This document reports on the authors’ retrospective review of cases, using in-house cardiovascular genetic testing, and their analysis of 20 genes associated with familial thoracic aortic dissection or rupture; they conclude that molecular testing of familial TADR-associated genes is a highly effective tool to identify the genetic cause of TADR sudden deaths.
Sudden deaths due to thoracic aortic dissection or rupture (TADR) are often investigated by forensic pathologists in the United States. Up to a quarter of reported TADR result from a highly penetrant autosomal dominant single gene variant. Testing genes associated with familial TADR provides an underlying etiology for the cause of death and informs effective sudden death prevention for at-risk family members. At the New York City Office of Chief Medical Examiner (NYC-OCME), TADR cases are routinely tested by the in-house, CAP-accredited Molecular Genetics Laboratory. In this retrospective study, TADR and cardiovascular cases were reviewed to understand the burden of TADR in sudden deaths, value of molecular diagnostic testing in TADR, and genotype-phenotype correlations in a demographically diverse TADR cohort. Between July 2019 and June 2022, the authors retrospectively reviewed cases with in-house cardiovascular genetic testing at NYC-OCME. They analyzed 20 genes associated with familial TADR using high throughput massive parallel sequencing on postmortem tissues or bloodspot cards, and conducted variant interpretation according to ACMG/AMP guidelines. The genes with the greatest prevalence of P/LPV were FBN1, followed by TGFBR2, TGFBR1, and MYLK. Highly penetrant P/LPV in TGFBR2, FBN1, and TGFBR1 were found in TADR individuals who died younger than 34 years old. Two P/LPV in FBN1 were secondary findings unrelated to cause of death. P/LPV in FBN1 included five truncating variants located in the N-terminal domains and one missense variant involved in the disulfide bonds of the EGF-like domain. All P/LPV in TGFBR1 and TGFBR2 were missense or in-frame deletion variants located in the protein kinase catalytic domain. Three variants were first reported in this study. Molecular testing of familial TADR-associated genes is a highly effective tool to identify the genetic cause of TADR sudden deaths and benefits surviving at-risk families. Publisher Abstract Provided