Sudden death with cardiac involvement in a neonate with carnitine-acylcarnitine translocase deficiency.

A female neonate born with normal Apgar scores at 38+2 weeks of gestational age unexpectedly passed away within less than 30 hours after birth. The situation mirrored her brother's earlier demise within 24 hours post-delivery, suggesting a possible genetic disorder. Gross examination revealed widespread cyanosis and distinct yellowish changes on the cardiac ventricles. Histopathological examination disclosed lipid accumulation in the liver, heart, and kidneys. Tandem mass spectrometry detected elevated levels of 10 amino acids and 14 carnitines in cardiac blood. Trio-whole genome sequencing (Trio-WGS) identified the SLC25A20 c.199-10T>G mutation associated with carnitine-acylcarnitine translocase disease (CACTD), a type of fatty acid oxidation disorders (FAODs) with a potential for sudden death. Further validation of gene expression confirmed the functional deficiency of SLC25A20, ultimately diagnosing CACTD as the underlying cause of the neonate's demise. This case highlights the importance of prenatal metabolic and genetic screening for prospective parents and emphasizes the need for forensic doctors to integrate metabolomic and genomic investigations into autopsies for suspected inherited metabolic diseases.

Multiomic Analysis of Neuroinflammation and Occult Infection in Sudden Infant Death Syndrome.

Importance: Antemortem infection is a risk factor for sudden infant death syndrome (SIDS)-the leading postneonatal cause of infant mortality in the developed world. Manifestations of infection and inflammation are not always apparent in clinical settings or by standard autopsy; thus, enhanced resolution approaches are needed. Objective: To ascertain whether a subset of SIDS cases is associated with neuroinflammation and occult infection. Design, Setting, and Participants: In this case-control study, postmortem fluids from SIDS cases and controls collected between July 2011 and November 2018 were screened for elevated inflammatory markers, specifically cerebrospinal fluid (CSF) neopterin and CSF and serum cytokines. CSF, liver, and brain tissue from SIDS cases with elevated CSF neopterin were subjected to metagenomic next-generation sequencing (mNGS) to probe for infectious pathogens. Brainstem tissue from a subset of these cases was analyzed by single-nucleus RNA sequencing (snRNAseq) to measure cell type-specific gene expression associated with neuroinflammation and infection. All tissue and fluid analyses were performed from April 2019 to January 2023 in a pathology research laboratory. Included was autopsy material from infants dying of SIDS and age-matched controls dying of known causes. Exposures: There were no interventions or exposures. Main Outcomes and Measures: CSF neopterin levels were measured by high-performance liquid chromatography. Cytokines were measured by multiplex fluorometric assay. mNGS was performed on liver, CSF, brain, and brainstem tissue. snRNAseq was performed on brainstem tissue. Results: A cohort of 71 SIDS cases (mean [SD] age, 55.2 [11.4] postconceptional weeks; 42 male [59.2%]) and 20 controls (mean [SD] age, 63.2 [16.9] postconceptional weeks; 11 male [55.0%]) had CSF and/or serum available. CSF neopterin was screened in 64 SIDS cases and 15 controls, with no exclusions. Tissues from 6 SIDS cases were further analyzed. For CSF neopterin measures, SIDS samples were from infants with mean (SD) age of 54.5 (11.3) postconceptional weeks (38 male [59.4%]) and control samples were from infants with mean (SD) age of 61.5 (17.4) postconceptional weeks (7 male [46.7%]). A total of 6 SIDS cases (9.3%) with high CSF neopterin were identified, suggestive of neuroinflammation. mNGS detected human parechovirus 3 (HPeV3) in tissue and CSF from 1 of these 6 cases. snRNAseq of HPeV3-positive brainstem tissue (medulla) revealed dramatic enrichment of transcripts for genes with predominately inflammatory functions compared with 3 age-matched SIDS cases with normal CSF neopterin levels. Conclusions and Relevance: Next-generation molecular tools in autopsy tissue provide novel insight into pathogens that go unrecognized by normal autopsy methodology, including in infants dying suddenly and unexpectedly.

