Autism and Intellectual Disability Comprehensive Panel

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

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