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Clinical Exomes Contribute to Monogenic Disease Diagnoses in Infant ICU, Study Finds

NEW YORK (GenomeWeb) – A new study suggests clinical exome sequencing can successfully diagnose single-gene disorders in more than one-third of infants with suspected single-gene conditions in an intensive care setting.

Researchers from the Baylor College of Medicine and elsewhere retrospectively tallied clinical exome sequencing outcomes for nearly 300 infants assessed at the Texas Children's Hospital in Houston between late 2011 and early 2017 for a study published in JAMA Pediatrics today. With these data, they reached diagnoses for just shy of 37 percent of the infants, leading to treatment or management changes in 52 percent of the newly diagnosed cases.

"Our study provides strong evidence that clinical exome sequencing uncovers monogenic disorders in a significant number of infants in NICUs and pediatric ICUs who are suspected to have genetic disorders, significantly affecting the medical care of more than half of infants who receive diagnoses," senior author Seema Lalani, a molecular and human genetics researcher at Baylor College of Medicine, and her co-authors wrote.

The team focused on 278 critically ill infants who had clinical exome sequencing done at some point during their first 100 days of life. The group included 176 infants who had their exomes sequenced individually, 39 infants sequenced as part of a parent-child trio, and 63 infants who sequenced under a rapid, critical trio exome protocol.

On average, the infants were 28.5 days old at the time of sequencing, the researchers noted, and 251 infants were in the NICU, pediatric ICU, or cardiovascular ICU when their samples were collected. The rapid exome sequencing strategy was used for infants with the most critical conditions — a selection informed with clinical assessments by clinical geneticists.

"For most infants who were selected for the rapid study, the indications included neuromuscular disease, syndromic congenital cardiovascular malformations, hypertrophic cardiomyopathy with an assessment for cardiac transplant, skeletal malformations and/or dysplasia, neonatal cholestasis and liver failure, and lung disease including alveolar capillary dysplasis, cystic renal disease, and metabolic disorders with persistent lactic acidosis," the authors wrote.

The clinical exome sequence data generated for these and other infants led to 106 conditions, diagnosed in 102 infants. Six more infants received a partial diagnosis, were diagnosed by using Southern blot analysis, or were found to have non-genetic conditions, while 150 of the remaining 170 infants were tested using clinical chromosomal microarrays.

The team noted that there was an uptick in the diagnostic yield in the infants who received critical exome trio sequencing. Nearly 51 percent of that group was diagnosed based on exome sequencing, compared to 32.4 percent of infants with proband sequencing and 32.4 percent of infants assessed by conventional parent-child trio exome sequencing.

"This study exposes a myriad of monogenic disorders that have been under-ascertained in critically ill neonates," Lalani and her co-authors wrote. "While a comprehensive clinical evaluation is vital in allowing single-gene or panel testing among a subset of sick infants in the ICU, the power of [next-generation sequencing] is indisputable in the expeditious detection of disorders that are clinically heterogeneous or atypical because of dual diagnoses."

In more than half of the diagnosed infants — almost 55 percent — clinical exome sequencing was used as a first-tier diagnostic test, the researchers noted. The diagnoses led to clinical management shifts for 30 of the 56 infants in that group, such as changes to medication, diet, access to medical procedures, and/or redirection of care or care by new sub-specialists. Among the 46 infants who had clinical exome sequencing as a second-tier test, they saw altered treatment or clinical management for 23 infants.

Again, the effect was most pronounced for infants assessed in the rapid, critical exome sequencing setting. Almost 72 percent of the 32 infants diagnosed in that arm of the study saw changes to their clinical management.

Despite these efforts, 30 of the 102 infants diagnosed by exome sequencing in the Baylor-led study died before reaching their 120th day, as did 28 of the infants not diagnosed by clinical exome sequencing test.

In a related JAMA Pediatrics editorial, University of Washington genome sciences researcher Mary-Claire King and Sarah Baxter, with the University of Washington and Seattle Children's Hospital, said the "most encouraging result of the study was the effect of genetic diagnoses on care."

The duo noted that "[g]enetic diagnoses for severely ill infants, based on either whole-exome or whole-genome sequencing, will be enormously benefitted over the few years by the rapid rate of discovery of genes that are responsible for congenital disorders."