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
  • Marisa Bergfield
  • Izabelle Manning
  • Charli Baynes
  • Stacey Simmonds
  • Rebecca Gluck
  • 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
  • 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.

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.”