Neurological
for early-onset epilepsy and epileptic encephalopathy with exome/genome sequencing
System Profile
Yield Comparison
Clinical Dimensions
- Seizures (early onset)
- Hypotonia
- Ataxia
- Neuropathy
- Episodic regression
- Stroke-like episodes
- Abnormal movements
- Epileptic encephalopathy
- Infantile spasms
- Leukodystrophies
- Congenital brain malformations
- Mitochondrial encephalopathy
- Cerebral palsy without risk factors
- Abnormal tone (hypotonia or spasticity)
- Abnormal reflexes
- Persistent primitive reflexes
- Ataxic gait
- Tremor
- Nystagmus
- Focal deficits
- Micro/macrocephaly
- Movement disorders
- Early-onset seizures
- Episodic developmental regression
- Chronic headaches or migraine-like episodes
- Abnormal movements
- Ataxia episodes
- Sensory changes
- Elevated lactate/pyruvate
- Elevated ammonia
- Abnormal CSF amino acids or neurotransmitters
- Abnormal VLCFA
- Abnormal acylcarnitine profile
- Copper/ceruloplasmin abnormalities
- MRI with corpus callosum agenesis
- Dandy-Walker
- Chiari
- Cortical dysplasia
- Heterotopias
- Leukodystrophy patterns
- Basal ganglia calcifications
- Cerebellar atrophy
- Mitochondrial stroke-like lesions
- EEG showing epileptic encephalopathy patterns
- EMG/NCS showing neuropathy or myopathy
- LP with abnormal neurotransmitters or lactate
- Evoked potentials delayed
- Neuropsych testing with global deficits
- Multiple anti-seizure meds with poor control
- Paradoxical responses
- Valproate intolerance (mitochondrial clue)
- Frequent sedative use for neuro irritability
- Paradoxical or severe neurologic reactions to standard neuro meds
- Sedation or agitation out of proportion
- MH reaction with anesthesia impacting CNS
- VP shunt placement
- Chiari decompression
- Epilepsy surgery
- Brain biopsy for unexplained lesions
- PT/OT/ST targeting abnormal tone, coordination, motor planning
- Repeated therapy across years for neurological deficits
- VP shunt
- VNS for seizures
- Walkers and wheelchairs for neuro disability
- Adaptive seating
- Early neurology referral
- Multiple neuro evaluations
- Tertiary epilepsy clinic involvement
- Neurologist recommending genetics for regression/epilepsy
- Epilepsy
- Early strokes
- Movement disorders
- Neuropathy
- Dementia
- Developmental regression
- Learning issues in multiple relatives
- Consanguinity
- Multiple affected siblings
- No history of trauma, abuse, or toxin exposure explaining neuro deficits
- Stable environment yet persistent neurologic symptoms
- Similar issues in siblings
- Neonatal seizures
- Floppy infant (hypotonia)
- Abnormal or high-pitched cry
- Poor suck/swallow
- Micro/macrocephaly at birth
- Early abnormal neuro exam
Red Flag Combinations
Clinical patterns that should prompt consideration of genetic testing
Seizures + developmental delay + hypotonia
Seizures + regression
Stroke-like episodes + lactic acidosis
Early epilepsy + structural brain anomalies
Neuropathy + cardiomyopathy
Screening Decision Pathway
When to consider genetic testing for neurological presentations
graph TD
START["Patient Presents with\nNeurological Concerns"] --> SCREEN{"Screen for\nRed Flags"}
SCREEN --> RF1["Abnormal newborn screen for metabolic or neurodege..."]
SCREEN --> RF2["Failed neurologic reflex checks"]
SCREEN --> RF3["Abnormal tone on routine newborn neuro screens"]
RF1 --> EVAL{"Multiple\nFlags Present?"}
RF2 --> EVAL{"Multiple\nFlags Present?"}
RF3 --> 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\n43-58% 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
- Abnormal newborn screen for metabolic or neurodegenerative disorders
- Failed neurologic reflex checks
- Abnormal tone on routine newborn neuro screens
Exome / Genome Sequencing Indications
Clinical scenarios supporting ES/GS as a diagnostic approach
- Unexplained early-onset epilepsy
- Developmental regression
- Multisystem neurologic involvement
- Negative first-tier tests (MRI/EEG/microarray)
- Strong family history of neuro disease
Key Evidence
Published studies supporting genetic testing for neurological conditions
| Study | Year | Type | Sample | Yield | Key Finding |
|---|---|---|---|---|---|
| Utility of Exome Sequencing for Diagnosis in Unexplained Ped... | 2023 | Cohort | None | 19% | 19% diagnostic yield for exome sequencing in unexplained pediatric epilepsy (100... |
| Early-Life Epilepsies and the Emerging Role of Genetic Testi... | 2017 | Cohort | None | None | Early-life epilepsies and the emerging role of genetic testing |
| Clinical exome sequencing for genetic identification of rare... | 2014 | Cohort | 814 | 26% | Clinical exome sequencing yielded 26% overall molecular diagnosis in 814 consecu... |
| Enhanced diagnostic yield in Meckel-Gruber and Joubert syndr... | 2016 | Cohort | 26 | 46% | 46% diagnostic yield in ciliopathy (Joubert/Meckel-Gruber) families with exome s... |
| Diagnostic Exome Sequencing Provides a Molecular Diagnosis f... | 2016 | Cohort | 314 | 38.2% | 38.2% positive/likely positive DES yield in epilepsy patients (vs 28.7% without ... |
| Effectiveness of Whole Exome Sequencing Diagnosis in the Cli... | 2018 | Review | None | 16-68% | WES diagnostic yield ranges 16-68% across IEM and neurogenetic disorder cohorts ... |
| Diagnostic Yield of Next-Generation Sequencing Applied to Ne... | 2018 | Cohort | None | 36.5% | RASopathies NGS panel with functional analysis improved diagnostic yield from 31... |
| 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% ... |
Updated: 2026-02-24
Curated by: human
Status: human reviewed