Postmortem genetic testing for cardiac ion channelopathies in stillbirths
| Autor: | Donald Peebles, Neil J. Sebire, Dominic Abrams, Darren J. Fowler, Patricia B. Munroe, Helen R. Warren, Andrew Tinker, Qadeer Aziz, Charles A. Mein, Sudhin Thayyil, Marta M Cohen, B Vadgama, Anna Terry, Andrew J. Taylor, Peter J Lally, James H. Cartwright, Monika Struebig, Ian Donaldson, S Addison, Stephen C Harmer |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine ERG1 Potassium Channel Candidate gene Cardiac & Cardiovascular Systems Autopsy 030204 cardiovascular system & hematology Sudden cardiac death cause of death 0302 clinical medicine CHANNEL Pregnancy Cause of death Brugada syndrome Genetics Genetics & Heredity medicine.diagnostic_test COMMON VARIANTS General Medicine ASSOCIATION KCNQ1 Potassium Channel Female stillbirth Life Sciences & Biomedicine Long QT syndrome Gestational Age LONG-QT SYNDROME Biology Polymorphism Single Nucleotide 1102 Cardiovascular Medicine And Haematology 03 medical and health sciences autopsy INFANT-DEATH-SYNDROME medicine Humans TORSADES-DE-POINTES Potassium Channels Inwardly Rectifying Genetic testing Genetic association 0604 Genetics Science & Technology POLYMORPHIC VENTRICULAR-TACHYCARDIA MUTATIONS DNA Sequence Analysis DNA medicine.disease 030104 developmental biology INTERVAL DURATION BRUGADA SYNDROME Cardiovascular System & Hematology fetal heart Cardiovascular System & Cardiology Channelopathies mutation |
| Popis: | Background Although stillbirth is a significant health problem worldwide, the definitive cause of death remains elusive in many cases, despite detailed autopsy. In this study of partly explained and unexplained stillbirths, we used next-generation sequencing to examine an extended panel of 35 candidate genes known to be associated with ion channel disorders and sudden cardiac death. Methods and Results We examined tissue from 242 stillbirths (≥22 weeks), including those where no definite cause of death could be confirmed after a full autopsy. We obtained high-quality DNA from 70 cases, which were then sequenced for a custom panel of 35 genes, 12 for inherited long- and short-QT syndrome genes (LQT1-LQT12 and SQT1-3), and 23 additional candidate genes derived from genome-wide association studies. We examined the functional significance of a selected variant by patch-clamp electrophysiological recording. No predicted damaging variants were identified in KCNQ1 (LQT1) or KCNH2 (LQT2). A rare putative pathogenic variant was found in KCNJ2 (LQT7) in 1 case, and several novel variants of uncertain significance were observed. The KCNJ2 variant (p. R40Q), when assessed by whole-cell patch clamp, affected the function of the channel. There was no significant evidence of enrichment of rare predicted damaging variants within any of the candidate genes. Conclusions Although a causative link is unclear, 1 putative pathogenic and variants of uncertain significance variant resulting in cardiac channelopathies was identified in some cases of otherwise unexplained stillbirth, and these variants may have a role in fetal demise. Clinical Trial Registration URL: https://www.clinical trials.gov . Unique identifier: NCT01120886. |
| Databáze: | OpenAIRE |
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