Sudden Infant Death Syndrome (SIDS) is described as a diagnosis of exclusion and is defined as unanticipated passing away of an infant < 1 year of age that remains unsolved even after thorough inquiries that includes a review of the clinical history, performance of complete autopsy, and examination of the death scene (1). Matturri et al. (2) proposed the definitions of SIDS as “the sudden death of an infant under 1 year of age which remains unexplained after a thorough case investigation, including the performance of a complete autopsy, examination of the death scene, and review of the clinical history” should be modified by adding, at the end, the following: “a complete autopsy with an in-depth histopathologic analysis of the cardiorespiratory innervation and specialized myocardium, performed only by an experienced, reliable pathologist.” In 2004, Krous et al. defined SIDS as “The sudden unexpected death of an infant less than 1 year of age, with onset of the fatal episode apparently occurring during sleep, that remains unexplained after a thorough investigation, including performance of a complete autopsy and review of the circumstances of death and the clinical history.” This definition was elaborated by Ottaviani as, “the findings in the cardiac conduction and autonomic nervous systems detected in SIDS can be morphological substrates for the sudden unexpected death (3). In 2016, Goldstein et al. (4) reported that “there is no consensus on the use of the term SIDS, as external factors, such as prone sleep position or bed sharing, may at times explain the cause of death as positional asphyxia or accidental suffocation.”

Therefore, an in-depth histopathological analysis of the cardiac conduction system and autonomic nervous system by expert pathologists is mandatory (3). According to the American Heart Association (5), congenital heart diseases occur in 0.8% of full term live births. Anomalies in the cardiac conduction system and cardiac channelopathies should be considered to be included in congenital heart disease (6). SIDS is diagnosed by eliminating all other known illnesses. Incidence of SIDS spikes between 2 and 4 months of age and greater than 90% happens in the period of first 6 months of the life of infants. Due to the global campaign of “Back To sleep” along with other campaigns, 50-90% drop in the cases of SIDS has been recorded since 1990 (7).

SIDS and Sudden intrauterine death (SIUD) have multifactorial etiology comprising of congenital anomalies of the cardiac conduction system and the autonomic nervous system, respiratory rhythm generation and arousal from sleep (8). Based on these considerations, the new common definition for the SIDS-SIUDS complex is “The sudden death of a fetus after the 25th gestational week or infant under 1 year of age which is unexpected by history and remains unexplained after a thorough case investigation, including examination of the death scene, performance of a general autopsy and examination of the fetal adnexa” (3). Routine autopsy fails to disclose any cause of death in such cases and a more in depth histopathological analysis of the cardiac conduction system and autonomic nervous system is required. Molecular autopsy should also be followed in this regard.

Triple risk model for SIDS as described by Filiano and Kinney, suggests three factors: a vulnerable infant, a critical developmental period in homeostatic control, and an exogenous stressor(s) (9). All three factors, when present together, may lead to SIDS. Neuropathological and Cardiovascular conduction system abnormalities are the main culprits involved in the vulnerability of the infant or fetus for Sudden perinatal death when it combines with the genetic predisposition (3). Sudden cardiac death (SCD) is defined as the unexpected death without an obvious non-cardiac cause that occurs within 1 h of witnessed symptom or within 24 h of unwitnessed symptom onset (10). SCD occurs by at least these three mechanisms: Ischemia induced by a perturbation in a coronary artery with rapid development of ventricular fibrillation, arrhythmia occuring in an early-stage of acute myocardial infarction associated with coronary thrombosis, primary ventricular arrhythmia not associated with new onset ischemia, related to a cardiomyopathy or channelopathy (11).

Genetic predisposition is responsible for vulnerability of an infant toward SIDS. So, genetics does not play its role alone, but it interacts with the epidemiological factors and stressors acting in a critical developmental phase of the infant (12). It is important to understand the genetics associated with SIDS in order to prevent such casualties by taking care of modifiable risk factors in vulnerable infants. So far there is a scarcity of literature available due to limited research on this aspect which led us to write a comprehensive and updated review. Genetics play its role either directly such as in cases with medium-chain acyl-coenzyme A dehydrogenase deficiency and cardiac arrest due to long QT syndrome or indirectly by acting as a predisposing factor for SIDS (13, 14). Inheritance pattern of genes contributing to SIDS is polygenic and acts in combination with environmental risk factors, e.g., male gender, prone sleeping position, carelessness of parents, winter, seasonal variations, night, botulism etc. Immune system, cardio-respiratory function and neurophysiology related genes have been prominent so far in association with SIDS (13).

