P716: Post-translational processing of GAA protein associated with GAA variants may explain the clinical variability observed amongst Pompe disease patients

cardiovascular issues (37.5%, 3/8 patients).Of the patients with complex phenotypes, 20.4% (66/323) received a genetic diagnosis.Diagnostic yield did not significantly vary by family structure, sex, ancestry, or prior genetic testing.Eighty-nine percent of patients and 91% of parents opted to receive secondary findings.Overall, SFs were identified in 7.4% of cases: 4.5% in probands and 2.9% in comparators.Seven (1.3%) patients received both a positive primary and secondary finding, while nine (1.7%) received only a secondary finding.Most SFs were associated with genes linked to breast and/or ovarian cancer and tachycardia phenotypes.The high rate of inconclusive results (47%) in our clinical ES cohort is partially due to the reporting of candidate gene findings.A candidate gene result alone was provided for 8% of probands.Many of these inconclusive findings hold potential for future reclassification to diagnostic status as additional evidence for pathogenicity emerges, including data from segregation analyses, case reports, and functional studies.This potential change in classification may be facilitated through active collaboration between the laboratory and ordering providers or via submission to GeneMatcher to identify phenotypically similar patients who harbor variation within the same gene.Conclusion: Our data further supports the utility of comprehensive genetic testing (exome sequencing) as part of the standard of care to reduce diagnostic delays and end the diagnostic odyssey for patients with rare diseases.Furthermore, we present ES findings from a large cohort of patients from the Midwestern US.