Epilepsy panels in clinical practice: Yield, variants of uncertain significance, and treatment implications

Abbott, Megan; Reed, Lee A.; Kammeyer, Ryan; Gibbons, Melissa; Angione, Katie; Bernard, Timothy J.; Gaskell, Amy; Demarest, Scott

doi:10.1016/j.eplepsyres.2023.107167

Cited by 3 publications

(2 citation statements)

References 37 publications

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“…However, several cases show variants of uncertain significance (VUS), and it is not always possible to identify (likely) pathogenic variants [7][8][9], leaving some cases unsolved [10,11].…”

Section: Introductionmentioning

confidence: 99%

Genetic Epilepsies and Developmental Epileptic Encephalopathies with Early Onset: A Multicenter Study

Cavirani,

Spagnoli,

Caraffi

et al. 2024

IJMS

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The genetic causes of epilepsies and developmental and epileptic encephalopathies (DEE) with onset in early childhood are increasingly recognized. Their outcomes vary from benign to severe disability. In this paper, we wished to retrospectively review the clinical, genetic, EEG, neuroimaging, and outcome data of patients experiencing the onset of epilepsy in the first three years of life, diagnosed and followed up in four Italian epilepsy centres (Epilepsy Centre of San Paolo University Hospital in Milan, Child Neurology and Psychiatry Unit of AUSL-IRCCS di Reggio Emilia, Pediatric Neurology Unit of Vittore Buzzi Children’s Hospital, Milan, and Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia). We included 168 patients (104 with monogenic conditions, 45 with copy number variations (CNVs) or chromosomal abnormalities, and 19 with variants of unknown significance), who had been followed up for a mean of 14.75 years. We found a high occurrence of generalized seizures at onset, drug resistance, abnormal neurological examination, global developmental delay and intellectual disability, and behavioural and psychiatric comorbidities. We also documented differing presentations between monogenic issues versus CNVs and chromosomal conditions, as well as atypical/rare phenotypes. Genetic early-childhood-onset epilepsies and DEE show a very wide phenotypic and genotypic spectrum, with a high risk of complex neurological and neuropsychiatric phenotypes.

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Section: Introductionmentioning

confidence: 99%

Genetic Epilepsies and Developmental Epileptic Encephalopathies with Early Onset: A Multicenter Study

Cavirani,

Spagnoli,

Caraffi

et al. 2024

IJMS

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show abstract

“…8 The Clinical Genome consortium (ClinGen) has since clarified these rules using a systematic, Bayesian approach that provides quantitative thresholds for strength of evidence and overall variant classification. 9 In parallel with the development of these criteria, the number of variants of uncertain significance (VUS) has grown exponentially as clinical genetic testing rapidly expands; 10,11 efforts to resolve variant pathogenicity are therefore increasingly critical. 12…”

Section: Introductionmentioning

confidence: 99%

Optimizing clinical interpretability of functional evidence in epilepsy-related ion channel variants

Parthasarathy,

Cohen,

Fitch

et al. 2024

Preprint

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Variants in genes encoding the voltage-gated ion channels are among the most common monogenic causes of epilepsy and neurodevelopmental disorders. Functional effects of a variant are increasingly important for diagnosis and therapeutic decisions. To incorporate knowledge regarding functional consequences in formal clinical variant interpretation, we developed an approach for evaluating multiple functional measurements within the Bayesian framework of the modified ACMG/AMP guidelines. We analyzed 216 functional assessments of 191 variants in SCN1A (n=74), SCN2A (n=66), SCN3A (n=18), and SCN8A (n=33). Of 20 commonly measured biophysical parameters, the most frequent drivers of overall functional consequence were persistent current (f=0.54), voltage dependence of activation (f=0.51), and voltage dependence of fast inactivation (f=0.40) for gain-of-function and peak current (f=0.87) for loss-of-function. By comparing measurements of 23 benign variants, we determined thresholds by which published data on these four parameters confer Strong evidence of variant pathogenicity (likelihood ratio > 18.7) under the ACMG/AMP rubric. Similarly, we delineated evidence weights for the most common epilepsy-related potassium channel gene, KCNQ2, through reports of 80 pathogenic and 24 benign variants, accounting for heterozygous and homozygous experimental conditions. We collected the resulting categorization of functional data into FENICS, a biomedical ontology of 152 standardized terms for coherent annotation of electrophysiological results. Across 271 variants in SCN1A/2A/3A/8A and KCNQ2, 1,731 annotations are available in ClinVar, facilitating use of this evidence in variant classification. In summary, we introduce and apply an ACMG/AMP-calibrated framework for electrophysiological studies in epilepsy-related channelopathies to delineate the impact of functional evidence on clinical variant interpretation.

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Navigating the Intersection of Technology and Depression Precision Medicine

Irmak-Yazicioglu,

Arslan

2024

Advances in Experimental Medicine and Biology

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Epilepsy panels in clinical practice: Yield, variants of uncertain significance, and treatment implications

Cited by 3 publications

References 37 publications

Genetic Epilepsies and Developmental Epileptic Encephalopathies with Early Onset: A Multicenter Study

Genetic Epilepsies and Developmental Epileptic Encephalopathies with Early Onset: A Multicenter Study

Optimizing clinical interpretability of functional evidence in epilepsy-related ion channel variants

Navigating the Intersection of Technology and Depression Precision Medicine

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