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Betegségjelentés · Neurological

Dravet Syndrome

Whole genome sequencing reads the complete SCN1A gene sequence, detecting mosaic and deep intronic variants that cause Dravet syndrome in genetically unresolved patients, and identifies the pharmacogenomic contraindications that determine which drugs can and cannot be used safely.

A betegségjelentés olyan ritka variánsokat keres, amelyekről ismert, hogy okozzák az általa lefedett betegségeket.

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A(z) condition ismertetése

A severe form of epilepsy that begins in infancy, characterized by frequent, prolonged seizures often triggered by fever, and associated with developmental delays.

Dravet syndrome (DS), formerly severe myoclonic epilepsy of infancy (SMEI), is a severe developmental and epileptic encephalopathy with onset in the first year of life, typically in a previously healthy infant. The condition is characterized by prolonged febrile and afebrile seizures (often clonic or hemiclonic), subsequent polymorphic seizure types (myoclonic, absence, focal), and progressive developmental slowing beginning in the second year of life. Dravet syndrome has a population prevalence of approximately 1 in 15,000-22,000 births and accounts for approximately 3-8% of epilepsies with onset in the first three years of life.

Pathogenic or likely pathogenic SCN1A variants are identified in approximately 70-85% of patients meeting clinical Dravet syndrome diagnostic criteria. SCN1A encodes the Nav1.1 alpha subunit of voltage-gated sodium channels, which is critical for inhibitory interneuron function. Loss-of-function disrupts GABAergic interneuron firing, producing cortical disinhibition and hyperexcitability. Approximately 95% of pathogenic SCN1A variants in Dravet syndrome are de novo (not inherited from a parent). Pathogenic variant types include truncating variants (nonsense, frameshift; approximately 40%), splice site variants, and missense variants (approximately 40%); large deletions or duplications account for approximately 2-3% and require copy number variant analysis for detection.

The SCN1A genotype has direct, life-critical pharmacogenomic implications. Sodium channel-blocking anti-seizure medications (including lamotrigine, carbamazepine, oxcarbazepine, phenytoin, and vigabatrin) worsen seizure control and can precipitate epileptic encephalopathy in SCN1A-positive patients by further reducing Nav1.1 function in inhibitory interneurons. This contraindication applies regardless of variant specific type. Treatments with established evidence in Dravet syndrome include valproate, clobazam, topiramate, stiripentol, and (in eligible patients) fenfluramine and cannabidiol (Epidiolex). An unresolved or misattributed diagnosis means the wrong drugs may be prescribed during the critical window when drug selection most affects long-term developmental outcome.

Approximately 15-30% of patients with a clinical Dravet syndrome diagnosis are SCN1A-negative on standard panel testing. A proportion of these carry deep intronic, mosaic, or structural SCN1A variants detectable by whole genome sequencing.

A vizsgált betegség

Autoszomális domináns

Dravet syndrome is a channelopathy with epilepsy of with onset during the first year of life, typically 4-5 months, characterized by status epilepticus and a variety of drug-resistant seizures often induced by fever, presenting in previously healthy children, and which frequently leads to cognitive and motor impairment. Dravet differs from other channelopathies usually due to a mutation in SCN1A.

Mit változtat a diagnózis

Valproate, clobazam, topiramate, stiripentol; fenfluramine (Fintepla) and cannabidiol (Epidiolex) for drug-resistant cases; sodium channel blockers (lamotrigine, carbamazepine, oxcarbazepine) are CONTRAINDICATED in SCN1A-positive patients

Vizsgált gének

Más néven

Dravet; DS; severe myoclonic epilepsy of infancy; SME; SMEB

MONDO:0100135MedGen 148243

Miért a teljes genom szekvenálás

Standard epilepsy panels detect coding SCN1A variants. They miss mosaic mutations, deep intronic splicing variants, and large structural rearrangements that account for a clinically significant fraction of SCN1A-negative Dravet syndrome.

Mosaic SCN1A variants require sequencing depth and breadth that panels cannot provide

Somatic mosaicism, where the SCN1A pathogenic variant is present in only a subset of cells, explains a portion of clinical Dravet syndrome cases with negative panel results. Mosaic variants at 10-30% allele frequency can be missed by standard panel sequencing, where clinical sensitivity is optimized for germline heterozygous variants at ~50% allele fraction. Studies using deep whole genome sequencing have identified mosaic SCN1A variants in 4-8% of panel-negative Dravet syndrome patients. Deep intronic SCN1A variants that create cryptic splice sites represent an additional category of panel-invisible pathogenic variants. Both require the breadth and depth of whole genome sequencing for reliable detection.

The SCN1A result determines which anti-seizure drugs are safe to prescribe

In Dravet syndrome, drug class selection is not a matter of optimization; it is a matter of safety. Sodium channel blockers are contraindicated in SCN1A loss-of-function and have been documented to trigger seizure worsening, status epilepticus, and in some cases acute encephalopathic deterioration. Multiple case series have documented patients with Dravet syndrome who worsened substantially after initiation of lamotrigine or carbamazepine before the genetic diagnosis was established. Confirming an SCN1A pathogenic variant provides the actionable genetic basis for avoiding sodium channel blockers and initiating evidence-based DS-specific therapies, a decision that acutely affects seizure burden and developmental trajectory.

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