NSGC Guideline: Genetic Testing & Counseling for Unexplained Epilepsies (2022)

This topic summarizes the 2022 National Society of Genetic Counselors (NSGC) evidence-based practice guideline on genetic testing and counseling for individuals with unexplained epilepsy, endorsed by the American Epilepsy Society (AES).

Guideline Overview

Source & Scope

• Organization: National Society of Genetic Counselors (NSGC), endorsed by AES (September 2022)
• Published: Journal of Genetic Counseling, Vol. 32, 2023, pp. 266–280
• Authors: Smith L, Malinowski J, Ceulemans S, Peck K, Walton N, Rosen Sheidley B, Lippa N
• Framework: GRADE Evidence to Decision — systematic evidence review + meta-analysis (Sheidley et al., 2022)
• Evidence: 5,985 articles screened → 154 in random-effects meta-analyses + 43 narratively synthesized; >30,000 individuals across 174 cohorts
• Population: Individuals of any age with unexplained epilepsy (not attributable to structural, metabolic, infectious, immunological, or acquired etiology)

Definition: “Unexplained Epilepsy”

• Seizures that cannot be attributed to a structural, metabolic, infectious, immunological, or acquired cause based on history, physical exam, imaging, and standard evaluations
• Metabolic or structural etiologies may themselves be genetic — targeted testing may be indicated separately
• If seizures are part of a multi-system presentation with extra-neurological features, consider targeted testing first (e.g., methylation for Angelman, triplet repeat for Fragile X)

Recommendations

Recommendation 1: Offer Genetic Testing (Strong)

Recommendation 2: Qualified Provider & Genetic Counseling (Strong)

• Qualified provider: Individual with specialized training/knowledge in genetics who can discuss scope, benefits, limitations, and psychological implications of testing
• Genetic counselors, medical geneticists, or neurologists with genetics expertise
• Non-genetics providers who order tests should have strong genetics grounding or partner with genetic counselors
• VUS interpretation is a critical skill — incorrect VUS handling has led to missed diagnoses and inappropriate precision therapy

Diagnostic Yield by Test Modality

• MGPs with >25 genes had consistently higher yield (20–25%) than smaller panels (<25 genes: 7%)
• ES yield may be underestimated — many cohorts had prior negative MGP before ES
• GS has the broadest detection capability but is the most expensive and complex to interpret
• 9–11% of pathogenic variants in epilepsy are exon-level deletions/duplications — CNV analysis is essential

Testing Modality Capabilities (Table 2)

+ routinely offered; (+) sometimes offered; Δ variable/limited; (–) not routinely; – not offered

Recommended Testing Algorithm

Pathway 1: No Specific Single-Gene Phenotype

1. First-tier: ES/GS (preferred) or large MGP (>25 genes with del/dup)
2. If positive → Diagnosis
3. If ES/GS negative → CNV analysis (CMA if adequate CNV analysis was not included)
4. If CNV analysis positive → Diagnosis
5. If still negative → ES/GS reanalysis periodically (new gene discoveries, VUS reclassification)

Pathway 2: Phenotype Suggests Specific Gene or Gene Class

1. First-tier: Targeted testing (single gene, methylation, repeat expansion, etc.)
2. If positive → Diagnosis
3. If negative → ES/GS
4. If ES negative → CNV analysis → ES/GS reanalysis

When to Use MGP as First-Tier Instead of ES/GS

• Defined epilepsy syndrome where a subset of genes should be interrogated more robustly than through ES
• Urgent results needed and rapid ES/GS is unavailable
• Limited access to ES/GS or limited genetic counseling resources
• Syndrome-based MGPs for specific phenotypic profiles (e.g., NCL, PME) — but beware phenotypic overlap between syndromes

Clinical Impact of a Genetic Diagnosis

Treatment & Management

• ASM selection: Genetic diagnosis may inform drug choice (e.g., avoid sodium channel blockers in SCN1A/Dravet; use quinidine for KCNT1)
• Ketogenic diet: Direct initiation for SLC2A1 (GLUT1 deficiency) and others
• Surgical planning: Alter approach based on genetic etiology
• Clinical trials: 12–80% of genetically diagnosed patients become eligible for gene-specific trials
• ASM weaning: Inform decisions in self-resolving epilepsies (e.g., PRRT2)
• Palliative care: Guide goals in life-limiting conditions

Prognosis

• Clarify developmental expectations
• Identify elevated SUDEP risk
• Guide monitoring device decisions (e.g., seizure detection alarms)
• End the “diagnostic odyssey” for families

Reproductive Counseling

• Enables recurrence risk estimation for future pregnancies
• Options: prenatal testing (amniocentesis, CVS), preimplantation genetic testing (PGT)
• Distinguish de novo variants (low recurrence) from inherited (e.g., autosomal dominant: 50% risk)
• Potential harm: newfound awareness of inherited risk may cause distress

Cascade Testing

• Genetic diagnosis enables testing of at-risk family members
• Particularly important for autosomal dominant conditions with variable expressivity

Populations with Highest Diagnostic Yield

• Neonatal/infantile-onset seizures — highest yield overall
• DEE (Developmental and Epileptic Encephalopathies)
• Epilepsy + neurodevelopmental comorbidities (intellectual disability, autism spectrum disorder)
• Later ages of onset and focal epilepsies still have significant yield — do not preclude testing
• Individuals with DEE are currently more likely to obtain a diagnosis, but this may reflect testing bias rather than lower yield in other populations

When to Consider Targeted Testing First

• Epilepsy phenotype associated with a specific gene or gene class
• Extra-neurological features suggesting a specific syndrome
• Examples:
  • Methylation studies for Angelman syndrome
  • Triplet repeat expansion for Fragile X
  • SCN1A testing when Dravet syndrome is suspected
• Referral to medical geneticist may be needed for multi-system presentations