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Rapid Genetic Testing for Neonatal & Pediatric Critical Care Patients

For acutely and critically ill babies, using rapid whole genome sequencing (rWGS) as a first-tier test can influence clinical management, reduce overall healthcare costs, and prevent a diagnostic odyssey.

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1 in 4 babies in the NICU is likely to have a genetic condition that could be diagnosed with rWGS1

Rapid WGS has been shown to:

Change clinical management
in 61% of patients2

Reduce healthcare costs
by $12K-16K per patient2

Reduce the length of NICU
stays by >457 days2

Test broadly to get to the root cause

For patients whose condition can’t be completely explained by trauma, infection, or prematurity, choose rapid genetic testing.

Graphic of 90%

of diagnoses made by rWGS would not have been predicted by clinical features3

Meet Billy*, an infant presenting with hypotonia at birth

Initial workup uncovered severe metabolic acidosis and lactic acidemia, and family history revealed Billy’s brother died on day 1 of life with similar presentation. Given the family history, Billy’s healthcare provider wanted answers quickly and ordered rapid whole exome sequencing.

Testing identified a homozygous pathogenic variant in the HLCS gene, which causes metabolic acidosis, organic aciduria, irritability, lethargy, hypotonia, dermatitis, and seizures. If left untreated, this condition can lead to intractable seizures, coma, developmental delay, and cerebral edema.

As a result of this genetic diagnosis, Billy’s care team made important, informed medical management changes and administered biotin, which resulted in improved feeding, increased alertness, and resolution of hypotonia.

The rapid exome test delivered actionable results within 5 days that helped determine the correct treatment for Billy and likely provided answers for the family regarding the loss of their other child.

Meet Anne*, a newborn presenting with colonic atresia

Following surgery to repair the colonic atresia, Anne was transferred to the NICU for post-operative monitoring and management. Anne developed multiple infections while in the NICU, so her doctors ordered a complete blood count (CBC) and flow cytometry as part of her workup, but the results didn’t fully explain her symptoms.

For clearer answers, her medical team ordered rapid whole genome sequencing (rWGS). Results revealed compound heterozygous variants in the TTC7A gene, which are associated with gastrointestinal defects and immunodeficiency syndrome 1 (GIDID1). Based on this testing, Anne’s team made important and informed medical management changes, including IgG replacement, administration of prophylactic medications, and her feeding intolerance was determined to be caused by her genetic condition vs. post-operative complications.

The rapid genome test delivered actionable results within 5 days, helped determine the correct treatment plan for Anne, and established a path forward for her family and care team.

Discover solutions for improved patient care

There are babies like Anne and Billy in every NICU, PICU, and CICU with rare genetic disorders that will remain undiagnosed without access to comprehensive genetic testing like rapid whole exome sequencing (rWES) and rWGS. However, identifying these patients isn’t always straightforward.

Phenotypic-driven rWGS and rWES testing in the NICU has been associated with an increased diagnostic yield over infants tested without phenotypic stratification.4-5 The criteria below can help you begin to identify patients in the NICU that could benefit from rapid genetic testing.4,6-9

If you have a patient presenting with one or more of the following, rapid genetic testing should be considered:

  • Seizures
  • Hypotonia
  • Multiple congenital anomalies
  • Complex metabolic phenotype (presence of clinical or biochemical features suspicious for a metabolic disorder, >1 possible condition in differential diagnosis, and cannot be distinguished with one easily available lab test)
  • Single major anomalies with syndromic features
  • Severe organ system dysfunction without a clear non-genetic explanation (respiratory failure in a term infant, congenital diarrhea, renal failure, etc.)

Help your patients get the care they need.

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Higher diagnostic yields. Fewer uncertain results.

For infants, the diagnostic yield of genome and exome testing is up to 4x greater than CMA and turns around results in 5-7 days.2,10,11

The power of the trio

Trio testing can increase diagnostic yield by 7-15%11-14 and significantly lower VUS rates (18.9% vs. 27.6%)15 compared to testing that does not include samples from both parents, leading to a more definitive diagnosis. Starting with trio testing reduces the need for follow-up testing, shortens the time to diagnosis, and improves the interpretation of genetic data.

GeneDx offers buccal swab kits as an additional sample collection method for our rapid genome (GenomeXpress®) and rapid exome (XomeDxXpress®) tests which can make it easier for providers to collect biological relative samples for trio testing.

Families want answers

Studies have shown that parents and caregivers of babies in the ICU see the benefits of this comprehensive testing.

For your patients with complex or rare diseases, a precise, timely diagnosis can mean more than changes in medical management; it can help families cope and determine the best path forward, whether it involves:

  • Clinical trial eligibility
  • Connection to advocacy and community groups
  • Prognostic information

 

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Graphic of 97%

of families whose infants received WGS reported testing was somewhat useful even if they did not receive a genetic diagnosis16

GeneDx: Your trusted genetic testing experts

  • Dedicated clinician support to help with test selection, results interpretation, and everything in between
  • Educational patient materials to assist in the consenting conversation
  • Post-test genetic counseling for your patients at no additional charge

Through our research and collaborations, we’re working to transform the standard of care for newborns. We are driven to improve infants’ quality of health through early diagnosis and treatment with genomic sequencing, and eventually expand standard newborn screening protocols:

SeqFirst Study

We are demonstrating the broad utility of rapid whole genome sequencing for critically ill babies. Results are expected to provide guidance about the best ways to help find a precise genetic diagnosis, better anticipate patient needs, and take advantage of new treatments.

