What genetic screening tests are recommended for a pediatric patient with unexplained developmental delay, intellectual disability, autism spectrum features, congenital anomalies, dysmorphic facial characteristics, or a family history of similar conditions?

Genetic Screening Tests for Pediatric Developmental Concerns

For any child with unexplained developmental delay, intellectual disability, autism spectrum features, congenital anomalies, or dysmorphic characteristics, chromosomal microarray (CMA) and Fragile X testing should be ordered as first-line genetic tests, regardless of whether dysmorphic features are present. 1, 2

First-Tier Testing Algorithm

Step 1: Initial Genetic Workup (Order for ALL patients)

• Chromosomal Microarray Analysis (CMA): This is the highest-yield first-line test, detecting clinically relevant copy number variants in 7.8% of patients with global developmental delay/intellectual disability and 10.6% of those with syndromic features 1, 3, 4
• Fragile X DNA Testing: Required for both males and females, with a combined diagnostic yield of at least 2% in patients with mild developmental delay/intellectual disability 1

Critical point: CMA has now replaced standard karyotype and FISH subtelomere testing as the first-line diagnostic approach 2. The degree of intellectual disability does not predict diagnostic yield, so testing should not be delayed based on severity 1.

Step 2: Targeted Testing Based on Clinical Features

For females with moderate-to-severe impairment:

• MECP2 gene sequencing and deletion/duplication analysis: Detects mutations in 1.5% of girls with moderate/severe developmental delay, even without classic Rett syndrome features 1

For males from families with X-linked inheritance pattern:

• Complete X-linked intellectual disability (XLID) gene panel: Diagnostic yield of 42% in males from definitely X-linked families and 17% from possibly X-linked families 1

For specific syndromic features:

• FISH or targeted molecular testing: Order when clinical examination suggests specific microdeletion/microduplication syndromes (e.g., DiGeorge syndrome, Williams syndrome) prior to or concurrently with CMA 1

Step 3: Metabolic Screening (Selective, Not Routine)

Order focused metabolic testing ONLY when specific indicators are present 1:

• Developmental regression or episodic decompensation
• Hepatosplenomegaly or coarse facial features on examination
• Parental consanguinity or family history suggesting metabolic disease
• Specific tests: serum amino acids, urine organic acids

Important caveat: Biochemical screening for inherited metabolic diseases has shown zero diagnostic yield in unselected populations with neurodevelopmental disorders 5. Do not order routine metabolic panels without clinical indicators.

Step 4: Additional Diagnostic Studies Based on Examination

Brain MRI indicated when:

• History of intrapartum asphyxia
• Microcephaly, macrocephaly, or abnormal cranial contour
• Focal motor findings, pyramidal signs, or extrapyramidal signs
• Cerebral palsy or epilepsy 1

Laboratory tests for specific presentations:

• Elevated creatine kinase (CK): For hypotonia with weakness (screens for Duchenne muscular dystrophy; CK typically >1000 U/L in affected males) 1
• Thyroid-stimulating hormone (TSH): For hypotonia or motor delays (acquired hypothyroidism can present with developmental delay) 1

Second-Tier Testing When First-Line Tests Are Normal

Multigene sequencing has superior diagnostic yield (8%) compared to CMA and Fragile X combined (4%) 5:

• Exome sequencing (ES) or comprehensive neurodevelopmental disorder gene panels
• Consider referral to clinical genetics for guidance on next-generation sequencing approaches 1

Subtelomere FISH testing: May be considered if chromosome analysis at 550-band resolution is normal, though CMA has largely replaced this approach 1

Critical Clinical Pitfalls to Avoid

• Never delay testing with "wait and see": Early identification enables timely intervention with significantly improved outcomes 6
• Do not skip testing in patients without dysmorphic features: Guidelines explicitly state that testing is indicated even in the absence of dysmorphic features, other clinical features, or positive family history 1
• Do not order standard karyotype as first-line test: CMA has replaced karyotype except when Down syndrome or another specific trisomy is clinically suspected and confirmation of translocation status is needed for recurrence risk counseling 1, 2
• Do not rely on normal prenatal testing: Postnatal blood karyotype should still be performed when indicated, as mosaicism may have been undetected and banding resolution is higher in postnatal preparations 1, 7

Diagnostic Yield Considerations

Higher diagnostic yields are seen in 5:

• Syndromic patients (odds ratio 3.09 compared to nonsyndromic)
• Female patients (odds ratio 3.21 compared to males)
• Patients with dysmorphic features (10.6% vs 7.8% without) 1

However, these differences should not exclude testing in lower-yield populations, as the absolute diagnostic rate remains clinically significant across all groups.

Essential Pre-Test Evaluation

Before ordering genetic tests, document 1:

• Three-generation family pedigree (assess for intellectual disability, psychiatric disorders, recurrent pregnancy loss, stillbirth, infant death)
• Prenatal and perinatal complications or exposures
• Timing of developmental concerns (onset before age 2 suggests autism spectrum disorder) 6
• Growth parameters and presence of microcephaly/macrocephaly
• Presence of congenital anomalies, especially cardiac defects (30% of pediatric patients with congenital heart disease have genetic disorders) 8
• Vision and hearing screening results
• Review state newborn screening results to avoid redundant testing 1