Explaining sudden infant death with cardiac arrhythmias: Complete exon sequencing of nine cardiac arrhythmia genes in Dutch SIDS cases highlights new and known DNA variants.

Previous studies suggested that Sudden Infant Death Syndrome (SIDS) can partially be genetically explained by cardiac arrhythmias; however, the number of individuals and populations investigated remain limited. We report the first SIDS study on cardiac arrhythmias genes from the Netherlands, a country with the lowest SIDS incidence likely due to parent education on awareness of environmental risk factors. By using targeted massively parallel sequencing (MPS) in 142 Dutch SIDS cases, we performed a complete exon screening of all 173 exons from 9 cardiac arrhythmias genes SCN5A, KCNQ1, KCNH2, KCNE1, KCNE2, CACNA1C, CAV3, ANK2 and KCNJ2 (∼34,000 base pairs), that were selected to harbour previously established SIDS-associated DNA variants. Motivated by the poor DNA quality from the paraffin embedded material used, the application of a conservative sequencing quality control protocol resulted in 102 SIDS cases surviving quality control. Amongst the 102 SIDS cases, we identified a total of 40 DNA variants in 8 cardiac arrhythmia genes found in 60 (58.8 %) cases. Statistical analyses using ancestry-adjusted reference population data and multiple test correction revealed that 13 (32.5 %) of the identified DNA variants in 6 cardiac arrhythmia genes were significantly associated with SIDS, which were observed in 15 (14.7 %) SIDS cases. These 13, and another three, DNA variants were classified as likely pathogenic for cardiac arrhythmias using the American College of Medical Genetics guidelines for interpretation of sequence variants. The 16 likely pathogenic DNA variants were found in 16 (15.7 %) SIDS cases, including i) 3 novel DNA variants not recorded in public databases ii) 7 known DNA variants for which significant SIDS association established here was previously unknown, and iii) 6 known DNA variants for which LQTS association was reported previously. By having replicated previously reported SIDS-associated DNA variants located in cardiac arrhythmia genes and by having highlighting novel SIDS-associated DNA variants in such genes, our findings provide additional empirical evidence for the partial genetic explanation of SIDS by cardiac arrhythmias. On a wider note, our study outcome stresses the need for routine post-mortem genetic screening of assumed SIDS cases, particularly for cardiac arrhythmia genes. When put in practise, it will allow preventing further sudden deaths (not only in infants) in the affected families, thereby allowing forensic molecular autopsy not only to provide answers on the cause of death, but moreover to save lives.

PHOX2B polyalanine repeat length is associated with sudden infant death syndrome and unclassified sudden infant death in the Dutch population.

Unclassified sudden infant death (USID) is the sudden and unexpected death of an infant that remains unexplained after thorough case investigation including performance of a complete autopsy and review of the circumstances of death and the clinical history. When the infant is below 1 year of age and with onset of the fatal episode apparently occurring during sleep, this is referred to as sudden infant death syndrome (SIDS). USID and SIDS remain poorly understood despite the identification of several environmental and some genetic risk factors. In this study, we investigated genetic risk factors involved in the autonomous nervous system in 195 Dutch USID/SIDS cases and 846 Dutch, age-matched healthy controls. Twenty-five DNA variants from 11 genes previously implicated in the serotonin household or in the congenital central hypoventilation syndrome, of which some have been associated with SIDS before, were tested. Of all DNA variants considered, only the length variation of the polyalanine repeat in exon 3 of the PHOX2B gene was found to be statistically significantly associated with USID/SIDS in the Dutch population after multiple test correction. Interestingly, our data suggest that contraction of the PHOX2B exon 3 polyalanine repeat that we found in six of 160 SIDS and USID cases and in six of 814 controls serves as a probable genetic risk factor for USID/SIDS at least in the Dutch population. Future studies are needed to confirm this finding and to understand the functional effect of the polyalanine repeat length variation, in particular contraction, in exon 3 of the PHOX2B gene.

Histological findings in unclassified sudden infant death, including sudden infant death syndrome.

