Pompe disease: a country-wide molecular screening in a cohort of 15,068 study participants

Introduction Pompe disease (PD) is a rare inherited recessive autosomal disorder caused by pathogenic nucleotide variants within the gene GAA , encoding Acid alpha-glucosidase (GAA), the lysosomal enzyme catalyzing glycogen breakdown to glucose. Methods We performed molecular screening in a cohort of 15,068 participants with suspected PD of a wide range of age from several regions of Russia. Two screenings had been undertaken from 2014 to 2025, and 2021 to 2025, respectively: 13,128 patients were screened using “two-tier one-gene” algorithm (measurement of GAA activity in dried blood spots followed by Sanger sequencing of the GAA) and 1940 patients were screened using Next-Generation Sequencing (NGS)-based algorithm (NGS of the panel of genes linked to neuromuscular disorders, ANO5, CAPN3, DYSF, FKRP, SGCA, SGCB, SGCD, SGCG, TCAP , and GAA , followed by measurement of GAA activity when needed). Results 63 causative nucleotide variants in the GAA gene were detected, the most common being c.-32-13T>G (28 patients) followed by c.2662G>T (10 patients). 25 novel nucleotide variants in the GAA gene were described. Of 1,940 patients screened using an NGS-based algorithm, 138 patients (7.1%) were diagnosed with various muscular dystrophies, myopathies, or PD. The majority of these individuals had biallelic variants in the CAPN3 gene (30%), indicative of calpainopathy. Total 57 (0.47%) and 8 (0.41%) patients were diagnosed with PD as a result of “two-tier one-gene” or NGS-based algorithms, respectively. Discussion Overall, our study is the first large-scale country-wide selective screening for PD in Russia based on sequencing and GAA activity measurement and providing the most comprehensive overview of genetics of PD in this study population.