Dravet syndrome pedigree: SCN1A inheritance, de novo variants and germline mosaicism

Short version. Dravet syndrome (ICD-10 G40.83; OMIM 607208) is a severe developmental and epileptic encephalopathy caused in 70 to 85% of cases by pathogenic loss-of-function variants in SCN1A. It is autosomal dominant with penetrance around 95% and is overwhelmingly de novo — approximately 90% of cases arise as new mutations in the proband. The typical pedigree is an isolated affected child with two or more unaffected siblings and two unaffected parents. Parental germline mosaicism accounts for approximately 7% of apparent de novo cases and is the reason sibling recurrence after an apparently sporadic Dravet case is counselled at under 1% rather than at background.

Dravet syndrome: clinical overview

Dravet syndrome, historically called severe myoclonic epilepsy of infancy, presents in the first year of life in a previously well infant. The typical course begins with prolonged febrile or afebrile seizures, often hemiclonic and often in the setting of minor infection or vaccination. Through the second year of life the seizure phenotype evolves to include myoclonic, focal, atypical absence, and tonic-clonic seizures; status epilepticus is frequent. Developmental progress plateaus and then regresses; intellectual disability, autism-spectrum features, gait and motor signs, and sleep disruption become defining features of the middle childhood and adult phenotype. Sudden unexpected death in epilepsy (SUDEP) is a recognised risk.

Diagnosis is clinical-molecular. The combination of febrile-triggered onset, hemiclonic prolonged seizures, subsequent multi-morphic seizures, and developmental regression in the second year of life is highly suggestive; an SCN1A pathogenic variant confirms the diagnosis in the majority of cases. A minority of Dravet-like phenotypes are caused by variants in PCDH19, SCN2A, SCN8A, GABRA1, STXBP1, HCN1, or other epileptic encephalopathy genes; these should be considered when SCN1A testing is negative.

Treatment centres on valproate and clobazam as first-line, with early addition of stiripentol, cannabidiol, or fenfluramine where available. Sodium channel blockers (carbamazepine, oxcarbazepine, lamotrigine, phenytoin, lacosamide) are generally contraindicated because they further reduce residual Nav1.1 function and can precipitate seizure worsening or status epilepticus. Ketogenic diet, vagus nerve stimulation, and emerging disease-modifying therapies targeting SCN1A upregulation complete the current therapeutic landscape.

SCN1A genetics and de novo dominance

SCN1A encodes the alpha-1 subunit of the voltage-gated sodium channel Nav1.1, which is preferentially expressed in GABAergic interneurons in the brain. Loss-of-function variants reduce interneuron excitability, disinhibit cortical networks, and produce the characteristic seizure phenotype. The variant spectrum is broad: truncating, splice-site, and intragenic deletions dominate, with missense variants clustering in the pore-forming and voltage-sensing domains.

Dravet syndrome is inherited in an autosomal dominant pattern. A single pathogenic variant in SCN1A is sufficient to produce the phenotype, and an affected individual transmits the variant to 50% of offspring on average. In principle, therefore, a vertical affected-to-affected pedigree should be possible; in practice, Dravet is a reproductively severe disorder and intergenerational transmission is rare. The overwhelming majority of pedigrees show de novo dominance: a single affected child with unaffected parents.

Penetrance for a bona fide pathogenic SCN1A variant is high, on the order of 95%. Variants of uncertain significance and milder SCN1A alleles may produce the broader Genetic Epilepsy with Febrile Seizures Plus (GEFS+) spectrum rather than Dravet; the boundary between Dravet and GEFS+ is driven by variant consequence, residual channel function, and genetic background. For a broader treatment of autosomal dominant transmission arithmetic, see our autosomal dominant calculator guide.

The de-novo-versus-mosaicism question

When a child with Dravet syndrome and an SCN1A pathogenic variant is born to unaffected parents whose blood testing is negative for the variant, there are three live hypotheses:

• True de novo: the variant arose in a single germ cell of one parent or in the proband's early post-zygotic development. Recurrence risk for future sibs is close to background, modified only by the residual probability of unobserved mosaicism.
• Parental germline mosaicism: a mutation arose in the precursor cells of one parent's germline. A fraction of that parent's oocytes or sperm carry the variant. Blood testing may be negative because the haematopoietic lineage is uninvolved, or may show a measurable low-level variant.
• Parental somatic-germline mosaicism: the mutation arose early in post-zygotic development of one parent, and both somatic and germline lineages are mosaic. Blood testing may show a measurable variant at low VAF; the parent's own phenotype may be subclinical.

