Is there genetic testing for Intellectual Disability and Developmental Delay?

Is there genetic testing for Intellectual Disability and Developmental Delay?

An overview of Intellectual Disability and Developmental Delay and how genetic testing for embryos can help parents.

Written by Maria Katz, MS, CGC, Reviewed by Xiaoli Du, PhD, FACMG, DABMGG, CGC,CGMBS

Dr. Du is an American Board of Medical Genetics and Genomics (ABMGG) certified geneticist. With a passion for precision medicine, she leverages cutting-edge molecular genetics and cytogenetics technology to improve outcomes for individuals affected by genetic conditions. Dr. Du has nine years of clinical genetic diagnosis experience in both the public and private sectors.

What is Intellectual Disability and Developmental Delay?

The Center for Disease Control and Prevention (CDC) reports that ~one in six (17%), of children under 18 have one or more developmental disabilities. Developmental delay refers to a noticeable lag in a child's physical, cognitive, emotional, or social growth. It can manifest as delays in reaching developmental milestones such as walking, talking, or cognitive abilities. While some children may catch up over time, others may require additional support and intervention to bridge the developmental gap. 

Intellectual disability, on the other hand, involves significant limitations in cognitive and adaptive abilities, often indicated by an intelligence quotient (IQ) below 70, and typically diagnosed prior to the age of 18. In many cases, a diagnosis of global developmental delay precedes an ID diagnosis, as it is challenging to accurately evaluate cognitive skills and IQ before the age of 65.

What causes Intellectual Disability and Developmental Delay?

Intellectual disability and developmental delay can be caused by a variety of factors. Research indicates that genetics plays a significant role in both intellectual disability and developmental delay, with over 30% of diagnosed cases being associated with a genetic cause1,3,4,7. Studies have identified various chromosomal differences and single gene disorders that contribute to these conditions. 

This is why a comprehensive evaluation by a medical geneticist, along with a brain MRI, proves beneficial in understanding and assessing these conditions. The involvement of a medical geneticist allows for a thorough examination of an individual's medical history, family history, and physical characteristics. This aids in identifying potential genetic causes and provides personalized treatments and interventions for individuals, and future family planning if parents want more children

In cases where an underlying genetic cause cannot be identified, the cause is considered to be multifactorial. This implies that a combination of multiple genetic and environmental factors work together to contribute to intellectual disability and developmental delay.

Is there genetic testing for Intellectual Disability and Developmental Delay?

Yes, there are genetic testing options available for individuals with Intellectual disability and/ or developmental delay. It's important to note that there isn't a single test that can identify all the causes of intellectual disability and/or developmental delay.

The genetics community generally recommends genetic testing for intellectual disability and developmental delay to include evaluations such as karyotype testing (chromosome evaluation) and chromosome microarray analysis (to detect extra or missing chromosome pieces). Additionally, single gene testing can be performed for genes commonly associated with intellectual disability/developmental delay, such as inborn errors of metabolism5. As genetic testing techniques have advanced, there has been a shift towards comprehensive evaluations of our entire genome, using exome or whole-genome sequencing7.

Various laboratories in the United States, including Blueprint Genetics, Fulgent and Prevention Genetics, offer intellectual disability and developmental delay gene panels specifically designed for individuals displaying symptoms of intellectual disability and/or developmental delay. These gene panels allow for the examination of multiple genes simultaneously to identify potential changes.

Can I test my embryo? 

Yes! Orchid's embryo screening reads the embryo’s entire genome, with a particular focus on regions of the chromosomes and genes that are associated with intellectual disability and developmental delay.

Research studies have indicated that approximately 15-20% of individuals with neurodevelopmental disorders have extra or missing segments of chromosomes4. For example, individuals with a portion of chromosome 4 missing may have a condition called Wolf-Hirschhorn syndrome. This condition affects various parts of the body including the brain resulting in developmental delay, intellectual disability, and seizures. Affected individuals typically have birth defects and other health concerns8. Only through Orchid's embryo screening is there the option to screen for a defined set of chromosome regions recognized by a consortium of experts in the field of genetics (clinical domain group) as associated with intellectual disability/developmental delay.

Research studies have revealed that roughly 10% of individuals with intellectual disability/developmental delay (and other neurodevelopmental disorders) have a malfunctioning gene causing their symptoms3,7. Only through Orchid's embryo screening (PGT-WGS) is there the option of screening for a defined set of genes (recognized by the clinical domain group) as being linked to intellectual disability, developmental delay and other neurodevelopmental disorders5.

