No association between SCN9A and monogenic human epilepsy disorders

Fasham, James; Leslie, Joseph S; Harrison, James W.; Deline, James; Williams, Katie B; Kuhl, Ashley; Schwoerer, Jessica Scott; Cross, Harold E.; Crosby, Andrew H.; Baple, Emma L.

doi:10.1371/journal.pgen.1009161

Cited by 14 publications

(5 citation statements)

References 33 publications

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“…In addition to pain-related diseases, mutations of SCN9A were associated with epilepsy in some case reports [20,21]. Nevertheless, a recent study reported no association between SCN9A and monogenic epilepsy disorders [22]. Of notice, the study by Robinson et al reported that rare mutations of SCN9A were associated with autism spectrum disorders (ASDs).…”

Section: Discussionmentioning

confidence: 99%

Involvement of Rare Mutations of SCN9A, DPP4, ABCA13, and SYT14 in Schizophrenia and Bipolar Disorder

Chen

Huang

Fang

2021

IJMS

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Rare mutations associated with schizophrenia (SZ) and bipolar disorder (BD) usually have high clinical penetrance; however, they are highly heterogeneous and personalized. Identifying rare mutations is instrumental in making the molecular diagnosis, understanding the pathogenesis, and providing genetic counseling for the affected individuals and families. We conducted whole-genome sequencing analysis in two multiplex families with the dominant inheritance of SZ and BD. We detected a G327E mutation of SCN9A and an A654V mutation of DPP4 cosegregating with SZ and BD in one three-generation multiplex family. We also identified three mutations cosegregating with SZ and BD in another two-generation multiplex family, including L711S of SCN9A, M4554I of ABCA13, and P159L of SYT14. These five missense mutations were rare and deleterious. Mutations of SCN9A have initially been reported to cause congenital insensitivity to pain and neuropathic pain syndromes. Further studies showed that rare mutations of SCN9A were associated with seizure and autism spectrum disorders. Our findings suggest that SZ and BD might also be part of the clinical phenotype spectra of SCN9A mutations. Our study also indicates the oligogenic involvement in SZ and BD and supports the multiple-hit model of SZ and BD.

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Section: Discussionmentioning

confidence: 99%

Involvement of Rare Mutations of SCN9A, DPP4, ABCA13, and SYT14 in Schizophrenia and Bipolar Disorder

Chen

Huang

Fang

2021

IJMS

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“…Variants in SCN9A are abundant in the normal population and often do not cause disease making it likely that they are benign mutations. 13 Furthermore, as mentioned above, her father is asymptomatic and has the same SCN1A and SCN9A mutations lowering the likelihood that these two mutations are contributing to her specific epilepsy syndrome.…”

Section: Discussion/conclusionmentioning

confidence: 97%

Refractory Jeavons Syndrome from Birth Symptomatic to PLCB1 Mutation

Spurgeon

Keaveney

2023

Child Neurology Open

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Jeavons syndrome is a common, often misdiagnosed or overlooked epileptic syndrome presenting with a triad of eyelid myoclonia with or without absence seizures, eye closure-induced EEG paroxysms, and photosensitivity. We present a seven-year-old female who presented with eyelid myoclonia evident since birth with absence seizures and migraines with associated photosensitivity. An EEG with photic stimulation confirmed the diagnosis of Jeavons syndrome. Genetic testing showed a heterozygous mutation in the PLCB1 gene which has been linked to early onset epilepsies and encephalopathic epilepsies. This mutation and her clinical presentation identifies another etiology of Jeavons syndrome and confirms it can begin from birth. Its presence highlights the importance of genetic testing in epileptic patients to better understand the links between genetics and epilepsy syndromes so appropriate treatment can be initiated.

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“…When results do not show pathogenic or likely pathogenic variants, a specific review of the pathogenicity of VUS is warranted. The same critical thinking could be applied when hastily attributing an etiological condition to a (likely) pathogenic variant (e.g., the relationship of likely pathogenic variants in SCN9A with epilepsy phenotypes is still under discussion) ( 68 ).…”

Section: Considerations On Interpreting the Results Of Genetic Testingmentioning

confidence: 99%

Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies

Beltrán‐Corbellini

Aledo‐Serrano

Møller³

et al. 2022

Front. Neurol.

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This review aims to provide an updated perspective of epilepsy genetics and precision medicine in adult patients, with special focus on developmental and epileptic encephalopathies (DEEs), covering relevant and controversial issues, such as defining candidates for genetic testing, which genetic tests to request and how to interpret them. A literature review was conducted, including findings in the discussion and recommendations. DEEs are wide and phenotypically heterogeneous electroclinical syndromes. They generally have a pediatric presentation, but patients frequently reach adulthood still undiagnosed. Identifying the etiology is essential, because there lies the key for precision medicine. Phenotypes modify according to age, and although deep phenotyping has allowed to outline certain entities, genotype-phenotype correlations are still poor, commonly leading to long-lasting diagnostic odysseys and ineffective therapies. Recent adult series show that the target patients to be identified for genetic testing are those with epilepsy and different risk factors. The clinician should take active part in the assessment of the pathogenicity of the variants detected, especially concerning variants of uncertain significance. An accurate diagnosis implies precision medicine, meaning genetic counseling, prognosis, possible future therapies, and a reduction of iatrogeny. Up to date, there are a few tens of gene mutations with additional concrete treatments, including those with restrictive/substitutive therapies, those with therapies modifying signaling pathways, and channelopathies, that are worth to be assessed in adults. Further research is needed regarding phenotyping of adult syndromes, early diagnosis, and the development of targeted therapies.

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No association between SCN9A and monogenic human epilepsy disorders

Cited by 14 publications

References 33 publications

Involvement of Rare Mutations of SCN9A, DPP4, ABCA13, and SYT14 in Schizophrenia and Bipolar Disorder

Involvement of Rare Mutations of SCN9A, DPP4, ABCA13, and SYT14 in Schizophrenia and Bipolar Disorder

Refractory Jeavons Syndrome from Birth Symptomatic to PLCB1 Mutation

Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies

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