HEDGE Study

HEDGE Study, the search for the genetic cause of hEDS
To find preventions and treatments for hEDS, we have to understand the cause. Genetic studies like this one provide a path towards that goal. — Joel Hirschhorn, MD, PhD
If we are successful in identifying the underlying genes for hypermobile EDS, the opportunities for earlier diagnosis and more comprehensive treatment and care are virtually limitless. We are incredibly grateful to the generous donors who have made this possible. — Lara Bloom
Understanding the genetic causes of hypermobile EDS is absolutely crucial to the EDS community. It will allow us to make unequivocal diagnoses. Understanding of the genetic pathways leading to hypermobile EDS will inform the search for rational therapies for this disorder, and hopefully, eventually, a cure. — Clair Francomano, MD

In 2018, the groundbreaking Hypermobile Ehlers Danlos Genetic Evaluation (HEDGE) was launched. Never before has there been a worldwide collaborative effort of this magnitude devoted to finding the underlying genetic markers for hypermobile EDS (hEDS). The study will also look for other blood findings that may add to our understanding of hEDS and help in the search for a diagnostic test.

Of the 14 subtypes of the group of connective tissue disorders known collectively as the Ehlers-Danlos syndromes (EDS), only the hypermobile type does not yet have identified genetic markers.

“To find preventions and treatments for hEDS, we have to understand the cause. Genetic studies like this one provide a path towards that goal,” said Joel Hirschhorn, MD, PhD, Concordia Professor of Pediatrics and Professor of Genetics at Boston Children’s Hospital/Harvard Medical School, and a member of the Hypermobility Biology Network.

Since the announcement of the extraordinary “Moonshot” donation in early 2018, which was then followed by a generous matching donation in early 2019, The Ehlers-Danlos Society brought together a highly experienced international group of physicians, geneticists, and technical volunteers to form the Hypermobile EDS Genetic Research Network which has now evolved to become the Hypermobility Biology Network, dedicated to finding the genetic cause, or causes of hEDS.

Over 2019, 2020, and 2021,  the HEDGE study will recruit, screen, and undertake genetic sequencing tests on 1000 individuals who have been diagnosed with hypermobile EDS by the most recent clinical criteria established in 2017.

The HEDGE study would not be possible without the EDS  and HSD Global Registry & Repository, another ambitious worldwide research effort spearheaded by The Ehlers-Danlos Society. Launched in July of 2018, it is a collection of standardized health information provided by thousands of patients with all forms of EDS and hypermobility spectrum disorders (HSD), allowing researchers to compare and analyze patient data on a much larger scale than possible in individual research studies alone. The Registry & Repository has the potential to unlock countless discoveries about all forms of EDS and HSD and lays the groundwork for large-scale research efforts like the HEDGE study. All potential study participants must first join the Global Registry.

The first HEDGE enrollment event took place at The Ehlers-Danlos Society European Learning Conference in Madrid, Spain, in April 2019. Twelve in-person screening events have taken place around the world and enrolled 413 individuals with hEDS into the study: each participant has given a blood sample towards the 1000-participant goal. When the COVID pandemic came to force in early 2020 the study team quickly adapted to virtually enrolling the remaining people needed and this is being rolled out in 2021. We are delighted to be able to offer the opportunity to include people globally through this method. 

Based on research and expert opinion, to date there have only been less than 200 people with hypermobile EDS who have had whole-genome sequencing, and, less than 500 who have had whole-exome sequencing with EDS around the world. To have the collection of data from this study will enable us to take giant leaps forward in research and discovery for our community. There has been an enormous amount of interest from members of our community wishing to take part in this study.

“Understanding the genetic causes of hypermobile EDS is absolutely crucial to the EDS community,” said Clair Francomano, MD, chair of The Ehlers-Danlos Society’s Medical and Scientific Board, former Director of The Ehlers-Danlos Society Center for Clinical Care and Research at the Harvey Institute of Human Genetics in Baltimore, MD, and a member of the Hypermobility Biology Network. “It will allow us to make unequivocal diagnoses, for one thing. Further, understanding the genetic pathways leading to hypermobile EDS will inform the search for rational therapies for this disorder, and hopefully, eventually, a cure.”

