388 - Utility of Genomic Autopsy for Infant Mortality

Publication Number: 388.7018

Monica Wojcik, Boston Children's Hospital, Boston, MA, United States; Casie A. Genetti, Boston Children's Hospital, Boston, MA, United States; Malika Sud, Boston Children's Hospital, Boston, MA, United States; Jill Madden, Boston Children's Hospital, Somerville, MA, United States; Kathleen Garvey, Boston Children's Hospital, Boston, MA, United States; Ikeoluwa Osei-Owusu, Boston Children's Hospital, Cambridge, MA, United States; Nicole Groussis, Boston Children's Hospital, Boston, MA, United States; Sundos N. Al-Husayni, Boston Children's Hospital, Boston, MA, United States; Pankaj B.. Agrawal, University of Miami Leonard M. Miller School of Medicine, Miami, FL, United States; Richard D. Goldstein, Boston Children's Hospital, Boston, MA, United States; Heidi Rehm, Massachusetts General Hospital, Boston, MA, United States; Anne O'Donnell-Luria, Boston Children's Hospital, Boston, MA, United States; Alan H.. Beggs, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States; Ingrid A. Holm, Boston Children's Hospital, Boston, MA, United States

Background: Postmortem genomic sequencing, or “genomic autopsy”, has high diagnostic yield for fetal loss or stillbirth. However, incorporation of a genomic autopsy into the investigation of infant deaths is infrequent, in part due to lack of awareness of the diagnostic potential and clinical impact. Consequently, the genomic landscape of infant mortality remains poorly understood, and many families are left without the answers a genomic autopsy could provide.

Objective: To use exome or genome sequencing (ES/GS) to identify Mendelian disorders leading to death in infancy in order to define diagnostic, clinical, and psychosocial utility.

Design/Methods: For a cohort of infants who died prior to one year of age, we obtained detailed phenotype information from medical records, collected DNA samples from the infant, parents (if available), and affected siblings (if pertinent), performed ES/GS, and returned diagnostic results to the families. 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.

Results: 91 infants were enrolled from 89 families, including 71 trios, 3 quads, 7 duos, and 8 proband-only cases. Most decedents were male (53, 58%), born preterm (52, 58%) and had at least one major congenital anomaly (54, 59%). Median age at death was 0.3 months (IQR 0.03-1.95). Families received ES (54, 60%) or GS (40, 45%); 3 families had long read GS, and 6 families had more than one of these. Five 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%) (Figure 1). 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 and pregnancy planning (Figure 2). 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(s): Genomic sequencing had a high diagnostic yield in an infant mortality cohort, illuminating novel disease-gene relationships, with high parent-perceived importance.

Figure 1. Genomic Autopsy Process and Findings
Genomic sequencing and analysis for enrolled families leads to identification of causal variants and candidate variants in known disease genes and elucidates potential novel disease-gene associations.

Figure 2. Perceived Utility of a Postmortem Genetic Diagnosis Upon Enrollment
Parent-reported agreement with various statements related to the value of a genetic diagnosis is reported on a 5-point Likert scale.

Figure 1. Genomic Autopsy Process and Findings
Genomic sequencing and analysis for enrolled families leads to identification of causal variants and candidate variants in known disease genes and elucidates potential novel disease-gene associations.

Figure 2. Perceived Utility of a Postmortem Genetic Diagnosis Upon Enrollment
Parent-reported agreement with various statements related to the value of a genetic diagnosis is reported on a 5-point Likert scale.