Exome Sequencing
Esophageal Achalasia
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March 2016 Affiliated with Columbia University College of Physicians and Surgeons and Weill Cornell Medical College
Exome Sequencing Reveals Underlying Disease That Tailors Treatment

The notion of precision medicine can be traced back to Hippocrates’ famous quote: “It is far more important to know what person the disease has than what disease the person has.” Yet 2,500 years later, traditional standard care practices rely primarily on a “one-size-fits-all” approach, which can prove ineffective when rare and misunderstood diseases present themselves.

But within the realm of pediatric gastroenterology, physicians at the NewYork-Presbyterian/Morgan Stanley Children’s Hospital at Columbia University Medical Center are revamping this approach by using next-generation sequencing of the genome to diagnose rare disorders and identify tailored treatment plans.

Deep Dive Into the Exome

“Much genetic work provides a window into how disease mechanisms work,” explained Joseph Picoraro, MD, a 2014 recipient of a National Institutes of Health–awarded T32 Medical Genetics Training Grant. While a fellow in Pediatric Gastroenterology at NYP/Morgan Stanley Children’s and the Department of Pediatrics at Columbia University Medical Center, Dr. Picoraro encountered a baffling presentation of congenital diarrhea—one that would forge his future in gastroenterology and medical genetics forever.

Dr. Picoraro’s 2-week-old patient faced severe intestinal failure and did not respond to any therapies that are traditionally used to treat malabsorption and congenital diarrhea. Blood tests and multiple endoscopies were performed, but every finding lacked the characteristics of a known disorder. As the diagnostic odyssey pressed on, the patient required months-long hospitalization to manage recurrent episodes of life-threatening dehydration.

Lacking answers, Dr. Picoraro and his team ordered an exome sequencing test, hoping that a better understanding of the patient’s genetic blueprint would provide insight into the etiology and prognosis for this unknown disease.

Microvillus Inclusion Disease

Although constituting only 1.5% of the 3-billion base sequence genome, the exome consists of over 21,000 protein-coding genes and is considered the highest yield area for uncovering how the body performs its myriad functions. In extremely rare cases, pinpointing abnormalities within genes that are already known to cause problems may help gastroenterologists and other specialists fine-tune a treatment strategy, even when the pathology of the disease remains elusive.

Dr. Picoraro’s patient was found to have an abnormality in the MYO5B gene. While these specific changes in the gene had yet to be described in the literature, his team suspected that it was a rare manifestation of microvillus inclusion disease.

“Microvillus inclusion disease is usually something that can be diagnosed by biopsies,” Dr. Picoraro explained. “But because we found a change in this gene, we needed to look more carefully to see if this is perhaps an atypical presentation of microvillus inclusion disease.” When Dr. Picoraro and his team returned to the biopsy, they found unusual patterns that were characteristic of this unusual form of microvillus inclusion disease. The finding provided information that proved invaluable when forming a personalized strategy for the infant.

“There’s no cure for microvillus inclusion disease,” Dr. Picoraro explained, “but it is understood that patients with a MYO5B gene abnormality have unique changes in the liver that gastroenterologists are only beginning to understand.” In light of the potentially deleterious effects that intravenous nutrition can have on the liver, the team was especially delicate in handling the patient’s nutrition plan. Dr. Picoraro also noted that the gene defect would matter when considering an intestinal transplant in the future.

Dr. Picoraro’s colleague Joel E. Lavine, MD, PhD, Chief of Gastroenterology, Hepatology and Nutrition at NYP/Morgan Stanley Children’s and tenured Professor of Pediatrics at Columbia University College of Physicians and Surgeons, reflected on the wider effect of this bench-to-bedside approach: “One of the really powerful things about genetic technology is the ability to take extremely rare diseases, bring all of our resources together under one hood, and connect the frontier of research to clinical care.”

Dr. Lavine cited another instance in which a mutation in the DGAT1 gene was found in identical twins who were unable to absorb fats. While it has been broadly understood that the DGAT1 gene may play a role in the obesity epidemic, little else was known about how it might affect the intestine’s absorption of nutrients. But after the gene was given an identifiable name, some more cases came to the surface. Working alongside colleagues at other institutions enabled the team at NYP/Morgan Stanley Children’s to best manage the boys’ care, primarily by instituting a special formula that the child could absorb and metabolize.

“Pooling together a few rare examples, we not only have a better understanding of how we might go about treating individual cases, but we also have a better understanding of the ‘normal’ way in which the intestine absorbs nutrients,” Dr. Picoraro added. “The snippets at the edges help us better understand the center.”

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