Parental germline mosaicism in SCN1A-related Dravet syndrome is estimated at approximately 7%. That is, about 1 in 14 apparently de novo cases reflect a mosaic parent. This is a high enough rate that parental testing with sensitive methods — deep sequencing of blood, and, where feasible, sperm sequencing in fathers — has a clinically useful yield.

A pedigree example: the isolated proband

No image is included here; the typical Dravet syndrome pedigree is simple enough to describe in words. Picture a nuclear family: two unaffected parents drawn as an unshaded square (father) connected by a horizontal mating line to an unshaded circle (mother). Three children descend from the mating line: an unshaded square (unaffected older brother), a filled square or circle (the affected proband, whose sex depends on the child), and an unshaded circle (unaffected younger sister). An arrow, drawn at a 45-degree angle with an open arrowhead, identifies the proband. Disease annotation under the proband reads "Dravet syndrome (G40.83); SCN1A c.[insert] p.[insert], de novo pending parental testing".

Standard practice is to annotate parental testing status explicitly on the pedigree. After parental blood testing returns negative with appropriate sensitivity, the posterior probability of true de novo is approximately 99.3% and the posterior probability of unobserved parental germline mosaicism is approximately 0.7%. Recurrence risk for a subsequent pregnancy is therefore counselled at under 1%, distinct from — but low enough to approach — the population background risk of Dravet syndrome in general. When sperm sequencing is performed in the father and returns negative at reasonable sensitivity, the residual mosaicism probability shrinks further; when it returns positive at even a low allele fraction, recurrence risk rises substantially and should be quoted as a posterior with its assumptions stated.

Recurrence risk counselling in Dravet syndrome

Recurrence risk counselling in Dravet syndrome follows the same Bayesian logic as other autosomal dominant de novo disorders, but with parameters specific to SCN1A:

• Proband with SCN1A pathogenic variant, both parents blood-negative, no other affected sibs: posterior probability of parental germline mosaicism approximately 0.7%; recurrence risk for a subsequent sibling under 1%.
• Two affected sibs with the same SCN1A variant, parents blood-negative: posterior probability of parental germline mosaicism approaches certainty; recurrence risk for subsequent sibs is driven by the germline fraction and the transmission probability.
• Measurable parental VAF in blood or sperm: recurrence risk can be calibrated directly from the germline fraction estimate; sperm VAF is a better proxy for male germline risk than blood VAF.
• Affected proband's own reproductive counselling: 50% transmission per conception if they reach reproductive age, modified by penetrance and by the severity of their own phenotype.

Prenatal and preimplantation genetic testing for the familial variant is technically straightforward once the proband's variant is identified. Counselling should cover the high transmission probability if a parent is germline-mosaic, the residual risk if parents are blood-negative, the distinction between SCN1A-related Dravet and the broader GEFS+ spectrum, and the psychosocial weight of these figures for a family in early bereavement or early adjustment after a Dravet diagnosis.

How Evagene supports Dravet syndrome pedigrees

Dravet syndrome is a first-class catalogue entry in Evagene. The record carries ICD-10 G40.83, OMIM 607208, autosomal dominant inheritance, penetrance ~0.95, a de novo rate of ~0.9, and a germline mosaicism rate of ~0.07. Annotating the proband with Dravet syndrome automatically exposes these parameters to every downstream analysis, so the clinician does not need to manually enter them when running the inheritance or mosaicism calculators.

The autosomal dominant calculator produces per-individual transmission probabilities across the pedigree given the observed affection status pattern. The germline mosaicism posterior jointly models both parents, accepting optional blood VAF for each and optional sperm VAF for the father; it returns a calibrated posterior for each parent and a recurrence estimate for the next pregnancy. When two or more siblings are affected, the joint-parent posterior identifies the likely mosaic parent and updates recurrence accordingly.

AI-assisted clinical interpretation using bring-your-own-key Anthropic Claude or OpenAI GPT models generates a structured report covering the SCN1A inheritance pattern, the mosaicism posterior with its assumptions, the antiepileptic drugs to favour and avoid (sodium channel blocker contraindication is a high-priority output in Dravet reports), the cascade testing plan for reproductive counselling, and the unresolved data gaps. See our rare disease pedigree software overview for the broader rare-disease analysis pipeline, and our companion Rett syndrome pedigree for a contrasting X-linked dominant example.

Frequently asked questions

Related reading

• Germline mosaicism posterior calculator
• Autosomal dominant calculator
• Rare disease pedigree software
• Rett syndrome pedigree
• Mendelian inheritance calculator
• Inheritance pattern identifier