Rapid whole-genome sequencing (rWGS) should become part of the assessment tools as a possibility of diagnosing pediatric patients with lysosomal acid lipase deficiency (LAL-D) who require intensive care unit (ICU) admission, according to a study recently published in Genome Medicine.
“A middle ground approach between the expedited analysis in this and other rWGS studies would be to perform a tier 1 expedited analysis, followed by a tier 2 complete analysis which can take longer but can include more in-depth analysis and interpretation to avoid missing diagnoses,” the authors said.
The case series reported 5 infants that presented with pathological findings involving various systems. All patients required hospitalization in the ICU and underwent rWGS. Results revealed a clear diagnosis in 3 of them in an average of 3 hours from the moment of the sample collection.
One of the patients was a 3-month-old female with Filipino heritage who presented with fever, jaundice, postprandial vomiting, and bloody stools. The rWGS showed a heterozygous variant of the LIPA gene, yielding a diagnosis of Wolman disease secondary to LAL-D.
Confirmatory tests validated the diagnosis and further allowed to rule out hemophagocytic lymphohistiocytosis, which was the initial thought. The timely and accurate detection of LAL-D allowed the healthcare team to consider a hematopoietic stem cell transplantation and enzyme replacement therapy, both potentially lifesaving approaches that would otherwise have not been initiated.
Read more about LAL-D testing
The other 2 patients with pathologic results in the rWGS had findings compatible with Pallister-Killian syndrome and muscular dystrophy-dystroglycanopathy.
Regardless of the promising outcomes of the routine implementation of rWGS in the pediatric ICU setting, many limitations are still present nowadays. For example, this tool requires considerable infrastructure and investment, making it unavailable in many countries. Also, the specific utility of the test that could justify the cost has yet to be defined, as explained by Halabi et al.
“The global distribution of rWGS is highly unequal with implementation in a number of centers within Europe, the USA, and Australia, 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 due to inbreeding,” they concluded.
Halabi N, Ramaswamy S, El Naofal M, et al. Rapid whole genome sequencing of critically ill pediatric patients from genetically underrepresented populations. Genome Med. Published online May 24, 2022. doi:10.1186/s13073-022-01061-7