Genetic variants of Pompe disease among a sample of Egyptian pediatric patients

Pompe disease is an autosomal recessive disorder initiated by the deficiency of lysosomal acid α-glucosidase enzyme (GAA) due to disease associated variants of the Alpha glucosidase (GAA) gene. We aimed at genetic screening of Egyptian pediatric patients diagnosed as Pompe disease, hence identifying GAA gene variants, and highlighting the significance of molecular testing for this fatal disease. A cross-sectional cohort study recruiting thirteen unrelated pediatric patients was performed. Confirmation of clinically suspect Pompe disease was accomplished by assessing GAA enzyme level using fluorometric technique, followed by molecular genetic analysis using Sanger sequencing method of GAA gene. Genetic diagnosis of 11/13 (84.6%) of the studied cohort was achieved through detecting the culprit disease causing variant in homozygous pattern in their GAA gene. According to the American College of Medical Genetics and Genomics (ACMG) classification evidence; 10/11 (90.9%) of those variants were classified as pathogenic, while 1/11 (9.1%) c.1979G>A (p. Arg660His) was classified as likely pathogenic. A novel variant g.11734 G>C c.956-1 G>C was identified in homozygous pattern in intron 5 of GAA gene in 1/11(9.1%) patient, using Mutation taster and Human splicing finder in-silico prediction tools to evaluate its pathogenicity, it was recognized that it is a disease-causing one. It results in alteration of the acceptor splicing site of intron 5 with consequent possible skipping of exon 6. Molecular analysis of GAA gene is of immense importance not only for confirming Pompe disease diagnosis but also for determination of treatment options, lifestyle, genetic counseling, and prenatal diagnosis.