Neuromuscular disease genetics in under-represented populations: increasing data diversity
Authors: Wilson Lindsay A , Macken William L , Perry Luke D , Record Christopher J , Schon Katherine R , Frezatti Rodrigo S S , Raga Sharika , Naidu Kireshnee , Köken Özlem Yayıcı , Polat Ipek , Kapapa Musambo M , Dominik Natalia , Efthymiou Stephanie , Morsy Heba , Nel Melissa , Fassad Mahmoud R , Gao Fei , Patel Krutik , Schoonen Maryke , Bisschoff Michelle , Vorster Armand , Jonvik Hallgeir , Human Ronel , Lubbe Elsa , Nonyane Malebo , Vengalil Seena , Nashi Saraswati , Srivastava Kosha , Lemmers Richard J L F , Reyaz Alisha , Mishra Rinkle , Töpf Ana , Trainor Christina I , Steyn Elizabeth C , Mahungu Amokelani C , van der Vliet Patrick J , Ceylan Ahmet Cevdet , Hiz A Semra , Çavdarlı Büşranur , Semerci Gündüz C Nur , Ceylan Gülay Güleç , Nagappa Madhu , Tallapaka Karthik B , Govindaraj Periyasamy , van der Maarel Silvère M , Narayanappa Gayathri , Nandeesh Bevinahalli N , Wa Somwe Somwe , Bearden David R , Kvalsund Michelle P , Ramdharry Gita M , Oktay Yavuz , Yiş Uluç , Topaloğlu Haluk , Sarkozy Anna , Bugiardini Enrico , Henning Franclo , Wilmshurst Jo M , Heckmann Jeannine M , McFarland Robert , Taylor Robert W , Smuts Izelle , van der Westhuizen Francois H , Sobreira Claudia Ferreira da Rosa , Tomaselli Pedro J , Marques Wilson , Bhatia Rohit , Dalal Ashwin , Srivastava M V Padma , Yareeda Sireesha , Nalini Atchayaram , Vishnu Venugopalan Y , Thangaraj Kumarasamy , Straub Volker , Horvath Rita , Chinnery Patrick F , Pitceathly Robert D S , Muntoni Francesco , Houlden Henry , Vandrovcova Jana , Reilly Mary M , Hanna Michael G 
Published: July 2023

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.