Exome sequencing as first-tier genetic testing in infantile-onset pharmacoresistant epilepsy: diagnostic yield and treatment impact

Boonsimma, Ponghatai; Ittiwut, Chupong; Kamolvisit, Wuttichart; Ittiwut, Rungnapa; Chetruengchai, Wanna; Phokaew, Chureerat; Srichonthong, Chalurmpon; Poonmaksatit, Sathida; Desudchit, Tayard; Suphapeetiporn, Kanya; Shotelersuk, Vorasuk

doi:10.1038/s41431-022-01202-x

Cited by 17 publications

(33 citation statements)

References 50 publications

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“…Consistent with prior reports, 16,35 our diagnostic yield was highest in patients with higher severity, with earlier age at onset, DEE or intellectual disability, and motor impairment. Specifically, diagnostic yield for DEE (32%) was more than twice that for the other groups (14%-15%).…”

Section: Discussionsupporting

confidence: 91%

Utility of Exome Sequencing for Diagnosis in Unexplained Pediatric-Onset Epilepsy

Koh,

Smith,

Wiltrout

et al. 2023

JAMA Netw Open

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ImportanceGenomic advances inform our understanding of epilepsy and can be translated to patients as precision diagnoses that influence clinical treatment, prognosis, and counseling.ObjectiveTo delineate the genetic landscape of pediatric epilepsy and clinical utility of genetic diagnoses for patients with epilepsy.Design, Setting, and ParticipantsThis cohort study used phenotypic data from medical records and treating clinicians at a pediatric hospital to identify patients with unexplained pediatric-onset epilepsy. Exome sequencing was performed for 522 patients and available biological parents, and sequencing data were analyzed for single nucleotide variants (SNVs) and copy number variants (CNVs). Variant pathogenicity was assessed, patients were provided with their diagnostic results, and clinical utility was evaluated. Patients were enrolled from August 2018 to October 2021, and data were analyzed through December 2022.ExposuresPhenotypic features associated with diagnostic genetic results.Main Outcomes and MeasuresMain outcomes included diagnostic yield and clinical utility. Diagnostic findings included variants curated as pathogenic, likely pathogenic (PLP), or diagnostic variants of uncertain significance (VUS) with clinical features consistent with the involved gene’s associated phenotype. The proportion of the cohort with diagnostic findings, the genes involved, and their clinical utility, defined as impact on clinical treatment, prognosis, or surveillance, are reported.ResultsA total of 522 children (269 [51.5%] male; mean [SD] age at seizure onset, 1.2 [1.4] years) were enrolled, including 142 children (27%) with developmental epileptic encephalopathy and 263 children (50.4%) with intellectual disability. Of these, 100 participants (19.2%) had identifiable genetic explanations for their seizures: 89 participants had SNVs (87 germline, 2 somatic mosaic) involving 69 genes, and 11 participants had CNVs. The likelihood of identifying a genetic diagnosis was highest in patients with intellectual disability (adjusted odds ratio [aOR], 2.44; 95% CI, 1.40-4.26), early onset seizures (aOR, 0.93; 95% CI, 0.88-0.98), and motor impairment (aOR, 2.19; 95% CI 1.34-3.58). Among 43 patients with apparently de novo variants, 2 were subsequently determined to have asymptomatic parents harboring mosaic variants. Of 71 patients who received diagnostic results and were followed clinically, 29 (41%) had documented clinical utility resulting from their genetic diagnoses.Conclusions and RelevanceThese findings suggest that pediatric-onset epilepsy is genetically heterogeneous and that some patients with previously unexplained pediatric-onset epilepsy had genetic diagnoses with direct clinical implications.

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Section: Discussionsupporting

confidence: 91%

Utility of Exome Sequencing for Diagnosis in Unexplained Pediatric-Onset Epilepsy

Koh,

Smith,

Wiltrout

et al. 2023

JAMA Netw Open

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“…The clinical characteristics of the patients are summarized in Table 1 . Clinical characteristics and molecular findings in 8 patients (patient 1–3 and 5–9) have been described in the authors’ previous work 21 .…”

Section: Resultsmentioning

confidence: 96%

“…From June 2016 to December 2020, we studied 104 patients with infantile-onset pharmaco-resistant epilepsy, defined as failure of adequate trials of two antiepileptic drugs 20 who underwent exome or genome sequencing at King Chulalongkorn Memorial Hospital. The cohort is described in the authors’ previous work 21 . Nine patients were found to harbor pathogenic or likely pathogenic variants in the KCNQ2 gene.…”

Section: Methodsmentioning

confidence: 99%

“…There were calculated by the Boltzmann function: I = 1/[1 + exp(V½–V)/k], V½ = half-activating voltage, k = slope, at tail current amplitudes at − 40 mV. The membrane resistance (Rm) was calculated according to Ohm’s law (V = IR), I is the current, V is the voltage and R is the resistance detected the resistance of the cell membrane when ions flow through it 21 . The membrane time constant (Tau) were calculated by Rm·Cm, Cm is membrane capacitance detected time of change membrane potential 25 .…”

Section: Methodsmentioning

confidence: 99%

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Nine patients with KCNQ2-related neonatal seizures and functional studies of two missense variants

Chokvithaya

Caengprasath

Buasong

et al. 2023

Sci Rep

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Mutations in KCNQ2 encoding for voltage-gated K channel subunits underlying the neuronal M-current have been associated with infantile-onset epileptic disorders. The clinical spectrum ranges from self-limited neonatal seizures to epileptic encephalopathy and delayed development. Mutations in KCNQ2 could be either gain- or loss-of-function which require different therapeutic approaches. To better understand genotype–phenotype correlation, more reports of patients and their mutations with elucidated molecular mechanism are needed. We studied 104 patients with infantile-onset pharmacoresistant epilepsy who underwent exome or genome sequencing. Nine patients with neonatal-onset seizures from unrelated families were found to harbor pathogenic or likely pathogenic variants in the KCNQ2 gene. The p.(N258K) was recently reported, and p. (G279D) has never been previously reported. Functional effect of p.(N258K) and p.(G279D) has never been previously studied. The cellular localization study demonstrated that the surface membrane expression of Kv7.2 carrying either variant was decreased. Whole-cell patch-clamp analyses revealed that both variants significantly impaired Kv7.2 M-current amplitude and density, conductance depolarizing shift in voltage dependence of activation, membrane resistance, and membrane time constant (Tau), indicating a loss-of-function in both the homotetrameric and heterotetrameric with Kv7.3 channels. In addition, both variants exerted dominant-negative effects in heterotetrameric with Kv7.3 channels. This study expands the mutational spectrum of KCNQ2- related epilepsy and their functional consequences provide insights into their pathomechanism.

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“…Three genes previously considered suitable for clinical screening were now only recommended for research, whereas 10 other stroke-genes were strengthened and now fulfill the criteria for clinical testing. Smuk et al report novel phenotypic insights from genome sequencing of epilepsy genes [13] and Boonsimma et al treatment implications from exome testing in epilepsy [14].…”

mentioning

confidence: 99%

The value of exomes across the ages

McNeill

2023

Eur J Hum Genet

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Exome sequencing as first-tier genetic testing in infantile-onset pharmacoresistant epilepsy: diagnostic yield and treatment impact

Cited by 17 publications

References 50 publications

Utility of Exome Sequencing for Diagnosis in Unexplained Pediatric-Onset Epilepsy

Utility of Exome Sequencing for Diagnosis in Unexplained Pediatric-Onset Epilepsy

Nine patients with KCNQ2-related neonatal seizures and functional studies of two missense variants

The value of exomes across the ages

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