Abstract
Febrile infection‐related epilepsy syndrome (FIRES) is a devastating epilepsy characterized by new‐onset refractory status epilepticus with a prior febrile infection. We performed exome sequencing in 50 individuals with FIRES, including 27 patient–parent trios and 23 single probands, none of whom had pathogenic variants in established genes for epilepsies or neurodevelopmental disorders. We also performed HLA sequencing in 29 individuals with FIRES and 529 controls, which failed to identify prominent HLA alleles. The genetic architecture of FIRES is substantially different from other developmental and epileptic encephalopathies, and the underlying etiology remains elusive, requiring novel approaches to identify the underlying causative factors.
Highlights
Febrile infection-related epilepsy syndrome (FIRES) is a severe epileptic encephalopathy with new-onset superrefractory status epilepticus that presents with a febrile illness prior to seizure onset.[1]
We aimed to identify the genetic basis of FIRES using whole exome sequencing, reasoning that the clinical features are related to developmental and epileptic encephalopathies (DEE) where genetic causes are routinely identified
We do not observe the same rate of pathogenic variants in established epilepsy genes that we would expect in an -sized cohort of individuals with DEE, such as Infantile Spasms or Lennox-Gastaut Syndrome where the diagnostic rate is 15% or higher
Summary
Febrile infection-related epilepsy syndrome (FIRES) is a severe epileptic encephalopathy with new-onset superrefractory status epilepticus that presents with a febrile illness prior to seizure onset.[1] Status epilepticus in individuals with FIRES is highly refractory, and, even though a cytokine-mediated mechanism has been proposed, the pathophysiology remains entirely unknown.[2,3] FIRES shares many clinical features with developmental and epileptic encephalopathies (DEE). Over the last two decades, genetic studies have identified the underlying cause of many previously poorly understood epilepsy syndromes, including disease-causing SCN1A variants in up to 90% of individuals with Dravet Syndrome[4] and disease-causing KCNT1 variants in a significant fraction of individuals with epilepsy with migrating focal seizures.[5] Genetic testing has become a common diagnostic modality and is routinely performed in children and adults with DEE. The diagnostic yield is considered 15– 20%6,7 and reaches up to 50% in individuals with neonatal epileptic encephalopathies,[8] largely due to de novo variants in genes encoding ion channels or synaptic proteins
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