Patricia B Munroe1, Shea Addison2, Dominic J Abrams2, Neil J Sebire2, James Cartwright2, Ian Donaldson2, Marta M Cohen2, Charles Mein2, Andrew Tinker2, Stephen C Harmer2, Qadeer Aziz2, Anna Terry2, Monika Struebig2, Helen R Warren2, Bhumita Vadgama2, Darren J Fowler2, Donald Peebles2, Andrew M Taylor2, Peter J Lally2, Sudhin Thayyil1. 1. From the Clinical Pharmacology (P.B.M., S.A., J.C., A.T., S.C.H., Q.A., H.R.W.) and National Institute for Health Research Barts Cardiovascular Biomedical Research Unit (P.B.M., A.T., H.R.W.), William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, United Kingdom; Genome Centre, Queen Mary University of London, United Kingdom (I.D., C.M., A.T., M.S., B.V.); Centre for Perinatal Neuroscience, Imperial College London, United Kingdom (S.A., P.J.L., S.T.); Paediatric Cardiology, Children's Hospital Boston, MA (D.J.A.); Histopathology, Great Ormond Street Hospital, London, United Kingdom (N.J.S.); Histopathology, Sheffield Children's Hospital, United Kingdom (M.M.C.); Histopathology, Southampton General Hospital, United Kingdom (D.J.F.); Institute for Women's Health, San Antonio, TX (D.P.); and Institute for Cardiovascular Science, University College London, United Kingdom (A.M.T.). s.thayyil@imperial.ac.uk p.b.munroe@qmul.ac.uk. 2. From the Clinical Pharmacology (P.B.M., S.A., J.C., A.T., S.C.H., Q.A., H.R.W.) and National Institute for Health Research Barts Cardiovascular Biomedical Research Unit (P.B.M., A.T., H.R.W.), William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, United Kingdom; Genome Centre, Queen Mary University of London, United Kingdom (I.D., C.M., A.T., M.S., B.V.); Centre for Perinatal Neuroscience, Imperial College London, United Kingdom (S.A., P.J.L., S.T.); Paediatric Cardiology, Children's Hospital Boston, MA (D.J.A.); Histopathology, Great Ormond Street Hospital, London, United Kingdom (N.J.S.); Histopathology, Sheffield Children's Hospital, United Kingdom (M.M.C.); Histopathology, Southampton General Hospital, United Kingdom (D.J.F.); Institute for Women's Health, San Antonio, TX (D.P.); and Institute for Cardiovascular Science, University College London, United Kingdom (A.M.T.).
Abstract
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.clinicaltrials.gov. Unique identifier: NCT01120886.
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.clinicaltrials.gov. Unique identifier: NCT01120886.
Authors: James H Cartwright; Qadeer Aziz; Stephen C Harmer; Sudhin Thayyil; Andrew Tinker; Patricia B Munroe Journal: Hum Mol Genet Date: 2020-07-21 Impact factor: 6.150
Authors: Dana A Muin; Martina Kollmann; Jasmin Blatterer; Gregor Hoermann; Peter W Husslein; Ingrid Lafer; Erwin Petek; Thomas Schwarzbraun Journal: Sci Rep Date: 2021-03-24 Impact factor: 4.379