P170: Leveraging a genotype-first approach in All of Us cohort to describe prevalence and phenotypic spectrum of rare genetic disorders*

the reverse phenotyping cohort, two out of four participants agreed to complete follow up clinical testing for features of LDS.Both participants had previously been diagnosed with stable aortic root dilation.One participant heterozygous for TGFB3 NM_0003239.5:c.638delp.(Leu213*) met molecular diagnostic criteria for LDS after reverse phenotyping.One participant heterozygous for SMAD3 NM_005902.3:c.1091A>Gp.(Tyr364Cys) did not meet diagnostic criteria but did have a positive family history for a clinical diagnosis Marfan syndrome.This participant had previously tested negative for variants in COL3A1, TGFBR1 and TGFBR2.Conclusion: Genomic ascertainment through EHR-linked biobanks like All of Us provides an opportunity to assess genotype-phenotype associations and trends in diagnosis and screening at large scale, while reverse phenotyping enables more comprehensive evaluation.Given the phenotypic heterogeneity and potential for unrecognized phenotypes in LDS, genomic ascertainment can provide a unifying diagnosis for individuals with presenting symptoms and the opportunity to screen at-risk individuals lacking obvious features of LDS.