Use of a Dynamic Genetic Testing Approach for Childhood-Onset Epilepsy

Balciuniene, Jorune; DeChene, Elizabeth T.; Akgumus, Gozde; Romasko, Edward J.; Cao, Ke; Dubbs, Holly; Mulchandani, Surabhi; Spinner, Nancy B.; Conlin, Laura K.; Marsh, Eric D.; Goldberg, Ethan M.; Helbig, Ingo; Sarmady, Mahdi; Tayoun, Ahmad Abou

doi:10.1001/jamanetworkopen.2019.2129

Cited by 45 publications

(37 citation statements)

References 27 publications

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“…For in‐house testing, we performed a comprehensive exome‐based sequencing and copy number analysis of 100 epilepsy‐associated genes. Genomic DNA was extracted from peripheral blood to obtain DNA material for sequencing and an in‐house bioinformatics pipeline was used for analysis . After filtering, variants were classified using published guidelines from the American College of Medical Genetics and Genomics …”

Section: Methodsmentioning

confidence: 99%

A single‐center SCN8A‐related epilepsy cohort: clinical, genetic, and physiologic characterization

Zaman

Tayoun

Goldberg

2019

Ann Clin Transl Neurol

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Objective Pathogenic variants in SCN8A, encoding the voltage‐gated sodium (Na+) channel α subunit Nav1.6, is a known cause of epilepsy. Here, we describe clinical and genetic features of all patients with SCN8A epilepsy evaluated at a single‐tertiary care center, with biophysical data on identified Nav1.6 variants and pharmacological response to selected Na+ channel blockers. Methods SCN8A variants were identified via an exome‐based panel of epilepsy‐associated genes for next generation sequencing (NGS), or via exome sequencing. Biophysical characterization was performed using voltage‐clamp recordings of ionic currents in heterologous cells. Results We observed a range in age of onset and severity of epilepsy and associated developmental delay/intellectual disability. Na+ channel blockers were highly or partially effective in most patients. Nav1.6 variants exhibited one or more biophysical defects largely consistent with gain of channel function. We found that clinical severity was correlated with the presence of multiple observed biophysical defects and the extent to which pathological Na+ channel activity could be normalized pharmacologically. For variants not previously reported, functional studies enhanced the evidence of pathogenicity. Interpretation We present a comprehensive single‐center dataset for SCN8A epilepsy that includes clinical, genetic, electrophysiologic, and pharmacologic data. We confirm a spectrum of severity and a variety of biophysical defects of Nav1.6 variants consistent with gain of channel function. Na+ channel blockers in the treatment of SCN8A epilepsy may correlate with the effect of such agents on pathological Na+ current observed in heterologous systems.

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Section: Methodsmentioning

confidence: 99%

A single‐center SCN8A‐related epilepsy cohort: clinical, genetic, and physiologic characterization

Zaman

Tayoun

Goldberg

2019

Ann Clin Transl Neurol

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“…LGI1 has been reported associated with the etiology of epilepsy [ 34 ]. LGI1 is located at a linkage region on chromosome 10q24.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic variants identified by whole-exome sequencing in 43 patients with epilepsy

et al. 2020

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Background Epilepsy is a group of neurological disorders characterized by recurrent epileptic seizures. Epilepsy is affected by many factors, approximately 20–30% of cases are caused by acquired conditions, but in the remaining cases, genetic factors play an important role. Early establishment of a specific diagnosis is important to treat and manage this disease. Methods In this study, we have recruited 43 epileptic encephalopathy patients and the molecular genetic analysis of those children was performed by whole-exome sequencing (WES). Results Fourteen patients (32.6%, 14/43) had positive genetic diagnoses, including fifteen mutations in fourteen genes. The overall diagnostic yield was 32.6%. A total of 9 patients were diagnosed as pathogenic mutations, including 4 variants had been reported as pathogenic previously and 6 novel variants that had not been reported previously. Therefore, WES heralds promise as a tool for clinical diagnosis of patients with genetic disease. Conclusion Early establishment of a specific diagnosis, on the one hand, is necessary for providing an accurate prognosis and recurrence risk as well as optimizing management and treatment options. On the other hand, to unveil the genetic architecture of epilepsy, it is of vital importance to investigate the phenotypic and genetic complexity of epilepsy.

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“…Early-onset epileptic encephalopathy (EOEE) represents a heterogeneous group of disorders in which epilepsy appears in the first 6 months of life and is usually associated with a severe neurodevelopmental disorder, among other symptoms [Heyne et al, 2018;Carvill, 2019]. Currently, a genetic etiology can be identified in about 30% of cases [Mercimek-Mahmutoglu et al, 2015;Balciuniene et al, 2019], mainly as pathogenic variants in genes encoding neuronal ion channels, proteins involved in synaptic transmission, or transcriptional regulatory proteins [Mercimek-Mahmutoglu et al, 2015;Heyne et al, 2018;Balciuniene et al, 2019].…”

Section: Discussionmentioning

confidence: 99%

Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy

et al. 2020

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Epileptic encephalopathy related to CACNA1E has been described as a severe neurodevelopmental disorder presenting with early-onset refractory seizures, hypotonia, macrocephaly, hyperkinetic movements, and contractures and is associated with an autosomal dominant inheritance pattern. Most pathogenic variants described to date are missense variants with a gain of function effect, and the role of haploinsufficiency has yet to be clarified. We describe 2 cases of CACNA1E encephalopathy. Notable findings include congenital contractures and movement disorders predating onset of epilepsy, particularly dystonia. We further compared the key phenotypic features depending on variant location. In conclusion, the appearance of congenital contractures, areflexia, and movement disorders before the onset of epilepsy may provide key guidance in the diagnosis of epileptic CACNA1E encephalopathy. A genotype-phenotype correlation was found between the presence of movement disorders and severe intellectual disability and the location of the variant in the CACNA1E gene.

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Use of a Dynamic Genetic Testing Approach for Childhood-Onset Epilepsy

Cited by 45 publications

References 27 publications

A single‐center SCN8A‐related epilepsy cohort: clinical, genetic, and physiologic characterization

A single‐center SCN8A‐related epilepsy cohort: clinical, genetic, and physiologic characterization

Pathogenic variants identified by whole-exome sequencing in 43 patients with epilepsy

Dystonia and Contractures are Potential Early Signs of <b><i>CACNA1E</i></b>-Related Epileptic Encephalopathy

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