The Value of Molecular Autopsy: Genetic Testing Reveals Long QT Mutations in an Autopsy-Negative,Postpartum Sudden Unexpected Death

Abstract

In forensic pathology, genetic testing is a luxury that is not readily entertained. With molecular advances, genetic testing can provide critical information to conclude cause and manner of death in otherwise sudden, undetermined deaths. An autopsy was performed on a 30-year-old woman who died suddenly three months postpartum. The patient's history was unremarkable and included a negative electrocardiogram test prior to pregnancy. Toxicology results were negative and there were no gross or histologic findings on a complete postmortem examination including the conduction system. Prompted by personal interest and knowledge, the spouse, an electrophysiology fellow, requested genetic testing be performed and personally financed the tests. The results revealed two genetic mutations strongly associated with Type 1 Long QT Syndrome, expected to be familial. This provided a cause and manner of death and also instigated preventive measures for testing in the child. This case supports previous studies that acknowledge the need for molecular testing in the autopsy-negative, sudden unexpected death cases in young patients. Forensic pathologists have a duty to the public to serve as their physicians and this may prove to be a key area that can contribute to the preventative medicine effort and provide closure to families that may have loved ones left with an undetermined cause and manner of death. Although financially a problem, the future of pathology is undeniably heading in the direction of molecular testing and an attempt to adjust an internal budget in order to include expenses for these tests should be considered.

Keywords

Forensic pathology Long QT Postpartum Molecular Genetic Sudden unexpected death

Get full access to this article

View all access options for this article.

References

Tester

D.J.

, Medeiros-Domingo

, Will

M.L.

. Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsy-negative sudden unexplained death referred for postmortem genetic testing. Mayo Clin Proc. 2012 Jun; 87(6): 524–39.

UpToDate [Internet]. Waltham (MA): Wolters Kluwer Health; c2014. Clinical features of congenital long QT syndrome; [cited 2014 Aug 20]. Available from: http://www.uptodate.com/contents/clinical-features-of-congenital-long-qt-syndrome?source=search_result&search=Clinical+features+of+congenital+long+QT+syndrome.&selectedTitle=1%7E66.

UpToDate [Internet]. Waltham (MA): Wolters Kluwer Health; c2014. Genetics of congenital and acquired long QT syndrome; [cited 2014 Aug 20]. Available from: http://www.uptodate.com/contents/genetics-of-congenital-and-acquired-long-qt-syndrome?source=search_result&search=Genetics+of+congenital+and+acquired+long+QT+syndrome&selectedTme=1%7E150.

Schwartz

P.J.

, Priori

S.G.

, Spazzolini

. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation. 2001 Jan 2; 103(1): 89–95.

Splawski

, Shen

, Timothy

K.W.

. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000 Sep 5; 102(10): 1178–85.

Priori

SG1

, Napolitano

, Schwartz

P.J.

Low penetrance in the long-QT syndrome: clinical impact.

Circulation. 1999 Feb 2; 99(4): 529–33.

Schwartz

P.J.

, Stramba-Badiale

, Segantini

. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med. 1998 Jun 11; 338(24): 1709–14.

Zareba

, Moss

A.J.

, Schwartz

P.J.

. Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med. 1998 Oct 1; 339(14): 960–5.

Takenaka

, Ai

, Shimizu

. Exercise stress test amplifies genotype-phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome. Circulation. 2003 Feb 18; 107(6): 838–44.

10.

UpToDate [Internet]. Waltham (MA): Wolters Kluwer Health; c2014. Ventricular arrhythmias during pregnancy; [cited 2014 Aug 20]. Available from: http://www.uptodate.com/contents/ventricular-arrhythmias-during-pregnancy?source=search_result&search=Ventricular+arrhythmias+during+pregnancy&selectedTitle=1%7E150.

11.

Rashba

E.J.

, Zareba

, Moss

A.J.

. Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome. LQTS Investigators. Circulation. 1998 Feb 10; 97(5): 451–6.

12.

Khositseth

, Tester

D.J.

, Will

M.L.

. Identification of a common genetic substrate underlying postpartum cardiac events in congenital long QT syndrome. Heart Rhythm. 2004 May; 1(1): 60–4.

13.

UpToDate [Internet]. Waltham (MA): Wolters Kluwer Health; c2014. Diagnosis of congenital long QT syndrome; [cited 2014 Aug 20]. Available from: http://www.uptodate.com/contents/diagnosis-of-congenital-long-qt-syndrome?source=search_result&search=Diagnosis+of+congenital+long+QT-t-syndrome&selectedTitle=1%7E66.

14.

Garson

Jr. , Dick

2nd , Fournier

. The long QT syndrome in children. An international study of 287 patients. Circulation. 1993 Jun; 87(6): 1866–72.

15.

Skinner

J.R.

, Crawford

, Smith

. Prospective, population-based long QT molecular autopsy study of postmortem negative sudden death in 1 to 40 year olds. Heart Rhythm. 2011 Mar; 8(3): 412–9.

16.

Chugh

S.S.

, Senashova

, Watts

. Postmortem molecular screening in unexplained sudden death. J Am Coll Cardiol. 2004 May 5; 43(9): 1625–9.

17.

Di Paolo

, Luchini

, Bloise

, Priori

S.G.

Postmortem molecular analysis in victims of sudden unexplained death.

Am J Forensic Med Pathol. 2004 Jun; 25(2): 182–4.

18.

Creighton

, Virmani

, Kutys

, Burke

Identification of novel missense mutations of cardiac ryanodine receptor gene in exercise-induced sudden death at autopsy.

J Mol Diagn. 2006 Feb; 8(1): 62–7.

19.

Gladding

P.A.

, Evans

C-A

, Crawford

. Posthumous diagnosis of long QT syndrome from neonatal screening cards. Heart Rhythm. 2010 Apr; 7(4): 481–6.

20.

Kauferstein

, Kiehne

, Jenewein

. Genetic analysis of sudden unexplained death: a multidisciplinary approach. Forensic Sci Int. 2013 Jun 10; 229(1-3): 122–7.

21.

Napolitano

, Priori

S.G.

, Schwartz

P.J.

. Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA. 2005 Dec 21; 294(23): 2975–80.