In July 2025, the American Academy of Pediatrics (AAP) published updated recommendations for the evaluation of children with global developmental delay (GDD)/intellectual disability (ID). The recommendations include using exome or genome sequencing as a first-tier test for diagnosing GDD/ID, citing their superior diagnostic yield and cost-effectiveness (Rodan et al., 2025). 

With these new recommendations, the AAP has joined a growing cadre of professional organizations that have recognized the clinical value of using whole genome sequencing (WGS) and whole exome sequencing (WES) as an initial testing strategy. Since 2012, the American College of Medical Genetics and Genomics (ACMG) has recommended WES/WGS as a first- or second-tier test for patients with congenital anomalies or developmental delay/ID (ACMG Board of Directors, 2025), and the National Society of Genetic Counselors (NSGC) recommends WES/WGS for individuals of all ages with unexplained seizures. 

Proven Advantages of WES/WGS

Clinical data from recent studies to evaluate the efficacy of genomic sequencing assays continue to support WES/WGS as a valuable testing strategy in patient-focused care. In the absence of clear clinical indicators for targeted testing, ordering one comprehensive test at the outset can dramatically reduce the time to reach a precise diagnosis, aiding in the determination of prognosis, recurrence risk assessments, disease surveillance measures and specialized medical management strategies. 

WES/WGS offer improved diagnostic yields over more targeted testing strategies, with WGS outperforming WES. A recent meta-analysis found that the diagnostic yield for WGS was 30.6% and 23.2% for WES in pediatric patients with rare and undiagnosed genetic diseases (Pandey et al., 2025). In cases of DD, ID and autism spectrum disorders (ASDs), the diagnostic yield using WES is 28% to 43%.¹ Estimates for the diagnostic yield of WGS for patients with DD/ID/ASDs are not yet available. 

A study to assess the implementation of WES/WGS as a firstline testing strategy in noncritical pediatrics wards found that the use of WES/WGS as an initial testing strategy significantly reduced the time to diagnosis, from 289 days to 13 days (Keefe et al., 2025). Additional studies have demonstrated that WES/WGS can also reduce overall care costs by reducing the need for additional testing and limiting inpatient stays (Moore et al., 2025; Dimmock et al., 2021).

Accurate interpretation of WES/WGS laboratory results relies on phenotypic information, and providing a thorough clinical history can increase the likelihood of correctly identifying pathogenic variants and achieving a precise diagnosis. 

Future Directions

While WES/WGS present exciting possibilities for patient care, the rapid advancement of genetic diagnostic technologies has made clinical adoption challenging. Third-party payors have been slow to offer coverage for genomic sequencing, but reimbursement rates are improving. This rapid evolution can be challenging even for specialized practitioners; therefore, it is critical to ensure more generalized practitioners are aware of emerging genomic testing modalities, updated recommendations and the potential benefits for their patients.  

For a complete overview of the current state of genomic sequencing, its applications, and supporting clinical data, download the free white paper, “Genomic Sequencing: An Evolving Standard in Molecular Genetic Diagnosis,” from ARUP Laboratories. This white paper can serve as a valuable tool to inform general practice clinicians about the value of WES/WGS testing and the scenarios in which it can optimize diagnosis. 

References

1. Rodan LH, Stoler J, Chen E, et al (2025). Genetic evaluation of the child with intellectual disability or global developmental delay: clinical report. Pediatrics,156(1):e2025072219.
2. ACMG Board of Directors (2012). Points to consider in the clinical application of genomic sequencing. Genet Med,14(8):759-761.
3. Pandey R, Brennan NF, Trachana K, et al (2025). A meta-analysis of diagnostic yield and clinical utility of genome and exome sequencing in pediatric rare and undiagnosed genetic diseases. Genet Med,27(6):101398.
4. Keefe AC, Scott AA, Kruidenier L, et al (2025). Implementation of first-tier rapid genome sequencing in non-critical care pediatric wards. J Pediatr,286:114699. 
5. Moore C, Arenchild M, Waldman B, et al (2025). Rapid whole-genome sequencing as a first-line test is likely to significantly reduce the cost of acute care in a private payer system. J Appl Lab Med,10(4):833-842.
6. Dimmock D, Caylor S, Waldman B, et al (2021). 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,108(7):1231-1238.

Heidi Wiltse, MS, LCGC

Heidi Wiltse, MS, LCGC, is currently a medical writer/editor at ARUP Laboratories. Her career has spanned reproductive genetic counseling, genetic test utilization program management, molecular diagnostic laboratory genetic counseling and medical writing.

Steven Friedman, PhD

Steven Friedman, PhD, is the director of the Sequencing and Clinical Analytics (SCA) Division at ARUP Laboratories. Friedman joined ARUP in 2017 as a clinical variant scientist and has also served as the group manager of the SCA Division.