Neurodevelopmental Disorders

Neurodevelopmental disorders (NDDs) affect more than 4.6 million Americans1 and include both intellectual disabilities (ID) and autism spectrum disorders (ASD). There is a growing body of evidence that shows strong support for the role of genetics in NDDs. To better serve the growing needs of clinicians and patients, Ambry offers a range of diagnostic testing options for these indications.

NDDs are disabilities associated primarily with the functioning of the brain and neurological system. Individuals often present with intellectual disabilities (ID) and/or characteristics of autism spectrum disorders (ASD). The overlapping and non-specific nature of these symptoms can bring diagnostic challenges, as these clinical signs can exist in combination with other medical concerns or on their own. Making this distinction is a critical step in arriving at an accurate diagnosis.

Quick Links to Relevant Resources

 

Genetic Testing Strategy for the Child With Unexplained ID +/- Characteristics of ASD

In the absence of other indications, this testing strategy could be considered. It incorporates recommendations from the American College of Medical Genetics and Genomics (ACMG), the Amercican Academy of Neurology (AAN), and the American Academy of Pediatrics(AAP).2,3,4,5 Clinical evaluation(s) may suggest that single gene testing or karyotyping are more appropriate initial steps.

A tiered approach offers the option of fragile X DNA analysis with chromosomal microarray, with a reflex to several tests most appropriate to the patient phenotype. ExomeNext is available as a reflex test if initial testing is inconclusive.

Intellectual Disability (ID)
ID is a developmental consequence of both syndromic and non-syndromic origins. Causes include complex inherited conditions resulting from chromosome or single gene changes, errors during embryogenesis, prenatal and perinatal complications, and inborn errors of metabolism.

DSM-56 defines ID as:

  • Intelligence quotient (IQ) approximately 70 or below
  • Onset before age 18 years  
  • Impairments in adaptive functioning in at least 2 of the following areas: communication, social/interpersonal skills, use of community resources, self-direction, functional academic skills, work, leisure, health, and safety


X-linked intellectual disability (XLID) affects approximately 1/600-1/1,000 males and a significant number of females.3 XLID is associated with more than 200 inherited conditions linked to >90 genes on the X chromosome.Ambry’s XLID genetic test uses next generation sequencing to simultaneously analyze 81 genes linked to X-linked intellectual disability. Research suggests that approximately 42% of patients with XLID will present with a mutation in one of these genes.8

Autism Spectrum Disorders (ASD)
Children with signs of an ASD may have co-occurring inherited conditions, such as fragile X syndrome, Rett syndrome, and PTEN-related disorders. Ambry offers testing for these conditions to help clinicians accurately determine the underlying genetic cause of a child’s symptoms. Confirmation of a genetic cause helps tailor medical management and recommendations for an individual/family.

Test Name Description TAT
Fragile X syndrome FMR1 7-14 days
Rett/Atypical Rett syndrome MECP2, CDKL5, FOXP2, MEF2C 7-42 days
XLID panel 81 genes for X-linked intellectual disability 84-112 days
PTEN-related macrocephaly and autism spectrum disorder PTEN 7-21 days
Autism spectrum disorder FMR1, PTEN, MECP2, CDKL5, FOXP2, MEF2C, chromosomal microarrays (SNP+CGH and 180K oligo options) 7-42 days
Intellectual disability FMR1, XLID panel, chromosomal microarrays (SNP+CGH and 180K oligo options) 7-112 days
Chromosomal microarray SNP+CGH and 180K oligo options 10-21 days
ExomeNext ExomeNext and ExomeNext-Rapid 14-84 days


References

  1. Larson SL, et al. Prevalence of mental retardation and/or developmental disabilities: Analysis of the 1994/1995 NHIS-D. MR/DD Data Brief. Minneapolis, MN: Institute on Community Integration, University of Minnesota. 2000.
  2. Moeschler JB, et al. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics. 2014 Sep;134(3):903-918.
  3. Miller DT, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010 May 14;86(5):749-764.
  4. Schaefer GB, et al. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013 May;15(5):399-407.
  5. Michelson DJ, et al. Evidence report: Genetics and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2011 Oct 25;77(17):1629-1635.
  6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Washington, DC. 2013.
  7. Lisik M, et al. X-linked mental retardation. Med Sci Monit. 2008 Nov;14(11):RA221-229.
  8. Gecz J, et al. The genetic landscape of intellectual disability arising from chromosome X. Trends in Genetics. 2009 Jul;25(7):308-316.