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Genetic determinants in sudden infant death syndrome (SIDS) and sudden unexplained death syndrome (SUDS)

English title Genetic determinants in sudden infant death syndrome (SIDS) and sudden unexplained death syndrome (SUDS)
Applicant Haas Cordula
Number 149456
Funding scheme Project funding (Div. I-III)
Research institution Institut für Rechtsmedizin Universität Zürich-Irchel
Institution of higher education University of Zurich - ZH
Main discipline Congenital Disorders
Start/End 01.10.2013 - 31.03.2017
Approved amount 311'000.00
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All Disciplines (4)

Discipline
Congenital Disorders
Genetics
Cardiovascular Research
Methods of Epidemiology and Preventive Medicine

Keywords (5)

Molecular genetics; Channelopathies; Exome sequencing; SUDS; SIDS

Lay Summary (German)

Lead
Der plötzliche Säuglingstod (SIDS) und der plötzliche und unerklärbare Tod bei Jugendlichen und Erwachsenen (SUDS) sind Syndrome, bei welchen die Todesursache auch nach einer umfassenden Obduktion nicht festgestellt werden kann. Für beide Syndrome werden genetische Prädispositionen als mögliche Risikofaktoren in Betracht gezogen. Wir möchten SIDS- und SUDS-Fälle mit neusten molekulargenetischen Analysen untersuchen, um Erkenntnisse zu möglichen Krankheitsmechanismen zu erlangen.
Lay summary

Abklärung von genetischen Risikofaktoren beim plötzlichen Säuglingstod (SIDS) und beim plötzlichen und unerklärbaren Tod bei Jugendlichen und Erwachsenen (SUDS)

Lead

Der plötzliche Säuglingstod (SIDS) und der plötzliche und unerklärbare Tod bei Jugendlichen und Erwachsenen (SUDS) sind Syndrome, bei welchen die Todesursache auch nach einer umfassenden Obduktion nicht festgestellt werden kann. Für beide Syndrome werden genetische Prädispositionen als mögliche Risikofaktoren in Betracht gezogen. Wir möchten SIDS- und SUDS-Fälle mit neusten molekulargenetischen Analysen untersuchen, um Erkenntnisse zu möglichen Krankheitsmechanismen zu erlangen.

Inhalt und Ziel des Forschungsprojekts

Am Institut für Rechtsmedizin in Zürich haben wir eine Biobank und Register eingerichtet, um SIDS- und SUDS-Fälle systematisch zu erfassen und Gewebeproben zu sammeln. Das Ziel unseres Forschungsprojekts ist die genetische Untersuchung dieser SIDS- und SUDS Fälle mittels Exom-Sequenzierung. Dazu sollen bisher international publizierte Hypothesen in unseren SIDS/SUDS-Kohorten überprüft und neue Kandidatengene gefunden werden.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

SIDS- und SUDS-Todesfälle stellen schwer verkraftbare und belastende Ereignisse für die Hinterbliebenen dar. Neue genetische Erkenntnisse und die Durchführung einer molekularen Autopsie können zur Aufklärung solcher Todesfälle beitragen.

Direct link to Lay Summary Last update: 10.10.2013

Responsible applicant and co-applicants

Publications

Publication
Functional characterization of a novel SCN5A variant associated with long QT syndrome and sudden cardiac death
Neubauer Jacqueline, Wang Zizun, Rougier Jean-Sebastien, Abriel Hugues, Rieubland Claudine, Bartholdi Deborah, Haas Cordula, Medeiros-Domingo Argelia (2019), Functional characterization of a novel SCN5A variant associated with long QT syndrome and sudden cardiac death, in International Journal of Legal Medicine, online(online), 1-10.
Exome analysis in 34 sudden unexplained death (SUD) victims mainly identified variants in channelopathy-associated genes
Neubauer Jacqueline, Lecca Maria Rita, Russo Giancarlo, Bartsch Christine, Medeiros-Domingo Argelia, Berger Wolfgang, Haas Cordula (2018), Exome analysis in 34 sudden unexplained death (SUD) victims mainly identified variants in channelopathy-associated genes, in International Journal of Legal Medicine, 132(4), 1057-1065.
Functional implications of a rare variant in the sodium channel b1B subunit (SCN1B) in a 5-month-old male sudden infant death syndrome case
Neubauer Jacqueline, Rougier Jean-Sebastien, Abriel Hugues, Haas Cordula (2018), Functional implications of a rare variant in the sodium channel b1B subunit (SCN1B) in a 5-month-old male sudden infant death syndrome case, in HeartRhythm Case Reports, 4(5), 187-190.
Sex-dependent differences in the in vivo respiratory phenotype of the TASK-1 potassium channel knockout mouse
Jungbauer Stefan, Buehler Philipp Karl, Neubauer Jacqueline, Haas Cordula, Heitzmann Dirk, Tegtmeier Ines, Sterner Christina, Barhanin Jacques, Georgieff Michael, Warth Richard, Thomas Jörg (2017), Sex-dependent differences in the in vivo respiratory phenotype of the TASK-1 potassium channel knockout mouse, in Respiratory Physiology & Neurobiology, 245, 13-28.
Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases
Neubauer Jacqueline, Lecca Maria Rita, Russo Giancarlo, Bartsch Christine, Medeiros-Domingo Argelia, Berger Wolfgang, Haas Cordula (2017), Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases, in European Journal of Human Genetics, 25(4), 404-409.
Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases
Neubauer Jacqueline, Haas Cordula, Bartsch Christine, Medeiros-Domingo Argelia, Berger Wolfgang (2016), Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases, in International Journal of Legal Medicine, (4), 1011-1021.

