The ICGNMD has established a remote transcontinental partnership to reduce genetic data inequality and benefit patients globally.

Genetic neuromuscular diseases (NMDs) affect around 15 million people globally. Most affected families live in low-middle income countries outside Europe, however, the majority of published genetic data is from populations of European ancestry. Whilst DNA-based diagnosis has transformed care pathways and led to tailored interventions, including emerging gene therapies, this data inequality is holding back global understanding of NMD genetic diversity, accurate genetic diagnoses, tailored treatments and prognoses across all income settings.

The ICGNMD partnership (connecting 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK) addressed this inequality through assessing genetic architecture of NMDs across diverse populations from aligned, international studies with consent to share data internationally.

Partners co-developed a cloud-based study database and tailored bioinformatics pipeline alongside training 17 international neurology fellows in clinical genomic data interpretation. Results from whole exome and single gene analyses were reviewed by the international teams in global webinars, alongside clinical and phenotypic data, to inform genetic outcome decisions. Over 6,000 study participants formed the basis of the first cross-site paper, published this week in Brain.

This showed that in-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% “solved and ∼13% “possibly solved” outcome.  Almost 29% of disease-causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort.

The study data provides a large resource from underrepresented populations for genetic and translational research. The study’s findings have potential to enable improved genetic counselling and care pathways and to expand eligibility for gene-specific trials.

Lead PI, Professor Mike Hanna (Director, UCL Queen Square Institute of Neurology) said: “The ICGNMD builds on international neuromuscular diseases partnerships we have developed over many years. Genetics is now transforming many areas of neuromuscular disease and indeed neurology practice, especially for single gene disorders through accurate genetic diagnosis and advanced therapy development. However, it is a striking fact that 86% of all human genetic data ever collected is derived from European ancestry. This dramatic genomic data inequality is a missed opportunity to deeply understand gene function and hinders accurate genetic diagnosis and access to therapies in non-European ancestry groups both in the UK and globally. I am very pleased we have been able to brings together a fantastic research team in 17 centres across four continents to develop a deeper understanding of the genetic architecture of neuromuscular diseases in underrepresented populations. I believe this type of diverse data collection will have multiple benefits for research and patient care.  Similar virtual partnerships could be adopted by other areas of genomic neurological practice, to reduce genetic data inequality and benefit patients globally.”
Co-first author, Dr Lindsay Wilson (Centre Research Manager, ICGNMD, UCL Queen Square Institute of Neurology), said: “The ICGNMD cohort and linked genetic data continue to grow rapidly: we are deeply grateful to all partners and patients around the world for this and work to define important new sub-cohorts for further new insights and translational benefits.”
Professor Henry Houlden (Head of IoN Neurogenetics, ICGNMD global genetic analysis programme lead) said “ I am very pleased to see this work published in Brain. Collecting genomic data from diverse populations is extremely important to deeply understand gene function and determine the mechanisms of genetic neurological diseases. Genetic data from diverse cohorts, like this ICGNMD cohort, is providing crucial new insights that aid genetic diagnosis and treatment development.”
Dr Jana Vandrovcova (lead Bioinformatician for ICGNMD), said "This has been an exciting and challenging project collating genomic data with 14 different LMIC Centres. Working with the global team I was pleased to develop a bespoke neuromuscular gene variant analysis pipeline which has proved very successful in solving a significant proportion of cases enabling genetic diagnosis. Studying diverse populations is important in order to understand gene function and it is notable that 29% of the pathogenic variants we discovered had not been described before - emphasising the importance of inclusivity in rare disease and genetics research”
Professor Alan Thompson (UCL's Pro Provost for London and Dean of the UCL Faculty of Brain Sciences), said “I want to congratulate the team led from UCL FBS for excellent progress in this very ambitious project. This programme linking 14 Lower and Middle countries across four continents is significantly adding to our understanding of the genetic diversity underpinning these important neurological diseases. It is great to see detailed data on the first 6001 patients now published in Brain”

Ciaran Moynihan (Director of UCL Global Engagement), said: “Rare, inherited diseases need global partnerships in order to assemble sufficient data to understand their causes and optimise care and treatment pathways. The ICGNMD is an excellent example of co-creation and multilateral co-operation, supporting the development of local capacity alongside critical patient cohorts and linked data.”

The work was funded primarily by a £3.6m MRC Strategic Award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1.  Additional funding support is received from the National Brain Appeal, Guarantors of Brain, MDUK and partner site host-matched funding.

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