Molecular diagnosis of patients with epilepsy and developmental delay using a customized panel of epilepsy genes

Ortega-Moreno, Laura; Giráldez, Beatriz G.; Soto-Insuga, Víctor; Pozo, Rebeca Losada-Del; Rodrigo-Moreno, María; Alarcón-Morcillo, Cristina; Sánchez-Martín, Gema; Díaz-Gómez, Esther; Guerrero, Rosa; Serratosa, Joan; Infancia, Grupo de Genética de las Epilepsias de Español la

doi:10.1371/journal.pone.0188978

Cited by 56 publications

(56 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

“…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

View full text Add to dashboard Cite

show abstract

“…Epilepsy and intellectual disability (ID) are common neuropsychiatric disorders with an approximate prevalence of 0.3 to 2% . A subgroup of cases is due to pathogenic variants in potassium channels, which, however, might also present with a range of additional neurological features, such as ataxia .…”

Section: Introductionmentioning

confidence: 99%

KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum

Park

Koko

Hedrich

et al. 2019

Ann Clin Transl Neurol

View full text Add to dashboard Cite

A recurrent de novo missense variant in KCNC1, encoding a voltage‐gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic‐clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant‐negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism.

show abstract

“…To date, many studies have reported on the clinical utility of epilepsy gene panel testing. Although many custom-designed epilepsy gene panels produce similar lists of genes with pathogenic variants, there is substantial variability in their diagnostic rates, which range from 10 to 50% (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). This suggests that the diagnostic yield in these studies depends more on which patients are selected than on which custom-designed panel is used.…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have focused on early-onset epileptic encephalopathy patients, who may be at the severe end of the phenotypic spectrum (4,12). Recent epilepsy gene panel testing studies have analyzed large numbers of patients with broad epilepsy phenotypes (8,9,11,13,14). Since most studies report the results of referral-based tests, they include large variability in seizure onset, epilepsy type, familial occurrence, and the presence of development delay or encephalopathy.…”

Section: Introductionmentioning

confidence: 99%

“…This variability might lead to lower diagnostic yields, which are generally <20% of the tested patients. One finding common among these studies has been the suggestion that patients with early-onset epilepsy, especially neonatal or early infantile onset, tend to have higher diagnostic rates (8,9,11,14). However, few epilepsy gene panel studies have specifically targeted infantile-onset epilepsy patients and analyzed the diagnostic rate.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Diagnostic Yield of Epilepsy Panel Testing in Patients With Seizure Onset Within the First Year of Life

Jang

Kim

et al. 2019

Front. Neurol.

View full text Add to dashboard Cite

Purpose: We aimed to evaluate the diagnostic yield of epilepsy gene panel testing in epilepsy patients whose seizures began within the first year after birth. We included 112 patients with seizure onset before 12 months and no known etiology.Methods: Deep targeted sequencing with a custom-designed capture probe was performed to ensure the detection of germline or mosaic sequence variants and copy number variations (CNVs).Results: We identified pathogenic or likely pathogenic variants in 53 patients (47.3%, 53/112), including five with pathogenic CNVs. Two putative pathogenic mosaic variants in SCN8A and KCNQ2 were also detected and validated. Those with neonatal onset (61.5%, 16/26) or early infantile onset (50.0%, 29/58) showed higher diagnostic rates than those with late infantile onset (28.5%, 8/28). The diagnostic rate was similar between patients with a specific syndrome (51.9%, 27/52) and those with no recognizable syndrome (43.3%, 26/60).Conclusion: Epilepsy gene panel testing identified a genetic cause in nearly half of the infantile onset epilepsy patients. Since the phenotypic spectrum is expanding and characterizing it at seizure onset is difficult, this group should be prioritized for epilepsy gene panel testing.

show abstract

Molecular diagnosis of patients with epilepsy and developmental delay using a customized panel of epilepsy genes

Cited by 56 publications

References 73 publications

Novel and de novo mutations in pediatric refractory epilepsy

Novel and de novo mutations in pediatric refractory epilepsy

KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum

Diagnostic Yield of Epilepsy Panel Testing in Patients With Seizure Onset Within the First Year of Life

Contact Info

Product

Resources

About