Revisiting the association of sudden infant death syndrome (SIDS) with polymorphisms of NHE3 and IL13.

OBJECTIVES: Disturbances of the central nervous system and immune system are thought to play a role in sudden infant death syndrome (SIDS). Dysregulated expression of sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) in the brainstem and of interleukin 13 (IL13) in the lungs has been observed in SIDS. An association of single-nucleotide polymorphisms (SNPs) in NHE3 and IL13 with SIDS has been proposed, but controversial results were reported. Therefore, there is a need to revisit the association of SNPs in NHE3 and IL13 with SIDS. METHODS: Genotyping of rs71597645 (G1131A) and rs2247114 (C2405T) in NHE3 and rs20541 (+ 4464A/G) in IL13 was performed in 201 SIDS cases and 338 controls. A meta-analysis was performed after merging our data with previously published data (all from European populations). RESULTS: Polymorphisms rs2247114 (NHE3) and rs20541 (IL13) were significantly associated with SIDS overall and in multiple subgroups, but no association was found for rs71597645 (NHE3). After combining our data with previously published data, a fixed-effect meta-analysis showed that rs2247114 in NHE3 retained a significant association with SIDS under a recessive model (OR 2.78, 95%CI 1.53 to 5.06; p = 0.0008). CONCLUSION: Our findings suggest an association of NHE3 variant rs2247114 (C2405T), though not rs71597645 (NHE3), with SIDS. A potential role of rs20541 (IL13) still has to be elucidated. Especially NHE3 seems to be an interesting topic for future SIDS research.

Aberrant colon metabolome and the sudden infant death syndrome.

BACKGROUND: The Sudden Infant Death Syndrome (SIDS) has been associated with increased peripheral serotonin and an abnormal colonic microbiome, suggesting the colonic metabolome may also be abnormal. This study addresses this potential correlation by comparing colonic autopsy tissue from SIDS to age-matched non-SIDS controls. METHODS: Untargeted metabolomic analysis by mass spectrometry is used to assess human colonic metabolomic differences including serotonin. Expression of genes associated with colonic serotonin synthesis and transport (TPH1, TPH2, DDC, SCL6A4) is measured by qRT-PCR. Microbiome analysis is performed to compare the SIDS and non-SIDS colonic microbiome. RESULTS: Unsupervised hierarchical cluster and principal component analyses of metabolomic data shows increased variability in the SIDS cohort and separation of SIDS cases from the non-SIDS controls. There is a trend toward increased serotonin in the SIDS cohort but there is no significant difference in expression of the serotonin synthesis and transport genes between SIDS and non-SIDS control cohorts. Microbiome analysis shows no significant difference between the SIDS and non-SIDS control cohorts. CONCLUSIONS: This study demonstrates increased variability in the colonic metabolome and a trend towards increased colonic serotonin in SIDS. The underlying cause of colon metabolomic variability, and its potential role in SIDS pathogenesis, warrants further investigation. IMPACT STATEMENT: The key message of this article is that SIDS is associated with an aberrant colonic metabolome. This is a novel observation suggesting another component in the pathophysiology underlying SIDS. Investigation of why the colonic metabolome is aberrant may offer new insights to SIDS pathogenesis and new strategies to reduce risk.

Exome analysis focusing on epilepsy-related genes in children and adults with sudden unexplained death.

