Autism and Intellectual Disability Comprehensive Panel

Method

Tandem Mass Spectrometry, Electrophoresis/Spectrophotometry, Gas Chromatography/Mass Spectrometry, Liquid Chromatography/Tandem Mass Spectrometry, and Quantitative Liquid Chromatography/Tandem Mass Spectrometry, Genomic Microarray (Oligo-SNP Array), Polymerase Chain Reaction/Capillary Electrophoresis

  • Comprehensive genetic evaluation of individuals with ASD and/or ID
  • Includes cytogenomic microarray, fragile X methylation analysis, and comprehensive metabolic disorders analysis
Test Components

May be ordered separately

  • Preferred first-tier test for DD, ID, ASD, and multiple anomalies
  • Testing is performed on peripheral blood
  • CytoScan HD platform (Thermo Fisher Scientific) to detect copy number changes, including deletions and duplications as well as copy-neutral regions of homozygosity
  • Preferred first-tier test for DD, ID, ASD, and multiple anomalies
  • Testing is performed on buccal sample
  • Preferred test to diagnose fragile X syndrome and carrier screening in individuals with a positive family history
  • If fragile X testing detects a CGG repeat of 100 or greater by polymerase chain reaction and capillary electrophoresis, methylation analysis will be added

Evaluate for ASD, DD, and/or ID in individuals who have had negative FMR1 (fragile X) and cytogenomic SNP microarray testing

Autism spectrum disorder (ASD) and intellectual disability (ID) represent a neurodevelopmental continuum with significant comorbidity and overlapping etiologies. ASD is classified by varying degrees of social impairment, communication limitations, repetitive behaviors, and/or restricted interests. Symptoms typically present by age 3. ID is classified by broad impairment in cognitive and adaptive functioning, typically with an IQ below 70, and presents before age 18. A global developmental delay (DD) diagnosis often precedes a diagnosis of ID, as cognitive skill or IQ cannot be reliably assessed prior to age 6. Those with severe DD diagnosed before age 6 are most likely to develop ID.

ASD and IDs are often comorbid and may be a feature in various genetic syndromes associated with chromosomal copy number variants (CNVs), fragile X syndrome, and inborn errors of metabolism (IEMs). Literature suggests ~10-15% of individuals with ASD and/or ID have detectable chromosomal abnormalities, CNVs, and fragile X syndrome.

Disease Overview

Indications for Ordering (Testing)

  • Comprehensive evaluation of an individual with ASD and/or ID (with or without comorbidities)
  • Assist with decisions about treatment and management of an individual with ASD and/or ID
  • Confirmation of a clinical diagnosis of ASD and/or ID

Heritability

  • ASD: ~90%
  • ID: ~50%

Prevalence

  • ASD: ~1/68 (1/42 males, 1/189 females)
  • ID: ~1/100
  • ASD and ID combined incidence: ~1/250

Test Limitations

Autism and intellectual disability panel testing limitations:

  • Other etiologies of ASD and ID, such as single gene disorders, may not be identified
  • Uninformative results may occur due to variants of uncertain clinical significance
  • Results may not predict disorder severity

Cytogenomic SNP microarray limitations:

  • The genome-wide resolution is approximately 25-50 kb for copy number changes and approximately 3 Mb for regions of homozygosity
  • Testing does not detect
    • CNVs below the limit of resolution of this platform
    • Sequence-level variants (mutations) including point mutations and indels
    • Low-level mosaicism (generally, less than 20-30%)
    • Balanced chromosomal rearrangements (translocations, inversions, and insertions)
    • Genomic imbalance in repetitive DNA regions (centromeres, telomeres, segmental duplications, and acrocentric chromosome short arms)
    • Mitochondrial DNA alterations
  • For further review, see Additional Technical Information for Cytogenomic SNP Microarray 2003414  

Fragile X testing limitations:

  • Estimated size is not provided for full mutations with >200 repeats
  • Rare mutations in FMR1 unrelated to trinucleotide expansion will not be detected
  • Diagnostic errors can occur due to rare sequence variations
  • For further review, see Additional Technical Information for Fragile X (FMR1) with Reflex to Methylation Analysis 2009033
    References