Illustrative Variant-Positive Molecular Autopsy Series: Autopsy-Led Concordance of Loeys-Dietz Spectrum Findings in Eight Florida Sudden Deaths.

Background/Objectives: Molecular autopsy increasingly identifies rare variants in heritable aortopathy and Loeys-Dietz spectrum genes among sudden-death decedents, yet classification and causal attribution remain challenging when a syndromic diagnosis was never established during life. We reviewed eight unrelated Florida medical examiner decedents ascertained by sudden or unexpected death under medical examiner jurisdiction, including laboratory-reported heterozygous missense variants spanning the Loeys-Dietz syndrome (LDS)/familial thoracic aortic aneurysm and dissection (FTAAD) gene spectrum (TGFBR1, TGFBR2, TGFB2, and SMAD3). None had a premortem clinical diagnosis of LDS; ascertainment was therefore a variant-positive molecular autopsy series, not clinically diagnosed LDS. This illustrative series of eight cases cannot estimate prevalence, diagnostic yield, penetrance, or incidental-finding frequency. Methods: Autopsy (±premortem) phenotype-variant concordance was graded as strong, limited, discordant, or not assessable without treating death as evidence of pathogenicity or equating laboratory detection with clinical LDS diagnosis. Grades were assigned by the authors using predefined rules, were not blinded to laboratory class, and were reconciled by consensus discussion; inter-rater reliability was not quantified. Population, computational, and ClinVar annotations, together with multi-axis molecular triangulation, were retained as supplementary context only. Results: Laboratory classifications were pathogenic in one case (TGFBR1 p.Arg487Gln, Case 1), likely pathogenic in another (TGFBR2 p.Glu428Asp, Case 3), and variants of uncertain significance (VUS) in the remaining cases. Strong phenotype-variant concordance mapped to two aortic-catastrophe decedents (Cases 1 and 3), limited concordance to two cases (Cases 4 and 5), and discordant presentations to four (Cases 2, 6, 7, and 8), including pulmonary thromboembolism without aortopathy, infant sudden death with competing cardiomyopathy-gene context, and ethanol-related death with a normal aorta (SMAD3 Case 8). Conclusions: In this illustrative variant-positive series, 2/8 cases had strong autopsy-led concordance, 2/8 limited, and 4/8 discordant. Autopsy-led concordance grading distinguished two LDS-spectrum variants with strong phenotype-variant concordance for fatal ascending aortic catastrophe from six variants with limited or discordant support. Rare variants in TGFBR1, TGFBR2, TGFB2, or SMAD3 should not be conflated with an LDS diagnosis or with the cause of death without concordant autopsy evidence.