Whole Exome Sequencing Reveals Severe Thrombophilia in Acute Unprovoked Idiopathic Fatal Pulmonary Embolism.
BACKGROUND
Acute unprovoked idiopathic fatal pulmonary embolism (IFPE) causes sudden death without an identifiable thrombogenic risk. We aimed to investigate the underlying genomic risks of IFPE through whole exome sequencing (WES).


METHODS
We reviewed 14years of consecutive out-of-hospital fatal pulmonary embolism records (n=1478) from the ethnically diverse population of New York City. We selected 68 qualifying IFPE cases for WES. We compared the WES data of IFPE cases to those of 9332 controls to determine if there is an excess of rare damaging variants in the genome using ethnicity-matched controls in collapsing analyses.


RESULTS
We found nine of the 68 decedents (13·2%) who died of IFPE had at least one pathogenic or likely pathogenic variant in one of the three anti-coagulant genes: SERPINC1 (Antithrombin III), PROC, and PROS1. The odds ratio of developing IFPE as a variant carrier for SERPINC1 is 144·2 (95% CI, 26·3-779·4; P=1·7×10-7), for PROC is 85·6 (95% CI, 13·0-448·9; P=2.0×10-5), and for PROS1 is 56·4 (95% CI, 5·3-351·1; P=0·001). The average age-at-death of anti-coagulant gene variant carriers is significantly younger than that of non-carriers (28·56years versus 38·02years; P=0·01).


CONCLUSIONS
This study showed the important role of severe thrombophilia due to natural anti-coagulant deficiency in IFPE. Evaluating severe thrombophilia in out-of-hospital fatal PE beyond IFPE is warranted.
Institute for Genomic Medicine, Columbia University Medical Center, United States.
Matt
M
Halvorsen
Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, United States.
Ying
Y
Lin
Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, United States.
Barbara A
BA
Sampson
Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, United States.
Dawei
D
Wang
Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, United States.
Bo
B
Zhou
Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, United States.
Lucy S
LS
Eng
Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, United States.
Sung Yon
SY
Um
Department of Neurology, NYU Langone Medical Center, United States.
Orrin
O
Devinsky
Institute for Genomic Medicine, Columbia University Medical Center, United States.
David B
DB
Goldstein
Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, United States. Electronic address: ytang@ocme.nyc.gov.
Yingying
Y
Tang
D000328:Adult; D000990:Antithrombin III / Q000235:genetics; D001798:Blood Proteins / Q000235:genetics; D016022:Case-Control Studies; D003645:Death, Sudden; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D011486:Protein C / Q000235:genetics; D017293:Protein S; D011655:Pulmonary Embolism / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D019851:Thrombophilia / Q000150:complications / Q000175:diagnosis / Q000235:genetics*
D001798:Blood Proteins; C523390:PROS1 protein, human; D011486:Protein C; D017293:Protein S; C542513:SERPINC1 protein, human; D000990:Antithrombin III
Idiopathic fatal pulmonary embolism; Natural anticoagulant deficiency; Severe thrombophilia; Whole exome sequencing