Andreas Brunklaus

Objective SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype–phenotype associations remain poorly understood. Methods We assessed data from a retrospective cohort of 1018 individuals with SCN1A‐ related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype. Results DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p < .001). In silico variant scores were higher in DS versus GEFS+ ( p < .001). Patients with missense variants in functionally important regions (conserved N‐terminus, S4–S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p = .003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p = .036) and were more likely to have GEFS+ (15/29, χ 2 = 19.16, p < .001). A minority of protein‐truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p < .001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p = .001) and GEFS+ (8.0 vs. 11.0 months, p = .043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS. Significance Understanding genotype–phenotype associations in SCN1A ‐related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS.

We performed a systematic literature review and narrative synthesis according to a pre‐registered protocol (Prospero: CRD42022376561) to identify the evidence associated with the burden of illness in Dravet syndrome (DS), a developmental and epileptic encephalopathy characterized by drug‐resistant epilepsy with neurocognitive and neurobehavioral impairment. We searched MEDLINE, Embase, and APA PsychInfo, Cochrane's database of systematic reviews, and Epistemonikos from inception to June 2022. Non‐interventional studies reporting on epidemiology (incidence, prevalence, and mortality), patient and caregiver health‐related quality of life (HRQoL), direct and indirect costs and healthcare resource utilization were eligible. Two reviewers independently carried out the screening. Pre‐specified data were extracted and a narrative synthesis was conducted. Overall, 49 studies met the inclusion criteria. The incidence varied from 1:15 400–1:40 900, and the prevalence varied from 1.5 per 100 000 to 6.5 per 100 000. Mortality was reported in 3.7%–20.8% of DS patients, most commonly due to sudden unexpected death in epilepsy and status epilepticus. Patient HRQoL, assessed by caregivers, was lower than in non‐DS epilepsy patients; mean scores (0 [worst] to 100/1 [best]) were 62.1 for the Kiddy KINDL/Kid‐KINDL, 46.5–54.7 for the PedsQL and 0.42 for the EQ‐5D‐5L. Caregivers, especially mothers, were severely affected, with impacts on their time, energy, sleep, career, and finances, while siblings were also affected. Symptoms of depression were reported in 47%–70% of caregivers. Mean total direct costs were high across all studies, ranging from $11 048 to $77 914 per patient per year (PPPY), with inpatient admissions being a key cost driver across most studies. Mean costs related to lost productivity were only reported in three publications, ranging from approximately $19 000 to $20 000 PPPY ($17 596 for mothers vs $1564 for fathers). High seizure burden was associated with higher resource utilization, costs and poorer HRQoL. The burden of DS on patients, caregivers, the healthcare system, and society is profound, reflecting the severe nature of the syndrome. Future studies will be able to assess the impact that newly approved therapies have on reducing the burden of DS.

The recent explosion of epilepsy genetic testing has created challenges for interpretation of gene variants. Assessments of the functional consequences of genetic variants either by predictive or experimental strategies can contribute to estimating pathogenicity, but there is no consensus on which approach is best. The Special Interest Group on Epilepsy Genetics hosted a session during the Annual American Epilepsy Society Meeting in December 2022 to discuss this topic. The session featured a debate of the relative advantages and limitations of predicting (prophecy) versus experimentally determining (empiricism) variant function using ion channel gene variants as examples. This commentary summarizes these discussions.