Genomic sequencing recommended earlier in evaluation of developmental delay, with Christine Eng, MD

Genetic evaluation for children with developmental delay and intellectual disability has shifted significantly in recent years. Christine Eng, MD, professor of Genetics at Baylor College of Medicine and chief medical officer at Baylor Genetics, explained that physicians historically used a stepwise testing approach. “Generally, physicians would start with a screening test, such as a karyotype for cytogenetic abnormalities,” she said. Additional tests, including Fragile X evaluation or targeted next-generation sequencing, were added if no diagnosis was found, which “takes time, adds costs, and sometimes delays making a critical diagnosis.”

Why exome and genome sequencing are being used first

Eng noted that Baylor Genetics has shifted toward exome sequencing and genome sequencing as first-line diagnostic tools. She described these as comprehensive because “genome testing really encompasses all of these types of modalities, all in one test.” Genome sequencing can detect single-nucleotide variants, copy-number variants, cytogenetic-level changes, and mitochondrial genome findings.

This approach “can increase the diagnostic yield” while providing “an answer in a much more rapid fashion using just one modality.” Growing support from professional societies, payers, and the recent AAP guidelines contributes to earlier use of these tests. Pediatricians are also “becoming increasingly more comfortable in ordering genetic testing themselves,” which may expand access.

How multi-gene panels limit diagnostic yield

Traditional multi-gene panels evaluate a limited set of genes linked to a specific phenotype. For patients with complex presentations or conditions involving newly described genes, this may “really limit the findings that can be identified.” In contrast, “exome and genome sequencing really allows for a much broader interrogation of genes in order to find answers.”

Diagnostic yields for developmental delay and intellectual disability at Baylor Genetics are “in the 40 to 50% range,” a rate Eng described as significantly higher than yields from many panels and consistent with other published data.

How reanalysis strengthens long-term diagnostic value

Even when initial results from exome or genome sequencing are nondiagnostic, reanalysis offers continued clinical value. “The data obtained can always be reanalyzed as we learn more about the genome,” Eng said. Reanalysis can be performed at routine annual visits or when symptoms change, potentially yielding new diagnostic insights over time.

How a definitive diagnosis impacts medical management

A confirmed genetic diagnosis can influence multiple aspects of clinical care. It may “identify a treatment,” or—if no targeted therapy exists—clarify risks for other medical issues that can be monitored proactively. A diagnosis can guide decision-making regarding treatment aggressiveness and help determine whether additional specialists should be involved.

Participation in clinical trials is one of the most significant benefits of receiving a diagnosis. Eligibility for investigational therapies “can really make a difference, not only for that patient and the family, but for all the other individuals who may become diagnosed with that condition as well,” Eng said.

Disclosure: Eng is the chief medical officer of Baylor Genetics.

Reference:

Rodan LH, Stoler J, Chen E, et al. Genetic Evaluation of the Child With Intellectual Disability or Global Developmental Delay: Clinical Report. Pediatrics. Published online June 23, 2025. doi:https://doi.org/10.1542/peds.2025-072219