An example of one of the more common (~1 in 10,000) progressive genetic neurodevelopmental disorders is Rett syndrome. In the first 6-18 months of life, individuals with Rett syndrome typically experience normal psychomotor development, followed by a period of developmental stagnation and then a rapid regression in language and motor skills2. There is no cure for Rett syndrome, treatment is focused on reducing symptoms related to seizures and poor nutrition. Orchid is able to screen Rett syndrome and other similar conditions prior to pregnancy.

Can Orchid identify all causes of Intellectual Disability/ Developmental delay?

No! There is no test that can detect all possible genetic causes of intellectual disability/developmental delay. Intellectual disability/developmental delay are very common, and not all cases are caused by genetic factors. These non-genetic factors are not included in genetic tests. Additionally, an embryo that screens negative may still be at risk for genetic diseases not in scope of the test (i.e., variants and or genes that are currently unknown to cause intellectual disability/developmental delay but do, genes that cause other genetic diseases).

What if I do not have a family history of Intellectual Disability/Developmental Delay?

Regardless of your family history, anyone has a chance of having a child affected with a genetic intellectual disability and/or developmental delay. This is because a large proportion of genetic neurodevelopmental disorders happen by chance in an individual (called "de novo")10.

For example, the cause for >99% of individuals with Rett syndrome is a genetic variant that occurs randomly in embryos. These individuals have no family history of Rett syndrome and likely would not think to screen for this condition. Orchid's neurodevelopmental disorder embryo screen can identify hundreds of non-inherited (de novo) genetic changes in addition to inherited genetic changes known to cause intellectual disability/developmental delay, and other neurodevelopmental disorders, in one single screen.

If you have a family history of intellectual disability or developmental delay, it is recommended that you review your family history with a genetic counselor. 

References
  1. Battaglia, A., Doccini, V., Bernardini, L., Novelli, A., Loddo, S., Capalbo, A., Filippi, T., & Carey, J. C. (2013). Confirmation of chromosomal microarray as a first-tier clinical diagnostic test for individuals with developmental delay, intellectual disability, autism spectrum disorders and dysmorphic features. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 17(6), 589–599. https://doi.org/10.1016/j.ejpn.2013.04.010
  2. Kyle, S. M., Vashi, N., & Justice, M. J. (2018). Rett syndrome: a neurological disorder with metabolic components. Open biology, 8(2), 170216. https://doi.org/10.1098/rsob.170216
  3. Manickam, K., McClain, M. R., Demmer, L. A., Biswas, S., Kearney, H. M., Malinowski, J., Massingham, L. J., Miller, D., Yu, T. W., Hisama, F. M., & ACMG Board of Directors (2021). Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genetics in medicine : official journal of the American College of Medical Genetics, 23(11), 2029–2037. https://doi.org/10.1038/s41436-021-01242-6
  4. Miller, D. T., Adam, M. P., Aradhya, S., Biesecker, L. G., Brothman, A. R., Carter, N. P., Church, D. M., Crolla, J. A., Eichler, E. E., Epstein, C. J., Faucett, W. A., Feuk, L., Friedman, J. M., Hamosh, A., Jackson, L., Kaminsky, E. B., Kok, K., Krantz, I. D., Kuhn, R. M., Lee, C., … Ledbetter, D. H. (2010). Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. American journal of human genetics, 86(5), 749–764. https://doi.org/10.1016/j.ajhg.2010.04.006
  5. Moeschler, J. B., Shevell, M., & Committee on Genetics (2014). Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics, 134(3), e903–e918. https://doi.org/10.1542/peds.2014-1839
  6. Schaefer, G. B., Mendelsohn, N. J., & Professional Practice and Guidelines Committee (2013). Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genetics in medicine : official journal of the American College of Medical Genetics, 15(5), 399–407. https://doi.org/10.1038/gim.2013.32
  7. Srivastava, S., Love-Nichols, J. A., Dies, K. A., Ledbetter, D. H., Martin, C. L., Chung, W. K., Firth, H. V., Frazier, T., Hansen, R. L., Prock, L., Brunner, H., Hoang, N., Scherer, S. W., Sahin, M., Miller, D. T., & NDD Exome Scoping Review Work Group (2019). Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genetics in medicine : official journal of the American College of Medical Genetics, 21(11), 2413–2421. https://doi.org/10.1038/s41436-019-0554-6
  8. Weise, A., Mrasek, K., Klein, E., Mulatinho, M., Llerena, J. C., Jr, Hardekopf, D., Pekova, S., Bhatt, S., Kosyakova, N., & Liehr, T. (2012). Microdeletion and microduplication syndromes. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society, 60(5), 346–358. https://doi.org/10.1369/0022155412440001

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