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Original Investigation
Caring for the Critically Ill Patient
December 4, 2017

Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management

Author Affiliations
  • 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
  • 2Baylor Genetics Laboratory, Houston, Texas
  • 3Department of Pediatrics, Section of Neonatology, Baylor College of Medicine, Houston, Texas
  • 4Texas Children’s Hospital, Houston
  • 5The Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas
  • 6Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas
  • 7Department of Pediatrics, Genetics Division, University of Tennessee Health Science Center, Memphis
  • 8Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas
  • 9Department of Pediatrics, Baylor College of Medicine, Houston, Texas
JAMA Pediatr. 2017;171(12):e173438. doi:10.1001/jamapediatrics.2017.3438
Key Points

Question  What is the clinical use of exome sequencing when used in neonatal and pediatric intensive care units?

Findings  In this study of 278 infants within the first 100 days of life who were referred to undergo clinical exome sequencing, 36.7% received a genetic diagnosis, and the medical management was affected for 52.0% of the patients with diagnoses; critical trio exome testing results yielded a higher diagnostic rate at an earlier age and were more likely to affect medical management.

Meaning  Using exome sequencing in intensive care units may affect the medical care of critically ill infants who are suspected to have genetic disorders.


Importance  While congenital malformations and genetic diseases are a leading cause of early infant death, to our knowledge, the contribution of single-gene disorders in this group is undetermined.

Objective  To determine the diagnostic yield and use of clinical exome sequencing in critically ill infants.

Design, Setting, and Participants  Clinical exome sequencing was performed for 278 unrelated infants within the first 100 days of life who were admitted to Texas Children’s Hospital in Houston, Texas, during a 5-year period 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 effect on medical management among a group of critically ill infants who were suspected to have genetic disorders.

Results  The mean (SEM) age for infants participating in the study was 28.5 (1.7) days; of these, the mean (SEM) age was 29.0 (2.2) days for infants undergoing proband exome sequencing, 31.5 (3.9) days for trio exome, and 22.7 (3.9) days for critical trio exome. Clinical indications for exome sequencing included a range of medical concerns. Overall, a molecular diagnosis was achieved in 102 infants (36.7%) by clinical exome sequencing, with relatively low yield for cardiovascular abnormalities. The diagnosis affected medical management for 53 infants (52.0%) and had a substantial effect on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome sequencing revealed a molecular diagnosis in 32 of 63 infants (50.8%) at a mean (SEM) of 33.1 (5.6) days of life with a mean (SEM) turnaround time of 13.0 (0.4) days. Clinical care was altered by the diagnosis in 23 of 32 patients (71.9%). The diagnostic yield, patient age at diagnosis, and medical effect in the group that underwent critical trio exome sequencing were significantly different compared with the group who underwent regular exome testing. For deceased infants (n = 81), genetic disorders were molecularly 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 intensive care units and its use has a notable effect on clinical decision making.