Inflammation and infections are also contributing factors in SIDS (15). Viral infections, particularly of the respiratory tract, are also among one of the etiological factors for SIDS. Epidemiology and pathology related to SIDS, provides evidence for this concept. But the results are conflicting regarding the isolation of specific viruses due to technical issues, lack of proper controls and many other reasons. However, another very important contributing factor for SIDS is an immunological response (16). Mucosal immune system is activated in SIDS in different studies (17, 18). Higher IgG and IgA immunocyte density in the tonsils of SIDS victims has been observed (18). Elevated expression of CD45+ stromal leucocytes and highly variable expression of human leukocyte antigen-antigen D(HLA-DR) and enhanced expression of HLA class I and II have also been observed in salivary glands in SIDS. It shows that the immune system is stimulated in SIDS with the release of cytokines, which then up-regulate the epithelial expression of HLA-DR (19). Bacteriological findings have also been reported and Staphylococcal aureus and staphylococcal endotoxins have been found to be prevalent in SIDS (20).

Altered immunological homeostasis has been hypothesized as an important factor for SIDS etiology. Cytokines are essential mediators for infant health by monitoring the cell activity during inflammation. The pro-inflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-8, IL-12, IL-18, TNF-α, and IFN-γ potentiates inflammation. The anti-inflammatory cytokines, e.g., interleukin-1 receptor antagonist (IL-1ra), IL-4, IL-10, IL-11, and IL-13 control them. Cytokine genes and their variants may explain the vulnerability of infants to infection. The genes encoding IL-1, IL-6, IL-10, and TNF-α are the most studied in SIDS. Genes involved in the immune system are important in SIDS and specific haplotypes in the IL-10 gene promoter have been associated with SIDS due to infection (21). In toddlers who had SIDS, polymorphism inside the gene IL10 (inflammatory cytokine interleukin 10) at promoter place could impel the reduction in production of antibodies or it can act as a substitute to enhance production of inflammatory cytokine (22). Immunogenetics and cytokine network are very complex to understand and need further exploration (23).

According to certain studies, genetic anomalies that are associated with channelopathies (arrhythmia) may also play a part in SIDS. Main lethal arrhythmias give rise to sudden cardiac death due to genetic variations such as: CPVT (catecholaminergic polymorphic ventricular tachycardia), LQTS (long QT syndrome), SQTS (short QT syndrome) and BrS (Brugada syndrome) (24). So far about 30 genes have been found linked with that of major principal cardiac arrhythmic ailment but mainly 4 genes (RyR2, SCN5A, KCNQ1, and KCNH2) have been taken into account. The chief answerable for each ailment: SQTS (KCNH2 20% and KCNQ1 30%), CPVT (RyR2 50%), BrS (SCN5A 25%), and LQTS (SCN5A 15%, KCNH2 30% and KCNQ1 40%) (25).

Ten to fifteen percent of the SIDS cases are thought to be caused by cardiac arrhythmias (26), particularly CPVT and LQT (27, 28). Furthermore, polymorphism in genes that linked to sleep trouble disorders have been seen to be effective as a potential hazard in terms of genes for SIDS (29). Phenomenon of polymorphism is also acknowledged in 5-HTT (serotonin transporter gene) that will enhance activity of serotonin transporter, on the contrary lessening the concentrations of serotonin at endings of nerves (30, 31). In addition, polymorphism was recognized in genes that affected the enhancement of autonomic apprehensive device (EN1, TLX3, ECE1, RET, PHOX2a) (32).

The progress of SIDS lingers to be solved, but 1 out of 10 cases is linked with mutations of cardiac ion channel gene, it also include the genes that encode the βeta subunits (33). p.S206L in SCN4B and p.V54G and p.V36M mutations in SCN3B have been associated to SIDS (34). Significantly, p.V36M mutation in SCN3B has also been associated to ventricular fibrillation of unknown cause, which is a possible lethal cardiac arrhythmia, and p.S206L in SCN4B also give rise to unusual excitableness in ventricular muscle cells of rat (34, 35). On the other hand there has been one occurrence of SIDS in a baby with a p.R214Q in β1B, which is also linked with Brugada Syndrome (36). β1B regulates function of Nav1.5, significantly assigning a causal method for cardiac malfunction associated with SCN1B (37). Up till now, no variations in SCN2B have been associated to SIDS. A huge figure of genes are thought to be the genetic reason of SIDS. Regardless of innovative progress in the turf of medical science, up to this time a very few facts with regard to genetics of SIDS are present (38). Similar to other heart ailments, variation in ion channel gene is as well a potential cause for SIDS (39).

