A novel GAA variant reveals potential mechanisms of proteostasis disruption in late onset Pompe disease

Abstract Pompe disease (PD) is a rare neuromuscular disorder caused by variants in the GAA gene, leading to an acid alpha-glucosidase enzyme deficiency. An exploratory analysis for protein interactions was conducted through STRING platform to investigate the molecular consequences of lysosomal dysfunction in PD. However, despite the absence of clinically validated correlations between functional enrichment and the phenotype, the analysis facilitated the identification of a network of proteins involved in pivotal metabolic processes. In this study, we report a previously unreported heterozygous variant identified in a 55-year-old male patient presenting with symptoms suggestive of late-onset PD (LOPD). Based on clinical presentation and reduced enzyme activity, genetic testing identified the novel c.944G > A (p.Ser315Asn) mutation in exon 5, compound heterozygous with the known causative c.2560 C > T (p.Arg854Ter) mutation in exon 18. Various analytical procedures and a family segregation study determined the pathogenicity of this new variant. Absent from public databases, the variant has been classified as likely pathogenic according to ACMG criteria. This approach is crucial for interpreting variants of uncertain significance and expanding the molecular understanding of PD. Incorporating exploratory use of computational tools clarifies the biological mechanisms underlying the disease, opening future prospects for better prognostic stratification and clinical management of complex neuromuscular cases.