What is the Diagnostic Yield for Genetic Testing of Children with Neurodevelopmental Delays?

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Patient Presentation
An 18-month-old male with known agenesis of the corpus callosum and developmental delays was seen for his well-child examination. He was in the process of being evaluated and followed by neurology and developmental disabilities specialists, but already had physical, occupational and speech therapies. His mother said that genetic testing was recommended but that she and his father had not decided yet about if they wanted the testing done. “I’m still confused about what the test could show and if in the end anything will change for him,” she said.

The pertinent physical exam showed a non-verbal male with normal vital signs and growth parameters, with a head circumference at the 5% and tracking. He had increased reflexes in all extremities and generalized hypotonia.

The diagnosis of a child with global developmental delay was again confirmed. The pediatrician answered as many of the parent’s questions as he could about risks and benefits of testing. “One thing to remember is that the testing results can take a long time to come back. Sometimes there is no result and sometimes more testing is needed. Doing it or not doing it now is a choice, and you can also decide later. Testing isn’t what I do everyday, but I will still be here to help you and your son whatever you decide,” he offered. The patient’s clinical course over the next year showed that he did have testing which showed a rare pathogenic mutation that had an understood natural history. The family was grateful to have the information and was seeking to participate in clinical research trials.

Discussion
Children having significant neurodevelopmental disabilities are common with 17% of 3-17 year olds children having some type of such disability. Many are recommended to have genetic testing. Three main reasons for testing are determining the etiology, potential availability of targeted treatment or intervention, and determination of recurrence risk. But there are other pros and some cons to genetic testing which include:

  • Pros
    • Diagnosis is determined
    • Improved understanding of diagnosis, natural history and prognosis for patient and family including decreased anxiety/guilt
    • “Can end the diagnostic odyssey”
    • Diagnosis specific treatment or management can be offered
    • Improved medical services including access services/interventions, monitoring and followup and patient/family support groups
    • Genetic counseling access for prenatal diagnosis and familial risk
    • Access to research trials
  • Cons
    • Risks of venipuncture
    • Diagnosis not determined
    • Generally does not lead to a cure
    • May not lead to changes in access to inventions/services
    • Incidental findings identified
    • Risk of insurability
    • Risk of stigmatization, anxiety, guilt
    • Families may not understand the testing and its potential implications

One study noted that “[n]ormal results were identified as the worst results because it would not help explain the diagnosis and would lead to more investigations.”

Learning Point
While there are differences in recommendations from different professional societies, children with intellectual disability, global developmental delay and autism spectrum disorders are recommended to have

  • Chromosomal microarray – tests for microdeletions and microduplications
  • Fragile X testing – for all males and some females
  • Testing for indicated specific genetic syndromes that may be clinically relevant (e.g. Rett syndrome, Down syndrome, etc.)

Additional testing is often considered, including in the case of unresolved clinical findings if the testing above is non-diagnostic, and can include:

  • Chromosomal analysis (i.e. karyotype)
  • Exome sequencing (i.e. next generation sequencing)
  • Mitochondrial DNA testing
  • Testing of family members may be indicated in some cases

Diagnostic yield of genetic testing depends on the study design, population tested, and phenotype, but overall the yield for patients with intellectual disability, global developmental delay and autism is reported as:

  • Chromosomal microarray – 15-20%, with incidental findings of <1%
  • Exome sequencing – 31-36%, incidental findings are widely variable = 2-6%
  • Fragile X testing – 2% males, 1% females

According to one group of authors, “[t]he cumulative diagnostic yield for all three tests, therefore, is over 50% for individuals with [intellectual disability/global developmental delay] and over 25% for individuals with primarily [autism spectrum disorder].”

Post-testing genetic counseling is needed to understand the results and consider next steps.
For example chromosomal microarray results are categorized into five categories:

  • Pathogenic – thought to be associated with disease
  • Likely pathogenic – thought to be associated with disease but additional research evidence will be helpful
  • Uncertain significance – not enough information to determine if benign or pathologic
  • Likely benign – thought to not be associated with disease but additional research evidence will be helpful
  • Benign – not though to be associated with disease

Questions for Further Discussion
1. What is the role of a general pediatrician in genetic testing for children with neurodevelopmental delays?
2. Who locally can help support genetic testing?
3. When should a patient who had some genetic testing in the past be retested?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Genetic Testing and Developmental Disabilities.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Muhle RA, Reed HE, Vo LC, et al. Clinical Diagnostic Genetic Testing for Individuals With Developmental Disorders. J Am Acad Child Adolesc Psychiatry. 2017;56(11):910-913. doi:10.1016/j.jaac.2017.09.418

Tremblay I, Laberge AM, Cousineau D, Carmant L, Rowan A, Janvier A. Paediatricians’ expectations and perspectives regarding genetic testing for children with developmental disorders. Acta Paediatr. 2018;107(5):838-844. doi:10.1111/apa.14203

Savatt JM, Myers SM. Genetic Testing in Neurodevelopmental Disorders. Front Pediatr. 2021;9. Accessed April 17, 2023. https://www.frontiersin.org/articles/10.3389/fped.2021.526779

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

Published