Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths

Patricia B Munroe; Shea Addison; Dominic J Abrams; Neil J Sebire; James Cartwright; Ian Donaldson; Marta M Cohen; Charles Mein; Andrew Tinker; Stephen C Harmer; Qadeer Aziz; Anna Terry; Monika Struebig; Helen R Warren; Bhumita Vadgama; Darren J Fowler; Donald Peebles; Andrew M Taylor; Peter J Lally; Sudhin Thayyil

doi:10.1161/CIRCGEN.117.001817

Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths

Patricia B Munroe, Shea Addison, Dominic J Abrams, Neil J Sebire, James Cartwright, Ian Donaldson, Marta M Cohen, Charles Mein, Andrew Tinker, Stephen C Harmer, Qadeer Aziz, Anna Terry, Monika Struebig, Helen R Warren, Bhumita Vadgama, Darren J Fowler, Donald Peebles, Andrew M Taylor, Peter J Lally, Sudhin Thayyil

School of Physiology, Pharmacology & Neuroscience

Research output: Contribution to journal › Article (Academic Journal) › peer-review

21 Citations (Scopus)

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.

Original language	English
Article number	e001817
Number of pages	10
Journal	Circulation: Genomic and Precision Medicine
Volume	11
Issue number	1
Early online date	7 Nov 2017
DOIs	https://doi.org/10.1161/CIRCGEN.117.001817
Publication status	Published - 11 Jan 2018

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10.1161/CIRCGEN.117.001817

http://hdl.handle.net/10044/1/63477Licence: CC BY-ND

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Munroe, P. B., Addison, S., Abrams, D. J., Sebire, N. J., Cartwright, J., Donaldson, I., Cohen, M. M., Mein, C., Tinker, A., Harmer, S. C., Aziz, Q., Terry, A., Struebig, M., Warren, H. R., Vadgama, B., Fowler, D. J., Peebles, D., Taylor, A. M., Lally, P. J., & Thayyil, S. (2018). Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths. Circulation: Genomic and Precision Medicine, 11(1), Article e001817. https://doi.org/10.1161/CIRCGEN.117.001817

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title = "Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths",

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.",

author = "Munroe, {Patricia B} and Shea Addison and Abrams, {Dominic J} and Sebire, {Neil J} and James Cartwright and Ian Donaldson and Cohen, {Marta M} and Charles Mein and Andrew Tinker and Harmer, {Stephen C} and Qadeer Aziz and Anna Terry and Monika Struebig and Warren, {Helen R} and Bhumita Vadgama and Fowler, {Darren J} and Donald Peebles and Taylor, {Andrew M} and Lally, {Peter J} and Sudhin Thayyil",

note = "{\textcopyright} 2018 American Heart Association, Inc.",

year = "2018",

month = jan,

day = "11",

doi = "10.1161/CIRCGEN.117.001817",

language = "English",

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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, no. 1, e001817. https://doi.org/10.1161/CIRCGEN.117.001817

TY - JOUR

T1 - Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths

AU - Munroe, Patricia B

AU - Addison, Shea

AU - Abrams, Dominic J

AU - Sebire, Neil J

AU - Cartwright, James

AU - Donaldson, Ian

AU - Cohen, Marta M

AU - Mein, Charles

AU - Tinker, Andrew

AU - Harmer, Stephen C

AU - Aziz, Qadeer

AU - Terry, Anna

AU - Struebig, Monika

AU - Warren, Helen R

AU - Vadgama, Bhumita

AU - Fowler, Darren J

AU - Peebles, Donald

AU - Taylor, Andrew M

AU - Lally, Peter J

AU - Thayyil, Sudhin

PY - 2018/1/11

Y1 - 2018/1/11

N2 - 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.

AB - 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.

UR - http://hdl.handle.net/10044/1/63477

U2 - 10.1161/CIRCGEN.117.001817

DO - 10.1161/CIRCGEN.117.001817

M3 - Article (Academic Journal)

C2 - 29874177

SN - 2574-8300

VL - 11

JO - Circulation: Genomic and Precision Medicine

JF - Circulation: Genomic and Precision Medicine

IS - 1

M1 - e001817

ER -

Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths

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