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Publication - Dr Stephen Harmer

    Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths


    Munroe, PB, Addison, S, Abrams, DJ, Sebire, NJ, Cartwright, J, Donaldson, I, Cohen, MM, Mein, C, Tinker, A, Harmer, SC, Aziz, Q, Terry, A, Struebig, M, Warren, HR, Vadgama, B, Fowler, DJ, Peebles, D, Taylor, AM, Lally, PJ & Thayyil, S, 2018, ‘Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths’. Circulation: Genomic and Precision Medicine, vol 11.


    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: Unique identifier: NCT01120886.

    Full details in the University publications repository