Two big wins for rare disease

Two new developments offer glimmers of hope to patients with rare, hard-to-diagnose conditions—validation of the power of crowd sourcing and the prospect of bringing cognitive computing to rare disease diagnosis. Both developments were announced at the Boston Children’s Hospital Global Pediatric Innovation Summit + Awards (#PedInno15).

The crowd-sourcing challenge, CLARITY Undiagnosed, yesterday announced the findings of 21 teams that competed from seven countries. The winning team, Nationwide Children’s Hospital (Columbus, OH), was awarded $25,000. Invitae Corporation (San Francisco) and Wuxi NextCODE Genomics (Cambridge, MA) were named runners-up.

Each team received DNA sequences and clinical data from five families whose illnesses had eluded many prior diagnostic attempts—in some cases, even prior genomic sequencing.

“These were the toughest of the tough,” says Alan Beggs, PhD, co-organizer of CLARITY Undiagnosed and director of the Manton Center for Orphan Disease Research at Boston Children’s.

The Challenge’s main goal was less to find genetic “smoking guns” than it was to generate reports that would be meaningful to patients, families and physicians, establishing an industry standard.

“The three top teams produced reports that were easy to follow, had results that made sense from a clinical point of view and presented the key information on the first page, so clinicians and families wouldn’t have to go digging,” says Beggs. “The judges valued reports that clearly stated the reasons for reporting a genetic variant and provided guidance to physicians.”

Bringing the experts to the patient

The Challenge did identify some plausible new genetic variants for several of the families, opening new avenues for investigation.


Alex Yiu, 10, who has an unknown progressive neurologic condition, was one of the patients. He has been in the hospital nine times this year alone for G-tube placement surgery, seizures, respiratory distress, pneumonia and infection. He suffers from painful muscle contractions and can no longer talk, though he can indicate a yes/no with his eyes. In the past year, Alex has had respiratory issues requiring breathing therapies and sometimes oxygen support.

“It’s exhausting just to keep up with his medicines and his therapies,” says his mother, Caroline Yiu.

The family spent four years going to neurologists and research institutes in multiple states and internationally, with many rounds of blood work and invasive testing.

That’s typical for families with rare disease.

“Medicine as it is practiced today is, at best, a series of solo performances,” says Challenge co-organizer Isaac Kohane, MD, PhD, chair of the DBMI at Harvard Medical School. “CLARITY Undiagnosed brought many teams, many doctors, many researchers to the patient so they could get the benefit of all those medical opinions without the trauma, heartbreak and cost.”

CLARITY Undiagnosed results

For Alex, that meant confirmation of two “variants of unknown significance” (VUS) identified by previous research teams. The third flagged a variant in a gene that prior investigators had ruled out. All three variants will require more work to establish as causative.


Jeremy Hobbs, age 7, has a complex syndrome that includes low muscle tone and craniosynostosis, in which the plates that form the skull fuse too soon, putting pressure on the brain and causing transient blindness. He’s endured multiple operations to separate the skull bones, which have relieved the pressure and restored his vision temporarily, but his skull bones have repeatedly re-fused, causing recurrent painful headaches. Jeremy’s 38 surgeries to date also include urologic operations and two heart operations. All prior genetic tests came up negative.

Through the Challenge, Jeremy was found to have small deletion in the gene EFNB1 that occurred in a “mosaic” pattern, affecting only some of his cells. Prior genetic evaluations, including exome sequencing, had missed it.

“We were surprised to see that they found something and I’m curious to see where this goes,” says Angie, Jeremy’s mother. “It would make a difference to be able to tell the doctors that there’s a diagnosis, so they’ll be less scared about treating him.”


A third family had two children, Dominic and Bridget Nuccitelli, who died from cardiorespiratory arrest in infancy. Six living siblings, as well as their parents, each have varying symptoms that are chronic but not currently life-threatening, including a small jaw (micrognathia), eosinophilic esophagitis (an allergic reaction that inflames the esophagus), dystonia and developmental delays.

It’s been hard finding a doctor that feels able to care for them, as one specialist’s field of expertise often doesn’t cover all the issues. “We get bounced around a lot,” says Marie, the children’s mother. “There’s always that question of, ‘is there going to be another crisis event? Is there a day when another one of my children stops breathing?’”


