Exome sequencing identifies molecular diagnosis in children with drug‐resistant epilepsy

Tsang, Mandy Ho-Yin; Leung, Gordon K. C.; Ho, Alvin Chi Chung; Yeung, Kit San; Mak, Christopher C. Y.; Pei, Steven L. C.; Yu, Mullin H.C.; Kan, Anita Sik‐Yau; Chan, Kelvin Yuen-Kwong; Kwong, Karen L.; Lee, So Lun; Yung, A; Fung, Cheuk‐Wing; Chung, Brian Hon‐Yin

doi:10.1002/epi4.12282

Cited by 28 publications

(31 citation statements)

References 44 publications

(82 reference statements)

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“…Genetic Characteristics In Drug-resistant Epilepsy Of Published Studies Table 3 provides a summary of previous studies about genetic characteristics in DRE [12][13][14][15][16][17][18][19][20][21]. Regardless of varied molecular diagnostic tool used between studies, some gene mutations were found to appear repeatedly, such as SCN1A (5.6%, n = 74/1308), followed by SCN8A (1.37%, n = 18/1308), TSC2 (1.22%, n = 16/1308), SCN2A (1.07%, n = 14/1308) and KCNQ2 (0.99%, n = 13/1308) 3).…”

Section: Discussionmentioning

confidence: 99%

Genetic factors and the risk of drug-resistant epilepsy in young children with epilepsy and neurodevelopment disability: A Prospective Study and Updated Meta-Analysis

Lin

Chou

Hong

2020

Preprint

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Background Drug-resistant epilepsy (DRE) affects 7–20% of children with epilepsy. Although some risk factors for DRE have been identified, the results have not been consistent. Moreover, data regarding the risk factors for epilepsy and its seizure outcome in the first 2 years of life are limited. Methods We analyzed data for children aged 0–2 years with epilepsy and neurodevelopmental disability (NDD) from January, 2013, through December, 2017. These patients were followed up to compared the risk of DRE in patients with genetic defect (genetic group) with that without genetic defect (nongenetic group). Additionally, we conducted a meta-analysis to identify the pooled prevalence of genetic factors in children with DRE Results A total of 96 patients were enrolled. A total of 68 patients were enrolled in the nongenetic group, whereas 28 patients were enrolled in the genetic group. The overall DRE risk in the genetic group was 6.5 times (95% confidence interval [CI], 2.15–19.6; p = 0.03) higher than that in the nongenetic group. Separately, a total of 1308 DRE patients were participated in the meta-analysis. The pooled prevalence of these patients with genetic factors was 22.8% (95% CI 17.4–29.3) Conclusions The genetic defect plays a crucial role in the development of DRE in younger children with epilepsy and NDD. The results can serve as a reference for further studies of epilepsy panel design and may also assist in the development of improved treatments and prevention strategies for DRE.

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Section: Discussionmentioning

confidence: 99%

Genetic factors and the risk of drug-resistant epilepsy in young children with epilepsy and neurodevelopment disability: A Prospective Study and Updated Meta-Analysis

Lin

Chou

Hong

2020

Preprint

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“…(7) For the subsequent 25 cases, WES was performed at the Department of Paediatric and Adolescent Medicine of HKU. (25) The exome library was prepared using the TruSeq Rapid Exome Library Prep Kit (Illumina) and sequenced using the Illumina NextSeq500 system. The in-house bioinformatics pipeline was used for data analysis.…”

Section: Whole-exome Sequencingmentioning

confidence: 99%

Delineation of molecular findings by whole exome sequencing for suspected cases of paediatric-onset mitochondrial diseases in the Southern Chinese population

Tsang

Kwong

Chan

et al. 2020

Preprint

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BackgroundMitochondrial diseases (MDs) are a group of clinically and genetically heterogeneous disorders characterized by defects in oxidative phosphorylation. Since clinical phenotypes of MDs may be non-specific, genetic diagnosis is crucial for guiding disease management. In the current study, whole-exome sequencing (WES) was performed for our paediatric-onset MD cohort of a Southern Chinese origin, with the aim of identifying key disease-causing variants in the Chinese patients with MDs.MethodsWe recruited Chinese patients who had paediatric-onset MDs and a minimum mitochondrial disease criteria (MDC) score of 3. Patients with positive target gene or mitochondrial DNA sequencing results were excluded. WES was performed, variants with population frequency ≤1% were analysed for pathogenicity on the basis of the American College of Medical Genetics and Genomics guidelines.ResultsSixty-six patients with pre-biopsy MDC scores of 3–8 were recruited. The overall diagnostic yield was 35% (23/66). Eleven patients (17%) were found to have mutations in MD-related genes, with COQ4 having the highest mutation rate owing to the Chinese-specific founder mutation (4/66, 6%). Twelve patients (12/66, 18%) had mutations in non-MD-related genes: ATP1A3 (n=3, two were siblings), ALDH5A1 , ARX , FA2H , KCNT1 , LDHD , NEFL , NKX2-2 , TBCK , and WAC.ConclusionsWe confirmed that the COQ4 :c.370G>A, p.(Gly124Ser) variant was a recurrent founder mutation among the Southern Chinese population. Screening for this mutation should therefore be considered while diagnosing Chinese patients suspected to have MDs. Furthermore, WES has proven to be useful in detecting variants in patients suspected to have MDs because it helps to obtain an unbiased and precise genetic diagnosis for these diseases, which are genetically heterogeneous.