PURPOSE: Genetic studies in sudden infant death syndrome (SIDS) and sudden unexplained death (SUD) cohorts have indicated that cardiovascular diseases might have contributed to sudden unexpected death in 20-35 % of autopsy-negative cases. Sudden unexpected death can also occur in people with epilepsy, termed as sudden unexpected death in epilepsy (SUDEP). The pathophysiological mechanisms of SUDEP are not well understood, but are likely multifactorial, including seizure-induced hypoventilation and arrhythmias as well as genetic risk factors. The sudden death of some of the SIDS/SUD victims might also be explained by genetic epilepsy, therefore this study aimed to expand the post-mortem genetic analysis of SIDS/SUD cases to epilepsy-related genes. METHODS: Existing whole-exome sequencing data from our 155 SIDS and 45 SUD cases were analyzed, with a focus on 365 epilepsy-related genes. Nine of the SUD victims had a known medical history of epilepsy, seizures or other underlying neurological conditions and were therefore classified as SUDEP cases. RESULTS: In our SIDS and SUD cohorts, we found epilepsy-related pathogenic/likely pathogenic variants in the genes OPA1, RAI1, SCN3A, SCN5A and TSC2. CONCLUSION: Post-mortem analysis of epilepsy-related genes identified potentially disease-causing variants that might have contributed to the sudden death events in our SIDS/SUD cases. However, the interpretation of identified variants remains challenging and often changes over time as more data is gathered. Overall, this study contributes insight in potentially pathophysiological epilepsy-related mechanisms in SIDS, SUD and SUDEP victims and underlines the importance of sensible counselling on the risk and preventive measures in genetic epilepsy.

Screening of Genes Co-Associated with Sudden Infant Death Syndrome and Infectious Sudden Death in Infancy and Bioinformatics Analysis of Their Regulatory Networks.

OBJECTIVES: The common differentially expressed mRNAs in brain, heart and liver tissues of deceased sudden infant death syndrome (SIDS) and infectious sudden death in infancy (ISDI) confirmed by autopsy was screened by bioinformatics to explore the common molecular markers and pathogenesis of SIDS and ISDI. METHODS: The datasets of GSE70422 and GSE136992 were downloaded, the limma of R software was used to screen differentially expressed mRNA in different tissue samples of SIDS and ISDI decedents for overlapping analysis. The clusterProfiler of R software was used to conduct gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The protein-protein interaction (PPI) network was constructed by STRING database, while the hub gene was screened by cytoHubba plug-in. RESULTS: Compared with the control group, there were 19 significant differentially expressed genes in the tissue samples of SIDS and ISDI decedents, among which 16 in the heart tissue and 3 in the liver tissue, and the astrotactin 1 (ASTN1) gene expression difference in the heart tissue was most significant. The PPI network identified Ras homolog family member A (RHOA), integrin subunit alpha 1 (ITGA1), and H2B clustered histone 5 (H2BC5) were hub genes. The analysis of GO and KEGG showed that differentially expressed genes were enriched in the molecular pathways of actin cytoskeleton regulation, focal adhesion and response to mycophenolic acid. CONCLUSIONS: ASTN1, RHOA and ITGA1 may participate in the development of SIDS and ISDI. The enrichment of differentially expressed genes in immune and inflammatory pathways suggests a common molecular regulatory mechanism between SIDS and ISDI. These findings are expected to provide new biomarkers for molecular anatomy and forensic identification of SIDS and ISDI.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and Sudden Infant Death Syndrome: A Potential Model for Investigation.

Sudden infant death syndrome (SIDS) represents a significant cause of post-neonatal mortality, yet its underlying mechanisms remain unclear. The triple-risk model of SIDS proposes that intrinsic vulnerability, exogenous triggers, and a critical developmental period are required for SIDS to occur. Although case-control studies have identified potential risk factors, no in vivo model fully reflects the complexities observed in human studies. Pituitary adenylate cyclase-activating polypeptide (PACAP), a highly conserved neuropeptide with diverse physiological functions, including metabolic and thermal regulation, cardiovascular adaptation, breathing control, stress responses, sleep-wake regulation and immunohomeostasis, has been subject to early animal studies, which revealed that the absence of PACAP or its specific receptor (PAC1 receptor: PAC1R) correlates with increased neonatal mortality similar to the susceptible period for SIDS in humans. Recent human investigations have further implicated PACAP and PAC1R genes as plausible contributors to the pathomechanism of SIDS. This mini-review comprehensively synthesizes all PACAP-related research from the perspective of SIDS and proposes that PACAP deficiency might offer a promising avenue for studying SIDS.

Cardiac Genetic Investigation of Sudden Infant and Early Childhood Death: A Study From Victims to Families.

