Targeted gene panel and genotype-phenotype correlation in children with developmental and epileptic encephalopathy

Ko, Ara; Youn, Song Ee; Kim, Se Hee; Lee, Joon Soo; Kim, Sang Woo; Choi, Jong Rak; Kim, Heung Dong; Lee, Seung Tae; Kang, Hoon Chul

doi:10.1016/j.eplepsyres.2018.02.003

Cited by 84 publications

(90 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Stars indicate approximate locations of the eight variants identified in the present study. Circles indicate previously published missense (dark blue) and in‐frame deletion (pink) variants, and truncating variants are indicated by triangles: nonsense (red), frameshift (light blue), and splice‐site (orange) . Variant positions are based on the previously published LeuT crystal structure .…”

Section: Resultsmentioning

confidence: 99%

SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

et al. 2018

View full text Add to dashboard Cite

Previous reports have identified SLC6A1 variants in patients with generalized epilepsies, such as myoclonic-atonic epilepsy and childhood absence epilepsy. However, to date, none of the identified SLC6A1 variants has been functionally tested for an effect on GAT-1 transporter activity. The purpose of this study was to determine the incidence of SLC6A1 variants in 460 unselected epilepsy patients and to evaluate the impact of the identified variants on γ-aminobutyric acid (GABA)transport. Targeted resequencing was used to screen 460 unselected epilepsy patients for variants in SLC6A1. Five missense variants, one in-frame deletion, one nonsense variant, and one intronic splice-site variant were identified, representing a 1.7% diagnostic yield. Using a [ H]-GABA transport assay, the seven identified exonic variants were found to reduce GABA transport activity. A minigene splicing assay revealed that the splice-site variant disrupted canonical splicing of exon 9 in the mRNA transcript, leading to premature protein truncation. These findings demonstrate that SLC6A1 is an important contributor to childhood epilepsy and that reduced GAT-1 function is a common consequence of epilepsy-causing SLC6A1 variants.

show abstract

Section: Resultsmentioning

confidence: 99%

SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

et al. 2018

View full text Add to dashboard Cite

show abstract

“…KCNT1 is associated with epilepsy of infancy with migrating focal seizures, autosomal dominant nocturnal frontal lobe epilepsy, and other types of early onset epileptic encephalopathies [87–89]. Ohba et al [88] found 11 KCNT1 mutations in a total of 362 epilepsy patients: 9/18 epilepsy of infancy with migrating focal seizures cases (50%), 1/180 West syndrome cases (0.56%), and 1/66 unclassified early onset epileptic encephalopathy cases (1.52%), suggesting that KCNT1 may be a causal gene for West syndrome.…”

Section: Discussionmentioning

confidence: 99%

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

“…It is absent from the gnomAD database; the resulting amino acid substitution is predicted damaging by several pathogenicity programs. This variant has been described in four reports on patients with epileptic encephalopathy, leading to SUDEP in one case (Ko et al, ; Lindy et al, ; Parrini et al, ; Xiao et al, ).…”

Section: Case Reportmentioning

confidence: 85%

SCN8Aheterozygous variants are associated with anoxic‐epileptic seizures

Ranza

Z'Graggen

Lidgren

et al. 2020

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Anoxic-epileptic seizures (AES) are rare outcomes of common childhood reflex anoxic syncope that trigger a true epileptic seizure. The term AES was coined by Stephenson in 1983, to differentiate these events from convulsive syncopes and the more common reflex anoxic syncopes. A genetic susceptibility for AES has been postulated; but, its molecular basis has up to now been elusive. We report here two illustrative cases and show the association of de novo SCN8A variants and AES. One of them had focal or generalized seizures and autonomic symptoms triggered by orthostatism; the second had breath-holding spells triggered by pain or exercise leading to tonic-clonic seizures; both had repeatedly normal EEGs and a family history of reflex syncope. The data of three additional AES patients further suggest, for the first time, a link between SCN8A pathogenic variants and AES. The neurodevelopment of four patients was abnormal. Four of the five SCN8A mutations observed here were previously described in patients with seizure disorders. Seizures responded particularly well to sodium channel blockers. Our observation enriches the spectrum of seizures linked with SCN8A pathogenic variants. K E Y W O R D S AES, anoxic-epileptic seizures, childhood epilepsy, SCN8A, sodium channel blockers ‡ Deb K. Pal and Christian M. Korff contributed equally to the work presented

show abstract

Targeted gene panel and genotype-phenotype correlation in children with developmental and epileptic encephalopathy

Cited by 84 publications

References 33 publications

SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

SLC6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

Novel and de novo mutations in pediatric refractory epilepsy

SCN8Aheterozygous variants are associated with anoxic‐epileptic seizures

Contact Info

Product

Resources

About