Is genetic testing recommended for individuals with autism spectrum disorder (ASD)?

Genetic Testing in Autism Spectrum Disorder

Genetic testing is strongly recommended for all individuals diagnosed with autism spectrum disorder (ASD) as it can identify an underlying etiology in 30-40% of cases, which may impact medical management, treatment options, and family planning. 1

First-Tier Genetic Testing for All ASD Patients

1. Comprehensive Clinical Evaluation

   • Three-generation family history with pedigree analysis
   • Detailed physical examination with focus on dysmorphic features
   • Assessment for signs of known genetic syndromes

2. Chromosomal Microarray (CMA)

   • First-line test for all individuals with ASD
   • Expected diagnostic yield: approximately 10% 1
   • Types: oligonucleotide array-comparative genomic hybridization or single-nucleotide polymorphism array

3. Sex-Specific Testing

   • Males:

     • DNA testing for Fragile X syndrome (yield: 1-5%) 1
     • MECP2 duplication testing only if suggestive features present (drooling, recurrent respiratory infections, hypotonic facies) 1

   • Females:

     • MECP2 sequencing (yield: 4% of females with ASD) 1
     • Fragile X testing only if clinical features or family history suggest it 1

Second-Tier Testing (Based on Clinical Features)

1. Macrocephaly (head circumference >98th percentile or >2.5 SD above mean)

   • PTEN gene sequencing (yield: 5% in ASD with macrocephaly) 1
   • Yield increases to exceptionally high rates in patients with head circumference >4 SD above mean 1

2. Metabolic Testing

   • Consider when specific clinical indicators are present:
     • Cyclic vomiting, acid/base disturbances
     • Developmental regression with illness
     • Lethargy, multisystem involvement
     • Neurodegeneration outside typical ASD speech loss 1

3. Neuroimaging (MRI)

   • Not recommended routinely
   • Indicated only with specific features:
     • Microcephaly
     • Regression
     • Seizures
     • History of stupor/coma 1

Clinical Impact of Genetic Testing

Identifying a genetic etiology has several benefits:

1. Medical Management

   • Guides screening for associated medical conditions 2
   • Directs targeted medical interventions 2
   • Allows monitoring for known comorbidities

2. Family Planning

   • Provides accurate recurrence risk counseling
   • For negative tests: empiric sibling recurrence risk is 3-10% (may be higher in newer studies) 1
   • For positive tests: specific genetic counseling based on identified mutation 1

3. Treatment Implications

   • May identify treatable risk factors that could improve outcomes 3
   • Can inform medication selection through pharmacogenetics 3

Common Pitfalls and Caveats

1. Interpreting Results

   • Variants of unknown significance are common (up to 34.8% in some studies) 4
   • Negative testing does not rule out genetic etiology

2. Follow-up Challenges

   • Ensure proper follow-up after testing (43.5% of patients may be lost to follow-up) 4
   • Consider referral to genetics specialists for result interpretation

3. Testing Limitations

   • Current testing identifies etiology in 30-40% of cases, meaning 60-70% remain unexplained 1
   • Genetic heterogeneity of ASD means multiple genes likely interact in most cases 5

4. Access Issues

   • Insurance coverage may be limited despite clear medical utility 2
   • Consider advocating for coverage based on potential for clinically actionable results

Evolving Landscape

Newer testing modalities such as whole exome sequencing and whole genome sequencing are increasingly available and may eventually replace first-tier testing due to higher diagnostic yield and comprehensive coverage of multiple variant types 3.

The genetic evaluation of ASD continues to evolve rapidly, with emerging evidence suggesting that genetic testing can lead to improved outcomes in up to half of cases through targeted interventions for associated symptoms 3.