Developmental
for global developmental delay/intellectual disability with exome sequencing
System Profile
Yield Comparison
Clinical Dimensions
- Global delay
- Speech apraxia
- Autism with dysmorphism
- Intellectual disability
- Plateauing or loss of milestones
- ASD with dysmorphism
- Idiopathic intellectual disability
- Global developmental delay of unknown cause
- Severe speech apraxia
- Poor eye contact
- Lack of joint attention
- Poor social reciprocity
- Dysarthric or absent speech
- Toe-walking
- Stereotypies
- Regression of skills on exam
- Delayed speech and motor milestones
- Learning issues
- Social delay
- Difficulty with transitions
- Sensory aversions
- Loss of previously acquired skills
- Abnormal newborn metabolic screen
- Lactate elevation
- Low carnitine
- Microarray or Fragile X abnormalities
- Methylation defects (Angelman/Prader-Willi)
- Thyroid dysfunction
- MRI showing global atrophy or white matter changes without hypoxic injury
- Abnormal gyral patterns
- Ventriculomegaly
- Asymmetry of hemispheres
- Formal developmental testing (Bayley, DP-4, Vineland) showing multi-domain delays
- ADOS confirming ASD with dysmorphism
- Adaptive skills far below age
- Multiple behavior meds (stimulants, antipsychotics, SSRIs) with limited benefit or paradoxical worsening
- Polypharmacy for ADHD/ASD
- Behavioral worsening with certain food dyes/additives or medications
- Suggesting metabolic/neurologic sensitivity
- Surgeries prompted by congenital anomalies affecting development
- Gastrostomy for feeding
- Multiple early procedures without a unifying acquired cause
- Early intervention services
- Special education
- ABA
- Intensive speech and occupational therapy for ASD/DD
- Persistent therapy needs despite good engagement
- AAC devices
- Communication boards
- Tablets with speech apps
- Specialized educational tech supports
- Developmental pediatrics following since early childhood
- Early intervention teams
- Special education and multi-therapist involvement
- Dev-peds recommending genetics
- Autism
- Developmental delay
- Intellectual disability
- Learning disabilities
- Severe speech delay
- Special education in multiple family members
- Known chromosomal/genetic diagnosis in relatives
- Adequate stimulation, stable caregiving, good schooling yet multi-domain delays
- Absence of neglect
- Similar delays in siblings or relatives
- Poor feeding
- Hypotonia
- Delayed early milestones noted in nursery
- Low activity
- Poor consolability
- Early concerns documented by NICU staff
Red Flag Combinations
Clinical patterns that should prompt consideration of genetic testing
Autism + dysmorphic features
Global delay + congenital anomalies
Intellectual disability + seizures
Developmental plateau + micro/macrocephaly
Screening Decision Pathway
When to consider genetic testing for developmental presentations
graph TD
START["Patient Presents with\nDevelopmental Concerns"] --> SCREEN{"Screen for\nRed Flags"}
SCREEN --> RF1["ASQ failures in multiple domains"]
SCREEN --> RF2["M-CHAT high-risk results"]
SCREEN --> RF3["Abnormal Vineland or DP-4"]
SCREEN --> RF4["Poor adaptive functioning on standardized tools"]
RF1 --> EVAL{"Multiple\nFlags Present?"}
RF2 --> EVAL{"Multiple\nFlags Present?"}
RF3 --> EVAL{"Multiple\nFlags Present?"}
RF4 --> EVAL{"Multiple\nFlags Present?"}
EVAL -->|Yes| TEST["Order Genetic Testing\n(ES/GS)"]
EVAL -->|No| MONITOR["Continue Monitoring\nRe-evaluate if New Findings"]
TEST --> DX["Molecular Diagnosis\n27-41% yield"]
style TEST fill:#dcfce7,stroke:#16a34a,color:#14532d
style DX fill:#bbf7d0,stroke:#16a34a,color:#14532d
style MONITOR fill:#fef3c7,stroke:#d97706,color:#92400e
Screening Red Flags
Findings on routine screening that may indicate genetic etiology
- ASQ failures in multiple domains
- M-CHAT high-risk results
- Abnormal Vineland or DP-4
- Poor adaptive functioning on standardized tools
Exome / Genome Sequencing Indications
Clinical scenarios supporting ES/GS as a diagnostic approach
- Global developmental delay or ID of unknown cause
- ASD with dysmorphism or seizures
- Multiple congenital anomalies
- Negative microarray/Fragile X
- Family history of similar DD
Key Evidence
Published studies supporting genetic testing for developmental conditions
| Study | Year | Type | Sample | Yield | Key Finding |
|---|---|---|---|---|---|
| Genetic Evaluation of the Child With Intellectual Disability... | 2025 | Guideline | None | 20-80% | 2025 AAP guidelines: ~80% yield in severe ID, ~20% in mild ID, higher yields wit... |
| Genomic Diagnosis of Rare Pediatric Disease in the United Ki... | 2023 | Cohort | None | 41% | DDD Study achieved 41% diagnostic yield using combined clinical and computationa... |
| Clinical exome sequencing for genetic identification of rare... | 2014 | Cohort | 814 | 26% | Clinical exome sequencing yielded 26% overall molecular diagnosis in 814 consecu... |
| Exome sequencing in 152 consanguineous families with neurode... | 2017 | Cohort | 152 | 36.8% | 36.8% diagnostic yield in consanguineous NDD families by ES; identified 30 novel... |
| Semiautomated WES workflow for neurodevelopmental disorders | 2019 | Cohort | 106 | 41% | 41% diagnostic yield for duo/quad/trio and 28% for singleton WES in NDD cohort u... |
| Meta-analysis and multidisciplinary consensus statement: exo... | 2019 | Meta-Analysis | None | 36% | Meta-analysis of 37 studies establishes ES as first-tier test for NDDs with 36% ... |
| Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops... | 2020 | Cohort | 127 | 29% | Exome sequencing identified a genetic diagnosis in 29% of NIHF cases after stand... |
| Clinical Sequencing Yield in Epilepsy, Autism Spectrum Disor... | 2021 | Meta-Analysis | 32331 | 23.7% | Meta-analysis of 103 studies/32,331 individuals: overall 23.7% yield; epilepsy 2... |
Updated: 2026-02-24
Curated by: human
Status: human reviewed