Laboratory Testing and Follow-Up for Autism Spectrum Disorder
All children with confirmed ASD should undergo a tiered genetic evaluation with chromosomal microarray and Fragile X testing as first-line studies, followed by periodic clinical reevaluations negotiated between the family, primary care physician, and medical geneticist for those without an identified etiology. 1
Initial Laboratory Evaluation
Pre-Evaluation Requirements
Before initiating genetic testing, confirm the ASD diagnosis by a trained professional using objective criteria, obtain a formal audiogram to exclude hearing loss, perform cognitive testing, and verify newborn screening results 2.
First-Tier Testing (Highest Yield)
The following tests should be performed initially:
- Chromosomal microarray (comparative genomic hybridization) - detects clinically relevant genetic abnormalities in approximately 7.9% of cases 1, 3
- Fragile X DNA testing - essential for all patients 2
- Physical examination with attention to dysmorphic features including Woods lamp evaluation for tuberous sclerosis 2
Metabolic screening only if clinical indicators present:
- Urine mucopolysaccharides and organic acids
- Serum lactate, amino acids, ammonia, and acylcarnitine profile
- Note: Recent data shows metabolic disorders are rarely identified (0% in one study), so these should be reserved for specific clinical suspicion 3
Second-Tier Testing (Conditional)
Proceed with these tests based on specific clinical features:
- MECP2 gene testing - females only 2
- PTEN gene testing - if head circumference is ≥2.5 SD above mean 2
- Fibroblast karyotype - if leukocyte karyotype normal but clonal pigmentary abnormalities noted 2
Third-Tier Testing (Specialized)
Consider in specific circumstances:
- Brain MRI - based on clinical indication, not routine 2
- Serum and urine uric acid with purine/pyrimidine panel if abnormal 2
- EEG - only if clinical suspicion of seizures (yields abnormalities in 9% but 57% show nonspecific findings of unclear significance) 2, 3
Tests NOT Routinely Recommended
The 2013 guidelines explicitly state insufficient evidence for routine testing of: CDKL5, cholesterol/7-dehydrocholesterol, chromosome 15 methylation, mitochondrial gene sequencing, selected neurometabolic screening panels, and various other specialized tests 1. These should only be ordered with specific clinical indication.
Follow-Up Schedule
The timing of follow-up consultations should be negotiated among the patient/family, primary care medical home, and medical geneticist 1. This individualized approach is necessary because:
For Patients WITH Identified Etiology
- Management depends on the specific diagnosis
- Often co-managed by clinical geneticist and primary care physician
- Follow-up dictated by the identified condition 1
For Patients WITHOUT Identified Etiology
- Periodic reevaluations are recommended as technology advances and phenotypes evolve may ultimately lead to diagnosis 1
- Genetic counseling should be provided using empiric recurrence risk data (3-10% for full siblings, higher if affected child is female at 7% vs. 4% if male, ≥30% if two or more affected children) 1
- Consider retesting as new technologies emerge - diagnostic yield has increased from 6-10% to 30-40% with modern testing 1
Critical Practice Points
Common Pitfall: Studies show 76.8% of clinicians order inappropriate tests not recommended by guidelines, while 10-40% fail to order recommended genetic tests 4. Avoid ordering large panels of metabolic tests without clinical indication - this is invasive, wasteful, and unlikely to generate useful data 5.
Emerging Evidence: Whole genome sequencing and trio (child plus parents) sequencing are increasingly favored as they can detect all variant types at lower total cost than individual test orders, with improved outcomes reported in up to 50% of cases when treatable risk factors are identified 6. However, these are not yet included in formal guidelines.
Genetic Consultation: A genetic consultation should be offered to ALL persons/families with ASD across the entire spectrum, as clinically actionable results can be found regardless of phenotypic severity 1, 6. The primary care physician and geneticist should partner in ordering, scheduling, and coordinating diagnostic tests 2.