Background Sudden infant death syndrome (SIDS) is the leading cause of death up to age 1. Sudden unexplained death in childhood (SUDC) is similar but affects mostly toddlers aged 1 to 4. SUDC is rarer than SIDS, and although cardiogenetic testing (molecular autopsy) identifies an underlying cause in a fraction of SIDS, less is known about SUDC. Methods and Results Seventy-seven SIDS and 16 SUDC cases underwent molecular autopsy with 25 definitive-evidence arrhythmia-associated genes. In 18 cases, another 76 genes with varying degrees of evidence were analyzed. Parents were offered cascade screening. Double-blind review of clinical-genetic data established genotype-phenotype correlations. The yield of likely pathogenic variants in the 25 genes was higher in SUDC than in SIDS (18.8% [3/16] versus 2.6% [2/77], respectively; P=0.03), whereas novel/ultra-rare variants of uncertain significance were comparably represented. Rare variants of uncertain significance and likely benign variants were found only in SIDS. In cases with expanded analyses, likely pathogenic/likely benign variants stemmed only from definitive-evidence genes, whereas all other genes contributed only variants of uncertain significance. Among 24 parents screened, variant status and phenotype largely agreed, and 3 cases positively correlated for cardiac channelopathies. Genotype-phenotype correlations significantly aided variant adjudication. Conclusions Genetic yield is higher in SUDC than in SIDS although, in both, it is contributed only by definitive-evidence genes. SIDS/SUDC cascade family screening facilitates establishment or dismissal of a diagnosis through definitive variant adjudication indicating that anonymity is no longer justifiable. Channelopathies may underlie a relevant fraction of SUDC. Binary classifications of genetic causality (pathogenic versus benign) could not always be adequate.

Polymorphisms of the hypothalamic-pituitary-adrenal axis may lead to an inadequate response to stress and contribute to sudden infant death syndrome.

AIM: Impaired resilience to stress may be a factor in sudden infant death syndrome (SIDS). However, no comprehensive studies have been performed on polymorphisms that are relevant to the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the stress hormone cortisol. METHODS: We analysed 22 relevant single nucleotide polymorphisms (SNPs) in 206 anonymised SIDS cases who died at a mean of 131 days (range: 5-343) and 256 adult controls who were recruited from paternity testing cases. Additional stratified analyses were performed for sex, age and season of death. Both the cases and the controls were Caucasian. RESULTS: Variants for rs2235543 (HSD11B1) and rs3779250 (CRHR2) were associated with SIDS in the overall analysis, and borderline for rs2446432 (CRH), at least before corrections for multiple testing. A combination of these three variants was observed in 52.9% of SIDS cases but only 43.0% of controls (p = 0.039). Five or more variants showed an association in the subgroups. CONCLUSION: Our findings suggest that the HPA axis influences SIDS and supports the hypothesis that an inadequate stress response may add to the risk. The associated variants for rs2235543, rs3779250 and rs2446432 appeared to decrease the cortisol concentration and impair an appropriate stress response.

Brain water content in sudden unexpected infant death.

The extensive and rapid development of the human brain during the first years of life complicates the postmortem diagnosis of brain edema in infancy. The aim of this study was to describe brain water content, the brain weight/body weight ratio, and the brain weight/head circumference ratio throughout the first years of life. Furthermore, we examined the relationship between these parameters and rs2075575 in the AQP4 gene. Our hypothesis was that dysregulated water homeostasis might be a risk factor for sudden infant death syndrome (SIDS), which may be reflected by increased water content in the brain. The study included 90 subjects with sudden unexpected death < 4 years of age: 22 cases of sudden infant death syndrome, 11 cases of sudden unexplained death in childhood, 47 cases of death due to disease, and 10 cases of accident/violent death. Brain water content, brain weight/body weight ratio, and brain weight/head circumference ratio were investigated according to corrected age, diagnosis group, attempt to resuscitate, and presence of brain edema. We found that brain water content and brain weight/body weight ratio were significantly reduced with increasing age, while brain weight/head circumference were increased. Brain weight/head circumference was correlated with brain water content. Cases with brain edema had a significantly higher brain weight/head circumference than the non-edematous cases. No differences were found between the diagnosis groups for any of the investigated parameters. In summary, the findings contribute to the current body of knowledge regarding brain growth during the first months of life.

