Genetic Screening Could Have Promise for Reducing Infant Deaths

An analysis of 112 infant deaths found that the contribution of genetic diseases to mortality was higher than previously known, and that treatments are available for 30% of the genetic diseases uncovered by the study.

Early implementation of treatment for genetic diseases could curb infant mortality, according to a new study published in JAMA Network Open. The study also found that the association between infant mortality and genetic diseases was higher than was previously believed.

The United States maintains a higher infant mortality rate at 1 in 200 live births, with malformations accounting for more than one-fifth of all infant deaths. Etiologic classification is vital for families and the public to be informed about potential risks but underdiagnosis of genetic diseases could lead to inaccuracies in death certificate classification. This study aimed to report the results of a cohort of infants who died between 2015 and 2020 who received diagnostic whole-genome sequencing (WGS).

The retrospective cohort study used indications for infant WGS from Blue Shield-California and postmortem WGS was obtained from all infants with blood samples archived in the Rady Children’s bioreposity from 2015 to 2019. All participants had standard genetic testing. WGS was performed with blood samples or dried blood spots.

Race and ethnicity were extracted from the electronic health record. Infants were categorized as American Indian or Alaska Native, Asian, Black or African American, Hispanic, Native Hawaiian or Pacific Islander, non-Hispanic, White, or other if they did not categorize themselves in these classifications. Structured adjudication of indications, contraindications, efficacy, and evidence of efficacy in 9911 drug, device, dietary, and surgical interventions for childhood genetic diseases was also undertaken by an expert panel.

There were 112 infants who died that were included and had WGS information in Rady’s Children’s Hospital or University of California, San Diego, health records. These 112 WGS datasets found 47 single-locus genetic diseases in 46 deaths, of which 39 had been previously reported as being linked to childhood mortality.

There were 5 known risk factors for infant death that differed between the 46 infant deaths associated with genetic diseases and the 66 that weren’t associated. Infant deaths without genetic deaths were more likely caused by premature birth, placental abruption, and maternal infection whereas polyhydramnios was more common in infants with genetic disease–associated deaths.

The 112 infants who died were compared with the 434 infants who survived, all of whom had WGS information. Single-locus genetic diseases were found to be more common in infants who died than survivors (41% vs 26%). Genetic diseases found in infants who had died were different compared with the infants who survived, with only 6 genetic disorders found in both survivors and deaths out of 148. Specific genetic etiology had prognostic value (predictive value for death, 85%; predictive value for survival, 89%).

Genetic disease heterogeneity was also greater in infant deaths compared with survivors, with 95.7% unique to a single patient in infant deaths compared with 83.2% in survivors.

The researchers also found that only 36% of the death certificates evaluated included the genetic etiology of the death. Several of these deaths could have been avoided if these genetic diseases were identified earlier, such as CACNa1C long QT syndrome 8, PPA2 infantile sudden cardiac failure, and NFKB1 common variable immunodeficiency with autoimmunity.

Genetic disease was found to be the leading cause of death (41.1%) when evaluating and reclassifying the single-locus genetic disease as a single category. Genetic diseases were not found to be associated with infant deaths with known nongenetic risk factors.

There were some limitations to this study. The small sample size in a single US county limits the generalizability of the study. There was also uncertainty about whether genetic diseases were associated with infant mortality and uncertainty that was associated with counterfactual clinical courses that had diagnosis and treatment that occurred before death. Underrepresentation of deaths at home, in the emergency department, and on the first 4 days of life were also limits.

The researchers concluded that genetic etiology was underrepresented in death certificates. WGS was also able to materially change the etiology of the leading causes of infant mortality.


Owen MJ, Wright MS, Batalov S, et al. Reclassification of the etiology of infant mortality with whole-genome sequencing. JAMA Netw Open. 2023;6(2):e2254069. doi:10.1001/jamanetworkopen.2022.54069

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