Reevaluating the pathogenicity of the mutation c.1194 +5 G>A in GAA gene by functional analysis of RNA in a 61-year-old woman diagnosed with Pompe disease by muscle biopsy.

Glycogen storage disease type II, or Pompe disease, is an autosomal recessive disorder caused by deficiency of lysosomal acid alpha-glucosidase (GAA). We performed genetic analysis to confirm the diagnosis of Pompe disease in a 61-year-old patient with progressive weakness in extremities, severe Sleep Apnea-Hypopnea Syndrome, a significant reduction of alpha-glucosidase in liquid sample of peripheral blood and muscular biopsy diagnosis. GAA gene sequencing showed the patient is homozygous for the splice-site mutation c.1194+5G>A, considered as nonpathogenic in Pompe Center mutation database. Further molecular RNA characterization of GAA transcripts allowed us to identify abnormal processing of pre-mRNA, leading to aberrant transcripts and a significant reduction of GAA mRNA levels. Our results indicate that c.1194+5G>A is a pathogenic splice-site mutation and should be considered as such for diagnostic purposes. This study emphasizes the potential role of functional studies to determine the consequences of mutations with no evident pathogenicity.