Furthermore, variations in a number of heart channel genes have also been taken into consideration as a reason of SIDS and variations in genes associated with ion channels of heart (KCNH2, LQTS,SCN5 and KCNQ) in 9.5 % of SIDS cases (40, 41). In a study, 38 out of 47 victims of SIDS were examined for alternatives in KCNH2, SCN5A, RYR2, and KCNQ1, exhibited that 8 (17%) of the victims of SIDS had variations in gene disturbing role of ion channels. Mutations in these genes will give rise to disorders of malfunctioning of ion channels which can lead to arrhythmias and sudden death due to hereditary heart ailments (42).

This study was planned to review the previous literature regarding the genetic predisposition in SIDS and investigate a link between genetic and epidemiological factors associated with SIDS.

This is an in silico study based on the existing data reported in literature related to the genes associated with SIDS. Very few studies have been found and the genes identified in these studies were gathered and analyzed for various properties through bioinformatics tools. These studies included 20 original articles and 7 case reports. After deleting the repetitive genes, a total of 42 unique genes were identified which were explored further. We have analyzed these genes for computational properties, pathway analysis, gene enrichment analysis, histone methylation and other properties.

We employed ShinyGo (https://academic.oup.com/bioinformatics/article/36/8/2628/5688742), for enrichment, pathway and gene characterization. All analysis were performed on ShinyGo V0.61. For histone mark enrichment, mircoRNAs and transcription factors targets we used an integrative web enrichment (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637064/). Protein-protein association network analysis were performed using String database.

SIDS is multifactorial and its cause remains undiagnosed so far. Genetic factors are least known and least explored. SIDS may be associated with variants in various genes. This study highlights the fact that genetic studies related to SIDS are scarce and there is insufficient literature reported so far. As there is genetic diversity due to genetic polymorphisms in different populations and also within same populations, so there is a dire need to explore SIDS on these lines.

A recent study from Germany (143) evaluated 31 SIDS cases via Next Generation Sequencing and reported the facts similar to our findings that cardiac channelopathy and cardiac myopathy genes should be investigated to find a link with SIDS. They used the pulmonary tissue samples after autopsy. We have also found the genes involved in cardiac channelopathy and cardiac myopathy to be associated with SIDS in various studies. In approximately 30% cases of SIDS, cardiac channelopathy linked genes were observed to be a monogenic cause of deaths (144). In 3.5% of the SIDS cases, a genetic polymorphism in a cardiac myopathy gene was reported (145). Although it is very important to detect and evaluate the genetic variants in order to counsel the family in a SIDS case, but it should be evaluated and labeled carefully as “pathogenic” or “informative” as 4.3% was found to be pathogenic and 13% as informative in the recent study mentioned above (143) which is much lower that assumed previously.

Various case reports have identified genetic predisposition in previously healthy infants who became victims of SIDS later on. In one report, SIDS with dysgenesis of the Testes syndrome (SIDDT), which is a rare condition caused by TSPYL1 gene, was reported for the first time in 2004. It is characterized by sudden cardiac or respiratory arrest, disordered testicular development, neurologic dysfunction. exome sequencing revealed homozygosity for a frameshift variant in TSPYL1 (c.725_726delTG, p.Val242GlufsTer52) consistent with a diagnosis of SIDDT, explaining many of the clinical features (146). Cerebellum has also been reported in a recent case series of four infant deaths and upon investigation, cerebellar heterotopia of infancy was found which is a distinct malformation of the cerebellum. It should be further explored (147). Exome sequencing was done in 10 SIDS cases and SCN1A was identified in two victims with hippocampal abnormalities. One had SCN1A G682V and other had 2 SCN1A variants in cis: L1296M and E1308D variants which were previously known to be associated with epilepsy (148).

In a rare case report of 15 day old infant who died unexpectedly and suddenly, whole exome sequencing was performed and two novel mutations in the CLCKB gene were found and lead to a molecular diagnosis of Bartter's syndrome Type III. This case highlights the importance of whole genome sequencing in such cases for proper diagnosis (149). In another case report, a 3 month old infant was found dead while sleeping and postmortem CT scan showed fatty attenuation in the liver parenchyma. Matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI–IMS) analysis was conducted to further investigate the underlying mechanism of lipid accumulation. This revealed a significant accumulation of C14:1 acylcarnitine in the liver, proposing a very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Genetic analysis showed two novel mutations in ACADVL gene (150).

