Importance:
While congenital malformations and genetic diseases are a leading cause of early infant death, the contribution of single-gene disorders in this group is undetermined.
Objective:
To determine the diagnostic yield and utility of clinical exome sequencing in critically ill infants.
Design, setting, participants:
Clinical exome sequencing was performed on 278 unrelated infants within the first 100 days of life, admitted to Texas Children’s Hospital in Houston, over a period of five years, between December 2011 and January 2017. Exome sequencing types included proband exome, trio exome, and critical trio exome, a rapid genomic assay for seriously-ill infants.
Main outcomes and measures:
Indications for testing, diagnostic yield of clinical exome sequencing, turnaround time, molecular findings, patient age at diagnosis, and impact on medical management in a group of critically ill infants suspected to have genetic disorders.
Results:
Clinical indications for exome sequencing included a wide range of medical concerns. Overall, molecular diagnosis was achieved in 102/278 infants by clinical exome sequencing with a diagnostic yield of 36.7%. The diagnosis affected medical management in 53/102 (52.0%) of infants, with substantial impact on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome revealed a molecular diagnosis in 32/63 infants (50.8%) at 33.1±5.6 days of life with turnaround time (TAT) of 13.0 ± 0.4 days. Clinical care was altered by the diagnosis in 23/32 (71.9%) patients. The diagnostic yield, patient age at diagnosis, and medical impact in the group that underwent critical trio exome is significantly different comparing to regular exome testing. For deceased infants (n=81), genetic disorders were molecular diagnosed in 39 (48.1%) by exome sequencing with implications for recurrence risk counseling.
Conclusions and relevance:
Exome sequencing is a powerful tool for the diagnostic evaluation of critically ill infants with suspected monogenic disorders in the neonatal and pediatric ICUs, leading to notable impact on clinical decision-making.
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