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Postmortem genetic testing of the ryanodine receptor 2 (RYR2) gene in a cohort of sudden unexplained death cases

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Abstract

The aim of this investigation was to identify pathogenic variants of the ryanodine receptor 2 (RYR2) gene in a cohort of persons aged 0–40 years who died of sudden unexpected death syndrome (SUD), including a cohort of infants who died of sudden infant death syndrome (SIDS). We genetically screened 29 of the 105 exons of the RYR2 gene associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) in 74 cases of SUD without reported structural abnormalities of the heart. Cases were selected from the case database at the Institute of Forensic Medicine, and subsequent mutational screening by DNA sequencing was performed to detect variants in DNA samples extracted from blood samples of deceased persons. A total of 7 of the examined 74 cases were heterozygous for a rare sequence variant in the RYR2 gene. We identified five novel missense variants (p.Q486H, p.D1872N, p.G2367R, p.E4213D, and p.H4579Y), one synonymous variant (p.L4767L), and one previously reported missense variant (p.G4315E). Follow-up studies were possible in family members of three probands (p.Q486H, p.D1872N, and p.H4579Y), and clinical examinations were conducted in family members of two of these probands (p.Q486H and p.H4579Y). In conclusion, we identified a higher prevalence of variants in the CPVT-associated gene RYR2 than in a previously reported cohort of SIDS (9.4% vs. 1–2%). Segregation studies show that one variant (p.H4579Y) co-segregates with CPVT and is presumed to be pathogenic.

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Acknowledgment

This work was supported by research grants from the Jørgen Møllers Foundation, the Augustinus Foundation, the Grosserer A. V. Lykfeldt and Wife Foundation, the Helga and Peter Kornings Foundation, the Grosserer Valdemar Foersom and Thyra Foersom Foundation, and Aarhus University.

Ethical standards

This study was approved by the regional ethical committees of Aarhus (M-20080178) and the Danish Data Protection Agency (2008-54-0558).

Conflict of interest

None declared

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Authors and Affiliations

  1. Department of Forensic Medicine, Faculty of Health Sciences, Aarhus University, Brendstrupgaardsvej 100, 8200, Aarhus N, Denmark

    M. K. Larsen, J. Hansen, I. B. Kristensen & J. Banner

  2. Unit for Cardiac and Cardiovascular Genetics, Oslo University Hopsital Rikshospitalet, Oslo, Norway

    K. E. Berge & T. P. Leren

  3. Department of Clinical Biochemistry, Aarhus University Hospital, Tage Hansens Gade, 8000, Aarhus C, Denmark

    P. H. Nissen

  4. Department of Cardiology, Aarhus University Hospital, Skejby, Brendstrupgaardsvej 100, 8200, Aarhus N, Denmark

    H. K. Jensen

Authors
  1. M. K. Larsen
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  2. K. E. Berge
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  3. T. P. Leren
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  4. P. H. Nissen
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  5. J. Hansen
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  6. I. B. Kristensen
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  7. J. Banner
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Corresponding author

Correspondence to M. K. Larsen.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplement 1

Primer sequences, location of the primers with respect to the exon/intron boundaries as well as conditions for thermal cycling used to generate PCR products for DNA sequencing of the translated exon RYR2. Unless otherwise indicated, the 5′ primer is used as sequencing primer (DOC 98 kb)

Supplement 2

Primer and probe sequences for RYR2 SNP PCR assays (DOC 38.5 kb)

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Larsen, M.K., Berge, K.E., Leren, T.P. et al. Postmortem genetic testing of the ryanodine receptor 2 (RYR2) gene in a cohort of sudden unexplained death cases. Int J Legal Med 127, 139–144 (2013). https://doi.org/10.1007/s00414-011-0658-2

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  • DOI: https://doi.org/10.1007/s00414-011-0658-2

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