Published diagnostic yields for the same test can range from 10% to 72%. Before citing any number clinically, understand the six key variables:

• Cohort selection — the biggest driver. Specialty-clinic cohorts enriched for severe/complex disease yield 40–72%; population-level cohorts with milder phenotypes yield 15–25%. Always ask: who was in the denominator?
• Singleton vs. trio — trio sequencing (proband + both parents) approximately doubles yield for de novo-enriched phenotypes (OR ~2.04, Clark et al. 2018). For severe DEE, GDD, or MCA, trio is essential.
• Prior testing — a post-CMA-negative WES cohort yields ~25–35%, while first-tier WES in the same phenotype yields ~30–45%. Prior negative tests remove diagnoses from the denominator.
• Database maturation — reanalysis of older WES data yields new diagnoses in ~10–25% of unsolved cases. A negative WES is time-stamped, not permanent.
• CMA platform — SNP arrays detect UPD and autozygosity (important for imprinting disorders); oligo-only arrays miss this.
• Severity — younger onset, multi-system involvement, epilepsy comorbidity, and distinctive features all independently predict higher yield. Mild isolated phenotypes (isolated ASD without ID) consistently show the lowest yields.

Chromosomal Microarray (CMA) — Pooled NDD yield: ~10%

• Detects CNVs ≥50–200 kb, aneuploidy; SNP arrays add UPD/autozygosity
• Does NOT detect SNVs, small indels, balanced rearrangements, or repeat expansions
• Inexpensive, rapid, decades of validation
• Still first-tier for MCA, IESS, and ID (complements WES)

Whole Exome Sequencing (WES) — Pooled NDD yield: ~36%

• Captures the ~2% of genome encoding proteins (SNVs + small indels)
• Misses deep intronic, regulatory, balanced SVs, and repeat expansions
• CNV detection possible but less sensitive than CMA
• Standard first-tier test for undiagnosed NDD/ID at most academic centres

Whole Genome Sequencing (WGS) — Pooled NDD yield: ~41%

• Adds balanced SVs, deep intronic/regulatory variants, improved mitochondrial coverage
• May screen for some STR disorders (ExpansionHunter), but sensitivity is variable
• WGS vs. WES yield is NOT significantly different overall (OR 1.13, p=0.50)
• Incremental gain concentrated in: post-WES-negative patients, leukodystrophies, atypical CP

Repeat expansion blind spot: Standard WES does NOT detect trinucleotide/pentanucleotide repeat expansions — Friedreich ataxia, SCA types, CANVAS, Fragile X/FXTAS, DM1/DM2, Huntington, C9orf72. Dedicated repeat-primed PCR, Southern blot, or long-read sequencing remain the gold standard. Always consider whether the phenotype suggests a repeat disorder before declaring testing complete.

NICU / Neonatal Encephalopathy

• rWES 20–35%; rWGS 35–50% (comparable in RCT, Maron et al. JAMA 2023)
• ~18% of NICU admissions carry a Mendelian disease
• Diagnosis changed management in 38–50% of cases — highest clinical utility in paediatric genetics

Developmental & Epileptic Encephalopathy (DEE)

• WES 24–40%, WGS 35–50%
• Highest yields in specific syndromes: EIMFS/Dravet ~78%, early infantile DEE ~43%

Infantile Epileptic Spasms (IESS)

• Meta-analysis: CMA 14%, WES 26% (CI 21–31%)
• Genetic diagnosis enables precision therapy in 61.6% of genetically explained cases

Non-DEE Epilepsy (focal or generalized, normal development)

• WES 10–18%; gene panel is a reasonable first step
• CMA rarely diagnostic for point-mutation epilepsies (SCN1A, GABRA1, GABRG2)

Drug-Resistant Epilepsy

• Drug resistance independently predicts higher yield
• All-epilepsy meta-analysis (Sheidley 2022, n=39,094): CMA 9%, WES 24%, WGS 48%

GDD (infant/toddler, unexplained)