The Challenge teams identified variants in three genes that have been linked to heart arrhythmias. Marie carries two of these variants and her husband, Chris, has one; Dominic and Bridget each got a double dose, perhaps explaining their deaths. The genes are known to be involved in ion channels responsible for sodium and calcium flow in and out of cells, which can regulate the heart’s rhythm.

Jeff with Connie (credit: Wick Beavers)
Jeff with Connie (credit: Wick Beavers)

There were also two adult patients. One, Jeff Lowe, 64, is a world-renowned mountain climber who developed a progressive neurologic disorder. The Challenge identified variants of potential significance in two different genes, while confirming that he does not have ALS.

Katia Moritz, 48, a Challenge organizer and director of a documentary film in production called Undiagnosed, was confirmed to be a carrier of two genetic variants, one associated with Gaucher disease and the other with familial Mediterranean fever. Whether these explain Moritz’s varied symptoms, which had their onset after an endoscopy, remains to be seen.


All five families have enrolled with the Manton Center to determine whether the variants identified are really disease-causing and, if so, to conduct functional studies to find out what those genes do. In some cases, researchers can model a patient’s disease in zebrafish and other animals and screen potential therapeutics.

“If I were a patient, a payer or a policymaker, and I saw the results of the CLARITY contest, I would say, ‘that’s what I want, that’s what I’ll pay for, that’s I what to incent the medical system to deliver,” says Challenge co-organizer Isaac Kohane, MD, PhD, chair of the DBMI at Harvard Medical School.


Read more about the five CLARITY Undiagnosed families and their results.

No stone unturned: IBM Watson to ponder rare disease cases

In a separate development, Boston Children’s and IBM announced their intent to tap IBM’s Watson cognitive platform to help clinicians identify options for the diagnosis and treatment of rare pediatric diseases.

Watson, hailed for winning Jeopardy a few years ago, could potentially crunch a patient’s genome and clinical data against a vast body of related medical literature.

“One of Watson’s talents is quickly finding hidden insights and connecting patterns in massive volumes of data,” says Deborah DiSanzo, general manager, IBM Watson Health. “Rare disease diagnosis is a fitting application for cognitive technology that can assimilate different types and sources of data to help doctors solve medical mysteries.”

In the collaboration, which will also involve the Manton Center, Watson will start with a rare genetic kidney disorder known as steroid-resistant nephrotic syndrome (SRNS) in collaboration with Friedhelm Hildebrandt, MD, chief of the Division of Nephrology at Boston Children’s. After Watson is trained in nephrology by “reading” the medical literature, experts at Boston Children’s intend to supplement that with genomic sequencing data from prior patients.

“Watson can help us ensure we’ve left no stone unturned in our search to diagnose and cure these rare diseases so we can uncover all relevant insights from the patient’s clinical history, DNA data, supporting evidence and population health data, says Christopher Walsh, MD, PhD, chief of the Division of Genetics and Genomics at Boston Children’s.

The 21 teams that completed the CLARITY Challenge, in alphabetical order:

  1. Bina Technologies (Redwood City, CA)
  2. Clinical Institute of Medical Genetics (Ljubljana, Slovenia)
  3. Codified Genomics, LLC (Houston, TX)
  4. Emory University School of Medicine (Atlanta, GA)
  5. Geisinger Health System (Danville, PA) and SimulConsult (Chestnut Hill, MA)
  6. (Austin, TX)
  7. Genomatix Software GmbH (Munich, Germany)
  8. Institute for Systems Biology (ISB) (Seattle, WA) and Inova Translational Medicine Institute (ITMI) (Falls Church, VA)
  9. intelliseq (Krakow, Poland)
  10. Invitae Corporation (San Francisco, CA) runner up
  11. Miti Medicine Inc. (Cambridge, MA)
  12. Nationwide Children’s Hospital (Columbus, OH) winner
  13. QIAGEN (Redwood, CA)
  14. Rare Genomics Institute (Hanover, MD)
  15. Seven Bridges Genomics (Cambridge, Massachusetts)
  16. SNPedia (Potomac, MD)
  17. Stanford University (Stanford, CA)
  18. University of Southern California (Los Angeles, CA)
  19. University of Utah (Salt Lake City, UT)
  20. Tel Aviv University (Tel Aviv, Israel), and Variantyx Ltd (Ashland, MA)
  21. WuXi NextCODE Genomics (Cambridge, MA) runner up

 Watch video highlights of the 2015 Global Pediatric Innovation Summit + Awards and in-depth coverage in Diagnostics World.