Infant Mortality

Infant mortality is one of the leading indicators of a nation’s health. We seek to better understand which infant deaths are linked to genetic diseases. That information can then be used to focus resources to improve diagnosis and treatment for those conditions.

In 2020, RCIGM and UC San Diego were jointly awarded a $3.6M, 5-year grant to study infant mortality from the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development.

2018 INFANT CAUSES OF DEATH

Researchers plan to decode genomes associated with 1,000 infant deaths from dried blood spots. By combining data about the genetic makeup of these infants with data about their environment, birth, and demographic risk factors they will examine the roles these different factors play in infant mortality. The goal is to detect the causes of previously unexplained deaths and use that to inform prevention and intervention strategies.

The study will also probe the ethical implications of returning results to bereaved families.

Research Study

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Christina Chambers, PhD, MPH

UC San Diego

San Diego, CA, Aug. 21, 2017-- Dr. Stephen Kingsmore.  Photo by Earnie Grafton.

Stephen Kingsmore, MD, DSc

Rady Children's Institute for Genomic Medicine

Publications

NPJ Genom Med. 2020 Nov 2;5:49. doi: 10.1038/s41525-020-00155-8. eCollection 2020.

ABSTRACT

Understanding causes of infant mortality shapes public health policy and prioritizes diseases for investments in surveillance, intervention and medical research. Rapid genomic sequencing has created a novel opportunity to decrease infant mortality associated with treatable genetic diseases. Herein, we sought to measure the contribution of genetic diseases to mortality among infants by secondary analysis of babies enrolled in two clinical studies and a systematic literature review. Among 312 infants who had been admitted to an ICU at Rady Children’s Hospital between November 2015 and September 2018 and received rapid genomic sequencing, 30 (10%) died in infancy. Ten (33%) of the infants who died were diagnosed with 11 genetic diseases. The San Diego Study of Outcomes in Mothers and Infants platform identified differences between in-hospital and out-of-hospital causes of infant death. Similarly, in six published studies, 195 (21%) of 918 infant deaths were associated with genetic diseases by genomic sequencing. In 195 infant deaths associated with genetic diseases, locus heterogeneity was 70%. Treatment guidelines existed for 70% of the genetic diseases diagnosed, suggesting that rapid genomic sequencing has substantial potential to decrease infant mortality among infants in ICUs. Further studies are needed in larger, comprehensive, unbiased patient sets to determine the generalizability of these findings.

PMID:33154820 | PMC:PMC7608690 | DOI:10.1038/s41525-020-00155-8

Cold Spring Harb Mol Case Stud. 2020 Feb 3;6(1):a004705. doi: 10.1101/mcs.a004705. Print 2020 Feb.

ABSTRACT

Neonatal encephalopathy with seizures is a presentation in which rapid whole-genome sequencing (rWGS) has shown clinical utility and improved outcomes. We report a neonate who presented on the third day of life with seizures refractory to antiepileptic medications and neurologic and computerized tomographic findings consistent with severe generalized brain swelling. rWGS revealed compound heterozygous variants in the molybdenum cofactor synthesis gene, type 1A (MOCS1 c.*7 + 5G > A and c.377G > A); a provisional diagnosis of molybdenum cofactor deficiency on day of life 4. An emergency investigational new drug application for intravenous replacement of the MOCS1 product, cyclic pyranopterin monophosphate, was considered, but felt unsuitable in light of the severity of disease and delay in the start of treatment. The patient died on day of life 9 despite having a precise molecular diagnosis within the first week of life. This case illustrates that an rWGS-based molecular diagnosis within the first week of life may be insufficient to improve outcomes. However, it did inform clinical decision-making with regard to resuscitation and predicted long-term outcome. We suggest that to achieve optimal reductions in morbidity and mortality, rWGS must be implemented within a comprehensive rapid precision medicine system (CRPM). Akin to newborn screening (NBS), CRPM will have onboarding, diagnosis, and precision medicine implementation components developed in response to patient and parental needs. Education of health-care providers in a learning model in which ongoing data analyses informs system improvement will be essential for optimal effectiveness of CRPM.

PMID:32014857 | PMC:PMC6996516 | DOI:10.1101/mcs.a004705

Pediatr Crit Care Med. 2019 Nov;20(11):1007-1020. doi: 10.1097/PCC.0000000000002056.

ABSTRACT

OBJECTIVES: Genetic disorders are a leading contributor to mortality in the neonatal ICU and PICU in the United States. Although individually rare, there are over 6,200 single-gene diseases, which may preclude a genetic diagnosis prior to ICU admission. Rapid whole genome sequencing is an emerging method of diagnosing genetic conditions in time to affect ICU management of neonates; however, its clinical utility has yet to be adequately demonstrated in critically ill children. This study evaluates next-generation sequencing in pediatric critical care.

DESIGN: Retrospective cohort study.

SETTING: Single-center PICU in a tertiary children’s hospital.

PATIENTS: Children 4 months to 18 years admitted to the PICU who were nominated between July 2016 and May 2018.

INTERVENTIONS: Rapid whole genome sequencing with targeted phenotype-driven analysis was performed on patients and their parents, when parental samples were available.

MEASUREMENTS AND MAIN RESULTS: A molecular diagnosis was made by rapid whole genome sequencing in 17 of 38 children (45%). In four of the 17 patients (24%), the genetic diagnoses led to a change in management while in the PICU, including genome-informed changes in pharmacotherapy and transition to palliative care. Nine of the 17 diagnosed children (53%) had no dysmorphic features or developmental delay. Eighty-two percent of diagnoses affected the clinical management of the patient and/or family after PICU discharge, including avoidance of biopsy, administration of factor replacement, and surveillance for disorder-related sequelae.

CONCLUSIONS: This study demonstrates a retrospective evaluation for undiagnosed genetic disease in the PICU and clinical utility of rapid whole genome sequencing in a portion of critically ill children. Further studies are needed to identify PICU patients who will benefit from rapid whole genome sequencing early in PICU admission when the underlying etiology is unclear.

PMID:31246743 | PMC:PMC6832787 | DOI:10.1097/PCC.0000000000002056

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