Investigating genetic variants in microRNA regulators of Neurokinin-1 receptor in sudden infant death syndrome.

Sudden infant death syndrome (SIDS) occurs more often in male than in female infants, suggesting involvement of the X-chromosome. Histopathological studies have suggested that altered expression of the Neurokinin-1 receptor may also play a role in the pathogenesis of SIDS. It was hypothesised that genetic variants in three X-chromosome-encoded microRNA (miRNA/miR), known to down-regulate expression of the Neurokinin-1 receptor, may contribute to SIDS. AIM: To identify sequence variants in the miRNAs within a study cohort (27 cases of SIDS and 28 controls) and determine if there was a difference in the frequencies in male and female SIDS infants. METHODS: Genomic DNA prepared from stored blood spots was amplified and sequenced to identify genetic variants in miR500A, miR500B and miR320D2. RESULTS: No novel variants in the miRNAs were identified in our study cohort. We identified one known single-nucleotide polymorphism (SNP) in miR320D2: rs5907732 G/T, in both cases and controls. No significant difference in the SNP frequency was observed between male and female SIDS cases. CONCLUSION: This pilot study suggests that sequence variants in three miRNAs do not contribute to the reported higher prevalence of SIDS in male infants and do not contribute to the pathogenesis of SIDS in our cohort.

Screening of Genes Co-Associated with Sudden Infant Death Syndrome and Infectious Sudden Death in Infancy and Bioinformatics Analysis of Their Regulatory Networks / 法医学杂志

OBJECTIVES@#The common differentially expressed mRNAs in brain, heart and liver tissues of deceased sudden infant death syndrome (SIDS) and infectious sudden death in infancy (ISDI) confirmed by autopsy was screened by bioinformatics to explore the common molecular markers and pathogenesis of SIDS and ISDI.@*METHODS@#The datasets of GSE70422 and GSE136992 were downloaded, the limma of R software was used to screen differentially expressed mRNA in different tissue samples of SIDS and ISDI decedents for overlapping analysis. The clusterProfiler of R software was used to conduct gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The protein-protein interaction (PPI) network was constructed by STRING database, while the hub gene was screened by cytoHubba plug-in.@*RESULTS@#Compared with the control group, there were 19 significant differentially expressed genes in the tissue samples of SIDS and ISDI decedents, among which 16 in the heart tissue and 3 in the liver tissue, and the astrotactin 1 (ASTN1) gene expression difference in the heart tissue was most significant. The PPI network identified Ras homolog family member A (RHOA), integrin subunit alpha 1 (ITGA1), and H2B clustered histone 5 (H2BC5) were hub genes. The analysis of GO and KEGG showed that differentially expressed genes were enriched in the molecular pathways of actin cytoskeleton regulation, focal adhesion and response to mycophenolic acid.@*CONCLUSIONS@#ASTN1, RHOA and ITGA1 may participate in the development of SIDS and ISDI. The enrichment of differentially expressed genes in immune and inflammatory pathways suggests a common molecular regulatory mechanism between SIDS and ISDI. These findings are expected to provide new biomarkers for molecular anatomy and forensic identification of SIDS and ISDI.

The added value of molecular-based diagnostics in the African forensic medical setting.

Sudden unexpected infant death (SUDI) is reported to be an extraordinarily high burden in sub-Saharan Africa, with the incidence rate in South Africa among the highest in the world. It is common for the cause of many such infant deaths to remain unexplained even after a full medico-legal death investigation, and then to be categorised as a sudden unexplained infant death (SUID). Fortunately, advances in molecular-based diagnostics allow researchers to identify numerous underlying inherited cardiac arrhythmogenic disorders in many SUDI cases, with a predominance of variants identified in the SCN5A gene. Such cardiac arrhythmogenic-related sudden deaths generally present with no structural alterations of the heart that are macroscopically identifiable at autopsy, therefore highlighting the importance of post mortem genetic testing. We report on a significant genetic finding that was made on a SUDI case in which the cause was ascribed to an acute bacterial pneumonia but it was still subjected to post mortem genetic testing of the SCN5A gene. The literature shows that many SUDI cases diagnosed with inherited cardiac arrhythmogenic disorders have demonstrated a viral prodrome within days of their death. It is therefore not uncommon for these cardiac disorders in infants to be mistaken for flu, viral upper respiratory tract infection or pneumonia, and without the incorporation of post mortem genetic testing, any other contributory causes of these deaths are often disregarded. This study highlights the need for research reporting on the genetics of inherited cardiac disorders in Africa.

