Review Article | Published:

Sudden infant death syndrome and inherited cardiac conditions

Nature Reviews Cardiology volume 14, pages 715726 (2017) | Download Citation

Abstract

Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant mortality in developed countries, characterized by the death of infants for no obvious reason and without prior warning. The complex interaction of multiple factors in the pathogenesis of SIDS is illustrated by the 'triple risk hypothesis', which proposed that SIDS results from a convergence of three overlapping risk factors: a critical developmental period, an exogenous stressor, and underlying genetic and/or nongenetic vulnerability in the infant. Rare variants in genes associated with inherited arrhythmia syndromes and cardiomyopathies have been proposed as the substrate for an infant's critical vulnerability in a small subset of SIDS cases. Given the potential risk of inherited cardiac disease, current guidelines recommend post-mortem genetic testing (molecular autopsy) and cardiological investigation of the surviving family, complemented by targeted genetic testing if appropriate. In this Review, we highlight the latest developments in understanding the spectrum and prevalence of cardiac-mediated SIDS, and discuss the clinical implications of SIDS in the surviving family and the general population.

Key points

  • An ultra-rare variant in an inherited cardiac condition-related gene that might have contributed to an arrhythmogenic sudden death of the infant is identified in 14% of sudden infant death syndrome (SIDS) cases

  • Current data indicate that the diagnostic yield of nonsynonymous, ultra-rare variants in inherited cardiac condition-related genes in SIDS cohorts is not higher than in the general population

  • This 'reality check' highlights the importance of understanding that causation of SIDS is complex and multifactorial, and that highly-penetrant, monogenic cardiac disorders contribute to only a small number of SIDS cases

  • Simultaneous genetic evaluation of the deceased infant and the parents might offer the only ready way to interpret ultra-rare and novel variants for clinical use

  • When a gene mutation is identified by molecular autopsy, initial familial genetic testing should focus on the parents to determine whether the mutation is inherited or arose de novo in the deceased

  • Specialized, multidisciplinary, cardiac genetic teams have a pivotal role in management of the surviving family; cardiological investigation of surviving relatives might identify a genetic risk, although limited evidence supports this assertion

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Acknowledgements

A.-E.B.'s research work is supported by a research grant of the ESC and by research funds from Cardiac Risk in the Young.

Author information

Affiliations

  1. Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Institute, St George's University of London, Cranmer Terrace, London SW17 0RE, UK.

    • Alban-Elouen Baruteau
    •  & Elijah R. Behr
  2. Department of Congenital Cardiology, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH, UK.

    • Alban-Elouen Baruteau
  3. Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.

    • David J. Tester
    • , Jamie D. Kapplinger
    •  & Michael J. Ackerman
  4. Department of Cardiovascular Diseases, Division of Heart Rhythm Services, and Department of Pediatrics, Division of Pediatric Cardiology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.

    • David J. Tester
    •  & Michael J. Ackerman

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Contributions

A.-E.B. researched data for the article and wrote the manuscript. M.J.A. and E.R.B. conceptualized and designed the article. All authors provided substantial contribution to the discussion of contents and critically reviewed and/or edited the manuscript before submission.

Competing interests

M.J.A. is a consultant for Boston Scientific, Gilead Sciences, Invitae, Medtronic, MyoKardia, and St. Jude Medical; M.J.A. and Mayo Clinic received royalties from Transgenomic for their FAMILION-LQTS and FAMILION-CPVT genetic tests, but none of these entities was involved in this article. The other authors declare no competing interests.

Corresponding author

Correspondence to Elijah R. Behr.

Supplementary information

PDF files

  1. 1.

    Supplementary information S1 (table)

    Variants in arrhythmia syndrome-related genes reported in SIDS cases: Na+ channel

  2. 2.

    Supplementary information S2 (table)

    Variants in arrhythmia syndrome-related genes reported in SIDS cases: K+ channels

  3. 3.

    Supplementary information S3 (table)

    Variants in arrhythmia syndrome-related genes reported in SIDS cases: Ca2+-handling and other ion channels

  4. 4.

    Supplementary information S4 (table)

    Variants in inherited cardiomyopathy-related genes reported in SIDS cohort studies

  5. 5.

    Supplementary information S5 (box)

    Analytical methods for Table 3

Glossary

De novo genetic variants

A genetic variant that is present for the first time in one family member as a result of a genetic alteration in a germ cell of one of the parents, or a variant that arises in the fertilized egg itself during early embryogenesis.

Loss-of-function mutations

A mutation that results in reduced or abolished protein function.

Gain-of-function mutations

A mutation that results in an increased protein function.

Whole-exome sequencing

Sequencing of the protein-coding (exonic) regions in the genome and related sequences, which represents approximately 1% of the DNA sequence.

Next-generation sequencing

A high-throughput method used to determine a portion of the nucleotide sequence of an individual's genome; utilizes sequencing technologies capable of processing multiple DNA sequences in parallel.

Sanger sequencing

A low-throughput method used to determine a portion of the nucleotide sequence of an individual's genome; involves polymerase chain reaction (PCR) amplification of genetic regions of interest followed by sequencing of PCR products.

Diagnostic yield

The likelihood that a test or procedure will provide the information needed to establish a diagnosis.

Linkage studies

Gene-hunting technique that traces patterns of disease in families at high risk to locate a disease-causing gene by identifying genetic markers of known chromosomal location that are co-inherited with the trait of interest.

Minor allele frequency

Frequency at which the second most common allele occurs in a given population.

Mendelian inherited disorders

Disorders caused by gene mutations that are transmitted from parents to children according to Mendel's laws.

Segregation studies

Process of fitting formal genetic models to data on expressed disease characteristics (phenotype) in biological family members to determine the most probable mode of inheritance for the trait or disease.

Proband

The individual through whom a family with a genetic disorder is ascertained; also called a propositus.

Penetrance

A characteristic of a genotype; refers to the likelihood that a clinical condition will occur when a particular genotype is present.

Trio analyses

Genetic analysis of a case and two parents to determine whether a genetic variant is transmitted or occurred de novo.

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DOI

https://doi.org/10.1038/nrcardio.2017.129

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