Global developmental delay and intellectual disability (GDD/ID) in children are common concerns primary care pediatricians face.
GDD/ID have diverse etiologies, but genetic disorders account for a substantial percentage. Establishing a genetic diagnosis provides multiple benefits for the patient and family, including improvements in patient care and determination of recurrence risk.
But how should pediatricians approach the daunting task of genetic testing in a patient with GDD/ID?
The updated AAP clinical report Genetic Evaluation of the Child With Intellectual Disability or Global Developmental Delay reviews basic genetic concepts and provides a step-by-step approach.
The report, from the Council on Genetics, is available at https://doi.org/10.1542/peds.2025-072219 and will be published in the July issue of Pediatrics.
Diagnostic approaches
When possible, a “phenotype-driven” approach should be used. This approach relies on identifying key clinical distinguishing features that can facilitate or narrow the differential diagnosis to a specific disorder or group of disorders. If none of these distinguishing features are present, it is advised to use a hypothesis-free “agnostic” approach guided by predicted diagnostic yield of tests based on published data, test complexity and effect on management.
The clinical report provides general guidance. It is not intended to preclude evaluation by specialists, such as neurologists, developmental pediatricians and clinical geneticists.
Key actions and recommendations
The clinical report includes the following recommendations for practice:
- Consider beginning the genetic evaluation with a phenotype-driven approach, evaluating developmental and medical history, family history, and clinical exam with focus on dysmorphology, growth parameters and neurological examination. Consider corollary testing, including vision and hearing testing and neuroimaging with brain MRI.
- If the developmental and medical history, family history, clinical examination and corollary testing are not indicative of a potential diagnosis, then a hypothesis-free (“agnostic”) algorithmic approach can be used. The agnostic approach is divided into three tiers:
- Tier 1: genome sequencing or exome sequencing and chromosome microarray
- Tier 2: Fragile X CGG expansion testing and metabolic (biochemical) evaluation with focus on treatable inborn errors of metabolism
- Tier 3: consideration of genome sequencing if not performed previously, testing for an imprinting disorder, testing for trinucleotide repeat disorder, mitochondrial DNA testing if not performed previously, additional biochemical evaluation for an inborn error of metabolism, karyotype to evaluate for balanced chromosome rearrangements, analysis for intragenic deletion/duplications not detected on exome sequencing and consideration of exome/genome re-analysis every one to two years
- Additional emerging test strategies include genome-wide methylation signature testing and facial recognition genetic software.
Dr. Stoler is a lead author of the clinical report and a member of the AAP Council on Genetics. Dr. Rodan is a lead author of the report. Emily Chen, M.D., Ph.D., and Timothy A. Geleske, M.D., FAAP, lead authors of the report, contributed to this article.
