Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort

Zeng, Qi; Yang, Xiaoling; Zhang, Jing; Liu, Aijie; Yang, Zhixian; Liu, Xiaoyan; Wu, Ye; Wu, Xiru; Wei, Liping; Zhang, Yuehua

doi:10.1038/s10038-017-0359-x

Cited by 17 publications

(19 citation statements)

References 35 publications

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“…We observed a number of patients presenting with focal seizures beyond the neonatal period (one at 3 months and two at 4 months). Post-neonatal presentation with KCNQ2 -related seizures has been reported before ( Millichap et al , 2017 ; Zeng et al , 2018 ). In our cohort early onset of seizures appeared to be associated with better outcomes.…”

Section: Resultsmentioning

confidence: 74%

Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort

Symonds

Zuberi

Stewart

et al. 2019

Brain

263

233

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Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children’s hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9–57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26–14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93–12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24–9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07–7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.

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Section: Resultsmentioning

confidence: 74%

Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort

Symonds

Zuberi

Stewart

et al. 2019

Brain

263

233

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“…A total of 72 unrelated epilepsy patients with heterozygous SCN2A variants were collected. Among them, patients 1–8 have been reported in a previous study of benign familial epilepsy ( Zeng et al, 2018 ). Fifty-nine SCN2A variants were identified, including 54 missense variants (91.5%, 54/59), 2 frameshift variants, 2 in-frame deletion variants, and 1 non-sense variant.…”

Section: Resultsmentioning

confidence: 99%

SCN2A-Related Epilepsy: The Phenotypic Spectrum, Treatment and Prognosis

Zeng

Yang

Duan

et al. 2022

Front. Mol. Neurosci.

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ObjectiveThe aim of this study was to analyze the phenotypic spectrum, treatment, and prognosis of 72 Chinese children with SCN2A variants.MethodsThe SCN2A variants were detected by next-generation sequencing. All patients were followed up at a pediatric neurology clinic in our hospital or by telephone.ResultsIn 72 patients with SCN2A variants, the seizure onset age ranged from the first day of life to 2 years and 6 months. The epilepsy phenotypes included febrile seizures (plus) (n = 2), benign (familial) infantile epilepsy (n = 9), benign familial neonatal-infantile epilepsy (n = 3), benign neonatal epilepsy (n = 1), West syndrome (n = 16), Ohtahara syndrome (n = 15), epilepsy of infancy with migrating focal seizures (n = 2), Dravet syndrome (n = 1), early infantile epileptic encephalopathy (n = 15), and unclassifiable developmental and epileptic encephalopathy (n = 8). Approximately 79.2% (57/72) patients had varying degrees of developmental delay. All patients had abnormal MRI findings with developmental delay. 91.7% (55/60) patients with de novo SCN2A variants had development delay, while only 16.7% (2/12) patients with inherited SCN2A variants had abnormal development. 83.9% (26/31) SCN2A variants that were located in transmembrane regions of the protein were detected in patients with development delay. Approximately 69.2% (9/13) SCN2A variants detected in patients with normal development were located in the non-transmembrane regions. Approximately 54.2% (39/72) patients were seizure-free at a median age of 8 months. Oxcarbazepine has been used by 38 patients, and seizure-free was observed in 11 of them (11/38, 28.9%), while 6 patients had seizure worsening by oxcarbazepine. All 3 patients used oxcarbazepine and with seizure onset age > 1 year presented seizure exacerbation after taking oxcarbazepine. Valproate has been used by 53 patients, seizure-free was observed in 22.6% (12/53) of them.ConclusionThe phenotypic spectrum of SCN2A-related epilepsy was broad, ranging from benign epilepsy in neonate and infancy to severe epileptic encephalopathy. Oxcarbazepine and valproate were the most effective drugs in epilepsy patients with SCN2A variants. Sodium channel blockers often worsen seizures in patients with seizure onset beyond 1 year of age. Abnormal brain MRI findings and de novo variations were often related to poor prognosis. Most SCN2A variants located in transmembrane regions were related to patients with developmental delay.

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“…Genetic pathogenic variants have been identified as the most important factors in epilepsy syndromes. Hence, targeted genetic sequencing studies have been extensively and intensively applied in epilepsy syndromes, especially epileptic encephalopathy (EE) in infants . It also remains important to evaluate the genetic etiology of epilepsy cases that occur in subjects with no known family history who were therefore previously considered idiopathic.…”

Section: Introductionmentioning

confidence: 99%

Genotype and phenotype analysis using an epilepsy‐associated gene panel in Chinese pediatric epilepsy patients

et al. 2018

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Epilepsy is a common and genetically heterogeneous disorder among children. Advances in next-generation sequencing have revealed that numerous epilepsy genes, helped us improve the understanding of mechanisms underlying epileptogenesis, and guided the development of treatments. We identified 39 candidate variants in 21 genes, including 37 that were pathogenic or likely pathogenic variants according to the American College of Medical Genetics and Genomics scoring system and two variants of uncertain significance that were considered causative after they were associated with clinical characteristics. Thirty were de novo variants (76.9%), and 20 variants had not previously been reported (51.3%). We obtained a diagnosis in 39 of the 141 probands (27.7%). The most frequently mutated gene was SCN1A; KCNQ2, KCNT1, PCDH19, STXBP1, SCN2A, TSC2, and PRRT2 were mutated in more than one individual; ANKRD11, CDKL5, DCX, DEPDC5, GABRB3, GRIN2A, IQSEC2, KCNA2, KCNB1, KCNJ6, TSC1, SCN9A, and SCN1B were mutated in a single individual. In addition, we detected a nonsense variant in a candidate gene KCND1 and considered it as a new candidate epilepsy gene, which needed further functional study. Consequently, large number of unreported variants were detected, diverse phenotypes were associated with known epilepsy genes. Changes in clinical management beyond genetic counseling were suggested.

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Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort

Cited by 17 publications

References 35 publications

Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort

Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort

SCN2A-Related Epilepsy: The Phenotypic Spectrum, Treatment and Prognosis

Genotype and phenotype analysis using an epilepsy‐associated gene panel in Chinese pediatric epilepsy patients

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