Generalized epilepsy with febrile seizures

Generalized epilepsy with febrile seizures, GEFSP, Generalized epilepsy with febrile seizures plus; GEFSP, GEFS+, Familial febrile seizures, FEB

Autosomal dominant

Epilepsy (generalized) with febrile seizures is a complex autosomal dominant disorder characterized by generalized febrile convulsions. Febrile seizures are the most common convulsive event occurring in 2-6% of the population ¹. The lifetime prevalence of febrile seizures is estimated at 3-4% of all children in Europe and North America and is even higher in Japan and Scandinavia ^{2, 3}. About 40% of children with a first febrile seizure will have a recurrence, with one third of patients with only febrile seizures and two thirds with a variety of epilepsy syndromes, both focal and generalized. Febrile seizures most commonly present at the age of 18 months with about 80% of incident febrile seizures occurring between 1 and 3 years of age ^{1, 2}.

Epidemiologic studies have led to the division of febrile seizures into 3 groups, as follows:

• Simple febrile seizures
• Complex febrile seizures
• Symptomatic febrile seizures

Children with simple febrile seizures are neurologically and developmentally healthy before and after the seizure. In the absence of fever they do not experience a seizure. The seizure is described as either a generalized clonic or a generalized tonic-clonic seizure. Simple febrile seizure activity usually lasts for 15 minutes or less, although a postictal period of sleepiness or confusion can extend beyond these 15 minutes. Simple febrile seizures often occur with the initial temperature elevation at the onset of illness and they could be the first indication of the disease. Symptomatic febrile seizures are accompanied by the preexisting neurologic abnormality or acute illness.

Febrile seizures are considered a genetic disorder, most commonly reported with an autosomal dominant mode of inheritance. Several genes, which encode sodium or GABA receptor subunits, have been associated with febrile seizures phenotypes (see table):

• Idiopathic generalized epilepsy 10, generalized epilepsy with febrile seizures plus type 5 and juvenile myoclonic epilepsy 7 can be conferred by variations in the GABRD gene on chromosome 1p36.3, encoding GABA receptor subunit delta. Three heterozygous missense pathogenic variants have been reported in this gene so far: p.E177A, p.R220C, and p.R220H, all associated with generalized epilepsy with febrile seizures ⁴ (HGMD® Professional 2017.1).
• The GABRG2 gene encodes additional GABA receptor protein, and mutations in this gene have primarily been associated with generalized epilepsy with febrile seizures (7/26). Mutations in GABRG2 have also been associated with Rolandic epilepsy (2/26), childhood absence epilepsy (2/26), generalized epilepsy (2/26), and others (HGMD® Professional 2017.1).
• The SCN1A gene encodes the alpha subunit of the neuronal voltage-gated sodium channel. SCN1A-related seizure disorders are channelopathies characterized by seizures as their primary manifestation. The molecular abnormality causes neuronal dysfunction and hyperexcitability at the level of the cortical network, which is a morphological substrate for seizure disorders. More than 1300 pathogenic variants have been reported in SCN1A, primarily associated with Dravet syndrome (597/1378) (HGMD® Professional 2017.1), myoclonic epilepsy of infancy (407/1378), generalized epilepsy with febrile seizures plus (63/1378), and other seizure-related phenotypes. Generalized epilepsy with febrile seizures plus (GEFS+) is mostly associated with missense SCN1A pathogenic variants ⁵. Almost half the pathogenic variants associated with the severe myoclonic epilepsy in infancy and Dravet syndrome are truncating variants of SCN1A and the remainder includes missense SCN1A variants (39%-43%), splice site variants (7%), and deletions (3%) ⁶.
• Generalized epilepsy with febrile seizures plus-1 (GEFSP1) is caused by heterozygous mutations in the SCN1B gene on chromosome 19q13. The SCN1B gene encodes a beta-1 subunit of voltage-gated sodium channels that regulates generation and propagation of action potentials in nerve and muscle. Mutations in SCN1B have been associated with Brugada syndrome (5/20), generalized epilepsy with febrile seizures (5/20), atrial fibrillation (2/20), idiopathic and generalized epilepsy (2/20), and other conditions associated with neuronal membrane activity (HGMD® Professional 2017.1).
• Benign familial neonatal-infantile seizures-3 (BFIS3) is caused by heterozygous mutation in the SCN2A gene on chromosome 2q24. SCN2A encodes a subunit of sodium channel and similar to SCN1B regulates formation and propagation of action potential in neuronal and muscle cells. More than 160 pathogenic variants have been reported in this gene so far (HGMD® Professional 2017.1) and these have been assigned to autistic spectrum disorders (32/162), epileptic encephalopathy (20/162), neonatal-infantile seizures (18/162), benign infantile seizures (7/162), and other epilepsy-related phenotypes.
• Generalized epilepsy with febrile seizures plus, type 7 (GEFSP7) and familial febrile seizures-3B (FEB3B) are both caused by heterozygous mutations in the SCN9A gene on chromosome 2q24, encoding a subunit of sodium channel. More than 100 pathogenic variants in the SCN9A gene have been reported (HGMD® Professional 2017.1), associated with congenital insensitivity to pain (28/1049, erythromelalgia (12/104), febrile seizures (7/104), Dravet syndrome (17/104), and other phenotypes.

Treatment of generalized epilepsy with febrile seizures includes management of febrile status and short-term use of antiepileptic drugs (AED). Long-term AED treatment is rarely indicated ¹.

CENTOGENE offers sequencing and deletion/duplication analysis for genes in the Epilepsy (generalized) with febrile seizures panel (GABRD, GABRG2, SCN1A, SCN1B, SCN2A, SCN9A). We also offer single gene tests for each gene included in the panel.

The differential diagnosis of autosomal recessive forms of Epilepsy (generalized) with febrile seizures-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

• Generalized tonic-clonic seizures juvenile absence epilepsy
• Juvenile myoclonic epilepsy
• Acute disseminated encephalomyelitis
• Basilar artery thrombosis
• Meningococcal or neonatal meningitis
• Viral encephalitis or meningitis.

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for generalized epilepsy with febrile seizures using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the eneralized epilepsy with febrile seizures panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the generalized epilepsy with febrile seizures panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.

The following individuals are candidates for generalized epilepsy with febrile seizures gene testing:

• Individuals with a family history of generalized epilepsy with febrile seizures and presentation of the most common symptoms
• Individuals without a positive family history, but with symptoms resembling generalized epilepsy with febrile seizures
• Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Sequencing, deletion/duplication of generalized epilepsy with febrile seizures related genes should be performed in all individuals suspected of having this condition. In parallel, other genes reported to be related with generalized epilepsy with febrile seizures should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of generalized epilepsy with febrile seizures, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.

More information on CENTOGENE´s Epilepsy (generalized) with febrile seizures panel can be found in our genetic test catalogue.