What is the process for testing for neurodivergence?

Testing for Neurodivergence: A Structured Diagnostic Approach

For children and adolescents with suspected neurodevelopmental disorders (autism spectrum disorder, intellectual disability, or global developmental delay), begin with chromosomal microarray (CMA) and Fragile X testing as first-tier genetic tests, following comprehensive clinical evaluation. 1

Initial Clinical Evaluation

The diagnostic process starts with specific clinical assessments before any testing:

• Obtain a three-generation family history with pedigree analysis, specifically documenting any family members with Fragile X syndrome, undiagnosed intellectual disability, or consanguinity 1
• Perform targeted physical examination including measurement of head circumference (occipitofrontal circumference), neurological examination, dysmorphology assessment, and Wood's lamp skin examination 1
• Conduct hearing screening as part of the medical assessment 1
• Complete neuropsychiatric evaluation to characterize the specific neurodevelopmental profile 1

First-Tier Genetic Testing

When no specific syndrome is suspected based on clinical features, the American College of Medical Genetics (ACMG) and American Academy of Pediatrics (AAP) recommend:

• Chromosomal microarray (CMA) for all patients with unexplained autism, intellectual disability, or global developmental delay 1
• Fragile X testing for all patients (both males and females) with these presentations 1

These tests should be offered and discussed with families even when a specific diagnosis is not immediately apparent. 1

Targeted Testing for Specific Clinical Scenarios

If clinical features suggest a specific syndrome, proceed directly to targeted genetic testing rather than broad screening. 1

For Autism Spectrum Disorder with Specific Features:

• MECP2 sequencing and deletion/duplication analysis for females with autism 1
• MECP2 duplication testing for males with suggestive phenotype 1
• PTEN testing when head circumference exceeds 2.5 standard deviations above the mean 1

For X-Linked Inheritance Patterns:

• X-linked intellectual disability gene panel when family history suggests X-linked disorder 1
• High-density X-chromosome microarray in these cases 1
• X-inactivation skewing analysis in the mother of the affected child 1

Metabolic Testing Considerations

Metabolic testing should be performed selectively, not routinely:

• Order metabolic screening when specific clinical indicators are present, such as regression, episodic decompensation, or specific dysmorphic features 1
• Consider "round 1" metabolic testing in global developmental delay/intellectual disability when history and physical examination suggest metabolic etiology 1

Second-Tier Testing

When first-tier tests (CMA and Fragile X) are non-diagnostic, the ACMG recommends:

• Exome sequencing (ES) or whole genome sequencing (WGS) as second-tier testing for unexplained developmental delay, intellectual disability, or congenital anomalies 1
• Gene panels targeting specific neurodevelopmental pathways may be considered 1
• Karyotype or mitochondrial DNA testing in select cases 1

The 2021 ACMG guidelines specifically state that exome/genome sequencing should be considered a first- or second-tier test in all patients with unexplained developmental delay, intellectual disability, or congenital anomalies. 1

Referral to Clinical Genetics

Immediate referral to clinical genetics is appropriate when:

• Family history suggests X-linked inheritance pattern 1
• First-tier testing is unrevealing and further workup is needed 1
• Clinical presentation is complex or involves multiple organ systems 1

The AAP 2020 guidelines emphasize considering immediate genetics referral to guide the genetic evaluation process, particularly for autism spectrum disorder. 1

Assessment of Co-occurring Neurodivergent Traits

Recent evidence demonstrates that 71.8% of children referred for autism assessment show traits of additional neurodivergences (motor, learning, or attention domains). 2 Use validated questionnaires to systematically screen for co-occurring neurodevelopmental traits rather than focusing solely on the primary referral concern. 2

Critical Pitfalls to Avoid

• Do not rely on imaging findings alone (generalized versus focal, bilateral versus unilateral malformations) to distinguish genetic from non-genetic causes, as these cannot reliably make this distinction 1
• Do not assume a single neurodevelopmental diagnosis explains the entire clinical picture—systematically assess for co-occurring conditions 2
• Do not order exome sequencing without first completing CMA and Fragile X testing unless there are specific clinical indicators suggesting a monogenic disorder 1
• Avoid ordering metabolic testing routinely in all cases; reserve for those with specific clinical indicators 1

Quality Control for Interpretation

Final clinical interpretation should be performed by a qualified medical geneticist, ideally after interdisciplinary discussion with molecular geneticists, neuroradiologists, and neurologists. 1 Re-evaluation of clinical features and neuroimaging is essential when genetic variants are identified to confirm the variant fully explains the phenotype. 1