The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy

TY - JOUR

T1 - The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy

AU - Lahrouchi, Najim

AU - Raju, Hariharan

AU - Lodder, Elisabeth M

AU - Papatheodorou, Stathis

AU - Miles, Chris

AU - Ware, James S

AU - Papadakis, Michael

AU - Tadros, Rafik

AU - Cole, Della

AU - Skinner, Jonathan R

AU - Crawford, Jackie

AU - Love, Donald R

AU - Pua, Chee J

AU - Soh, Bee Y

AU - Bhalshankar, Jaydutt D

AU - Govind, Risha

AU - Tfelt-Hansen, Jacob

AU - Winkel, Bo G

AU - van der Werf, Christian

AU - Wijeyeratne, Yanushi D

AU - Mellor, Greg

AU - Till, Janice

AU - Cohen, Marta

AU - Tome-Esteban, Maria

AU - Sharma, Sanjay

AU - Wilde, Arthur A M

AU - Cook, Stuart A

AU - Sheppard, Mary N

AU - Bezzina, Connie R

AU - Behr, Elijah R

PY - 2020/1/1

Y1 - 2020/1/1

N2 - Sudden cardiac death (SCD) is often associated with structural abnormalities of the heart during autopsy. This study sought to compare the diagnostic yield of postmortem genetic testing in (1) cases with structural findings of uncertain significance at autopsy to (2) cases with autopsy findings diagnostic of cardiomyopathy. We evaluated 57 SCD cases with structural findings at cardiac autopsy. Next-generation sequencing using a panel of 77 primary electrical disorder and cardiomyopathy genes was performed. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. In 29 cases (51%) autopsy findings of uncertain significance were identified whereas in 28 cases (49%) a diagnosis of cardiomyopathy was established. We identified a pathogenic or likely pathogenic variant in 10 cases (18%); in 1 (3%) case with non-specific autopsy findings compared with 9 (32%) cases with autopsy findings diagnostic of cardiomyopathy (p = 0.0054). The yield of genetic testing in SCD cases with autopsy findings consistent with cardiomyopathy is comparable with the yield in cardiomyopathy patients that are alive. Genetic testing in cases with findings of uncertain significance offers lower clinical utility than in cardiomyopathy, with lower yields than detected previously. This highlights the need for stringent evaluation of variant pathogenicity.

AB - Sudden cardiac death (SCD) is often associated with structural abnormalities of the heart during autopsy. This study sought to compare the diagnostic yield of postmortem genetic testing in (1) cases with structural findings of uncertain significance at autopsy to (2) cases with autopsy findings diagnostic of cardiomyopathy. We evaluated 57 SCD cases with structural findings at cardiac autopsy. Next-generation sequencing using a panel of 77 primary electrical disorder and cardiomyopathy genes was performed. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. In 29 cases (51%) autopsy findings of uncertain significance were identified whereas in 28 cases (49%) a diagnosis of cardiomyopathy was established. We identified a pathogenic or likely pathogenic variant in 10 cases (18%); in 1 (3%) case with non-specific autopsy findings compared with 9 (32%) cases with autopsy findings diagnostic of cardiomyopathy (p = 0.0054). The yield of genetic testing in SCD cases with autopsy findings consistent with cardiomyopathy is comparable with the yield in cardiomyopathy patients that are alive. Genetic testing in cases with findings of uncertain significance offers lower clinical utility than in cardiomyopathy, with lower yields than detected previously. This highlights the need for stringent evaluation of variant pathogenicity.

U2 - 10.1038/s41431-019-0500-8

DO - 10.1038/s41431-019-0500-8

M3 - Journal article

C2 - 31534214

SN - 1018-4813

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

ER -