“If we are successful in identifying the underlying genes for hypermobile EDS, the opportunities for earlier diagnosis and more comprehensive treatment and care are virtually limitless,” stated Lara Bloom, President, and CEO of The Ehlers-Danlos Society. “We are incredibly grateful to the generous donors who’ve made this possible.”

This study has Institutional Review Board oversight and approval by the Genetic Alliance (IORG0003358) IRB (IRB00003999). The Genetic Alliance Federal Wide Assurance number is FWA00017292. Protocol EDS002 has been approved by the Genetic Alliance IRB (Federal registration number IORG0003358). Information can be found on this IRB by putting Genetic Alliance in the NAME search field on the Office of Human Research Protections website.

Enrollment Team

The following healthcare professionals and medical providers below assisted with the review, screening, and enrollment processes for HEDGE.

  • Woodrow Gandy, MD
  • Helen Cohen, EdD, OTR, FAOTA
  • Qasim Aziz, MBBS, FRCP, PhD
  • Lies Rombaut, PhD
  • Fransiska Malfait, MD, PhD
  • Alan Hakim, MA, FRCP
  • Jane Schubart, MBA, MS, PhD
  • Clair Francomano, MD
  • Jonathan Treadwell, MA
  • Erin Fox, RN
  • Anthony Vandersteen, MD, PhD, BM FRCP
  • Heidi Collins, MD
  • Brad Tinkle, MD, PhD
  • Howard Levy, MD, PhD
  • Tim Tramontana, MD
  • Erin Conboy, MD
  • Rubina Aktar, PhD
  • Hanna Kaz Kaz, BA, MSc, MB
  • Inge De Wandale, PT, MT, PhD
  • Alissa Zingman, MD, MPH
  • Alan Pocinki, MD, FACP
  • Irman Forghani, MD, FACMG
  • Amy Kontorovich, MD, PhD
  • Karrelle Benistan, MD
  • Laura Gandy
  • Maggie Buckley

Contributing previously sequenced Data that meets the HEDGE research criteria

  • Christina Laukaitis, MD, PhD, FACP, FACMG
  • Marina Colombi, PhD

Society Staff and Consultants involved with the study

  • Lara Bloom
  • Lakshmi Sravya Konakanchi
  • Charli Baynes
  • Stacey Simmonds
  • Rebecca Gluck
  • Scott Stoll
  • Izabelle Manning (no longer with the organization)
  • Marisa Bergfield (no longer with the organization)
  • Angela Ballard (no longer with the organization)
  • Brian Johnson (no longer with the organization)
  • Carol Everson (no longer with the organization)

Analysis Team

Joel Hirschhorn is board-certified in Medical Genetics, Endocrinology, and Pediatrics. He is the Concordia Professor of Pediatrics and Professor of Genetics at Boston Children’s Hospital and Harvard Medical School.

Christina Laukaitis is board-certified in Internal Medicine and Medical Genetics. She is an associate professor at the University of Illinois and the Carle Illinois College of Medicine.

Both Dr. Hirschhorn and Dr. Laukaitis will be leading the analysis of whole-genome sequencing data obtained for HEDGE.

Governance Committee

The Governance Committee will oversee the HEDGE study as a whole and ensure proper protocols and fund allocations are in place. Members of this committee are listed below.

  • Clair Francomano, MD
  • Woodrow Gandy, MD
  • Melanie Macleod, MD
  • Lara Bloom
  • Raymond Dalgleish, PhD
  • Joel Hirschhorn, MD, PhD
  • Christina Laukaitis, MD, PhD, FACP, FACMG

Publications Committee

The Publications Committee will oversee the peer review and publication process of all HEDGE study related research. Members of this committee are as follows:

  • Clair Francomano, MD
  • Joel Hirschhorn, MD, PhD
  • Christina Laukaitis, MD, PhD, FACP, FACMG
  • Fransiska Malfait, MD, PhD

Whole Genome Sequencing Provider

Decision pending on outcome of Request for Proposals.

Biobank

The Genetic Alliance Precision for Medicine Biobank is responsible for storing all collected blood samples for the HEDGE study.

Virtual Screening Blood Test Providers

For U.S. residents, a certified phlebotomist from ExamOne will obtain blood samples at the participant’s home or preferred lab location.

