PURPOSE: Epilepsies have a highly heterogeneous background with a strong genetic 
contribution. The variety of unspecific and overlapping syndromic and 
nonsyndromic phenotypes often hampers a clear clinical diagnosis and prevents 
straightforward genetic testing. Knowing the genetic basis of a patient's 
epilepsy can be valuable not only for diagnosis but also for guiding treatment 
and estimating recurrence risks.
METHODS: To overcome these diagnostic restrictions, we composed a panel of genes 
for Next Generation Sequencing containing the most relevant epilepsy genes and 
covering the most relevant epilepsy phenotypes known so far. With this method, 
265 genes were analyzed per patient in a single step. We evaluated this panel on 
a pilot cohort of 33 index patients with concise epilepsy phenotypes or with a 
severe but unspecific seizure disorder covering both sporadic and familial 
cases.
KEY FINDINGS: We identified presumed disease-causing mutations in 16 of 33 
patients comprising sequence alterations in frequently as well as in less 
commonly affected genes. The detected aberrations encompassed known and unknown 
point mutations (SCN1A p.R222X, p. E289V, p.379R, p.R393H; SCN2A p.V208E; STXBP1 
p.R122X; KCNJ10 p.L68P, p.I129V; KCTD7 p.L108M; KCNQ3 p.P574S; ARHGEF9 p.R290H; 
SMS p.F58L; TPP1 p.Q278R, p.Q422H; MFSD8 p.T294K), a putative splice site 
mutation (SCN1A c.693A> p.T/P231P) and small deletions (SCN1A p.F1330Lfs3X [1 
bp]; MFSD8 p.A138Dfs10X [7 bp]). All mutations have been confirmed by 
conventional Sanger sequencing and, where possible, validated by parental 
testing and segregation analysis. In three patients with either Dravet syndrome 
or myoclonic epilepsy, we detected SCN1A mutations (p.R222X, p.P231P, p.R393H), 
even though other laboratories had previously excluded aberrations of this gene 
by Sanger sequencing or high-resolution melting analysis.
SIGNIFICANCE: We have developed a fast and cost-efficient diagnostic screening 
method to analyze the genetic basis of epilepsies. We were able to detect 
mutations in patients with clear and with unspecific epilepsy phenotypes, to 
uncover the genetic basis of many so far unresolved cases with epilepsy 
including mutation detection in cases in which previous conventional methods 
yielded falsely negative results. Our approach thus proved to be a powerful 
diagnostic tool that may contribute to collecting information on both common and 
unknown epileptic disorders and in delineating associated phenotypes of less 
frequently mutated genes.