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

J Matern Fetal Neonatal Med. 2021 Dec 1:1-8. doi: 10.1080/14767058.2021.2008899. Online ahead of print.

ABSTRACT

OBJECTIVES: Many studies of sudden unexpected infant death (SUID) have focused on individual domains of risk factors (maternal, infant, and environmental), resulting in limited capture of this multifactorial outcome. The objective of this study was to examine the geographic distribution of SUID in San Diego County, and assess maternal, infant, and environmental risk factors from a large, administrative research platform.

STUDY DESIGN: Births in California between 2005 and 2017 were linked to hospital discharge summaries and death files. From this retrospective birth cohort, cases of SUID were identified from infant death files in San Diego County. We estimated adjusted hazard ratios (aHRs) for infant, maternal, and environmental factors and SUID in multivariable Cox regression analysis. Models were adjusted for maternal sociodemographic characteristics and prenatal nicotine exposure.

RESULTS: There were 211 (44/100,000 live births; absolute risk 0.04%) infants with a SUID among 484,905 live births. There was heterogeneity in geographic distribution of cases. Multiparity (0.05%; aHR 1.4, 95% confidence interval (CI) 1.1, 1.9), maternal depression (0.11%; aHR 1.8, 95% CI 1.0, 3.4), substance-related diagnoses (0.27%; aHR 2.3, 95% CI 1.3, 3.8), cannabis-related diagnosis (0.35%; aHR 2.7, 95% CI 1.5, 5.0), prenatal nicotine use (0.23%; aHR 2.5, 95% CI 1.5, 4.2), preexisting hypertension (0.11%; aHR 2.3, 95% CI 1.2, 4.3), preterm delivery (0.09%; aHR 2.1, 95% CI 1.5, 3.0), infant with a major malformation (0.09%; aHR 2.0, 95% CI 1.1, 3.6), respiratory distress syndrome (0.12%; aHR 2.6, 95% CI 1.5, 4.6), and select environmental factors were all associated with SUID.

CONCLUSIONS: Multiple risk factors were confirmed and expanded upon, and the geographic distribution for SUID in San Diego County was identified. Through this approach, prevention efforts can be targeted to geographies that would benefit the most.

PMID:34852708 | DOI:10.1080/14767058.2021.2008899

Cell. 2021 Aug 7:S0092-8674(21)00883-7. doi: 10.1016/j.cell.2021.07.024. Online ahead of print.

ABSTRACT

Throughout development and aging, human cells accumulate mutations resulting in genomic mosaicism and genetic diversity at the cellular level. Mosaic mutations present in the gonads can affect both the individual and the offspring and subsequent generations. Here, we explore patterns and temporal stability of clonal mosaic mutations in male gonads by sequencing ejaculated sperm. Through 300× whole-genome sequencing of blood and sperm from healthy men, we find each ejaculate carries on average 33.3 ± 12.1 (mean ± SD) clonal mosaic variants, nearly all of which are detected in serial sampling, with the majority absent from sampled somal tissues. Their temporal stability and mutational signature suggest origins during embryonic development from a largely immutable stem cell niche. Clonal mosaicism likely contributes a transmissible, predicted pathogenic exonic variant for 1 in 15 men, representing a life-long threat of transmission for these individuals and a significant burden on human population health.

PMID:34388390 | DOI:10.1016/j.cell.2021.07.024

Cold Spring Harb Mol Case Stud. 2021 Jun 11;7(3):a006091. doi: 10.1101/mcs.a006091. Print 2021 Jun.

ABSTRACT

Rapid whole-genome sequencing (rWGS) has shown that genetic diseases are a common cause of infant mortality in neonatal intensive care units. Dried blood spots collected for newborn screening allow investigation of causes of infant mortality that were not diagnosed during life. Here, we present a neonate who developed seizures and encephalopathy on the third day of life that was refractory to antiepileptic medications. The patient died on day of life 16 after progressive respiratory failure and sepsis. The parents had lost two prior children after similar presentations, neither of whom had a definitive diagnosis. Postmortem rWGS of a dried blood spot identified a pathogenic homozygous frameshift variant in the SUOX gene associated with isolated sulfite oxidase deficiency (c.1390_1391del, p.Leu464GlyfsTer10). This case highlights that early, accurate molecular diagnosis has the potential to influence prenatal counseling and guide management in rare, genetic disorders and has added importance in cases of a strong family history and risk factors such as consanguinity.

PMID:34117075 | DOI:10.1101/mcs.a006091

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