A targeted resequencing gene panel for focal epilepsy

Hildebrand, Michael S.; Myers, Candace T.; Carvill, Gemma L.; Regan, Brigid M.; Damiano, John A.; Mullen, Saul A.; Newton, Mark R.; Nair, Umesh; Gazina, Elena V.; Milligan, Carol J.; Reid, Christopher A.; Petrou, Steven; Scheffer, Ingrid E.; Berkovic, Samuel F.; Mefford, Heather C

doi:10.1212/wnl.0000000000002608

Cited by 48 publications

(48 citation statements)

References 33 publications

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“…Our results were similar to previous reports, with diagnostic yields ranging between 10% and 48.5% [49–56]. There were 60.5% (26/43) novel deleterious variants found in our study.…”

Section: Resultssupporting

confidence: 92%

Novel and de novo mutations in pediatric refractory epilepsy

et al. 2018

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Pediatric refractory epilepsy is a broad phenotypic spectrum with great genetic heterogeneity. Next-generation sequencing (NGS) combined with Sanger sequencing could help to understand the genetic diversity and underlying disease mechanisms in pediatric epilepsy. Here, we report sequencing results from a cohort of 172 refractory epilepsy patients aged 0–14 years. The pathogenicity of identified variants was evaluated in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria. We identified 43 pathogenic or likely pathogenic variants in 40 patients (23.3%). Among these variants, 74.4% mutations (32/43) were de novo and 60.5% mutations (26/43) were novel. Patients with onset age of seizures ≤12 months had higher yields of deleterious variants compared to those with onset age of seizures > 12 months (P = 0.006). Variants in ion channel genes accounted for the greatest functional gene category (55.8%), with SCN1A coming first (16/43). 81.25% (13/16) of SCN1A mutations were de novo and 68.8% (11/16) were novel in Dravet syndrome. Pathogenic or likely pathogenic variants were found in the KCNQ2, STXBP1, SCN2A genes in Ohtahara syndrome. Novel deleterious variants were also found in West syndrome, Doose syndrome and glucose transporter type 1 deficiency syndrome patients. One de novo MECP2 mutation were found in a Rett syndrome patient. TSC1/TSC2 variants were found in 60% patients with tuberous sclerosis complex patients. Other novel mutations detected in unclassified epilepsy patients involve the SCN8A, CACNA1A, GABRB3, GABRA1, IQSEC2, TSC1, VRK2, ATP1A2, PCDH19, SLC9A6 and CHD2 genes. Our study provides novel insights into the genetic origins of pediatric epilepsy and represents a starting-point for further investigations into the molecular pathophysiology of pediatric epilepsy that could eventually lead to better treatments.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0392-5) contains supplementary material, which is available to authorized users.

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“…Our results were similar to previous reports, with diagnostic yields ranging between 10% and 48.5% [49–56]. There were 60.5% (26/43) novel deleterious variants found in our study.…”

Section: Resultssupporting

confidence: 92%

Novel and de novo mutations in pediatric refractory epilepsy

et al. 2018

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“…The number of diagnosed cases is increasing as recognition of the gene has grown since 2008, and continues to grow as clinical genetic testing becomes more routine. Already, the phenotypic spectrum related to PCDH19 is broadening: patients with early onset epilepsy and ID with a phenotype milder than initially reported, and patients with sporadic focal epilepsy undergoing testing with epilepsy gene panels, have recently been found to harbor likely pathogenic variants in PCDH19 12,24 . Our series highlights the under recognition of many behavioral aspects of this condition.…”

Section: Introductionmentioning

confidence: 99%

PCDH19‐related epilepsy is associated with a broad neurodevelopmental spectrum

et al. 2018

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Our series represents a robust cohort with carefully curated PCDH19 variants. We observed seizures as a core feature with a range of seizure types and severity. Whereas the majority of individuals had ID, we highlight the possibility of average intellect in the setting of PCDH19-related epilepsy. We also note the high prevalence and severity of neurobehavioral phenotypes associated with likely pathogenic variants in PCDH19. Sleep dysregulation was also a major area of concern. Our data emphasize the importance of appropriate referrals for formal neuropsychological evaluations as well as the need for formal prospective studies to characterize the PCDH19-related neurodevelopmental syndrome in children and their genotype-positive parents.

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“…Historically, there has been a low yield for genetic diagnoses in focal seizures; in particular, those without a family history . However, in recent years, the list of genes has expanded, although a positive family history does still seem to be a common feature for many of those with a molecular diagnosis and non‐syndromic focal seizures . This section will discuss some of the known genetic causes of specific focal epilepsy syndromes, as well as some of the more common causes of focal epilepsy in general.…”

Section: Focal Epilepsy Syndromesmentioning

confidence: 99%

Epilepsy genetics: Current knowledge, applications, and future directions

2018

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The rapid pace of disease gene discovery has resulted in tremendous advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, and genomes are now available and have led to higher diagnostic rates and insights into the underlying disease processes. As such, the contribution to the care of patients by medical geneticists, neurogeneticists and genetic counselors are significant; the dysmorphic examination, the necessary pre- and post-test counseling, the selection of the appropriate next-generation sequencing-based test(s), and the interpretation of sequencing results require a care provider to have a comprehensive working knowledge of the strengths and limitations of the available testing technologies. As the underlying mechanisms of the encephalopathies and epilepsies are better understood, there may be opportunities for the development of novel therapies based on an individual's own specific genotype. Drug screening with in vitro and in vivo models of epilepsy can potentially facilitate new treatment strategies. The future of epilepsy genetics will also probably include other-omic approaches such as transcriptomes, metabolomes, and the expanded use of whole genome sequencing to further improve our understanding of epilepsy and provide better care for those with the disease.

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A targeted resequencing gene panel for focal epilepsy

Cited by 48 publications

References 33 publications

Novel and de novo mutations in pediatric refractory epilepsy

Novel and de novo mutations in pediatric refractory epilepsy

PCDH19‐related epilepsy is associated with a broad neurodevelopmental spectrum

Epilepsy genetics: Current knowledge, applications, and future directions

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