The combination of enzyme assay-targeted single-gene testing and a focused neuromuscular next-generation sequencing panel appears to be more effective for Pompe disease (PD) diagnosis than stand-alone new-generation sequencing (NGS), according to a recently published study in Molecular Genetics and Metabolism.
The Lantern Project, a complementary diagnostic program for PD, combines enzymatic, biomarker, and genetic testing to provide a quick and accurate PD diagnosis and distinguish it from other phenotypically similar conditions.
Close to 8000 patients were tested through the project from 2018 to 2021. Standard testing includes both genetic sequencing and enzymatic testing. When required, the Focused Neuromuscular (FNM) Panel is also available.
Enzymatic testing was added in cases where two GAA variants were found on the panel, which improved diagnosis in patients with variants of unknown significance (VUS).
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Approximately 6400 patients received NGS panel testing, while close to 1300 received PD-targeted testing. Of those, 140 patients were diagnosed with PD during the program, of which 40 were diagnosed through an NGS panel and the remaining 100 through targeted testing with GAA enzyme and DNA sequencing, including GAA gene sequencing. This represented a 0.6% yield for stand-alone NGS testing and a 7% diagnostic yield for targeted testing.
The most commonly provided clinical information was newborn screening. When symptoms were reported, the most common was proximal muscle weakness, followed by cardiac findings and nervous system symptoms.
“The Lantern Project demonstrates the combinatorial utility of a focused neuromuscular NGS panel, enzyme assay, and targeted genetic testing in diagnosing Pompe disease, which could be further extended to other conditions where an enzymatic assay could be used, especially for resolution of VUS,” the authors concluded.
Sniderman King L, Pan Y, Nallamilli BR, et al. Pompe disease ascertained through the Lantern Project, 2018–2021: Next-generation sequencing and enzymatic testing to overcome obstacles to diagnosis. Mol Genet Metab. Published online April 5, 2023. doi:10.1016/j.ymgme.2023.107565