Tandem Mass Spectrometry/Electrophoresis/Spectrophotometry/ Gas Chromatography-Mass Spectrometry/Liquid Chromatography-Tandem Mass Spectrometry/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
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
Polymerase Chain Reaction (PCR)/Capillary Electrophoresis
- 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
Tandem Mass Spectrometry/Electrophoresis/Spectrophotometry/ Gas Chromatography-Mass Spectrometry/Liquid Chromatography-Tandem Mass Spectrometry
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.
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
- ASD: ~90%
- ID: ~50%
- ASD: ~1/68 (1/42 males, 1/189 females)
- ID: ~1/100
- ASD and ID combined incidence: ~1/250
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
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Publishing; 2013.
U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Autism and Developmental Disabilities Monitoring (ADDM) Network. [Last reviewed: Aug 2019; Accessed: Feb 2020]
Campistol J, Díez-Juan M, Callejón L, et al. Inborn error metabolic screening in individuals with nonsyndromic autism spectrum disorders. Dev Med Child Neurol. 2016;58(8):842-847.
Ghaziuddin M, Al-Owain M. Autism spectrum disorders and inborn errors of metabolism: an update. Pediatr Neurol. 2013;49(4):232-236.
Karam SM, Riegel M, Segal SL, et al. Genetic causes of intellectual disability in a birth cohort: a population-based study. Am J Med Genet A. 2015;167(6):1204-1214.
Kaufman L, Ayub M, Vincent JB. The genetic basis of non-syndromic intellectual disability: a review. J Neurodev Disord. 2010;2(4):182-209.
Michelson DJ, Shevell MI, Sherr EH , et al. Evidence report: genetic 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;77(17):1629-1635.
Rauch A, Hoyer J, Guth S, et al. Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. Am J Med Genet A. 2006;140(19):2063-2074.
Sandin S, Lichtenstein P, Kuja-Halkola R, et al. The familial risk of autism. JAMA. 2014;311(17):1770-1777.
Sempere A, Arias A, Farré G, et al. Study of inborn errors of metabolism in urine from patients with unexplained mental retardation. J Inherit Metab Dis. 2010;33(1):1-7.
South ST, Lee C, Lamb AN, et al. ACMG standards and guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. Genet Med. 2013;15(11):901-909.
van Karnebeek CDM, Stockler S. Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. Mol Genet Metab. 2012;105(3):368-381.