Clinical Utility

Select publications evaluating changes in medical management as a result of WGS-derived test results
Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease: A Randomized Clinical Trial.
Krantz ID, Medne L, Weatherly JM, et al. JAMA Pediatr. 2021;175(12):1218-1226. doi:10.1001/jamapediatrics.2021.3496

In this randomized control trial, 354 critically ill infants received WGS and were randomized to receive results at 15 days (Early) or 60 days (Delayed) after enrollment. The most common indication for testing was the presence of multiple congenital anomalies (57%). A change in management was twice as likely (21% vs. 10%; p=0.009) with WGS vs. usual care testing. The most common being: subspecialty referrals, alternations in medication, surgery or other procedures.  A two-fold increase in diagnostic yield was found with WGS compared to usual care testing. The authors conclude that for acutely ill infants in the intensive care unit, first-line WGS is associated with a significant increase in clinical management compared to usual care. These data support WGS adoption and implementation in this setting.

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care – Preliminary Report.
Smedly D, Smith KR, Martin A, et al (100,000 Genomes Project Pilot Investigators) N Engl J Med. 2021 Nov 11;385(20):1868-1880.doi: 10.1056/NEJMoa2035790.

In 4660 participants of all ages who underwent WGS, a new diagnosis was reported in 25% who had no previous diagnosis from standard of care testing. Diagnostic yield was highly variable based on indication. Of those who received a diagnosis, 14% were found in regions of the genome that would have been missed by other testing modalities. Immediate implications were reported in 25% of those who received a diagnosis. Genome sequencing in a national health care system uncovered a new diagnosis across a broad range of rare diseases.

Leveraging Rapid Genome Sequencing to Alter Care Plans for Pediatric Patients in a Community Hospital Setting in the United States.
Beuschel J, Geyer H, Rich M, et al. J Pediatr. 2021; 2395-239.  doi: 0.1016/j.jpeds.2021.08.010.
Genome sequencing demonstrates high diagnostic yield in children with undiagnosed global developmental delay/intellectual disability: A prospective study.
Sun Y, Peng J, Liang D, et al. Hum Mutat. 2022 May;43(5):568-581.doi: 10.1002/humu.24347. Epub 2022 Mar 1.
A prospective study of parental perceptions of rapid whole-genome and -exome sequencing among seriously ill infants.
Cakici JA, Dimmock DP, Caylor SA, Gaughran M, Clarke C, Triplett C, Clark MM, Kingsmore SF, Bloss CS. Am J Hum Genet. 2020;107:953-962.
Diagnostic yield and treatment impact of whole-genome sequencing in paediatric neurological disorders.
Lee HF, Chi CS, Tsai CR. Dev Med Child Neurol. 2020:
An RCT of rapid genomic sequencing among seriously ill infants results in high clinical utility, changes in management and low perceived harm.
Dimmock DP, Clark MM, Gaughran M, Cakici JA, Caylor SA, Clarke C, Feddock M, Chowdhury S, Salz L, Cheung C, Bird LM, Hobbs C, Wigby K, Farnaes L, Bloss CS, Kingsmore SF. Am J Hum Genet. 2020; 107(5):942-952.
Genome sequencing as a diagnostic test in children with unexplained medical complexity.
Costain G, Walker S, Marano M, Veenma D, Snell M, Curtis M, Luca S, Buera J, Arje D, Reuter MS, Thiruvahindrapuram B, Trost B, Sung WWL, Yuen RKC, Chitayat D, Mendoza-Londono R, Stavropoulos J, Scherer SW, Marshall CR, Cohn RD, Cohen E, Orkin J, Meyn MS, Hayeems RZ. JAMA Netw Open. 2020;3(9):e2018109.

This prospective study  evaluated the analytical and clinical validity of whole genome sequencing (WGS) as a first-tier test compared to conventional genetic testing in a cohort of 49 children with medical complexity. The median number of conventional genetic tests was four per proband (1-13) including chromosomal microarray (n=48) and WES (n=33). For analytical validity evaluation, WGS at 36X detected 100%   of  variants (124). The overall diagnostic yield was 30.6% (15/49) and three new genetic conditions were discovered.  Clinical implications were noted in 12 patients, including an immediate medical management change in 7. The authors conclude that WGS has a role as a first-tier test in children with medical complexity.

Project baby bear: Rapid precision care incorporating rWGS in 5 California children’s hospitals demonstrates improved clinical outcomes and reduced costs of care.
Dimmock D, Caylor S, Waldman B, Benson W, Ashburner C, Carmichael JL, Carroll J, Cham E, Chowdhury S, Cleary J, D’Harlingue A, Doshi A, Ellsworth K, Galarreta CI, Hobbs C, Houtchens K, Hunt J, Joe P, Joseph M, Kaplan RH, Kingsmore SF, Knight J, Kochhar A, Kronick RG, Limon J, Martin M, Rauen KA, Schwarz A, Shankar SP, Spicer R, Rojas MA, Vargas-Shiraishi V, Wigby K, Zadeh N, Farnaes L. Am J Hum Genet. 2021 May 29S0002-9297(21)00192-0. doi: 10.1016/j.ajhg.2021.05.008. Epub ahead of print. PMID: 34089648.

Rapid WGS was performed on 184 critically ill infants with Medi-Cal who met study criteria. Outcomes were measured by healthcare provider questionnaires and modeled processes to estimate clinical management changes and cost savings to the hospital. A total of 74/184 (40%) infants received a diagnosis and 58 of 184 (32%) experience at least one change in medical care. Both positive and negative results led to changes in management and/or cost savings. Cost savings was calculated based on a smaller cohort of 31 infants whose length of stay was impacted by rWGS results. Considering the cost of rWGS for the entire cohort, the average cost savings was $2549-6294 per child. The authors concluded that rapid WGS can be deployed as a first-tier test in the NICU.

Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected diseases.
Clark MM, Stark Z, Farnaes L, Tan TY, White SM, Dimmock D, Kingsmore SF. NPJ Genom Med. 2018 Jul 9;3:16. doi: 10.1038/s41525-018-0053-8.

This meta-analysis examined 37 studies comprising 20,068 children from January 2011 to August 2017. Overall, the diagnostic utility was 8.3 times greater with WES/WGS (36%/41%) compared to CMA (10%). 25.7% of diagnostic variants identified by WGS were not apparent by WES. WGS detected diagnostic variants beyond the scope of WES, including intronic SNVs, SNVs in noncoding RNA, small CNVs, and mitochondrial DNA mutations, as well as exonic SNVs under-covered by WES.

The NSIGHT1-randomized controlled trial: rapid whole-genome sequencing for accelerated etiologic diagnosis in critically ill infants.
Petrikin JE, Cakici JA, Clark MM, Willig LK, Sweeney NM, Farrow EG, Saunders CJ, Thiffault I, Miller NA, Zellmer L, Herd SM, Holmes AM, Batalov S, Veeraraghavan N, Smith LD, Dimmock DP, Leeder JS, Kingsmore SF. NPJ Genom Med. 2018 Feb 9;3:6. doi: 10.1038/s41525-018-0045-8.

Rapid WGS plus standard clinical testing yielded higher genetic diagnosis rate and shorter time to diagnosis compared to standard clinical testing alone. In this partially blinded, randomized controlled trial, 65 infants (<4 months of age) with highly variable phenotypes had rapid WGS to determine diagnosis at 28 days post enrollment. Median time to diagnosis with WGS was 13 days vs. 107 days with standard clinical testing and median day of life at diagnosis was 25 days with WGS vs. 130 days with standard genetic testing. This study was terminated early due to equipoise and the growing inclusion of NGS in standard clinical testing strategies.

Whole genome sequencing expands diagnostic utility and improves clinical management in pediatric medicine
Stavropoulos DJ, Merico D, Jobling R, Bowdin S, Monfared N, Thiruvahindrapuram B, Nalpathamkalam T, Pellecchia G, Yuen RKC, Szego MJ, Hayeems RZ, Shaul RZ, Brudno M, Girdea M, Frey B, Alipanahi B, Ahmed S, Babul-Hirji R, Badilla Porras R, Carter MT, Chad L, Chaudhry A, Chitayat D, Jougheh Doust S, Cytrynbaum C, Dupuis L, Ejaz R, Fishman L, Guerin A, Hashemi B, Helal M, Hewson S, Inbar-Feigenberg M, Kannu P, Karp N, Kim RH, Kronick J, Liston E, MacDonald H, Mercimek-Mahmutoglu S, Mendoza-Londono R, Nasr E, Nimmo G, Parkinson N, Quercia N, Raiman J, Roifman M, Schulze A, Shugar A, Shuman C, Sinajon P, Siriwardena K, Weksberg R, Yoon G, Carew C, Erickson R, Leach RA, Klein R, Ray PN, Meyn MS, Scherer SW, Cohn RD, Marshall CR. NPJ Genomic Medicine, 2016; 1.

A prospective study evaluated the diagnostic yield of WGS compared to standard clinical testing on 100 consecutive children referred for chromosomal microarray. The authors concluded that as a first-tier test, WGS reduces the number of genetic investigations and potentially the time to diagnosis, ultimately acting as a more cost-effective approach. WGS diagnosis rate was 34% compared to 13% for the total from standard clinical testing (CMA plus targeted gene sequencing (P value = 0.0009). CNV resolution is greater for WGS than CMA, typically detecting >1,500 unbalanced changes that cannot be found using CMA. Split read mapping can further reveal complex overlapping CNVs missed by CMA.

Clinical whole genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico.
Scocchia A, Wigby KM, Masser-Frye D, Del Campo M, Galarreta CI, Thorpe E, McEachern J, Robinson K, Gross A, ICSL Interpretation and Reporting Team, Ajay SS, Rajan V, Perry DL, Belmont JW, Bentley DR, Jones MC, Taft R. NPJ Genom Med. 2019;4:5.

In a resource limited setting, clinical WGS was provided at no-cost to 60 children with a mean age of 7.6 years who met testing criteria. Indications included 77% with suspected pattern of malformation and 23% with primary neurological presentation. The overall diagnostic yield was 68%. 41/60 had a genomic finding consistent with the phenotype. This included 76% of those referred for suspected malformations and 43% referred for primary neurological presentation. (p=0.0455). Post-test counseling was modified for both patient with and without a molecular diagnosis. The absence of diagnosis helpful in 6 of 19 cases without molecular diagnosis.

Rapid whole genome sequencing has clinical utility in the PICU
Sanford EF, Clark MM, Farnaes L, Williams MR, Perry JC, Inguli EG, Sweeney NM, Doshi A, Gold JJ, Briggs B, Bainbridge MN, Feddock M, Watkins K, Chowdhury S, Nahas SA, Dimmock DP, Kingsmore SF, Coufal NG. Rapid whole genome sequencing has clinical utility in children in the PICU. PediatrCritCare Med. 2019 Jun 19. doi: 10.1097/PCC.0000000000002056.
Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization.
Farnaes L, Hildreth A, Sweeney NM, Clark MM, Chowdhury S, Nahas S, Cakici, JA, Benson W, Kaplan RH, Kronick R, Bainbridge MN, Friedman J, Gold JJ, Ding Y, Veeraraghavan N, Dimmock D, Kingsmore SF.  NPJ Genom Med. 2018 Apr 4;3:10. doi: 10.1038/s41525- 018-0049-4.

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