Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases

Abstract

Sudden infant death syndrome (SIDS) is described as the sudden and unexplained death of an apparently healthy infant younger than one year of age. Genetic studies indicate that up to 35% of SIDS cases might be explained by familial or genetic diseases such as cardiomyopathies, ion channelopathies or metabolic disorders that remained undetected during conventional forensic autopsy procedures. Post-mortem genetic testing by using massive parallel sequencing (MPS) approaches represents an efficient and rapid tool to further investigate unexplained death cases and might help to elucidate pathogenic genetic variants and mechanisms in cases without a conclusive cause of death. In this study, we performed whole-exome sequencing (WES) in 161 European SIDS infants with focus on 192 genes associated with cardiovascular and metabolic diseases. Potentially causative variants were detected in 20% of the SIDS cases. The majority of infants had variants with likely functional effects in genes associated with channelopathies (9%), followed by cardiomyopathies (7%) and metabolic diseases (1%). Although lethal arrhythmia represents the most plausible and likely cause of death, the majority of SIDS cases still remains elusive and might be explained by a multifactorial etiology, triggered by a combination of different genetic and environmental risk factors. As WES is not substantially more expensive than a targeted sequencing approach, it represents an unbiased screening of the exome, which could help to investigate different pathogenic mechanisms within the genetically heterogeneous SIDS cohort. Additionally, re-analysis of the datasets provides the basis to identify new candidate genes in sudden infant death.

SCN1A variants associated with sudden infant death syndrome

“…From a cohort of 10 infants with SIDS, we identified 2 cases with heterozygous SCN1A variants. The variants we report, similar to those we have cited, are predicted to be pathogenic using in silico assessments. These predictions are further strengthened by association with previously reported cases with epilepsy, location of the variants in critical, disease‐associated domains of the protein, and functional evidence that the variants present in both cases exhibit partial loss of function.…”

“…SCN1A ‐related mechanisms have been postulated to underlie a risk of SUDEP in patients with Dravet syndrome, with evidence from rodent models providing supporting evidence . In recent reports, SCN1A was not included in the panel of genes interrogated . A report of SCN1A Leu61Pro in association with SUDC underscores the potential for SIDS and SUDC to share SCN1A‐related mechanisms.…”

“…24 In recent reports, SCN1A was not included in the panel of genes interrogated. 9,20 A report of SCN1A Leu61Pro in association with SUDC 25 underscores the potential for SIDS and SUDC to share SCN1A-related mechanisms. Additional SCN1A variants associated with SUDEP 8 support the extension of the spectrum of SCN1A into the realm of SUDEP.…”

A Systematic Review of Molecular Autopsy Studies in Sudden Infant Death Cases

“…A total of 20 original research studies [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] and seven case reports [31][32][33][34][35][36][37] thus met the inclusion criteria for the review, which included at least one infant greater than 1-year-old in their study (►Table 1). One of the seven case reports, however, 34 was also represented in one original research article.…”

Sudden Death Syndrome and Other Indicators of Infant Death in Stavropol Region

“…Сегодня они дополняются данными биохимических, генетических, иммуногистохимических и иммунофлуо-ресцентных исследований в виде констатации тех или иных находок [18][19][20][21][22][23][24][25]. На этом фоне обращает на себя внимание фундаментальная и патогенетически «строй-ная» научная работа Парилова С.Л.…”