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“…It is related to DS, also denominated as early childhood epileptic encephalopathy type 6. [11][12][13] In this disease, particularly, there are 12 possibilities of deleterious alterations observed, being 50% missense type (c.829T> C, c.971A> C, c.2360T> G, c.4093G> T, c.5178G> T and c .5434T> C), 25% splice sites (IVS2 + 1A> G, IVS4 + 1G> A and IVS8 + 3G> T), 17% frameshift type (c.3719_3720insGATA and c.1242delA), 8% deletion of a triplet (c.5489_5491delAGT). 14 Mutations provide a great risk of SUDEP, because this is a rare and severe progressive encephalopathy without concrete treatment.…”

Section: Scn1amentioning

confidence: 99%

“…14 Mutations provide a great risk of SUDEP, because this is a rare and severe progressive encephalopathy without concrete treatment. 13,14,29,37 Image 1 Cytogenetic location of SCNA1 gene: 2q24.3. Adapted from: Genetics Home Reference.…”

Section: Scn1amentioning

confidence: 99%

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Genetics in epilepsy, Dravet and SUDEP: A systematic review

Aguiar¹,

Rocha²,

Avi³

et al. 2019

JNSK

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Introduction: Epilepsy is a neurologic condition and its patients have higher mortality rates than healthy individuals. One of the most frequent death causes in epilepsy is SUDEP. Moreover, another cause in epilepsy, although rare, is Dravet Syndrome and it's generally diagnosed in children in their first year of life. In around 70% of the patients there is a genetic inheritance involved and several genes have been described as related to SUDEP and Dravet Syndrome which the most prevalent were DNA and belonged to the voltagegated channel coding. Objectives: Identify genes related do Dravet Syndrome, SUDEP and Epilepsy in literature, analyze the convergence of results, and discuss the differences that were found, contributing to the study of genetic mapping. Methodology: Meta-analysis realized through a bibliographical research in the electronic data banks such as PUBMED, NCBI, Scholar Google and Scielo with the descriptors Epilepsy; Epilepsies, Myoclonic; Polymorphism, Single Nucleotide; MicroRNAs; Death, Sudden. The languages used to filter the articles were English, Spanish and Portuguese. The year was a filtering factor, selecting only articles published in the last 20 years. Results: About forty (40) genes were found to be SUDEP related and the most relevant was KCNH2, appearing more frequently than other genes. Additionally, in Epilepsy without risk for SUDEP twenty-eight (28) DNA genes were found, which the most frequently mentioned was HCN2, appearing six (6) times. Among Dravet syndrome patients, only two (2) genes were described: SCN1A and SCN9A, both of them were SUDEP risk related. In epilepsy nineteen (19) microRNA genes were found in five (5) different articles. Project: It was identified genes related to Dravet Syndrome, SUDEP and Epilepsy in literature and was noted that some genes appeared more frequently than others. Among the DNA related genes, the most prevalent were around those belonging to the voltage-gated channel coding, being them sodium, hydrogen and potassium. The results demonstrate that 25% of all articles mentioned SCN1A; 17,5% mentioned HCN2 and 15% mentioned KCNH2. Together these findings provide a basis for further investigation around the role of ionic channels in SUDEP and DS. On the other hand, regarding to MicroRNA linked genes data were scarce. Only five articles described changes on SUDEP and neither described changes compatible with DS. There was no most prevalent mRNA gene. Conclusion: A range of studies associated DNA mutations with Epilepsy, DS and SUDEP. However, MicroRNA research could not provide concrete evidence on its influence in the development of the epilepsy and epilepsy related conditions. The identification of possible etiological factors can allow a correct and early diagnosis, providing better prognosis and therapeutic outcome, besides it can evaluate the recurrence of the disease in the family. Still, further prospective studies in larger cohorts are required to further define the genetic predisposition to SUDEP, DS and Epilepsy.

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Exome sequencing identifies molecular diagnosis in children with drug‐resistant epilepsy

Cited by 28 publications

References 44 publications

Genetic factors and the risk of drug-resistant epilepsy in young children with epilepsy and neurodevelopment disability: A Prospective Study and Updated Meta-Analysis

Genetic factors and the risk of drug-resistant epilepsy in young children with epilepsy and neurodevelopment disability: A Prospective Study and Updated Meta-Analysis

Delineation of molecular findings by whole exome sequencing for suspected cases of paediatric-onset mitochondrial diseases in the Southern Chinese population

Genetics in epilepsy, Dravet and SUDEP: A systematic review

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