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Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing

Fecha de publicación:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Nunn LM
  • Lopes LR
  • Syrris P
  • Murphy C
  • Plagnol V
  • Firman E
  • Dalageorgou C
  • Murday V
  • Findlay I
  • Duncan A
  • Carr-White G
  • Robert L
  • Bueser T
  • Langman C
  • Fynn SP
  • Goddard M
  • White A
  • Bundgaard H
  • Ferrero-Miliani L
  • Wheeldon N
  • Suvarna SK
  • O'Beirne A
  • Lowe MD
  • McKenna WJ
  • Elliott PM
  • Lambiase PD

Grupos

Abstract

The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible. To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isolated from 59 SADS victims (mean age 25 years, range 1-51 years). Targeted exome sequencing of 135 genes associated with cardiomyopathies and ion channelopathies was performed on the Illumina HiSeq2000 platform. Non-synonymous, loss-of-function, and splice-site variants with a minor allele frequency < 0.02% in the NHLBI exome sequencing project and an internal set of control exomes were prioritized for analysis followed by < 0.5% frequency threshold secondary analysis. First-degree relatives were offered clinical screening for inherited cardiac conditions. Seven probands (12%) carried very rare (< 0.02%) or novel non-sense candidate mutations and 10 probands (17%) had previously published rare (0.02-0.5%) candidate mutations-a total yield of 29%. Co-segregation fully confirmed two private SCN5A Na channel mutations. Variants of unknown significance were detected in a further 34% of probands. Molecular autopsy using targeted exome sequencing has a relatively low diagnostic yield of very rare potentially disease causing mutations. Candidate pathogenic variants with a higher frequency in control populations are relatively common and should be interpreted with caution.

Datos de la publicación

ISSN/ISSNe:
1099-5129, 1532-2092

EUROPACE  OXFORD UNIV PRESS

Tipo:
Article
Páginas:
888-896
Factor de Impacto:
2,674 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 54

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Keywords

  • SADS; Sudden cardiac death; Molecular autopsy; Exome sequencing; Long QT syndrome; Brugada syndrome

Campos de estudio

Proyectos asociados

RED INVESTIGACION (RECAVA)

RD06/0014/0004 . INSTITUTO DE SALUD CARLOS III; FUNDACION PARA LA INV BIOMEDICA- HOSPITAL GREGORIO MARAÑON; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2006

CANALOPATIAS EN LA ATIOPATOGENIA DEL SINDROME DE MUERTE SUBITA DEL LACTANTE

Investigador Principal: ESTHER ZORIO GRIMA

PI07/0831 . INSTITUTO DE SALUD CARLOS III . 2007

RED DE BIOBANCOS (BIOBANCOS)

RD09/0076/00021 . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2010

ESTUDIO DE MICRORNAS IMPLICADOS EN LOS SISTEMAS HEMOSTÁTICO, PROTEOLÍTICO Y ANGIOGÉNICO: SU RELACIÓN CON LA TROMBOSIS Y LA PATOLOGÍA ENDOMETRIAL.

PROMETEO/2011/027 . FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA; CONSELLERIA DE EDUCACION . 2011

RED CARDIOVASCULAR

Investigador Principal: FRANCISCO ESPAÑA FURIO

RD12/0042/0029 . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2013

CARACTERIZACION METABOLOMICA DE LA MIOCARDIOPATIA ARRITMOGENICA

Investigador Principal: ESTHER ZORIO GRIMA

2013_0126_CRC_METABOLOMICA_ZORIO . FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2013

CARACTERIZACIÓN DEL PATRÓN DE MICRORNAS EN LA MUERTE SÚBITA CARDIACA DE ORIGEN ISQUÉMICO. ANÁLISIS DE SU RELACIÓN CON LA DISLIPEMIA, LA GRASA EPICÁRDICA, LA ESTEATOSIS NO ALCOHÓLICA Y FACTORES DE COAGULACION Y FIBRINOLISIS.

Investigador Principal: ESTHER ZORIO GRIMA

2013_0454_CRC_ZORIO . ASTRAZENECA FARMACÉUTICA SPAIN, S.A.; FUNDACION ESPAÑOLA DE TROMBOSIS Y HEMOSTASIA . 2014

MECANISMOS DE ENFERMEDAD EN LA MIOCARDIOPATIA ARRITMOGENICA, MEJORAS EN SU DIAGNOSTICO Y BUSQUEDA DE DIANAS TERAPEUTICAS.

Investigador Principal: ESTHER ZORIO GRIMA

PI14/01477 . INSTITUTO DE SALUD CARLOS III . 2015

VALIDACIÓN EXTERNA DE LA UTILIDAD DE LOS PARÁMETROS DE DEFORMACIÓN MIOCÁRDICA EN EL RECHAZO AGUDO DEL INJERTO.

Investigador Principal: LUIS ALMENAR BONET

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