Abstract Body (Do not enter title and authors here):
Introduction
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant condition with incomplete penetrance and variable expressivity. Given the increasing prevalence of sequencing and current guidelines on secondary finding disclosure, HCM P/LP alleles are increasingly being returned to patients who undergo genetic testing for other reasons. Whether individuals carrying P/LP HCM variants discovered in a genome-first context have progressive endophenotypes indicative of HCM remains poorly understood.

Methods
To evaluate the penetrance and phenotype conversion rate of adults with P/LP HCM variants, we leveraged the Massachusetts General Brigham Biobank (MGBB), which consists of 36,417 participants with genotyping array and clinical data. Primary images of the earliest and latest TTE studies were reviewed for measurements of the posterior wall (PW), interventricular septum (IVS), and left ventricular morphology. Phenotype-positive (P+) status was defined by a PW or IVS thickness of at least 13 mm.

Results
P/LP HCM variants were identified in 42 (0.1%) individuals with mean (SD) age 50.0 (16.6) years and 21 (50%) female sex. The most common HCM variants were in MYBPC3 (44%) and MYH7 (40%), followed by TNNI3(7%), MYL3 (7%), and TNNT2 (2%). Among the 42 genotype-positive (G+) individuals in MGBB, 17 (40%) had pre-existing HCM diagnoses prior to genomic return of results (gRoR). In contrast, 25 (60%) G+ individuals lacked a prior HCM diagnosis, among whom gRoR prompted TTE studies in 13 patients, revealing evidence of HCM in 9 individuals. Among the 42 G+ patients, 25 (58%) patients had completed at least two TTE studies, with a median [IQR] of 6 [3-9] TTE studies per patient, across a span of 10 [7-15] years follow-up. At the time of first TTE, 16 (64%) patients were P+ while 9 (36%) were P-. No G+, P- individuals converted to P+ over 10 years follow-up, nor was there any significant change in IVS or PW thickness. In contrast, individuals who were P+ at the initial TTE exhibited thickening PW (25% increase, CI 97.5% of 6 to 44) and IVS (26% increase, CI 97.5% of 4 to 49) over 8 years follow-up.

Conclusion
In a genome-first approach, we identified 42 individuals in the MGBB with a P/LP HCM variant, among whom 60% lacked a prior clinical diagnosis of HCM. Targeted phenotyping revealed that nearly half of this newly identified group were P+. Over a median of 10 years follow-up, we observed a 0% phenotype conversion rate among G+, P- adult carriers of HCM variants.