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Neuromuscular disease genetics in under-represented populations: increasing data diversity

Lookup NU author(s): Dr William Macken, Dr Mahmoud FassadORCiD, Dr Fei Gao, Krutik PatelORCiD, Dr Ana TopfORCiD, Dr Christina Trainor, Dr Anna Sarkozy, Professor Bobby McFarlandORCiD, Professor Robert Taylor, Professor Volker StraubORCiD, Professor Rita HorvathORCiD, Professor Patrick Chinnery, Dr Robert Pitceathly, Professor Michael Hanna



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' ∼56% probands overall. 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 dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.

Publication metadata

Author(s): Wilson LA, Macken WL, Perry LD, Record CJ, Schon KR, Frezatti RSS, Raga S, Naidu K, Koken OY, Polat I, Kapapa MM, Dominik N, Efthymiou S, Morsy H, Nel M, Fassad MR, Gao F, Patel K, Schoonen M, Bisschoff M, Vorster A, Jonvik H, Human R, Lubbe E, Nonyane M, Vengalil S, Nashi S, Srivastava K, Lemmers RJLF, Reyaz A, Mishra R, Topf A, Trainor CI, Steyn EC, Mahungu AC, van der Vliet PJ, Ceylan AC, Hiz AS, Cavdarli B, Semerci Gunduz CN, Ceylan GG, Nagappa M, Tallapaka KB, Govindaraj P, van der Maarel SM, Narayanappa G, Nandeesh BN, Wa Somwe S, Bearden DR, Kvalsund MP, Ramdharry GM, Oktay Y, Yis U, Topaloglu H, Sarkozy A, Bugiardini E, Henning F, Wilmshurst JM, Heckmann JM, McFarland R, Taylor RW, Smuts I, van der Westhuizen FH, Sobreira CFDR, Tomaselli PJ, Marques W, Bhatia R, Dalal A, Srivastava MVP, Yareeda S, Nalini A, Vishnu VY, Thangaraj K, Straub V, Horvath R, Chinnery PF, Pitceathly RDS, Muntoni F, Houlden H, Vandrovcova J, Reilly MM, Hanna MG

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2023

Volume: 146

Issue: 12

Pages: 5098-5109

Print publication date: 01/12/2023

Online publication date: 30/07/2023

Acceptance date: 04/07/2023

Date deposited: 18/12/2023

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press


DOI: 10.1093/brain/awad254

PubMed id: 37516995


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Funder referenceFunder name
MR/S005021/1Medical Research Council (MRC)
National Brain Appeal
University College London Global Engagement Funds