Epileptic encephalopathy as a new feature of the sudden infant death with dysgenesis of the testes syndrome caused by TSPYL1 variants.

Sudden infant death with dysgenesis of the testes syndrome (SIDDT) is a rare autosomal recessive disorder associating developmental sex disorder (DSD) in patients with 46,XY karyotype and visceroautonomic dysfunction responsible for sudden infant death. First described in 2004, very few patients have since been reported. We describe here a new patient with SIDDT and epileptic encephalopathy (EE). We provide the phenotypic description and genetic results of a boy carrying biallelic TSPYL1 deleterious variants. We also reviewed the data of the 26 previously described patients with SIDDT. Our patient presented gonadal dysgenesis, cardio-respiratory dysfunction, and repeated seizures, leading in 1 month to severe intractable EE. He died at age 10 months of cardiorespiratory arrest. Four other reported patients from two families presented with progressive epilepsy, including one with severe EE. No similar phenotype was described in the 22 other patients and the recurrent variant p.Val242Glufs*52 appears to be more frequently associated with seizures. To note, our patient is the first case with compound heterozygous TSPYL1 variants. These findings expand the phenotypic spectrum of SIDDT by reporting progressive epilepsy and severe EE as a possible outcome. This information may help in managing patients with SIDDT.

Thymic hypoplasia induced by copy number variations contributed to explaining sudden infant death based on forensic autopsies.

Thymic hypoplasia is a primary cellular immunodeficiency that causes susceptibility to serious infections leading to sudden death in infants. Some genetic disorders in humans could result in the evident permanent hypoplasia or occasional aplasia of the thymus at birth. However, determining the genetic etiology of thymic hypoplasia is challenging for the sudden infant death due to primary cellular immunodeficiency. In this study, in order to find the fundamental reasons for sudden death of infants with thymic hypoplasia, 5 infants with suspected thymic hypoplasia and 10 control infants were assessed, and the immunohistochemistry and DNA analysis were used to investigate whether the infants with thymic hypoplasia had DiGeorge syndrome (DGS) with copy number variations (CNVs) in 22q11.2 and other chromosomes. The results showed that the weight of the thymus was significantly lower than the normal except the case 4, and that all the infants had hypocalcemia and a significant decrease or even absence of the markers CD1a, CD2, CD3, CD4 and CD8, which are related to T-cell maturation. In addition, multiplex ligation-dependent probe amplification (MLPA) analysis showed that these infants carried CNVs in 22q11.2 and other associated chromosomes with deletion and duplication of 25 genes. The results of thymus weight, histopathology, molecular pathology and MLPA analysis suggested that DGS predominantly with thymic hypoplasia induced by CNVs caused the sudden death of these infants under various infections or other unexplained reasons, which may provide new insights into the diagnosis of sudden infant death and could help the parents of deceased infants to attach more importance of genetic screening and thymus ultrasound to reduce the postnatal mortality of the infant, and demonstrates the value of genetic diagnosis in the forensic pathology.

Variants in genes encoding the SUR1-TRPM4 non-selective cation channel and sudden infant death syndrome (SIDS): potentially increased risk for cerebral edema.