In a recent study, brain, heart, liver and kidney weights of SIDS victims were compared to controls. There was a large samples size of 291 SIDS and 294 controls obtained from Australia and Russia. Brain, thymus, liver and body weights were significantly higher among SIDS as compared to controls. Heart weight was significantly less in SIDS cases. Major difference was observed among thymus and brain weights and sizes. Heavier thymus points out to a possible infectious link to SIDS demises and larger brain sizes and weights shows a possible neuropathological roles (151). Larger thymus highlights the possible involvement of immunological genes which may be explored in this context. Genes related to neurotransmitters, their receptors and cardiopulmonary system should also be investigated further. Larger livers show a possible role of biochemical parameters and fatty acids (152) and need to be studied in detail. In another study, the frequency of extramedullary haematopoiesis (EMH) was observed to be significantly higher in SIDS victims as compared to controls which may be due to anemia associated with intrauterine hypoxia or infections (153).

Heterozygous gene mutation in PHOX2B, was reported in another case report of 28 day old female infant who died while lying on her bed in prone position. There were no pathological findings in postmortem investigation. PHOX2B gene is associated nervous system development and responsible for breathing control. Any mutation in this gene may lead to congenital central hypoventilation syndrome (154). Neonatal hypertrophic cardiomyopathy is a genetic disorder caused by mutations in MYBPC3 gene (p.Glu258Lys and IVS25-1G>A). It is associated with cardiac myopathy in neonates and leading cause of mortality and morbidity (155). In another case report, a sudden death of a 1 month old male infant while asleep was reported who was apparently healthy before the demise. This case was attributed to a combination of unavoidable events of congenital cardiac alterations, neuropathological alterations in brainstem and mutation in transporter gene (156). A case report on SIDS victim two female infants who were sisters as well, revealed a homozygous L2HGDH gene mutation. This gene is known to be associated with inherited metabolic disorders if mutated but it was first time reported in SIDS victims in this report published in 2009 (157).

Twin pregnancy and birth is also a risk factor for increased complications and SIDS. Koehler et al., published a review in 2001 on SIDS and Simultaneous Sudden Infant Death Syndrome (SSIDS) cases based on worldwide review of literature published from 1991 to 1998. SSIDS cases included the death of a pair of twins occurring suddenly without known reason. 41 SSIDS cases were found in this given time duration and they proposed a three point criteria for the cases to be considered as SSIDS and these included the location of death, a summary of the circumstances surrounding the deaths and the evaluation of these cases in terms of a proposed definition of SSIDS. According to this criteria, only 12 pairs of twins met all the three criteria and no conclusions were drawn (158). In a case report published in 2013, both the 10 weeks old twin infants died while sleeping on their backs. They were healthy and well before the sad event. Post-mortem investigations revealed petechial hemorrhages on the visceral pleura, epicardial surface and thymus gland. Histological findings showed pulmonary edema, intra-alveolar hemorrhage and minor lymphocytic infiltration in both infants, indicative of infection (159).

SIDS was significantly more common in monozygotic twins and of same gender during a retrospective study in England and Wales from 1993 to 2003 conducted by the office of National Statistics (160). In another study with conflicting results from United States, 23,464 singleton SIDS and 1,056 twin deaths were reported during 1987-1991. It was concluded that twins do not appear to be an increased risk factor for SIDS, twins dying of SIDS is uncommon while twins dying on same day is extremely rare incident (161). In another case report, a sudden infant death occurred in a 22 month old male twin infant while the other remained healthy. They contracted gastroenteritis and were given an antibiotic containing pivalic acid which is sometimes causing hypocarnitinemia. After post-mortem investigations and later on the genetic investigations, it was revealed that the fatal incident happened due to the deficiency of fatty acid oxidation accelerated by an antibiotic containing pivalic acid and the virus infection in this SIDS victim was containing the the thermolabile variant of carnitine palmitoyl transferase 2 (CPT2) gene. All factors alone are not fatal but cause SIDS when come in combination (162).

