NEW YORK – Based on findings from a small case series, a team of researchers based in the United Arab Emirates (UAE) is pursuing more widespread use of rapid whole-genome sequencing (rWGS) for infants being treated for complex, difficult-to-diagnose medical conditions, including pediatric cases from locations and populations that are underrepresented in genetic studies.
"[P]roviding a genetic diagnosis as early as possible will not only be life-saving, but will also significantly reduce healthcare costs in this setting by reducing unnecessary diagnostic workup and inappropriate treatments and interventions plans, both of which are very costly," senior and corresponding author Ahmad Abou Tayoun, a clinical molecular geneticist affiliated with the Al Jalila Children's Specialty Hospital and Center for Genomic Discovery at Mohammed Bin Rashid University of Medicine and Health Sciences, explained in an email.
As they reported in Genome Medicine on Tuesday, he and his colleagues performed rWGS on one male and four female infants being treated for complex conditions affecting multiple organ systems in the pediatric intensive care unit (ICU), along with their parents. The children were between the ages of 1 day and 90 days old, they noted, and came from the UAE, Kenya, Jordan, the Philippines, and Pakistan.
With genome sequence data on the infants and their parents, the team was able to make molecular diagnoses for three of the children, returning the results within 37 hours, on average.
"This study demonstrates the feasibility and clinical utility of performing rWGS locally for critically ill children from this genetically underrepresented population and highlights the need for investments in pediatric genomics within local healthcare institutions, in the Middle East and globally, to deliver timely diagnoses and management," the authors wrote.
The results contrast with standard-of-care testing — which ranges from targeted single-gene testing or chromosomal microarrays to exome sequencing — that is typically more time-consuming and currently limited to specific centers in the UAE and other parts of the Middle East, Abou Tayoun explained.
Such tests are often not available at local testing centers in the Middle East or Africa, necessitating testing outside of a patient's home country, he noted. That can cause wait times to stretch out several weeks, delaying diagnoses and treatment, while potentially contributing to poor communication of results, particularly if patients and providers do not have genetic counselors at centers nearby.
In contrast, Abou Tayoun explained, "rWGS has recently been shown to provide timely diagnoses (within a few hours) and management plans for critically ill patients in intensive care settings."
Indeed, results in the first five infants assessed suggested that the rWGS approach can provide answers for patients and families from populations that are often overlooked in genetic research, including sites where genomic resources may not be readily available.
In one of the children, a baby born prematurely in Jordan, the team tracked down a pathogenic variant affecting both copies of the chromosome 12 gene POM1, which led to a muscular dystrophy-dystroglycanopathy. While that diagnosis did not alter the care or treatment offered to the infant, the researchers reported, it did bring the infant's diagnostic odyssey to a conclusion and led to additional genetic counseling for family members.
On the other hand, the investigators did get treatment clues for another child diagnosed with the rWGS approach. In a 3-month-old girl from the Philippines, they tracked down pathogenic variants affecting one copy of the LIPA gene. Alterations in that gene have been linked to lower-than-usual levels of a lysosomal acid lipase enzyme, they noted, suggesting the child may benefit from an enzyme replacement therapy that has been approved by the US Food and Drug Administration.
The team also found chromosome 12 tetrasomy — molecular features linked to a condition known as Pallister-Killian syndrome — in a female infant from Pakistan who was tested when she was just a day old.
"This finding confirmed a clinical diagnosis of Pallister-Killian syndrome and guided management of the patient," the authors explained. "The identification of this tetrasomy using rWGS demonstrates the additional value of this testing where exome sequencing would, most likely, not have detected this arrangement, leading to significant delays in diagnosis until separately ordered clinical chromosomal microarray testing results are obtained."
Even so, Abou Tayoun explained that rWGS requires considerable investments in sequencing, informatics, and data storage technology, staffing, and more — factors that have contributed to the unequal distribution of rapid sequencing availability within and between countries.
"[T]he global distribution of rWGS is highly unequal, with implementation in a number of centers within Europe, the USA, and Australia," he wrote, "and lack of such service in other geographical regions such as the Middle East and Africa where the genetic disease burden, specifically recessive disorders, is expectedly high."
While these issues are exacerbated in sites with limited resources or genetics infrastructure, unequal access to rWGS has been documented even in relatively resource-rich settings, as shown through efforts to make rWGS broadly available in California.
"Significant investments in local healthcare infrastructure are needed, globally, for more equitable access of genomic medicine among vulnerable patients," authors of the Genome Medicine study argued.
To that end, Abou Tayoun suggested that some access issues may be overcome by centralizing rWGS at highly specialized tertiary centers in each country, since the price tag for new genomics facilities often reaches into the millions of dollars. Along with infrastructure investments, he explained, larger centers may be better poised to attract those with the expertise and experience needed to generate, analyze, interpret, and communicate clinical findings from the genome sequence-based tests.
In particular, Abou Tayoun highlighted the need for genetic counselors, molecular technologists, genomic analysts, bioinformatic scientists, clinical molecular geneticists, and specialized multidisciplinary pediatric teams to diagnose, treat, and manage pediatric patients with complex or rare genetic conditions.
The team is working to expand from the current study to reach many more pediatric ICU patients. In the process, Abou Tayoun said, the group hopes to "make a convincing case" for more widespread rWGS use in this clinical setting.
"Given its location in Dubai/UAE and the Middle East," he noted, "Al Jalila Children’s Specialty Hospital provides care for a diverse patient population of Middle Eastern, North African, and Asian origins, which is historically not well represented in genetic studies."