Hospital-wide access to genomic data advanced pediatric rare disease research and clinical outcomes.

Boston Children's Hospital has established a genomic sequencing and analysis research initiative to improve clinical care for pediatric rare disease patients. Through the Children's Rare Disease Collaborative (CRDC), the hospital offers CLIA-grade exome and genome sequencing, along with other sequencing types, to patients enrolled in specialized rare disease research studies. The data, consented for broad research use, are harmonized and analyzed with CRDC-supported variant interpretation tools.

Dysregulation of platelet serotonin, 14-3-3, and GPIX in sudden infant death syndrome.

Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant mortality, but the underlying cause(s) are unclear. A subset of SIDS infants has abnormalities in the neurotransmitter, serotonin (5-hydroxytryptamine [5-HT]) and the adaptor molecule, 14-3-3 pathways in regions of the brain involved in gasping, response to hypoxia, and arousal. To evaluate our hypothesis that SIDS is, at least in part, a multi-organ dysregulation of 5-HT, we examined whether blood platelets, which have 5-HT and 14-3-3 signaling pathways similar to brain neurons, are abnormal in SIDS.

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.

Seizures and Sudden Death Beyond SUDEP.

Many physicians and researchers are familiar with the tragic phenomenon known as sudden infant death syndrome (SIDS), the leading cause of postneonatal mortality in high-resource countries. A less familiar category of unexplained deaths is the problem of sudden unexplained death in childhood (SUDC), a more rare and unusual presentation of sudden death in children who are no longer infants and whose reasons for death defy explanation. A substantial body of research in SUDC now supports the possibility of an overlap with epilepsy and associated sudden death in that context (SUDEP).

Sudden Unexplained Death in Childhood: Current Understanding.

Sudden, Unexplained Death in Childhood (SUDC) is a term that encompasses apparently natural deaths in children over one year of age with no discernible cause despite a thorough assessment. Definitive underlying causes vary but most cases remain largely unexplained. Research has furthered the view that SUDC is not an accident, but rather a sentinel medical event for which a thorough postmortem investigation is indicated.

Sudden Unexplained Death in Childhood: Current Understanding.

Sudden unexplained death in childhood is a term that encompasses apparently natural deaths in children aged older than 1 year with no discernible cause despite a thorough assessment. Definitive underlying causes vary but most cases remain largely unexplained. Research has furthered the view that sudden unexplained death in childhood is not an accident, but rather a sentinel medical event for which a thorough postmortem investigation is indicated.

The fundamental need for unifying phenotypes in sudden unexpected pediatric deaths.

A definitive, authoritative approach to evaluate the causes of unexpected, and ultimately unexplained, pediatric deaths remains elusive, relegating final conclusions to diagnoses of exclusion in the vast majority of cases. Research into unexplained pediatric deaths has focused primarily on sudden infant deaths (under 1 year of age) and led to the identification of several potential, albeit incompletely understood, contributory factors: nonspecific pathology findings, associations with sleep position and environment that may not be uniformly relevant, and the elucidation of a role for serotonin that is practically difficult to estimate in any individual case. Any assessment of progress in this field must also acknowledge the failure of current approaches to substantially decrease mortality rates in decades.

Altered 5-HT2A/C receptor binding in the medulla oblongata in the sudden infant death syndrome (SIDS): Part I. Tissue-based evidence for serotonin receptor signaling abnormalities in cardiorespiratory- and arousal-related circuits.

The sudden infant death syndrome (SIDS), the leading cause of postneonatal infant mortality in the United States, is typically associated with a sleep period. Previously, we showed evidence of serotonergic abnormalities in the medulla (e.g.

Copy Number Variation and Structural Genomic Findings in 116 Cases of Sudden Unexplained Death between 1 and 28 Months of Age.

In sudden unexplained death in pediatrics (SUDP) the cause of death is unknown despite an autopsy and investigation. The role of copy number variations (CNVs) in SUDP has not been well-studied. Chromosomal microarray (CMA) data are generated for 116 SUDP cases with age at death between 1 and 28 months.

Medullary Serotonergic Binding Deficits and Hippocampal Abnormalities in Sudden Infant Death Syndrome: One or Two Entities?

Sudden infant death syndrome (SIDS) is understood as a syndrome that presents with the common phenotype of sudden death but involves heterogenous biological causes. Many pathological findings have been consistently reported in SIDS, notably in areas of the brain known to play a role in autonomic control and arousal. Our laboratory has reported abnormalities in SIDS cases in medullary serotonin (5-HT) receptor and within the dentate gyrus of the hippocampus.