• WES first-tier 30–40%; trio + CNV-seq up to 61% (Zhang 2024, n=434)
• Trio ~doubles yield vs. singleton (OR ~2.04)
• Strongest yield predictors: moderate-to-severe impairment, age 12–24 mo, craniofacial features

Intellectual Disability (child/adolescent)

• WES 30–45%; WGS 35–50%
• ACMG 2021 supports WES/WGS as first-/second-tier (Manickam et al.)
• DDD study (Wright et al. 2023): 41% trio WGS yield

Isolated ASD (without ID, epilepsy, or distinctive features)

• Lowest NDD yield: WES 10–15%
• Comorbid ID raises yield to ~25–30%
• CMA retains value for recurrence counseling even without diagnosis

Multiple Congenital Anomalies (MCA)

• CMA is productive first step at 15–25%
• WES/WGS 35–55%; MCA+ID up to 62%
• Consanguinity substantially raises recessive diagnosis yield

Cerebral Palsy (unexplained, no clear perinatal cause)

• WES overall 31% (CI 24–39%), pediatric-specific 35%, strict exclusion 42% (Gonzalez-Mantilla, JAMA Pediatr 2023)
• CP+ID yields 38% vs. 18% without ID

Macrocephaly

• WES 20–40%; key genes: PTEN, PIK3CA, NF1, RAS-MAPK pathway
• Somatic mosaic overgrowth (PIK3CA, AKT3) may need deep sequencing or tissue biopsy

Episodic Ataxia

• WES 20–35%; almost exclusively ion-channel point mutations (KCNA1, CACNA1A, ATP1A3)
• Gene panel competitive with WES for well-defined phenotype

Progressive (Hereditary) Ataxia

• WES ceiling ~50% in specialty cohorts (Fogel et al. 2020); WGS 40–55%
• Most common hereditary ataxias are NOT detected by WES/WGS — they require dedicated repeat testing:
• Friedreich ataxia (FXN GAA repeat) → repeat-primed PCR
• SCA types (CAG repeats) → repeat analysis
• CANVAS (RFC1 AAGGG repeat) → Southern blot or long-read sequencing
• FXTAS (FMR1 CGG premutation) → FMR1 PCR
• Always ask after a negative WES in ataxia: has dedicated repeat expansion testing been sent?

Leukodystrophy (MRI-selected, genetic suspected)

• WES 50–72% — among the highest yields in all of neurogenetics
• WGS 72–90%+ in dedicated programmes (Zerem et al. 2023: 89.6% with all modalities)
• GWMD cohort: 72% overall, 77% for onset <3 yr, 85% for hypomyelination
• MRI pattern recognition is the essential pre-test step — categorizing the white matter pattern (hypomyelination vs. demyelination vs. cystic vs. vacuolating) dramatically narrows the differential and raises yield; see the Hereditary Ataxias module for detailed ataxia clinical features

Pooled Yields Across Pediatric NDD Cohorts

Six take-home points

• CMA is not obsolete — uniquely detects aneuploidy, large CNVs, UPD; complements WES at lower cost
• Trio is essential for severe early-onset phenotypes — ~2× yield vs. singleton for de novo-enriched conditions
• WGS > WES only in specific scenarios — post-WES-negative, leukodystrophies, atypical CP
• Repeat expansions are a separate testing universe — Friedreich, SCA, CANVAS, DM1, HD, C9orf72 require dedicated testing
• Yield is dynamic — reanalysis at 12–24 months yields new diagnoses in ~10–25% of unsolved cases
• Leukodystrophy is the special case — MRI pattern recognition + WES/WGS yields 50–89%

Clinical utility ≠ diagnostic yield: A diagnosis changes management in 38–50% of NICU cases and enables precision therapy in 61.6% of genetically explained IESS. Examples: KCNQ2 → carbamazepine; GLUT1 → ketogenic diet; SLC6A1 → avoid vigabatrin; SCN1A → avoid sodium channel blockers.