Molecular genetics; Channelopathies; Exome sequencing; SUDS; SIDS
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.
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.
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.
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.
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.
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.
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.