Source: Dave Herholz

Clinical exome sequencing has been shown to be a promising tool for improving healthcare for critically ill newborns in a new study led by researchers at Baylor College of Medicine. The research, published in JAMA Pediatrics yesterday, observed the treatment of 278 critically ill infants at Texas Children’s Hospital between late 2011 and early this year. Of the patients involved, almost all (90.3%) were being treated in neonatal intensive care units (NICUs), paediatric intensive care units (PICUs), or cardiovascular intensive care units.

“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,” the authors wrote.

The study examined the medical information of 278 patients suspected of having a single gene disorder, who had undergone clinical exome sequencing in the first 100 days of life. Of these infants, 176 were sequenced individually, 39 were sequenced alongside their parents using a parent-child trio method, and the 63 most critically ill infants were sequenced according to a rapid, critical trio protocol. The average age at the time of sequencing was 28.5 days.

A range of conditions were being tested for, such as neuromuscular disease, skeletal malformations or dysplasia, lung disease, cystic renal disease, congenital cardiovascular malformations, and hypertrophic cardiomyopathy.

Ultimately, clinical exome sequencing was able to diagnose 106 conditions across 102 of the infants. A further 6 patients received a partial diagnosis, were found to have a non-genetic condition, or were diagnosed using Southern blot analysis. Of the 102 patients that received a diagnosis, 56 had undergone sequencing as a first tier diagnostic tool and 30 of those saw treatment or management changes as a result of their diagnosis. 23 of the remaining 46, who had been sequenced as a second-tier diagnostic tool, also had their treatment plan altered in response to their results.

Importantly, the team found that rapid, critical trio sequencing was the most effective was of diagnosing patients. 50.8% of the infants who received this testing were diagnosed, in comparison to 32.4% for those sequenced individually and 33.3% sequenced using traditional parent-child trio sequencing.

These results indicate that there is significant promise in the ability of clinical exome sequencing to provide a diagnosis for critically ill infants. Unfortunately, however, 30 infants who had received a diagnosis and 28 of those that hadn’t still died before they were 120 days old, regardless of any treatment changes. It is clear, therefore, that there is still work that needs to be done to improve our understanding in this area.  

“This study exposes a myriad of monogenic disorders that have been under-ascertained in critically ill neonates. 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 NGS is indisputable in the expeditious detection of disorders that are clinically heterogeneous or atypical because of dual diagnoses,” the authors concluded.

Using genomic data in a NICU setting is an idea that has started to gain significant traction in recent years, in no small part because of Dr Stephen Kingsmore and his team at Rady Children’s Hospital. Using next generation sequencing, together with Edico Genome and Illumina, the team have begun to expand their work of improving infant healthcare using their genomic data. Yesterday’s study is further evidence that this approach may be capable of significantly increasing our ability to treat critically ill newborns in the future.