O31: X-linked inheritance results in different sex-specific phenotypes, penetrance, disease course, diagnostic odysseys, and newborn screening sensitivity in Fabry disease

Methods: Geisinger's MyCode Community Health Initiative (MyCode) is a healthcare biobank linking electronic health record (EHR) and genomic data and returning P/LP variants in selected clinically actionable genes (ACMG Secondary Findings v3.2), including ACTA2, to participants.Returnable variants identified via analysis of research exome sequencing were clinically confirmed in a CLIA/CAP-certified laboratory and disclosed to participants and their primary care clinicians.Dual EHR review was performed for all adult participants with P/LP ACTA2 results disclosed through July 2023.Charts were reviewed for history of TAAD, most recent aortic measurements on echocardiogram and CT, history of premature CAD (males, <55 yrs; females, < 60 yrs), myocardial infarction, and completion of relevant imaging.Descriptive statistics of observed phenotypes were completed.Results: Of 175,500 participants with available exome sequences, P/LP ACTA2 variants were identified in 53 (0.03%).Of those, 44 adults (83.0%) received results and were included in the study.Median age at chart review was 56 yrs (range 20-91), 38.6% of participants were male, and all had the p.Arg118Gln variant.Two participants had prior clinical testing due to personal history of TAAD.Twenty participants (45.5%) had phenotypes consistent with ACTA2 P/LP variants, including TAAD, root or ascending aortic enlargement 40mm, and/or premature CAD.Seven (15.9%) had a thoracic aortic event (median onset 44 yrs (range 28-69)): 5 with type A dissections (median onset 44 yrs (range 28-69)) and 2 with elective repairs (43, 64 yrs).Of participants with dissections, 4 dissected prior to ACTA2 disclosure without previously diagnosed aortic enlargement.The fifth had a known aneurysm at results disclosure and dissected while scheduling elective repair prompted by results.Eleven participants (25%) had thoracic aortic aneurysms or diameters 40mm.Four (9.1%) had unrepaired ascending aneurysms measuring 45mm (median diagnosis 78 yrs (range 55-84)), all diagnosed prior to ACTA2 disclosure.Seven (15.9%) had aortic root or ascending aortic measurements of 40-44mm, four of which were identified through imaging ordered due to ACTA2 disclosure.Seven participants (15.9%) had mild root or ascending aortic enlargement or ectasia with diameters <40 mm, 14 (31.8%) had an echocardiogram and/or CT imaging with an unremarkable thoracic aorta, and 5 (11.4%) were unassessed.Overall, 11 individuals had their first echocardiogram or CT due to ACTA2 disclosure.Four individuals (9.1%; 2 male, 2 female) had premature CAD; the two females also had a history of premature myocardial infarction (43, 56 yrs).Conclusion: While the rate of aortic events in this unselected healthcare population with the ACTA2 p.Arg118Gln variant was lower compared to clinical cohorts, 45.5% of participants had phenotypes consistent with ACTA2 P/LP variants.Four dissections occurred prior to identification of the ACTA2 variant and without prior knowledge of aortic enlargement, highlighting the potential utility of early identification of genomic risk.Many participants had their first aortic imaging because of ACTA2 disclosure, suggesting that result disclosure can prompt necessary management.Identification of ACTA2 variants in unselected cohorts has potential to enable aortic aneurysm detection and intervention to prevent dissections.