Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome

Najim Lahrouchi; Hariharan Raju; Elisabeth M Lodder; Efstathios Papatheodorou; James S Ware; Michael Papadakis; Rafik Tadros; Della Cole; Jonathan R Skinner; Jackie Crawford; Donald R Love; Chee J Pua; Bee Y Soh; Jaydutt D Bhalshankar; Risha Govind; Jacob Tfelt-Hansen; Bo G Winkel; Christian van der Werf; Yanushi D Wijeyeratne; Greg Mellor; Jan Till; Marta C Cohen; Maria Tome-Esteban; Sanjay Sharma; Arthur A M Wilde; Stuart A Cook; Connie R Bezzina; Mary N Sheppard; Elijah R Behr

doi:10.1016/j.jacc.2017.02.046

Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome

Najim Lahrouchi, Hariharan Raju, Elisabeth M Lodder, Efstathios Papatheodorou, James S Ware, Michael Papadakis, Rafik Tadros, Della Cole, Jonathan R Skinner, Jackie Crawford, Donald R Love, Chee J Pua, Bee Y Soh, Jaydutt D Bhalshankar, Risha Govind, Jacob Tfelt-Hansen, Bo G Winkel, Christian van der Werf, Yanushi D Wijeyeratne, Greg MellorJan Till, Marta C Cohen, Maria Tome-Esteban, Sanjay Sharma, Arthur A M Wilde, Stuart A Cook, Connie R Bezzina, Mary N Sheppard, Elijah R Behr

Department of Clinical Medicine

112 Citations (Scopus)

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Abstract

BACKGROUND: Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology.

OBJECTIVES: This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives.

METHODS: We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls.

RESULTS: A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10-5). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%.

CONCLUSIONS: Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.

Original language	English
Journal	Journal of the American College of Cardiology
Volume	69
Issue number	17
Pages (from-to)	2134-2145
ISSN	0735-1097
DOIs	https://doi.org/10.1016/j.jacc.2017.02.046
Publication status	Published - 2 May 2017

Keywords

Adolescent
Adult
Child
Death, Sudden, Cardiac/etiology
Female
Genetic Testing
Humans
Male
Young Adult

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Lahrouchi, N., Raju, H., Lodder, E. M., Papatheodorou, E., Ware, J. S., Papadakis, M., Tadros, R., Cole, D., Skinner, J. R., Crawford, J., Love, D. R., Pua, C. J., Soh, B. Y., Bhalshankar, J. D., Govind, R., Tfelt-Hansen, J., Winkel, B. G., van der Werf, C., Wijeyeratne, Y. D., ... Behr, E. R. (2017). Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome. Journal of the American College of Cardiology, 69(17), 2134-2145. https://doi.org/10.1016/j.jacc.2017.02.046

Lahrouchi, N, Raju, H, Lodder, EM, Papatheodorou, E, Ware, JS, Papadakis, M, Tadros, R, Cole, D, Skinner, JR, Crawford, J, Love, DR, Pua, CJ, Soh, BY, Bhalshankar, JD, Govind, R, Tfelt-Hansen, J, Winkel, BG, van der Werf, C, Wijeyeratne, YD, Mellor, G, Till, J, Cohen, MC, Tome-Esteban, M, Sharma, S, Wilde, AAM, Cook, SA, Bezzina, CR, Sheppard, MN & Behr, ER 2017, 'Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome', Journal of the American College of Cardiology, vol. 69, no. 17, pp. 2134-2145. https://doi.org/10.1016/j.jacc.2017.02.046

@article{dc9e233232fc43c39fdbbf5c4881c7f0,

title = "Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome",

abstract = "BACKGROUND: Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology.OBJECTIVES: This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives.METHODS: We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls.RESULTS: A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10-5). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%.CONCLUSIONS: Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.",

keywords = "Adolescent, Adult, Child, Death, Sudden, Cardiac/etiology, Female, Genetic Testing, Humans, Male, Young Adult",

author = "Najim Lahrouchi and Hariharan Raju and Lodder, {Elisabeth M} and Efstathios Papatheodorou and Ware, {James S} and Michael Papadakis and Rafik Tadros and Della Cole and Skinner, {Jonathan R} and Jackie Crawford and Love, {Donald R} and Pua, {Chee J} and Soh, {Bee Y} and Bhalshankar, {Jaydutt D} and Risha Govind and Jacob Tfelt-Hansen and Winkel, {Bo G} and {van der Werf}, Christian and Wijeyeratne, {Yanushi D} and Greg Mellor and Jan Till and Cohen, {Marta C} and Maria Tome-Esteban and Sanjay Sharma and Wilde, {Arthur A M} and Cook, {Stuart A} and Bezzina, {Connie R} and Sheppard, {Mary N} and Behr, {Elijah R}",

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doi = "10.1016/j.jacc.2017.02.046",

language = "English",

volume = "69",

pages = "2134--2145",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

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TY - JOUR

T1 - Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome

AU - Lahrouchi, Najim

AU - Raju, Hariharan

AU - Lodder, Elisabeth M

AU - Papatheodorou, Efstathios

AU - Ware, James S

AU - Papadakis, Michael

AU - Tadros, Rafik

AU - Cole, Della

AU - Skinner, Jonathan R

AU - Crawford, Jackie

AU - Love, Donald R

AU - Pua, Chee J

AU - Soh, Bee Y

AU - Bhalshankar, Jaydutt D

AU - Govind, Risha

AU - Tfelt-Hansen, Jacob

AU - Winkel, Bo G

AU - van der Werf, Christian

AU - Wijeyeratne, Yanushi D

AU - Mellor, Greg

AU - Till, Jan

AU - Cohen, Marta C

AU - Tome-Esteban, Maria

AU - Sharma, Sanjay

AU - Wilde, Arthur A M

AU - Cook, Stuart A

AU - Bezzina, Connie R

AU - Sheppard, Mary N

AU - Behr, Elijah R

PY - 2017/5/2

Y1 - 2017/5/2

N2 - BACKGROUND: Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology.OBJECTIVES: This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives.METHODS: We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls.RESULTS: A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10-5). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%.CONCLUSIONS: Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.

AB - BACKGROUND: Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology.OBJECTIVES: This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives.METHODS: We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls.RESULTS: A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10-5). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%.CONCLUSIONS: Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.

KW - Adolescent

KW - Adult

KW - Child

KW - Death, Sudden, Cardiac/etiology

KW - Female

KW - Genetic Testing

KW - Humans

KW - Male

KW - Young Adult

U2 - 10.1016/j.jacc.2017.02.046

DO - 10.1016/j.jacc.2017.02.046

M3 - Journal article

C2 - 28449774

SN - 0735-1097

VL - 69

SP - 2134

EP - 2145

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 17

ER -

Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome

Abstract

Keywords

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