Increasing evidence suggests that brain edema might play an important role in the pathogenesis of sudden infant death syndrome (SIDS) and that variants of genes for cerebral water channels might be associated with SIDS. The role of the sulfonylurea receptor 1 (SUR1)-transient receptor potential melastatin 4 (TRPM4) non-selective cation channel in cerebral edema was demonstrated by extensive studies. Therefore, we hypothesized that variants at genes of the SUR1-TRPM4 channel complex might be linked to SIDS. Twenty-four polymorphisms in candidate genes involved in the SUR1-TRPM4 non-selective cation channel were investigated in 185 SIDS cases and 339 controls. One (rs11667393 in TRPM4) of these analyzed SNPs reached nominal significance regarding an association with SIDS in the overall analysis (additive model: p = 0.015, OR = 1.438, 95% CI = 1.074-1.925; dominant model: p = 0.036; OR = 1.468, 95% CI = 1.024-2.106). In the stratified analysis, further 8 variants in ABCC8 (encoding SUR1) or TRPM4 showed pronounced associations. However, none of the results remained significant after correction for multiple testing. This preliminary study has provided the first evidence for a genetic role of the SUR1-TRPM4 complex in the etiology of SIDS, and we suggest that our initial results should be evaluated by further studies.

Non-polyalanine repeat mutation in PHOX2B is detected in autopsy cases of sudden unexpected infant death.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS), which is caused by PHOX2B with phenotypic variations, has a point of controversy: CCHS is putatively involved in autopsy cases of sudden unexpected infant death (SUID) including sudden infant death syndrome. OBJECTIVE: The relation of CCHS to SUID cases was investigated by extensive genotyping of PHOX2B. METHODS: We analyzed 93 DNA samples of less than one-year-old SUID cases that were autopsied in our department. Unrelated adult volunteers (n = 942) were used as the control. RESULTS: No polyalanine tract expansion was detected in the SUID cases. The allelic frequencies of repeat contractions and SNP (rs28647582) in intron 2 were not significantly different from that in those control group. Further extensive sequencing revealed a non-polyalanine repeat mutation (NPARM) of c.905A>C in a sudden death case of a one-month-old male infant. This missense mutation (p.Asn302Thr), registered as rs779068107, was annotated to 'Affected status is unknown', but it might be associated with the sudden death. CONCLUSION: NPARM was more plausibly related to sudden unexpected death than expansions because of severe clinical complications. This finding indicates possible CCHS involvement in forensic autopsy cases without ante-mortem diagnosis.

Mitochondrial DNA content: a new potential biomarker for Sudden Infant Death Syndrome.

BACKGROUND: Sudden Infant Death Syndrome (SIDS) occurs in apparently healthy infants and is unpredictable and unexplained despite thorough investigations and enormous research efforts. The hypothesis tested in this case-control study concerns mitochondrial involvement in SIDS occurrence. METHODS: Mitochondrial DNA content (MtDNAcn) was measured in 24 SIDS cerebral cortex samples and 18 controls using real-time PCR. RESULTS: The median (interquartile range) mtDNAcn in SIDS and controls was 2578 (2224-3838) and 1452 (724-2517) copies per nuclear DNA, respectively (P = 0.0001). MtDNAcn values were higher in SIDS victims born to non-smoking parents (n = 7) 4984 (2832-6908) compared to the controls (n = 5) 2020 (478-2386) (P = 0.006). Increased levels of mtDNAcn have been observed in the SIDS cases with mild defects in nuclei not essential for life compared to those found in SIDS cases with severe alterations of respiratory function (P = 0.034) 3571 (2568-5053) (n = 14) 2356 (1909-3132) (n = 8), respectively. CONCLUSIONS: Our study revealed for the first time higher mtDNAcn in the cerebral cortex of the SIDS cases than the controls, indicating metabolic alterations. MtDNAcn plays an important role in compensatory mechanisms against environmental factors affecting human health. Despite the small sample size, mtDNA may prove to be a potential forensic biomarker for autopsied SIDS victims for gaining new insights into the etiology of SIDS. IMPACT: Mitochondrial DNA content evaluated in cerebral cortex samples is higher in SIDS victims than controls. These results represent a novel line of investigation for the etiology of SIDS and could have a significant role in the compensatory mechanism due to environmental factors affecting human health. These findings suggest that the mitochondria are involved in SIDS: mtDNA content may represent a biomarker of this syndrome.