Update: Understanding Global Genetic Diversity in FSHD and Building International Trial Readiness

Posted by Friends of FSH Research on Mar 19, 2025

Report by Dr. Bugiardini
See also Understanding global genetic diversity in FSHD and building international trial readiness

Collaborators

Prof Michael Hanna (ICGNMD Director) & Dr Stephanie Efthymiou, UCL Queen Square Institute of Neurology, London, UK
Dr Richard Lemmers & Prof Silvère van der Maarel, Leiden University Medical Centre, Leiden, The Netherlands
Dr Vishnu VY & Prof Padma Srivastava, All India Institute of Medical Sciences, Delhi, India
Dr Pedro Tomaselli & Prof Claudia Ferreira da Rosa Sobreira, FAEPA, University of Sao Paolo, Sao Paolo, Brazil

Facioscapulohumeral Dystrophy (FSHD) is a progressive genetic muscle disorder typically affecting muscles of the face, shoulder blades, and upper arms. Until now, most FSHD research has focused on individuals of European or Northeast Asian ancestry, revealing some differences in the size of the genetic defect leading to disease phenotype. However, we don’t know whether people from other parts of the world also have aspects of FSHD that are unique to them including India and Brazil, two of the world’s most populous and genetically diverse countries. Understanding FSHD in these populations is crucial, especially as new treatments are being developed. India and Brazil are expected to have large numbers of affected individuals, yet their populations remain underrepresented in research. Expanding studies to include these populations will help improve diagnosis, treatment, and access to clinical trials for individuals worldwide.

The ICGNMD AIIMS (Delhi) team, led by Vishnu VY and Padma Srivastava, recruited a very large cohort of suspected FSHD families from across India, for careful clinical assessment and sample collection. Subsets of samples were sent Silvère van der Maarel’s team at LUMC in the Netherlands, where Richard Lemmers and colleagues undertook Southern Blot analysis to test for FSHD, or to UCL Queen Square Institute of Neurology in the UK, for analysis using optical genome mapping by Enrico Bugiardini, Stephanie Efthymiou and colleagues.

With the financial support of Friends of FSH Research, we achieved important milestones. We tested a total of 145 probands from India with clinical symptoms consistent with FSHD. The study found an overlapping, but distinct spectrum of FSHD genetics in Indian participants, compared to published cohorts of predominantly European ancestry. People of Indian ancestry seem to be less susceptible to FSHD than people of European ancestry. This is particularly evident in the European FSHD1 repeat size range of 7–10 units, where we identified very few Indian patients. This is important when diagnosing a patient, as other types of dystrophy may need to be tested for too. It is also important for clinicians evaluating relatives of affected patients, to predict if they will also go on to develop FSHD. The study also found that, when FSHD is present, patients in India show the same severity of disease as other populations, highlighting the challenges patients and their families face day-to-day.

“A detailed description of the first genetically confirmed cohort of Facioscapulohumeral Muscular Dystrophy from Northern India” has now been published in a peer-reviewed scientific journal (https://www.nature.com/articles/s41431-024-01577-z) and has received much positive attention.

With Friends of FSH Research support, we additionally recruited 112 Brazilian participants across 59 families, in collaboration with Professor Wilson Marques Junior, Dr Claudia Ferreia da Rosa Sobreira and Dr Pedro Tomaselli at the University of São Paulo and Clinical Hospital of Ribeirão Preto in São Paulo, Brazil. Participants were recruited from across Brazil, which is the 7th largest country, by population. Our cohort includes different ethnicities from this very diverse country, which currently experiences only limited access to FSHD genetic testing. So far, 49 participants have received a genetic diagnosis of FSHD type 1, with deeper genetic analyses ongoing for FSHD-negative cases. Genetic findings were broadly consistent with ethnic background and provide valuable data to understand the epidemiology of FSHD within Brazil. This data in turn can underpin future, practical assessments of how Brazil’s FSHD patient population can best be diagnosed and treated.

In conclusion, we fully characterized two large, ethnically diverse international cohorts in FSHD. In addition to gaining insight into potential factors modulating disease severity and clinical manifestations, we have established two large and diverse cohorts of FSHD families accessible to future clinical studies, including trials.