Estimating prevalence for limb-girdle muscular dystrophy based on public sequencing databases

Abstract

Purpose: Limb Girdle Muscular Dystrophies (LGMD) are a genetically heterogeneous category of autosomal inherited muscle diseases. Many genes causing LGMD have been identified, and clinical trials are beginning for treatment of some genetic subtypes. However, even with the gene-level mechanisms known, it is still difficult to get a reliable and generalizable prevalence estimation for each subtype due to the limited amount of epidemiology data and the low incidence of LGMDs. Methods: Taking advantage of recently published whole exome and genome sequencing data from the general population, we used a Bayesian method to develop a reliable disease prevalence estimator. Results: This method was applied to nine recessive LGMD subtypes. The estimated disease prevalence calculated by this method were largely comparable to published estimates from epidemiological studies, however highlighted instances of possible under-diagnosis for LGMD2B and 2L. Conclusion: The increasing size of aggregated population variant databases will allow for robust and reproducible prevalence estimates of recessive disease, which is critical for the strategic design and prioritization of clinical trials..

A Small-Molecule Approach to Restore a Slow-Oxidative Phenotype and Defective CaMKIIβ Signaling in Limb Girdle Muscular Dystrophy

“…LGMDR1 is caused by loss of function mutations in CAPN3 27 and is believed to be the most prevalent of the known LGMDs. 28 Our work has revealed a remodeling defect in Capn3-deficient muscles, which was uncovered using experimental protocols that induce atrophy and growth (hindlimb unloading/reloading) or following exercise training. 9,12,13,17 Deconditioning occurs because muscles lacking Capn3 do not sense loading and do not activate the signaling pathways (especially CaMKII) necessary to maintain the SO gene transcription program.…”

The prevalence of hereditary neuromuscular disorders in Northern Norway

“…Worldwide, the most common LGMD is LGMD R1 calpain3‐related disease, but other subcategories may dominate in different ethnic groups and geographical areas (Liu et al., 2019). We found only four patients with recessive calpainopathy, but five with disease caused by the dominant LGMD D4 calpain3‐related disorder (Vissing et al., 2016).…”

Duchenne muscular dystrophy–like phenotype in an LGMD2I patient with novel FKRP gene variants

“…In addition, patients with LGMD2I caused by other variants have been described in previous reports as having DMD-like phenotypes 4 . The prevalence of dystrophinopathy (DMD and Becker-type muscular dystrophy) has been reported 5 to bẽ 2 per 10,000, whereas the prevalence of LGMD2I is 4.3 per million 6 . Thus, many physicians might not be familiar with LGMD2I.…”