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GUARDIAN Study

We are collaborating on the Genomic Uniform-Screening Against Rare Diseases in All Newborns (GUARDIAN) study to provide whole genome sequencing and interpretation services for a landmark genomic newborn screening study focused on screening 100,000 newborns for 250 genetic conditions not currently included in standard newborn screenings. Early diagnosis of a genetic condition can guide treatment options, medications, or interventions to prevent or reduce symptoms.10,17

Read more

With comprehensive care from start to finish, we offer more than just a test result. Experience the GeneDx difference and help your patients find answers.

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* for illustrative purposes only

References

  1. Kingsmore SF, Cakici JA, Clark MM, et al. A randomized, controlled trial of the analytic and diagnostic performance of singleton and trio, rapid genome and exome sequencing in ill infants. Am J Hum Genet. 2019 Oct 3;105(4):719-733. doi:10.1016/j.ajhg.2019.08.009. Epub 2019
  2. Dimmock D, Caylor S, Waldman B, et al. Project Baby Bear: Rapid precision care incorporating rWGS in 5 California children’s hospitals demonstrates improved clinical outcomes and reduced costs of care. Am J Hum Genet. 2021 Jul 1;108(7):1231-1238. doi:10.1016/j.ajhg.2021.05.008. Epub 2021 Jun 4.
  3. French CE, Delon I, Dolling H, et al. Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children. Intensive Care Med. 2019 May;45(5):627-636. doi: 10.1007/s00134-019-05552-x. Epub 2019 Mar 7.
  4. Gubbels, Cynthia S et al. “Prospective, phenotype-driven selection of critically ill neonates for rapid exome sequencing is associated with high diagnostic yield.” Genetics in medicine : official journal of the American College of Medical Genetics vol. 22,4 (2020): 736-744. doi:10.1038/s41436-019-0708-6
  5. Ceyhan-Birsoy, et al., 2019. Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. Am J Hum Genet. 2019 Jan 3; 104(1): 76–93. Published online 2019 Jan 3. doi: 10.1016/j.ajhg.2018.11.016
  6. Wojcik, MH, D’Gama, AM, and Agrawal, PB. A Model to implement genomic medicine in the neonatal intensive care unit. J Perinatol. 2023 Feb; 43(2):248-252
  7. Morton SU, Christodoulou J, Costain G, et al. Multicenter Consensus Approach to Evaluation of Neonatal Hypotonia in the Genomic Era: A Review. JAMA Neurol. 2022 Apr 1;79(4):405-412. doi:10.1001/jamaneurol.2022.0067
  8. Manickam K, McClain MR, Demmer LA, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021 Nov;23(11):2029-2037. doi: 10.1038/s41436-021-01242-6. Epub 2021 Jul 1.
  9. Smith L, Malinowski J, Ceulemans S, et al. Genetic testing and counseling for the unexplained epilepsies: An evidence-based practice guideline of the National Society of Genetic Counselors. J Genet Couns. 2022 Oct 24. doi.org/10.1002/jgc4.1646
  10. Callahan KP, Mueller R, Flibotte J, et al. Measures of Utility Among Studies of Genomic Medicine for Critically Ill Infants: A Systematic Review. JAMA Netw Open. 2022 Aug 1;5(8):e2225980. doi:10.1001/jamanetworkopen.2022.25980
  11. Clark MM, Stark Z, Farnaes L, et al. Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases. NPJ Genom Med. 2018 Jul 9;3:16. doi: 10.1038/s41525-018-0053-8. eCollection 2018.
  12. Lee, H., Deignan, J. L., Dorrani, N., Strom, S. P., Kantarci, S., Quintero-Rivera, F., Das, K., Toy, T., Harry, B., Yourshaw, M., Fox, M., Fogel, B. L., Martinez-Agosto, J. A., Wong, D. A., Chang, V. Y., Shieh, P. B., Palmer, C. G., Dipple, K. M., Grody, W. W., . . . Nelson, S. F. (2014). Clinical exome sequencing for genetic identification of rare Mendelian disorders. Jama, 312(18), 1880-1887. https://doi.org/10.1001/jama.2014.14604
  13. Farwell, K. D., Shahmirzadi, L., El-Khechen, D., Powis, Z., Chao, E. C., Tippin Davis, B., Baxter, R. M., Zeng, W., Mroske, C., Parra, M. C., Gandomi, S. K., Lu, I., Li, X., Lu, H., Lu, H. M., Salvador, D., Ruble, D., Lao, M., Fischbach, S., . . . Tang, S. (2015). Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med, 17(7), 578-586. https://doi.org/10.1038/gim.2014.154
  14. Sawyer, S. L., Hartley, T., Dyment, D. A., Beaulieu, C. L., Schwartzentruber, J., Smith, A., Bedford, H. M., Bernard, G., Bernier, F. P., Brais, B., Bulman, D. E., Warman Chardon, J., Chitayat, D., Deladoëy, J., Fernandez, B. A., Frosk, P., Geraghty, M. T., Gerull, B., Gibson, W., . . . Boycott, K. M. (2016). Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care. Clin Genet, 89(3), 275-284.
  15. Rehm H, Alaimo JT, Aradhya S, et al. The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change. MedRxiv. Preprint. January 10, 2023. Accessed April 28, 2023. doi: 10.1101/2022.09.21.22279949
  16. Cakici JA, Dimmock DP, Caylor SA, et al. A Prospective Study of Parental Perceptions of Rapid Whole-Genome and -Exome Sequencing among Seriously Ill Infants. Am J Hum Genet. 2020 Nov 5;107(5):953–962. doi: 10.1016/j.ajhg.2020.10.004.
  17. Fung JLF, Yu MHC, Huang S, et al. A three-year follow-up study evaluating clinical utility of exome sequencing and diagnostic potential of reanalysis. NPJ Genom Med. 2020 Sep 10;5(1):37. doi: 10.1038/s41525-020-00144-x. eCollection 2020.