Characteristics of the test : (includes 1 gene)
SCN1A (OMIM #182389)
Basic characteristics of the clinical phenotype:
Familial febrile seizures (FS +) - Age-related disease with epileptic seizures in infancy and early childhood. They usually disappear with the growth of the child in later stages of life, but sometimes febrile seizures plus (FS +) persist until a later age (6 years-old). FS provoking factor is high fever, a symptom of upper and lower respiratory tract infections, observed in 85-90% of the cases. The recurrent risk of the disease is 30% higher in a family with first degree sick relatives than the general population.
Generalized epilepsy with febrile seizures plus (GEFS + syndrome). When febrile generalized tonic-clonic seizures (GTCS) persist after the age of 6 and occur in combination with other types of afebrile generalized (myoclonic, atonic, absences) and partial seizures, we speak of generalized epilepsy syndrome with febrile seizures plus (GEFS + syndrome). The onset of seizures is between 6-months and 6 years of age. Psychomotor development is normal. GEFS + syndrome is characterized by spontaneous disappearance of seizures in later stages of the patient's life and preserved psychomotor development.
Severe myoclonic epilepsy in childhood (Dravet syndrome) - characterized by normal initial psychomotor development. The first manifestations are observed before 12 months of age, most often between 5 and 8 months of age, with fever-provoked generalized seizures. Between 1 and 4 years of age, another types of seizures are observed - myoclonic, atypical absences, tonic, etc. After the second year, there is a start of gradual decline of intellectual and motor development. Point mutations in the SCN1A gene are found in about 10% of patients with GEFS + syndrome, while the proportion of mutations in SCN1A in patients with Dravet syndrome is about 70-80%. 90% of the mutations in the SCN1A gene in Dravet syndrome cases occur de novo, and only 10% are inherited.
Reasons for referring:
All patients with simple/generalized febrile seizures in early childhood and suspected FS+ - sporadic or familial; presence of generalized tonic-clonic seizures and suspicion of GEFS + syndrome; presence of generalized tonic-clonic seizures, myoclonic seizures with gradual regression in intellectual development and suspicion of severe myoclonic epilepsy in childhood (SMEI / Dravet syndrome).
The detection of mutation in the SCN1A gene allows the diagnosis of epilepsy from the GEFS + spectrum, as well as providing a prognosis depending on the type of mutation and the severity of the disease.
In cases of loss-of-function mutations (frameshift, deletions, some splice-site mutations) in SCN1A and a diagnosis of Dravet syndrome, it is possible to select the most appropriate treatment to avoid seizure aggravation.
Genetic diagnosis will allow assessment of the recurrent risk for transmitting the pathogenic mutation to the future generations.
The genetic counselor will interpret and answer all questions about your result.
Method: Sanger sequencing (ABI 3130xl) and MLPA analysis
Sanger sequencing: The method involves bidirectional DNA sequencing of all coding exons and intron-exon boundaries of the SCN1A gene. When no point SCN1A mutations are detected by this method, it is recommended to look for larger SCN1A deletions/insertions affecting parts of or whole exons by the hybridization-based MLPA method (Test № 32). The laboratory offers single exon sequencing in relatives of patients to determine the carrier status in cases where the SCN1A mutation is known (Test № 128).
MLPA analysis is a semi-quantitative method for determining copy number variations of DNA. The methodology is used to detect intragenic or whole-gene deletions or duplications. The analysis for searching for large SCN1A gene deletions or insertions is performed using the kit SALSA MLPA KIT P137-B2 SCN1A, developed by MRC-Holland (Amsterdam, Holland).
In the presence of a complex epileptic phenotype in combination with mental retardation, autistic behavior and dysmorphic features, comprehensive genomic screening by microarray analysis (Tests № 130, 131) and/or next-generation sequencing (NGS) of a specific panel of genes depending on of specific clinical features (Tests № 40, 41, 42, 43, 44) is recommended.
Sensitivity of the method: Sanger sequencing - 99.5%; MLPA – 90%
What does the test involve?
• DNA isolation and sample storage.
• Direct sequencing of target genes / gene regions in search of point mutations and MLPA analysis of target genes / gene regions to detect pathogenic copy number variations.
• Forming a written result from the genetic test.
• Diagnostic interpretation of results and genetic counseling.
Biological material: Venous blood or DNA
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