed the last of many steps to get our adult whole genome sequencing clinic up and running. As I stepped out of my office to walk down the hallway, I received a call on my cell phone. “Hello Dr. Walton, would you be available now to talk with Dr. Jacobs about a patient?” Confused about what this was regarding and how this individual got my cell phone number, I said, “sure, put him through”. They put me through to an oncologist who had heard by word-of-mouth that we were opening a genome clinic for adults. He told me he had just finished seeing a patient and wanted to know if I could see them in my clinic. He described a very vague and confusing picture that involved neuropathies, muscle weakness, fluctuating lab values, shortness of breath, pesticide exposure, and a history of many specialists with no answers. This patient had been referred to him in oncology as a last resort and he was not sure where else to send him, since he had already been seen by almost every specialist outside of dermatology and dermatology wasn’t going to give him any answers. Unable to diagnose the root of the patient’s complaints, he was hoping to send him to our clinic that hadn’t even opened yet. I agreed to see the patient and we scheduled him into our very first clinic slot. I neglected to ask how he heard of the clinic or where he got my cell phone number. Word of the clinic spread quickly before any announcements were even made. We had a three-month backlog of patients before we saw our first patient. The fact that there was large volume of patient’s referred purely by word of mouth demonstrated a tremendous need for genomics in the adult population.

Excited and nervous about our first clinic day, I adjusted my camera angles and clicked connect on my computer to join a teleconference call with our first patient, John. “Hello, John! I’m Dr. Walton, how are you doing?” He said he was “doing well” although his composure did not reflect that. His first questions were less about his diagnosis and more about why he was even talking to me and what I could offer him. I explained how we interpreted the spelling of the code that instructed the development of the human body and all of its functions and looked for errors or misspellings in the code that might explain disease. I told him I would do everything I could to help him but confessed that there were limitations to our current knowledge that might prevent us from finding an answer. His frustration with the medical system was palpable during the encounter. He explained how he had seen several neurologists, some of whom he felt had written him off as a having a mental disorder. He described a similar experience with other specialists, several of whom did agree he was experiencing real symptoms but could not offer an explanation or cure for them.

John described living a normal, healthy, and active life up until his early 50’s. At that time, he moved to a rural area into a house adjacent to a farm. This farm had significant pesticide stores that were close to his house, which he felt were inadequately stored and disposed of. He drank well water from the house, which he suspected was contaminated by the pesticides. His whole family, wife and five children, all became ill after moving in. They were certain it was from the pesticide exposures. One of the children moved to another house, and their symptoms subsided, contributing to this theory. Eventually, the whole family moved out. While most of the family’s symptoms disappeared, some of John’s symptoms improved, but others got worse. Specifically, he had strange neurological symptoms, including neuropathies and weakness. John also began to have progressive shortness of breath. He was bounced around to more than a dozen different specialists who ordered multiple tests over a decade’s time, racking up over a hundred thousand dollars in medical charges.

After our encounter, I had whole genome sequencing performed on him. I was hoping that we would discover a small change that could elucidate the cause of his symptoms. Instead, we found a large 1.4 mega base deletion. A deletion that caused a known disorder called (hereditary neuropathy with liability to pressure palsies) HNPP. This is a neurological disorder that can be onset at nearly any time in life, usually in the second to third decade. Its onset can coincide with neurotoxic medication exposures, but pesticides, which are also neurotoxic, had not been previously described in the literature. This condition explained most of his symptoms. We got a quick answer and ended a decade-long diagnostic odyssey that consumed the time of more than a dozen specialists, hundreds of tests, and the cost of which exceeded the cost of the genome sequencing many times over.

Though I could not cure his disorder, just knowing the answer was incredible for John. He was so happy to have an answer after all these years. Erasing the doubt that many physicians had cast on his symptoms. There were also things he could do to better manage the condition and he knew more about his long-term prognosis.

This story is not unique. In fact, while taking the family history we discovered one of the patient’s adult sons, in his late 20s, was autistic. He had appeared in the background with John and his wife during the call. I couldn’t help but notice by his speech and his appearance that he also likely suffered from a different genetic disorder. With John having five children and this being the only one with autism, it is possible the son harbors a new variant in a gene that causes his condition. Twenty five years ago, when his son was diagnosed with autism, the genetic testing available was very limited, he had not been evaluated since that time. After our visit we also scheduled his son in the whole genome sequencing clinic, and who knows? Maybe we will get another answer to a question that has been lingering for over two decades.

Adult patients are a neglected population in the field of genomics. With most genetics clinics residing in pediatric hospitals, many are unaware that they also see adult patients. Even when they are aware, and refer the patients, it is harder for adult patients to get scheduled and they often go to the back of the line, in an already backed up system. It is critical that we do a better job delivering precision medicine to these patients, especially as we better understand the genetic basis of adult-onset conditions and start to use polygenic risk scores in clinical practice. There are likely millions of adults with undiagnosed genetic disorders who presented to the system when genetics was in its infancy and never received answers.

Dr. Nephi Walton completed his MD and masters in biomedical informatics at the University of Utah School of Medicine. He completed a combined residency in pediatrics and genetics at Washington University in St Louis. He is boarded in both clinical genetics and clinical informatics. At Geisinger, he successfully completed a pilat integration of genomics data into the EPIC HR system for both pharmacogenomics and CDC tier one genetic conditions. He currently serves as the associate medical director of Intermountain Precision Genomics where he co-leads the HerediCene genomic sequencing return of results program and runs the Intermountain precision genomics WGS clinic. He also serves as the associate medical director of Intermountain’s sequencing laboratory. He is the chair of genorios and translational bioinformatics for the American Medical Informatics Association and has presented at several meetings on translating the use of genomics into general medical practice, something he is actively pursuing at Intermountain Healthcare.

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