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Multidimensional Utility of Genomic Autopsy for Infant Mortality

Health Services and Implementation
  • Primary Categories:
    • Genomic Medicine
  • Secondary Categories:
    • Genomic Medicine
Introduction:
Genomic autopsy, or the application of genome-wide sequencing such as exome or genome sequencing (ES or GS) for postmortem diagnosis, has high diagnostic yield for fetal loss. However, incorporation of a genomic autopsy into the investigation of infant deaths is infrequent. This is due to lack of awareness of the diagnostic potential and clinical impact, in addition to financial and other logistical barriers. Consequently, the genomic landscape of infant mortality remains poorly understood, and many families are left without the answers a genomic autopsy could provide. We therefore applied exome or genome sequencing (ES/GS) to identify rare genetic conditions in a prospective infant mortality cohort with the goal to define diagnostic, clinical, and psychosocial utility.

Methods:
For a cohort of infants who died prior to one year of age, we obtained detailed phenotype information from medical records and collected DNA samples from the infant, parents (if available), and affected siblings (if pertinent). We performed ES or GS and returned diagnostic results to the families, with GS initially used for infants who had prior negative ES and now used as the first-line approach. When available, autopsy findings were reviewed. Parents were surveyed upon enrollment and one year later to evaluate clinical and psychosocial utility. A multivariable logistic regression model was constructed on the outcome of diagnosed status with clinical and demographic exposures considered as covariates.

Results:
We have enrolled 91 infants from 89 families, including 71 trios, 3 quads, 7 duos, and 8 proband-only cases. Most decedents were male (53, 58%), born preterm (< 37 weeks, 52, 58%) and had at least one major congenital anomaly (54, 59%). The median age at death was 0.3 months (interquartile range 0.03-1.95 months). Families received ES (54, 60%) or GS (40, 45%), 3 families had long read GS, and 6 families had more than one of these. Six families had RNA sequencing. Traditional autopsy data were available for 42 infants (46%).

 

Overall, 28 families (32%) were considered diagnosed or likely diagnosed, with candidate causal variants in found in an additional 17 (19%). Diagnostic variants were most commonly found in genes responsible for multiple anomaly syndromes (12/28, 43%) followed by isolated anomaly syndromes (6/28, 21%), neurodevelopmental disorders (6/28, 21%), and genetic metabolic conditions (4/28, 14%). Only 3/28 (11%) diagnoses were clinically suspected prior to death, and 10/28 (36%) represented a phenotype expansion of a known genetic disorder. For the candidate variants, 6/17 (35%) were in potential novel disease-associated genes. RNA sequencing supported the pathogenicity of the causal variant found in one family and has suggested candidate genes for three families. Age at death, sex, prematurity, presence of major congenital anomalies, lack of parental data, and lack of traditional autopsy data were not significantly associated with odds of diagnosis.

 

Preliminary parent-reported utility data at enrollment reflect high interest in a diagnosis: 25/31 (81%) reported that a diagnosis is very/extremely important, particularly for understanding the infant’s health problems (30/31, 97%, agree/strongly agree), pregnancy planning (28/31, 90%, agree/strongly agree), and the decision of whether to have more children (23/31, 74% agree/strongly agree). The ability of a diagnosis to help parents feel less alone or helping to connect was less highly endorsed (15/31, 48%, and 13/31, 42%, agree/strongly agree, respectively). On follow-up surveys post-ES/GS with 14 parents (4 diagnosed families, 10 undiagnosed), 6 (43%) met criteria for prolonged grief disorder, all parents whose infants remained undiagnosed.

Conclusion:
Genomic sequencing had a high diagnostic yield in an infant mortality cohort, illuminating novel disease-gene relationships, with high parent-perceived importance. Our findings support incorporation of genomics into postmortem care.

 

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