What are the updated American Academy of Pediatrics (AAP) guidelines for genetic testing in children?

Updated AAP Genetic Testing Guidelines for Neurodevelopmental Disorders

For children with suspected global developmental delay (GDD), intellectual disability (ID), or autism spectrum disorder (ASD), chromosomal microarray (CMA) and Fragile X testing should be offered as first-tier genetic tests, with consideration for immediate genetics referral to guide evaluation that may include exome sequencing (ES) or whole genome sequencing (WGS). 1

Current AAP Recommendations by Condition

For Autism Spectrum Disorder (2020)

The AAP recommends the following algorithmic approach for children with suspected ASD 1:

First-tier evaluation:

• Consider immediate referral to clinical genetics to guide the genetic evaluation 1
• If pursuing testing independently, perform comprehensive history and physical examination looking for dysmorphic features, macrocephaly (>2.5 SD above mean), family history of X-linked disorders, or features suggesting specific syndromes 1
• If a specific diagnosis is suspected based on phenotype, send targeted testing first 1

When no specific diagnosis is suspected:

• Discuss and offer CMA and Fragile X analysis to all patients 1
• For females, consider MECP2 testing 1
• If family history suggests X-linked disorder, refer to clinical genetics 1

Second-tier testing:

• If first-tier tests are unrevealing, consider referral to genetics for workup that might include ES 1

For Global Developmental Delay/Intellectual Disability (2014)

The AAP's 2014 guideline specifically for GDD/ID recommends 1:

First-line approach:

• CMA and Fragile X testing should be first-line tests in all children with unexplained GDD/ID 1
• Consider metabolic testing (round 1) if clinical indicators are present 1

For specific scenarios:

• If family history is suggestive of X-linked disorder, send X-linked ID panel and high-density X-CMA 1
• Consider testing for X-inactivation skewing in the mother of the proband 1
• If the patient is female, send MECP2 sequencing and deletion/duplication analysis 1

For Developmental Delay (Broader 2020 Statement)

The AAP's 2020 general statement on developmental disorders (including GDD and ASD) recommends 1:

• For suspected GDD/ID or ASD, perform CMA and Fragile X testing as first-tier tests 1
• For suspected GDD/ID, consider metabolic testing if indicated by history and physical examination findings such as regression, seizures, abnormal growth parameters, or specific dysmorphic features 1
• For suspected GDD/ID, second-tier testing may include ES and gene panels 1
• For suspected ASD, consider genetics consultation for second-tier evaluation 1

For Cerebral Palsy (2022)

The most recent AAP guideline on cerebral palsy states 1:

• Diagnostic evaluation may include CMA or genome sequencing 1

Important Caveats and Evolving Standards

The AAP guidelines are becoming outdated: The most recent AAP guideline specifically focused on GDD/ID is from 2014 (10 years old), and many recommendations do not reflect the current availability of next-generation sequencing technologies 1. ES became clinically available in 2011 and WGS in 2013, yet most AAP guidelines still recommend CMA as first-tier testing 1.

Contrast with ACMG 2021 recommendations: The American College of Medical Genetics and Genomics published updated guidelines in 2021 stating that ES/WGS should be a first- or second-tier test in all patients with unexplained DD/ID or congenital anomalies 1. This represents a paradigm shift that the AAP guidelines have not yet incorporated 1.

Diagnostic yield considerations: The total diagnostic yield of CMA plus Fragile X testing in children with ASD is estimated at 40%, which is higher than any other single study including EEG or neuroimaging 1. Clinical exome sequencing adds an estimated additional 15-25% diagnostic yield 1.

Practical Implementation Algorithm

Step 1: Initial Assessment

• Perform three-generation family history with pedigree analysis 1
• Complete physical examination specifically looking for: dysmorphic features, head circumference (measure and plot on growth chart), Wood's lamp examination for tuberous sclerosis, and signs suggesting metabolic disorders (regression, seizures, cyclic vomiting, lactic acidosis) 1

Step 2: Determine Testing Strategy

• If specific syndrome suspected (e.g., Down syndrome, tuberous sclerosis): Order targeted testing first 1
• If no specific syndrome suspected: Offer CMA and Fragile X testing 1
• Consider immediate genetics referral, particularly for ASD, as genetic specialists may proceed directly to ES/WGS 1

Step 3: Gender-Specific Considerations

• Males with ASD: CMA and Fragile X testing 1
• Females with ASD or GDD/ID: Add MECP2 sequencing and deletion/duplication analysis 1
• Any child with family history of X-linked disorder: Refer to genetics for X-linked ID panel and high-density X-CMA 1

Step 4: Phenotype-Specific Testing

• Macrocephaly (>2.5 SD above mean): Add PTEN testing 1
• Metabolic red flags (regression, seizures, abnormal growth, cyclic vomiting, lactic acidosis, microcephaly): Order metabolic testing 1

Step 5: Second-Tier Evaluation

• If first-tier testing unrevealing: Refer to genetics for consideration of ES or gene panels 1
• Genetic counseling should guide all testing decisions and interpretation of results 1, 2

Common Pitfalls to Avoid

Do not order extensive metabolic testing routinely: Metabolic or mitochondrial studies are not indicated unless the child has multiple specific signs such as anemia, gastrointestinal dysfunction, cyclic vomiting, lactic acidosis, microcephaly, or seizures 1.

Do not skip genetic counseling: Genetic testing has psychological effects and subjects families to risks of discrimination; counseling should occur before and after testing 2, 3.

Do not assume negative family history excludes genetic causes: Approximately 30-40% of genetic cases represent de novo mutations with no family history 4.

Do not perform karyotype as first-tier testing: Traditional karyotype has been superseded by CMA, which has higher diagnostic yield 1.

Recognize that guidelines lag behind technology: While AAP currently recommends CMA as first-tier, many genetics centers now use ES/WGS as first-tier testing given comparable cost and higher diagnostic yield 1.