Clinico‐genetic spectrum of limb‐girdle muscular weakness in Austria: A multicentre cohort study

Abstract

Background and purpose Hereditary myopathies with limb‐girdle muscular weakness (LGW) are a genetically heterogeneous group of disorders, in which molecular diagnosis remains challenging. Our aim was to present a detailed clinical and genetic characterization of a large cohort of patients with LGW. Methods This nationwide cohort study included patients with LGW suspected to be associated with hereditary myopathies. Parameters associated with specific genetic aetiologies were evaluated, and we further assessed how they predicted the detection of causative variants by conducting genetic analyses. Results Molecular diagnoses were identified in 62.0% (75/121) of the cohort, with a higher proportion of patients diagnosed by next‐generation sequencing (NGS) than by single‐gene testing (77.3% vs. 22.7% of solved cases). The median (interquartile range) time from onset to genetic diagnosis was 8.9 (3.7–19.9) and 17.8 (7.9–27.8) years for single‐gene testing and NGS, respectively. The most common diagnoses were myopathies associated with variants in CAPN3 (n = 9), FKRP (n = 9), ANO5 (n = 8), DYSF (n = 8) and SGCA (n = 5), which together accounted for 32.2% of the cohort. Younger age at disease onset (p = 0.043), >10× elevated creatine kinase activity levels (p = 0.024) and myopathic electromyography findings (p = 0.007) were significantly associated with the detection of causative variants. Conclusions Our findings suggest that an earlier use of NGS in patients with LGW is needed to avoid long diagnostic delays. We further present parameters predictive of a molecular diagnosis that may help to select patients for genetic analyses, especially in centres with limited access to sequencing.

The clinical and molecular landscape of congenital myasthenic syndromes in Austria: a nationwide study

“…Third, the identification of CMS cases may also depend on specific conventions in different countries and may be limited by a restricted access to NGS applications. It has already been demonstrated that NGS yields higher diagnostic rates in heterogeneous neuromuscular disorders than sequential gene-by-gene testing [13][14][15].…”

What Is in the Myopathy Literature?

“…10-fold elevated, and myopathic EMG findings. 20 This study is useful in providing a view of a nationwide population of hereditary limb-girdle syndromes with respect to the more common entities and factors that correlate with a higher yield of a molecular diagnosis. The yield should continue to improve as NGS becomes more available and extensive.…”

“…In comparison, Krenn et al 20 recently reported an Austrian study that evaluated patients with limb–girdle weakness irrespective of previous genetic or clinical approaches, and they included patients with diagnoses such as facioscapulohumeral muscular dystrophy and spinal muscular atrophy. Therefore, the study was not entirely limited to limb–girdle muscular dystrophy (LGMD), but mostly uncovered LGMD diagnoses.…”

“…Overall, the yield was higher with younger age of onset, CK > 10-fold elevated, and myopathic EMG findings. 20…”

Genetic Patterns of Selected Muscular Dystrophies in the Muscular Dystrophy Surveillance, Tracking, and Research Network

“… 3 - 8 Several geographically defined population-based studies have been conducted for one or more of these muscular dystrophies, primarily outside the United States. 9 - 14 Variants of unknown significance (VUSs) often complicate the interpretation of genetic test reports, either when they are the primary findings or when they are secondary findings in addition to pathogenic or likely pathogenic variants. The presence of such VUSs often leads to ambiguous conclusions from genetic test reports.…”