Our objective was to study histological variations and abnormalities in unclassified sudden infant death (USID), including sudden infant death syndrome (SIDS), in The Netherlands. Two hundred Dutch USID cases between 1984 and 2005 were identified. The histology slides and autopsy reports of 187 cases were available for systematic review, including brain autopsy in 135 cases. An explanation for the cause of death in 19 patients (10.2%) was found. Twelve patients had bronchopneumonia, 3 showed extensive aspiration, 2 had signs of a metabolic disorder, 1 had sepsis, and 1 had meningitis. Frequent nonspecific findings were congestion (66%), edema (47%), small hemorrhages (18%), and lymphoid aggregates (51%) in the lungs; congestion of the liver (23%); and asphyctic bleeding in the kidney (44%), adrenal gland (23%), and thymus (17%). Statistical associations were found for infection with starry sky macrophages in the thymus (P  =  0.004), with calcification (P  =  0.023), or with debris in the Hassal's corpuscles (P  =  0.034). In this study, in 10.2% of cases the histological findings were incompatible with SIDS or USID. Furthermore, several frequent nonspecific histological findings in the thymus that point toward an infection were found.

Postnatal parental smoking: an important risk factor for SIDS.

BACKGROUND: Sudden infant death syndrome (SIDS) is the unexpected death of an infant that remains unexplained after a thorough investigation of the circumstances, family history, paediatric investigation and complete autopsy. In Western society, it is the leading cause of post-neonatal death below 1 year of age. In the Netherlands, the SIDS incidence is very low, which offers opportunities to assess the importance of old and new environmental risk factors. For this purpose, cases were collected through pathology departments and the working group on SIDS of the Dutch Paediatrician Foundation. A total of 142 cases were included; these occurred after the parental education on sleeping position (1987), restricted to the international age criteria and had no histological explanation. Age-matched healthy controls (N = 2,841) came from a survey of the Netherlands Paediatric Surveillance Unit, completed between November 2002 and April 2003. A multivariate analysis was performed to determine the risk factors for SIDS, including sleeping position, antenatal maternal smoking, postnatal parental smoking, premature birth, gender, lack of breastfeeding and socio-economic status. Postnatal smoking was identified as an important environmental risk factor for SIDS (OR one parent = 2.5 [1.2, 5.0]; both parents = 5.77 [2.2, 15.5]; maternal = 2.7 [1.0, 6.4]; paternal = 2.4 [1.3, 4.5] ) as was prone sleeping (OR put prone to sleep = 21.5 [10.6, 43.5]; turned prone during sleep = 100 [46, 219]). Premature birth was also significantly associated with SIDS (OR = 2.4 [1.2, 4.8]). CONCLUSION: Postnatal parental smoking is currently a major environmental risk factor for SIDS in the Netherlands together with the long-established risk of prone sleeping.

Riolan's arch: confusing, misnomer, and obsolete. A literature survey of the connection(s) between the superior and inferior mesenteric arteries.

BACKGROUND: There are 2 interpretations of Riolan's arch: (1) Riolan's arch is identical to a central part of the marginal artery (MA), connecting the superior (SMA) and the inferior mesenteric (IMA) arteries; and (2) Riolan's arch represents a rare artery, connecting the SMA and the IMA. The current review aims to emphasize the clinical importance of the colon's vasculature and to show the feasibility of abolishing the terms "Riolan's arch" and "meandering mesenteric artery." METHODS: A literature survey was performed. RESULTS: It appears that no distinct identity can be ascribed to Riolan's arch and that the "meandering mesenteric artery" represents an angiographically hypertrophied MA and/or the ascending branch of the left colic artery. However, a rare, centrally located, communicating artery has been described. Generally, the MA is sufficient for left colic circulation after ligation of the IMA, but at the splenic flexure, patency of the ascending branch of the left colic artery can be primordial. CONCLUSION: As connections between the SMA and the IMA can be adequately described using structures mentioned in Terminologica Anatomica, the terms "Riolan's arch" and "meandering mesenteric artery" should be abolished.