For non-U.S. residents, a certified phlebotomist from MedScreen Medical will obtain blood samples at the participant’s home.

Blood Processing Provider

The ReproCell lab based in Maryland is the blood processing provider for the HEDGE Study by isolating DNA, serum, and plasma from drawn blood samples. Once processed, ReproCell is responsible for shipping samples to the GA Precision for Medicine Biobank.

The Hypermobile Ehlers-Danlos Genetic Evaluation (HEDGE) is an ongoing study that will obtain whole-genome sequences for 1000 people with hypermobile Ehlers-Danlos syndrome (hEDS) under the 2017 criteria, and seek to establish underlying genetic causation. 

Of the 14 subtypes of EDS, only the hypermobile type does not yet have identified genetic markers. If we are successful in identifying the underlying genes for hEDS, we can create vital opportunities for earlier diagnosis, and more comprehensive treatment and care.

Enrolling 1000 participants with hEDS

April 2019 – Mid 2021

To break down geographical barriers in research participation and to adapt to limitations on travel, The Ehlers-Danlos Society announced a new screening and enrollment process for the HEDGE study in 2020.  The exciting newly-established process will make it possible for individuals with hypermobile Ehlers-Danlos syndrome (hEDS) to enroll in the groundbreaking study, without traveling to an in-person event. Invitees can now have blood drawn at home or at other locations. 

415 individuals with hEDS have now been enrolled in the HEDGE study, with over 250 participants in the process to be enrolled this quarter. As more healthcare professionals are expected to join HEDGE by inviting their hEDS patients to enroll at the start of the new year, the goal number of 1,000 participants will soon be reached! 

To assist in the enrollment process The Ehlers-Danlos Society is delighted to announce its move to LunaDNA in partnership to host the Global EDS and HSD Registry and Repository. The new registry is now mobile-responsive, enabling participants to now enroll easily from a smartphone device or desktop from around the world. The EDS and HSD Global Registry will facilitate medical research for ALL types of EDS, HSD, and associated symptoms and comorbidities. If researchers can identify hEDS genetic variants, future studies can then examine patients with hypermobility spectrum disorders (HSD) to determine how often these variants appear in that population.

Whole-genome sequencing and analysis

Once all 1000 participants have been enrolled into HEDGE, whole-genome sequencing can begin. The results from the research will hopefully be published 12-24 months after analysis begins.

Following an open Request for proposals, geneticists Dr. Joel Hirschhorn, and Dr. Christina Laukaitis were awarded a grant to do the analysis collaboratively. Dr. Hirschhorn is the Concordia Professor of Pediatrics and Professor of Genetics at Boston Children’s Hospital/Harvard Medical School and an Institute Member of the Broad Institute. Christina M. Laukaitis, MD, Ph.D. Christina Laukaitis is an associate professor at the University of Illinois and the Carle Illinois College of Medicine. She is board-certified in Internal Medicine and Medical Genetics.

Publication and potential future studies

Based on research and expert opinion, to date there have only been less than 200 people with hypermobile EDS who have had whole-genome sequencing, and, less than 500 who have had whole-exome sequencing with EDS around the world. To have the collection of data from this study will enable us to take giant leaps forward in research and discovery for our community. 

Global Collaboration

When the HEDGE study was first funded, we assembled a global team of experts that made up the Hypermobile EDS Genetic Research Network, consisting of leading authorities in fields ranging from human genetics to neurosurgery, to function as the nucleus for research design, data collection, and analysis during the course of the genomic mapping. 

As the study progresses we have decided to evolve the network into The Hypermobility Biology Network so that it lives past the study on this essential subject so that it continues to be discussed. Read more about this network here. This network remains a collaborative review body for the HEDGE study. 

“Understanding the genetic causes of hypermobile EDS is absolutely crucial to the EDS community,” said Clair Francomano, MD, chair of The Ehlers-Danlos Society’s Medical and Scientific Board, Director of The Ehlers-Danlos Society Center for Clinical Care and Research at the Harvey Institute of Human Genetics in Baltimore, MD, and a member of The Hypermobility Biology Network. “It will allow us to make unequivocal diagnoses, for one thing. Further, understanding the genetic pathways leading to hypermobile EDS will inform the search for rational therapies for this disorder, and hopefully, eventually, a cure.”

