Latest Genetic Sequencing Techniques Reveal New Disease Mutations Associated With Epilepsy and Dravet Syndrome

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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Next-generation sequencing techniques have revealed that genetic mutations in the KCND3 gene may be responsible for more types of epilepsy than previously thought, and new candidate genes associated with Dravet syndrome have been identified, a new study reports.

The study, “Gene mutational analysis in a cohort of Chinese children with unexplained epilepsy: identification of a new KCND3 phenotype and novel genes causing Dravet syndrome,” was published in the journal Seizure.

Epilepsy is one of the most common neurological disorders found in children. Although the origins of epilepsy are quite complex and still poorly understood, there are many genetic factors contributing to disease development.

“Many genes have been associated with epilepsy, such as ion channel genes, genes related to transmitter trafficking, and genes associated with cell connections. Clarifying the genetic background of epilepsy is very important for its diagnosis, treatment, and prognosis. Importantly, it also facilitates genetic counseling and prenatal diagnosis,” researchers wrote.

However, the clinical and genetic diversity associated with epilepsy also means it is not easy, using conventional sequencing methods, to identify new candidate genes involved in disease onset.

In this study, a team of researchers from Peking University in China set out to determine the genetic causes of epilepsy in a group of Chinese children using next-generation sequencing technology (NGS). NGS is a term used to describe a number of different modern sequencing technologies that allow to sequence, or read, DNA and RNA much more quickly and inexpensively than traditional technologies.

The study involved 120 Chinese patients with unexplained epilepsy — 71 with early-onset epileptic encephalopathies and 16 with Dravet syndrome (including three with Dravet-like symptoms) who did not carry any mutations in the SCN1A gene associated with disease development.

Targeted NGS found a total of 24 disease variants in 14 different genes (KCND3, GRIN1, HCN1, PCDH19, CDKL5, SCN8A, KCNQ2, SCN2A, STXBP1, TBC1D24, CNKSR2, SMC1A, CHD2, KCTD7) in 22 patients (18%), including 10 new variants and 14 previously reported in literature.

Group analysis also identified a de novo mutation in the KCND3 gene (c.1174G>A, p.Val392Ile) in a boy with refractory epilepsy, gradual motor regression, attention deficits, and visual impairments. A de novo mutation is a mutation that appears for the first time in an individual, instead of being inherited from the parents.

Although previous studies have described the same KCND3 variant in a patient, the clinical outcomes were very different from those found in this study, namely sudden death at 20 years old without any medical history of neurological disorders.

This suggests that genetic mutations in KCND3 may be linked to other types of disease manifestations.

Finally, targeted NGS also identified new disease variants for the GRIN1 and HCN1 genes in four children with Dravet syndrome.

“Our study highlights the significant utility of NGS panels in the diagnosis of epileptic patients with unknown etiology [origin], especially patients with EOEEs [early-onset epileptic encephalopathies]. Our findings indicate that KCND3 pathogenic variants may be responsible for a wider phenotypic [symptoms’] spectrum than previously thought, by including childhood epileptic encephalopathy [and] provide evidence that GRIN1 and HCN1 are candidate genes for Dravet and Dravet-like [disorders],” researchers wrote.

“Additionally, we provided a more precise diagnosis for several patients that would not otherwise have been achieved simply by clinical assessment and conventional diagnostic approaches,” they concluded.