The article “Rapid genomic sequencing for genetic disease diagnosis and therapy in intensive care units” highlights the potential of ultra-rapid genome sequencing (URGS) in diagnosing genetic diseases in ICU patients, especially children. Genetic diseases are a major cause of childhood mortality and often have effective treatments if diagnosed early. The paper advocates URGS as a standard diagnostic tool to improve outcome.
What is URGS and how is it performed?
URGS, Ultra Rapid Genome Sequencing, is transforming NICUs by providing fast and comprehensive analysis of variants for critically ill infants with suspected genetic diseases, a leading cause of neonatal mortality.
Genomic DNA is extracted from blood and is prepared and subjected to NGS. The data is analysed through bioinformatic steps including variant calling and annotation. Geneticists and counsellors perform phenotype-genotype correlation to establish a clinical diagnosis.
Estimated incidence of rare disorders in India
Rare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis is complex due to lack of specialised medical professionals, testing labs, and limited therapeuticoptions. India being home to many population groups, of which several are endogamous, is likely
to have a higher burden of rare Genetic diseases, which is around 70 million according to ICMR.
In a study performed by Sheth. J., et al. (2024), nearly 80% of all rare diseases had a genetic etiology, highly targeting the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM). There must be new health policies primarily focused on
implementation of newborn screening and development of panels for affordable diagnosis of rare diseases to devise a treatment plan.
Clinical and diagnostic utility of URGS in NICU?
Genetic diseases are leading cause of infant mortality. Traditional phenotype-first diagnostic approaches in NICUs often leave 10-25% of critically ill infants with undiagnosed genetic disorders. Advancements in genomics and reduced costs enabled a shift towards genotype-first model, which improved diagnostic outcome.
Key benefits of rWGS/urWGS include faster diagnostic turnaround times (as low as 13.5 hours), high diagnostic yield (19-83% with a 36% average across studies), and improved clinical management in 27% of cases. This led to enhanced outcomes in 18% of affected infants. These advantages underline the urgency of incorporating genomic sequencing into NICU protocols to reduce neonatal mortality and optimize care.
The benefits of rWGS extend beyond just diagnosis – Tailoring treatment, predicting prognosis and recurrence risk and avoiding unnecessary treatments. A negative rWGS result can help rule out genetic causes, allowing clinicians to focus on other potential etiologies.
There are significant challenges, such as the incomplete understanding of genotype-phenotype relationships and the complexities of interpreting genetic variants. Despite these challenges, rWGS and urWGS offer significant advantages for diagnosing genetic diseases in NICUs.
However, integrating genomic data with other omics technologies like RNA sequencing and metabolomics could enhance diagnostic precision and enable the development of targeted therapies.
When is RWGS medically necessary?
- Signs/symptoms suggest a rare genetic condition that cannot be diagnosed by a standard
clinical work-up - The proband’s signs/symptoms suggest a broad, differential diagnosis that could require
multiple genetic tests - Early molecular diagnosis is necessary to guide clinical decision making
- At least one of the following clinical criteria apply:
o Multiple congenital anomalies, severe hypotonia, refractory seizures, unexplained
recurrent events
o Abnormal chemistry levels suggestive of inborn error of metabolism or a much
complex metabolic phenotype
o Abnormal response to therapy related to an underlying medical condition
affecting vital organs
o Abnormal cardiac diagnostic testing results suggestive of possible
channelopathies, arrhythmias, cardiomyopathies, myocarditis, or structural heart
disease.
o Family genetic history related to proband’s condition.
URGS offers significant potential to revolutionize NICU care, providing faster and more precise diagnoses. Ongoing improvements in sequencing technologies and AI integration promise greater diagnostic yields and wider clinical adoption. As URGS becomes standard practice, it could dramatically improve outcomes for critically ill infants by enabling early and targeted interventions.
References
- Kingsmore, S. F., Nofsinger, R., & Ellsworth, K. (2024). Rapid genomic sequencing for genetic disease diagnosis and therapy in intensive care units: a review. NPJ genomic medicine, 9(1), 17. https://doi.org/10.1038/s41525-024-00404-0
- Kingsmore, S. F., & Cole, F. S. (2022). The Role of Genome Sequencing in Neonatal Intensive Care Units. Annual review of genomics and human genetics, 23, 427–448. https://doi.org/10.1146/annurev-genom-120921-103442
- Sheth, J., Nair, A., Sheth, F. et al. Burden of rare genetic disorders in India: twenty-two years experience of a tertiary centre. Orphanet J Rare Dis 19, 295 (2024). https://doi.org/10.1186/s13023-024-03300-z
- https://www.researchgate.net/publication/350318459_National_guidelines_for_gene_therapy_product_2019_A_roadmap_to_gene_therapy_products_development_and_clinical_trials