Collaboration

Group / person Country
Types of collaboration
University of Berne Switzerland (Europe)
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
American Society of Human Genetics ASHG2016 Poster Whole exome sequencing in 161 sudden infant death syndrome (SIDS) cases with a focus on cardiovascular and metabolic genetic diseases 18.10.2016 Vancouver, Canada Berger Wolfgang; Haas Cordula; Bartsch Christine;
27. Jahrestagung der Deutschen Gesellschaft für Humangenetik Talk given at a conference Whole-exome sequencing in 161 sudden infant death syndrome (SIDS) cases identifies potentially disease-associated variants in one third of our cohort 16.03.2016 Lübeck, Germany Haas Cordula;
Sudden cardiac death symposium Talk given at a conference Genetic mechanisms involved in sudden infant death syndrome (SIDS): early experience with exome approach 06.11.2014 Berne, Switzerland Haas Cordula;
22. Arbeitsgespräch der AG deutschsprachiger Kinderpathologen Talk given at a conference Risk factors in sudden infant death syndrome (SIDS) 23.11.2013 Zurich, Switzerland Haas Cordula;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Plötzlicher Herztod: Recht, Genetik, Prävention German-speaking Switzerland 2019
Media relations: print media, online media Der plötzliche Herztod kann in der Familie liegen Tages-Anzeiger German-speaking Switzerland 2018

Abstract

Sudden infant death syndrome (SIDS) is the sudden death of an infant under 1 year old, unexpected and unexplained despite conventional autopsy. SIDS is one of the leading causes of death in infants in their first year of life. SIDS pathogenesis is understood as ‘triple risk hypothesis in which (1) a vulnerable infant, (2) in a critical developmental period, (3) exposed to exogenous stressors, co-occur to culminate in SIDS. Emerging evidence suggest an expanding number of genetic risk factors.Sudden unexplained death syndrome (SUDS) is the sudden death of an individual older than 1 year, unexpected and unexplained despite conventional autopsy. In cases older than 40 years the leading etiology is ischemic heart disease. However, in the young near one third could be explained by ion channel diseases, a group of genetic determined disorders providing vulnerability to lethal cardiac arrhythmias, commonly undetected in the affected individual.Considering that autopsy negative SIDS/SUDS accounts for a significant number of sudden deaths in the young and that approximately one-third of SUDS and 10% of SIDS stem from a lethal cardiac channelopathy, the cardiac channel molecular autopsy should be viewed as the standard of care for postmortem evaluation of SIDS/SUDS. Nevertheless, other non-cardiac diseases might be omitted with this approach and further broad genetic studies are needed to evaluate the impact of other non-cardiac diseases in SIDS and SUDS.During the last years, enormous technical progress has been achieved in the areas of DNA sequencing and genotyping-array technology, including exome sequencing, defined as the selective sequencing of all exons in a genome. This method is very useful to identify novel genes associated with rare and common diseases. It is estimated that the protein coding regions of the human genome constitute about 85% of disease-causing mutations. Within the next 3 years our aim is to perform exome sequencing in about 200 SIDS and 40 SUDS cases, all collected during postmortem examination at the Institute of Legal Medicine at the University of Zurich. From our exome analysis data, we in a first step will look at genes reported to be associated with SIDS and SUDS. We will try to replicate previously reported genetic mechanisms in our Swiss SIDS and SUDS cohorts. In a second step we want to identify new SIDS/SUDS candidate genes from the exome sequencing data using appropriate computational and statistical approaches. If we have evidence of clinical phenotype in other family members, we will use as well linkage-like analysis to complement our data.Based on our genetic results in the Swiss population, we will develop a Molecular Autopsy protocol with the inclusion of the major genes found in our SIDS or SUDS cohorts. We plan to build collaborations with other major forensic and genetic Institutes in Switzerland in order to standardize together a Swiss approach to SIDS and SUDS victims, complemented with international data reported before.We will also evaluate the frequency of underlying channelopathy in first degree relatives of SIDS/SUDS victims willing to participate in our study. We plan to establish in the future a clinical approach protocol for relatives of SIDS/SUDS victims left behind. The data collection for this aim will start during the development of this grant, however, since this is a prospective study, we will have adequate numbers beyond the time frame of this proposal.
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