The Hypermobile Ehlers-Danlos Genetic Evaluation (HEDGE) is an ongoing study that will obtain whole-genome sequences for 1000 people with hypermobile Ehlers-Danlos syndrome (hEDS) under the 2017 criteria, and seek to establish underlying genetic causation. 

Of the 14 subtypes of EDS, only the hypermobile type does not yet have identified genetic markers. If we are successful in identifying the underlying genes for hEDS, we can create vital opportunities for earlier diagnosis, and more comprehensive treatment and care.

Enrolling 1000 participants into HEDGE

Virtual enrolment for the HEDGE Study has been a success since its implementation in 2020 after the rise of the COVID-19 pandemic. The Ehlers-Danlos Society team is now able to remotely screen and invite individuals to the study via virtual record review of Global Registry data, ultimately removing any prior travel barriers. This has greatly increased accessibility to those interested in participating in HEDGE.  

 I would love to be a part of this study now that the travel barriers have been worked out! It is amazing what The Ehlers-Danlos Society has done for the Zebras in its care. I would be honored to advance that cause. interested HEDGE participant 

Eligibility screening through record reviews is still underway and will likely continue until the end of May 2021, or until 1,000 participants are consented and enrolled. We still encourage individuals to complete the survey and upload their documents onto the Global EDS and HSD registry if they are interested in joining HEDGE. 

Currently, 720 participants are enrolled in the HEDGE Study out of the 772 invited thus far. 

Enrolment Breakdown: 

  • 414 enrolled at screening events (prior to COVID-19 pandemic) 
  • 60 Whole Genome Sequencing (WGS) samples from Dr. Christina Laukaitis 
  • 246 virtually enrolled 

These numbers will continue to quickly rise as we continue eligibility screening. We also anticipate approximately forty more Whole Exome Sequencing (WES) samples to undergo WGS from Dr. Laukaitis. In addition, we are working with a group of healthcare professionals who are screening their patient base and funneling them into the Global Registry for HEDGE invitation. 

The Ehlers-Danlos Society is incredibly excited with the enrolment progress made despite challenges brought by the pandemic and grateful to all who have chosen to participate. This study will truly be a global effort with individuals enrolled in HEDGE from 23 countries around the world! 

Country Breakdown: 

  • Australia 
  • Austria 
  • Belgium 
  • Brazil 
  • Canada 
  • Dominican Republic 
  • France 
  • Germany 
  • Great Britain 
  • Hungary 
  • Iceland 
  • Ireland 
  • Israel 
  • Italy 
  • Kuwait 
  • Netherlands 
  • New Zealand 
  • Norway 
  • Spain 
  • South Africa 
  • Sweden 
  • Switzerland 
  • United States 

Blood Draws and Samples 

Blood samples of the 414 previously enrolled participants are being stored in the Genetic Alliance Biobank,  and the 60 WGS samples from Dr. Laukaitis are in her lab. Of the 246 virtually enrolled, 111 completed their blood draws with samples sent to ReproCell for processing tisolate DNA. 

The remainder of the individuals is either already scheduled to have blood drawn by ExamOne (for U.S. residents) or MedScreen Medical (for non-U.S. residents) at a later date or are still in the process of scheduling. HEDGE participants in countries outside of the U.S. are also experiencing further delays due to COVID-19 restrictions and lockdowns. 

The first batch of processed blood samples from ReproCell is set to be shipped to the Genetic Alliance Biobank by the end of April. The samples will then be stored at the biobank until sequencing is ready to commence.  

Goals 

The Ehlers-Danlos Society’s goal is to have identified and invited 1,000 participants to join the HEDGE Study by the end of April. The consent and enrolment processes will proceed into May of 2021. 

If 1,000 individuals have not enrolled by the end of May, the screening and invitation protocols will continue until that number is met.  

Next Steps 

The next phase of the HEDGE Study will be the sequencing of DNA samples to obtain data for analysis. Although the full 1,000 participants have not yet been reached, the sequencing of current samples is set to begin in May at the Broad Institute and will continue as more blood samples are drawn, processed, and shipped. 

Once sequencing is finalized (this timeframe is not yet known), analysis of data will begin, bringing the medical community one step closer to finding the gene(s) responsible for hypermobile Ehlers-Danlos syndrome.