A case of sudden death of 1 month old male infant was reported by Donatella Mecchia et al. (156), attributing the death to cardiac, nervous system and genetic involvement. Polymorphism in serotonin transporter gene 5-HTT was observed (156). In another case report, a genetic analysis of 104 sudden cardiac death related genes was performed through Next Generation Sequencing (NGS). NGS identified 7 variants, 2 variations in genes AKAP9, EN1 were known previously as pathogenic, four variations in genes KCNE3, PKP2, VCL, and TTN had no clinical significance known, 7th variation in gene TTN was novel (163). In a molecular autopsy study of 50 cases of sudden young death <45 years old, during a period of 2 years was performed by exome sequencing. For exome, variants in TTN gene were the most abundant, having 56 variants, followed by MUC16 having 53 variants and SSPO having 49 variants. TTN is the gene encoding titin which is the largest protein of the human genome having 305 kbs and is involved in cardiomyopathies. MUC16 or mucin 16 is a 132 kb gene coding for mucin protein which is a glycoprotein involved in cancers and SSPO (subcommissural organ spondin) is a 58 kb gene that codes for a protein involved in neuronal aggregation. All the above cases had negative autopsy findings but molecular autopsy revealed these genetic variations (164). Although these cases were not SIDS but it must be explored in SIDS as well and similar strategy may by used for molecular autopsy of SIDS.

In a whole exome sequencing study of 161 SIDS cases from Europe, 192 genes associated with cardiovascular and metabolic diseases were investigated. Potentially causative genes were identified in 20% of the SIDS cases, 9% of the genes were associated with channelopathies, 7% with cardiomyopathies, 1% with metabolic disorders (144). A molecular study conducted on 41 cases of sudden unexpected death in infancy, analyzed 86 sudden cardiac death related genes. 63 variants in 35 cases were validated. Most of these variants were located on cardiomyopathy genes or channelopathy genes (165). NGS was performed as a molecular autopsy tool for 16 cases of sudden unexpected deaths in youngs, <35 years old. Twenty three genes associated with inherited cardiac channelopathies were screened. An average 200 variants per case were identified and after correlating them with the clinical data and molecular findings, 4 likely pathogenic variants were identified in three cases in the genes KCNH2, ANK2, SCN5A, and RYR2 (166). In a molecular autopsy on 141 SIDS cases, <6 months of age and 133 non/infants (19-58 years old) six major channelpathy genes, KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RyR2 were characterize in 274 cases which were autopsy negative. 22 previously known variants linked to cardiac channelopathy and 24 novel variants were identified among infants (13.5%) and non-infants (19.5%). Most of these variants involved SCN5A gene (68.4% in infants and 50% in non-infants) which is a sodium channel alpha subunit. This study highlighted the role of cardiac channel genes in sudden deaths of infants and non-infants (167).

In our previous studies, including post-mortem studies, in silico and in vitro studies, we have proposed the involvement of Substance P/Neurokinin 1 Receptor and the gene encoding SP, Tachykinin 1 (Tac 1) to be involved in SIDS (168–172). We emphasize further studies to be conducted on this pathway as it is involved in the breathing control mechanism and a genetic mutation in its gene can be deleterious. We have also proposed the involvement of neuropathology in COVID-19 as well and proposed the same SP/ NK-1R mechanism which contributes in the neuropathology of SIDS. The same phenomenon may also be involved for lesser implications in children and infants as compared to the adults (173). Current study also presents the involvement of these candidate genes in other biological processes. We have also highlighted the importance of gene expression and its association with SIDS by discovering the histone methylations, gene enrichment pathways, transcription factors and micro RNAs reported so far. Gene regulation has utmost importance in these cases and must be investigated further. This study provides a comprehensive analysis and presents the genetic determinants which need further investigation. It will pave way for other researchers who are trying to find out the genetic causes of SIDS. Next Generation sequencing may be an important tool in this regard.

A number of genes mainly potassium and sodium channel genes may be associated with the devastating phenomenon of SIDS. Future studies should be conducted to explore the properties of these genes in relation to SIDS so that vulnerable infants and neonates may be diagnosed timely before the sad demise. Preventive measures can be adopted to avoid such incidences. Next generation sequencing and careful interpretation of the gene variants is required to reveal these facts.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.

RM and SAS planned, conceived, and designed and supervised the study. MK, MA, SAG, and SK did data extraction and write-up. HN, AM, HM, SH, and AH worked on revisions, write-up, and analysis. MA and AB did analysis, write-up, and critical review. All the authors have contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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