Parents as Advocates for Pediatric Palliative Care.

Caring for a child with a serious or life-limiting illness presents many challenges for families and health care providers. Through that experience (and, many times, as it ends), parents are compelled to find and make meaning from their ultimate loss and the many losses along the way. In this Advocacy Case Study, we describe the experiences that led a bereaved mother to seek to harness the insights from her own family's loss to help support other families facing the challenges and complexities of a child's serious illness.

The parental role before and after SIDS.

Role confusion is a prominent constituent symptom of Prolonged Grief Disorder in parents after their infants die from sudden infant death syndrome (SIDS). We interviewed 31 parents of SIDS infants 2-5 years post-loss examining the parental role before death, at the time of loss, and in bereavement. Thematic analysis found disruption of the role and re-imagined responsibilities for their child's physical security, emotional security, and meaning.

Genetic Factors Underlying Sudden Infant Death Syndrome.

Sudden Infant Death syndrome (SIDS) is a diagnosis of exclusion. Decades of research have made steady gains in understanding plausible mechanisms of terminal events. Current evidence suggests SIDS includes heterogeneous biological conditions, such as metabolic, cardiac, neurologic, respiratory, and infectious conditions.

A de novo BRPF1 variant in a case of Sudden Unexplained Death in Childhood.

Sudden Unexplained Death in Childhood (SUDC), the death of a child that remains unexplained after a complete autopsy and investigation, is a rare and poorly understood entity. This case report describes a 3-year-old boy with history of language delay and ptosis, who died suddenly in his sleep without known cause. A pathogenic de novo frameshift mutation in BRPF1, a gene which has been associated with the syndrome of Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP), was identified during a post-mortem evaluation.

The role of sodium channels in sudden unexpected death in pediatrics.

Background: Sudden Unexpected Death in Pediatrics (SUDP) is a tragic event, likely caused by the complex interaction of multiple factors. The presence of hippocampal abnormalities in many children with SUDP suggests that epilepsy-related mechanisms may contribute to death, similar to Sudden Unexplained Death in Epilepsy. Because of known associations between the genes SCN1A and SCN5A and sudden death, and shared mechanisms and patterns of expression in genes encoding many voltage-gated sodium channels (VGSCs), we hypothesized that individuals dying from SUDP have pathogenic variants across the entire family of cardiac arrhythmia- and epilepsy-associated VGSC genes.

Transitional objects of grief.

Background: Transitional objects provide security and symbolic connection with valued others when separated from them. Bereaved parents often keep, cherish and visit saved objects of their deceased child. This research examined the hypothesis that these objects behave as transitional objects of grief in bereaved mothers during three years following their infants' deaths from Sudden Infant Death Syndrome.

Inconsistent classification of unexplained sudden deaths in infants and children hinders surveillance, prevention and research: recommendations from The 3rd International Congress on Sudden Infant and Child Death.

This report details the proceedings and conclusions from the 3rd International Congress on Unexplained Deaths in Infants and Children, held November 26-27, 2018 at the Radcliffe Institute at Harvard University. The Congress was motivated by the increasing rejection of the diagnosis Sudden Infant Death Syndrome (SIDS) in the medical examiner community, leading to falsely depressed reported SIDS rates and undermining the validity and reliability of the diagnosis, which remains a leading cause of infant and child mortality. We describe the diagnostic shift away from SIDS and the practical issues contributing to it.

Maternal Smoking Before and During Pregnancy and the Risk of Sudden Unexpected Infant Death.

Objectives: Maternal smoking during pregnancy is an established risk factor for sudden unexpected infant death (SUID). Here, we aim to investigate the effects of maternal prepregnancy smoking, reduction during pregnancy, and smoking during pregnancy on SUID rates.

Methods: We analyzed the Centers for Disease Control and Prevention Birth Cohort Linked Birth/Infant Death Data Set (2007-2011: 20 685 463 births and 19 127 SUIDs).

Mutations in and in a patient with early-onset epileptic encephalopathy and respiratory depression.

Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation.

Pre-loss personal factors and prolonged grief disorder in bereaved mothers.

Background: Identifying characteristics of individuals at greatest risk for prolonged grief disorder (PGD) can improve its detection and elucidate the etiology of the disorder. The Safe Passage Study, a study of women at high risk for sudden infant death syndrome (SIDS), prospectively examined the psychosocial functioning of women while monitoring their healthy pregnancies. Mothers whose infants died of SIDS were followed in bereavement.