Targeted gene panel screening is an effective tool to identify undiagnosed late onset Pompe disease

Abstract

Mutations in the GAA gene may cause a late onset Pompe disease presenting with proximal weakness without the characteristic muscle pathology, and therefore a test for GAA activity is the first tier analysis in all undiagnosed patients with hyperCKemia and/or limb-girdle muscular weakness. By using MotorPlex, a targeted gene panel for next generation sequencing, we analyzed GAA and other muscle disease-genes in a large cohort of undiagnosed patients with suspected inherited skeletal muscle disorders (n = 504). In this cohort, 275 patients presented with limb-girdle phenotype and/or an isolated hyperCKemia. Mutational analysis identified GAA mutations in ten patients. Further seven affected relatives were identified by segregation studies. All the patients carried the common GAA mutation c.-32-13T >G and a second, previously reported mutation. In the subcohort of 275 patients with proximal muscle weakness and/or hyperCKemia, we identified late-onset Pompe disease in 10 patients. The clinical overlap between Pompe disease and LGMDs or other skeletal muscle disorders suggests that GAA and the genes causing a metabolic myopathy should be analyzed in all the gene panels used for testing neuromuscular patients. However, enzymatic tests are essential for the interpretation and validation of genetic results.

The Latin American experience with a next generation sequencing genetic panel for recessive limb-girdle muscular weakness and Pompe disease

“…LGMD [31,36,63,64]. The current study has now illustrated the effectiveness of NGS with the largest patient sample from a Latin American population.…”

“…Over 8 years of data with over 1200 patients from approximately 220 families in North America, Europe, and Asia have demonstrated that NGS is an effective strategy for improving the diagnosis of patients with proximal muscle weakness [3,5,33,36, and identifying patients with Pompe disease among those with unclassified…”

“…NGS may increase the molecular diagnosis of LGMD R because it generates more data at a lower cost, accelerating the process of identification of pathogenic variants and new genes associated with Mendelian diseases [32,33]. A growing number of studies using NGS have reported genes and variants associated with rare diseases [34][35][36]. These data are being compiled into databases of Mendelian diseases (OMIM) and variants with clinical significance (ClinVar) [37].…”

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

“…Increased prevalence (2.4-3.63%) in LOPD was observed previously in LGMD-suspected or hyperCKemia patients using targeted sequencing approach. [46][47][48] But these studies are different with regard to much lower number of patient cohort that unlike our study also included non-LGMD other NMD patients such as other congenital myopathies, distal myopathies, and isolated hyperCKemia in European population. Our results of prevalence of LOPD through targeted LGMD gene-panel testing in a very large strictly clinically LGMD-characterized or -suspected patients across US with multiple ethnicities indicate that LOPD should not be overlooked when considering potential diagnoses for LGMD patients even if clinical subtyping can be performed, that in turn will assist in ERT or recruitment for other clinical trials.…”

Selective screening of late-onset Pompe disease (LOPD) in patients with non-diagnostic muscle biopsies

“…The resulting lower costs and better technological improvements will make NGS approaches an effective first-tier screening method in the near future 62. At present, the gold standard for the LOPD screening tool is the DBS test, which is reliable, fast, cost-effective and easily accessible.…”