Reappraisal of variants previously linked with sudden infant death syndrome: results from three population-based cohorts

Christian Paludan-Mueller; Jonas Ghouse; Oliver B. Vad; Cecilie B. Herfelt; Pia Lundegaard; Gustav Ahlberg; Nicole Schmitt; Jesper H. Svendsen; Stig Haunso; Henning Bundgaard; Torben Hansen; Jurgen K. Kanters; Morten S. Olesen

doi:10.1038/s41431-019-0416-3

Reappraisal of variants previously linked with sudden infant death syndrome: results from three population-based cohorts

Christian Paludan-Mueller, Jonas Ghouse, Oliver B. Vad, Cecilie B. Herfelt, Pia Lundegaard, Gustav Ahlberg, Nicole Schmitt, Jesper H. Svendsen, Stig Haunso, Henning Bundgaard, Torben Hansen, Jurgen K. Kanters, Morten S. Olesen

3 Citationer (Scopus)

Abstract

We aimed to investigate the pathogenicity of cardiac ion channel variants previously associated with SIDS. We reviewed SIDS-associated variants previously reported in databases and the literature in three large population-based cohorts; The ExAC database, the Inter99 study, and the UK Biobank (UKBB). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Of the 92 SIDS-associated variants, 59 (64%) were present in ExAC, 18 (20%) in Inter99, and 24 (26%) in UKBB. Using the Inter99 cohort, we found no difference in J-point amplitude and QTc-interval between carriers and non-carriers for 14/18 variants. There was no difference in the risk of syncope (P = 0.32), malignant ventricular arrhythmia (P = 0.96), and all-cause mortality (P = 0.59) between carriers and non-carriers. The ACMG guidelines reclassified 75% of all variants as variant-of-uncertain significance, likely benign, and benign. We identified similar to 2/3 of variants previously associated with SIDS and found no significant associations with electrocardiographic traits, syncope, malignant ventricular arrhythmia, or all-cause mortality. These data indicate that many of these variants are not highly penetrant, monogenic causes of SIDS and underline the importance of frequent reappraisal of genetic variants to avoid future misdiagnosis.

Originalsprog	Engelsk
Tidsskrift	European Journal of Human Genetics
Vol/bind	27
Udgave nummer	9
Sider (fra-til)	1427-1435
ISSN	1018-4813
DOI	https://doi.org/10.1038/s41431-019-0416-3
Status	Udgivet - 1 sep. 2019

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10.1038/s41431-019-0416-3

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Paludan-Mueller, C., Ghouse, J., Vad, O. B., Herfelt, C. B., Lundegaard, P., Ahlberg, G., Schmitt, N., Svendsen, J. H., Haunso, S., Bundgaard, H., Hansen, T., Kanters, J. K., & Olesen, M. S. (2019). Reappraisal of variants previously linked with sudden infant death syndrome: results from three population-based cohorts. European Journal of Human Genetics, 27(9), 1427-1435. https://doi.org/10.1038/s41431-019-0416-3

Paludan-Mueller, C, Ghouse, J, Vad, OB, Herfelt, CB, Lundegaard, P, Ahlberg, G, Schmitt, N, Svendsen, JH, Haunso, S, Bundgaard, H , Hansen, T , Kanters, JK & Olesen, MS 2019, 'Reappraisal of variants previously linked with sudden infant death syndrome: results from three population-based cohorts', European Journal of Human Genetics, bind 27, nr. 9, s. 1427-1435. https://doi.org/10.1038/s41431-019-0416-3

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abstract = "We aimed to investigate the pathogenicity of cardiac ion channel variants previously associated with SIDS. We reviewed SIDS-associated variants previously reported in databases and the literature in three large population-based cohorts; The ExAC database, the Inter99 study, and the UK Biobank (UKBB). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Of the 92 SIDS-associated variants, 59 (64%) were present in ExAC, 18 (20%) in Inter99, and 24 (26%) in UKBB. Using the Inter99 cohort, we found no difference in J-point amplitude and QTc-interval between carriers and non-carriers for 14/18 variants. There was no difference in the risk of syncope (P = 0.32), malignant ventricular arrhythmia (P = 0.96), and all-cause mortality (P = 0.59) between carriers and non-carriers. The ACMG guidelines reclassified 75% of all variants as variant-of-uncertain significance, likely benign, and benign. We identified similar to 2/3 of variants previously associated with SIDS and found no significant associations with electrocardiographic traits, syncope, malignant ventricular arrhythmia, or all-cause mortality. These data indicate that many of these variants are not highly penetrant, monogenic causes of SIDS and underline the importance of frequent reappraisal of genetic variants to avoid future misdiagnosis.",

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AU - Vad, Oliver B.

AU - Herfelt, Cecilie B.

AU - Lundegaard, Pia

AU - Ahlberg, Gustav

AU - Schmitt, Nicole

AU - Svendsen, Jesper H.

AU - Haunso, Stig

AU - Bundgaard, Henning

AU - Hansen, Torben

AU - Kanters, Jurgen K.

AU - Olesen, Morten S.

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N2 - We aimed to investigate the pathogenicity of cardiac ion channel variants previously associated with SIDS. We reviewed SIDS-associated variants previously reported in databases and the literature in three large population-based cohorts; The ExAC database, the Inter99 study, and the UK Biobank (UKBB). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Of the 92 SIDS-associated variants, 59 (64%) were present in ExAC, 18 (20%) in Inter99, and 24 (26%) in UKBB. Using the Inter99 cohort, we found no difference in J-point amplitude and QTc-interval between carriers and non-carriers for 14/18 variants. There was no difference in the risk of syncope (P = 0.32), malignant ventricular arrhythmia (P = 0.96), and all-cause mortality (P = 0.59) between carriers and non-carriers. The ACMG guidelines reclassified 75% of all variants as variant-of-uncertain significance, likely benign, and benign. We identified similar to 2/3 of variants previously associated with SIDS and found no significant associations with electrocardiographic traits, syncope, malignant ventricular arrhythmia, or all-cause mortality. These data indicate that many of these variants are not highly penetrant, monogenic causes of SIDS and underline the importance of frequent reappraisal of genetic variants to avoid future misdiagnosis.

AB - We aimed to investigate the pathogenicity of cardiac ion channel variants previously associated with SIDS. We reviewed SIDS-associated variants previously reported in databases and the literature in three large population-based cohorts; The ExAC database, the Inter99 study, and the UK Biobank (UKBB). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Of the 92 SIDS-associated variants, 59 (64%) were present in ExAC, 18 (20%) in Inter99, and 24 (26%) in UKBB. Using the Inter99 cohort, we found no difference in J-point amplitude and QTc-interval between carriers and non-carriers for 14/18 variants. There was no difference in the risk of syncope (P = 0.32), malignant ventricular arrhythmia (P = 0.96), and all-cause mortality (P = 0.59) between carriers and non-carriers. The ACMG guidelines reclassified 75% of all variants as variant-of-uncertain significance, likely benign, and benign. We identified similar to 2/3 of variants previously associated with SIDS and found no significant associations with electrocardiographic traits, syncope, malignant ventricular arrhythmia, or all-cause mortality. These data indicate that many of these variants are not highly penetrant, monogenic causes of SIDS and underline the importance of frequent reappraisal of genetic variants to avoid future misdiagnosis.

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Reappraisal of variants previously linked with sudden infant death syndrome: results from three population-based cohorts

Abstract

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