Exome sequencing helps diagnose infants in the ICU

A recent study shows that whole-exome sequencing (WES) diagnoses in more than one-third of intensive care unit (ICU) infants with suspected single-gene conditions led to changes in medical management for more than half of babies with identified disorders.

A retrospective study of 278 severely ill infants sequenced at Texas Children's Hospital in Houston between late 2011 and early 2017 reports that 36.7% of the infants received diagnoses leading to changes in management for almost 52% of those babies. In close to 55% of all infants, WES was a first-tier diagnostic test (Meng et al, 2017).

The study is the latest to show the diagnostic power of WES, which has consistently yielded diagnoses in at least 25% of genetics patients with a variety of disorders.

“Whether it is redirection of care for a life-threatening condition or being able to offer life saving measures such as stem cell or organ transplant, exome sequencing promises a personalized approach to management of genetic diseases,” says senior author Seema Lalani, MD, Associate Professor of Molecular and Human Genetics at Baylor University in Houston. She hopes the findings will spur improved insurance coverage and wider use of WES.

The Study

The researchers studied seriously ill infants who received clinical exome sequencing within the first 100 days of life. Subjects included 176 babies who had individual sequencing (proband-only sequencing), 39 infants tested as part of parent-child trios (trio testing), and 63 more critically ill babies who had more rapid trio sequencing (critical exome trio testing). Critical exome trio testing for these 63 infants was informed by clinical assessments by geneticists, with results delivered in an average of 13 days. WES led to diagnoses of 106 conditions in 102 babies. Six infants received a partial diagnosis, one of which was delivered by Southern blot analysis, or a nongenetic disorder. Of the remaining 170 infants who received no diagnoses from WES, 150 had chromosomal microarray. Microarray yielded no diagnoses. Critical trio exome sequencing provided the highest diagnostic yield, 50.8%, compared to 32.4% for proband-only sequencing and 33.3% for trio testing.

For 52% of patients overall, diagnoses spurred new subspecialist care, change in medication or diet, major procedures like transplant, or a switch from curative to palliative care. For patients who had proband-only testing, diagnoses yielded management changes for 45.6% of patients. That figure was 33.3% for trio testing patients. It was highest, 71.9%, for children diagnosed by critical trio exome testing.

Despite these results, 30, or 29.4%, of the 102 infants diagnosed by WES died before reaching an age of 120 days, the researchers note.

This study exposes several single-gene disorders that have been underascertained in critically ill newborns, says Dr. Lalani. For example, multiple babies in the study had Kabuki syndrome, and many had recently discovered disorders, such as those caused by the gene PURA, discovered in 2014. PURA variations can cause low muscle tone, respiratory problems, and feeding difficulties. The researchers also saw several rare disorders, often with atypical presentations, that are difficult to diagnose by clinical exams of newborns, Dr. Lalani adds.

Reaction

The paper shows that babies in ICUs often have genetic conditions, says David Bick, MD, Chief Medical Officer, Hudson Alpha Institute for Biotechnology in Huntsville, Alabama, and former medical director of the genetics clinic at Children's Hospital of Wisconsin in Milwaukee. The institution was an early adopter of genomic sequencing, which can help doctors administer appropriate drugs to newborns in a timely fashion, Dr. Bick notes. He points to ALDH7A mutations that cause pyridoxine-responsive epilepsy, which should be treated as early as possible. “The more seizures a baby with this disorder has, the more damage there is to the brain. So pyridoxine is less effective with time,” he explains.

The paper also demonstrates that sequencing can determine when treatment will not help an infant, he adds. “There are a ton of tricks we can do in the NICU that can keep kids alive. But we may put a child through a lot of pain for no gain,” Dr. Bick says. But even rapid sequencing with 13-day turnaround “isn't fast enough for some kids.”

Sequencing helps diagnose serious disorders that are nonlethal in the neonatal period, when clinical features may be subtle or undetectable, notes Dr. Bick. He gives as examples RASopathies like Costello syndrome, cardiofaciocutaneous syndrome, and Noonan syndrome. Sometimes premature babies with Down syndrome will not have the telltale facial features until more than a month after birth, he adds.

Although the study's more rapid sequencing delivered favorable results, it may be difficult for many hospitals to perform, notes Jonathan S. Berg, MD, PhD, Assistant Professor in the Department of Genetics at the University of North Carolina at Chapel Hill, who is studying use of genomic sequencing in newborn screening. He points to the logistics and expense of having someone always available to receive samples, start lab work immediately, and speed up informatics procedures.

The clinical impact of genomic sequencing in the ICU needs further study, Dr. Berg adds. “We shouldn't overinterpret the results of this paper,” he says, pointing to its retrospective design and focus on a very selected group of patients from specialized ICUs. This design, plus inclusion of patients from regular, neonatal, and cardiac ICUs, leaves he study open to confounding factors and limits researchers’ ability to do a direct comparison of WES and microarray diagnostic yield, he explains.

Even so, this research and similar studies, especially controlled, prospective ones, can show insurance companies that genomic sequencing is really “just a drop in the bucket relative to the entire ICU stay,” even with the higher cost of sequencing relative to other tests, says Dr. Berg. “If establishing a diagnosis can help to adjust the management for some fraction of patients and hopefully improve the outcomes for some of those, then perhaps genomic sequencing would be considered a worthwhile expense,” he adds.

Overall, Dr. Bick is enthusiastic about the paper and believes clinical WES is no longer the test of the future. “For the most part, the day of using exome as a firstline test has arrived,” he says. “But you will still need someone with expertise in dysmorphology to make the best use of it.”