Approved Research

Assessment of the distribution of variants in genes underlying neuromuscular diseases

Lay summary

We seek to understand the distribution of variants in genes underlying neuromuscular diseases, including Duchenne Muscular Dystrophy (DMD), resulting from mutations in the DMD gene, and multiple subtypes of Limb-Girdle Muscular Dystrophy (LGMD), resulting from mutations in one of more than thirty genes. 

DMD is the most common, severe childhood form of muscular dystrophy. Inheritance follows an X-linked recessive pattern and is caused by mutations in the DMD gene. However, it is not clear if large structural variants and smaller variants in the DMD gene are naturally present in a general population. Interestingly, a less severe form of disease, called Becker Muscular Dystrophy also arises from mutations in the DMD gene; typically, these patients have in-frame mutations that create a shortened, yet functional, dystrophin protein. We seek to investigate DMD genetic variants within the UKBB population to understand which, if any, variants do not lead to clinical presentation of DMD.  The identification of these mutation types can help guide the development of therapies to treat this disease.

There are more than thirty different subtypes of LGMD, each corresponding to a different causal gene.  Unlike DMD, which typically leads to loss of ambulation around age 12 without interventions and death before age 30, LGMD has a varied disease progression, with disease onset and progression extending into adulthood for some subtypes. It is important to understand the relationship between genetic variation and clinical presentations in both symptomatic and asymptomatic individuals. 

We therefore propose to investigate, over a 36-month period, genetic variants, including structural variants (CNVs), single nucleotide variants (SNVs) and smaller insertions and deletions (indels) within the known disease causal genes of DMD and LGMD. In addition, when phenotypes are available for muscular dystrophy patients in UKBB (ICD10 code: G71), we will do genotype and phenotype association analyses. Given the small number of patients with these phenotypes, analyses will likely be limited to descriptive presentation of clinical presentation and disease progression over time.

A deeper understanding of genetic variation in genes causal for neuromuscular disease will advance the development of precision genetic therapies for patients living with these rare diseases.