Dataset Information

Genetic and Phenotype Analysis of a Chinese Cohort of Infants and Children With Epilepsy.

ABSTRACT: Background: Epilepsy in childhood is a common and diverse neurological disorder. We conducted a genetic and phenotype analysis of a Chinese cohort of infants and children with epilepsy. Methods: We conducted a pedigree analysis of 260 Chinese patients with epilepsy onset during infancy or childhood by whole exome sequencing (WES). Results: Of the 260 probands analyzed, a genetic diagnosis was established in 135 patients. One-hundred eighty-eight phenotypes were detected in those 135 positive/likely positive patients, 106 patients had more than two phenotypes, and 67 patients had more than three phenotypes. A total of 142 variants of 81 genes were detected among the positive/likely positive patients. Among these 142 variants, of which 87 of 66 genes were novel. Conclusion: Our findings extend the variant spectrum of genes related to epilepsy. Our results will be useful for genetic testing and counseling for patients with epilepsy.

SUBMITTER: Chuan Z

PROVIDER: S-EPMC9091957 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Genetic and Phenotype Analysis of a Chinese Cohort of Infants and Children With Epilepsy.

Chuan Zhang Z Ruikun Cai C Qian Li L Shiyue Mei M Shengju Hao H Yong Yuan Y Haibo Li L Neng Xiao X Yong Zhao Z Huiqin Xue X Weijia Wang W Ling Hui H Bingbo Zhou Z Zhang Qinghua Q Yan Wang W Zongfu Cao C Xu Ma M

Frontiers in genetics 20220427

Background: Epilepsy in childhood is a common and diverse neurological disorder. We conducted a genetic and phenotype analysis of a Chinese cohort of infants and children with epilepsy. Methods: We conducted a pedigree analysis of 260 Chinese patients with epilepsy onset during infancy or childhood by whole exome sequencing (WES). Results: Of the 260 probands analyzed, a genetic diagnosis was established in 135 patients. One-hundred eighty-eight phenotypes were detected in t ...[more]

PMID: 35571021

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Project description:ObjectiveTo summarize the clinical features and genetic mutation characteristics of Chinese children with KCNQ2-related epilepsy.MethodsA cohort of children with genetically caused epilepsy was evaluated at Linyi People's Hospital from January 2017 to December 2023. After next-generation sequencing and pathogenicity analysis, we summarized the medical records and genetic testing data of the children who had KCNQ2 gene mutations.ResultsWe identified 23 KCNQ2 gene mutations. 73.9% (n = 17) of the mutation sites were located in S5-S6 segments and the C-terminal region. In addition to the common phenotypes, 2 new phenotypes were identified: infantile convulsion with paroxysmal choreoathetosis (ICCA) and febrile seizure plus (FS+). Of all the cases with abnormal video-electro-encephalography, three cases with self-limited familial infantile epilepsy (SeLNE) exhibited a small number of multifocal discharges. Of the patients who have taken a particular antiepileptic drug, the statistics on the number of patients who have responded to the drug are as follows: oxcarbazepine (8/9, 88.9%), levetiracetam (5/7, 71.4%), phenobarbital (9/16, 56.3%), and topiramate (2/5, 40.0%). However, the efficacy of phenobarbital varied widely in treating SeLNE and KCNQ2-DEE. At the final follow-up, 1 case with SeLNE had a transient developmental regression and 7 cases with KCNQ2-DEE had mild to severe developmental backwardness.SignificanceAlthough clinically rare, we report 10 new KCNQ2 mutations and two new phenotypes: ICCA and FS+. This further expands genetic and phenotypic spectrum of KCNQ2-related epilepsy. The gene mutation sites are mostly located in S5-S6 segments and the C-terminal region, and the former is usually associated with KCNQ2-DEE. Sodium channel blockers (including oxcarbazepine and topiramate) and levetiracetam should be prioritized over phenobarbital for KCNQ2-DEE. Some cases with KCNQ2-related epilepsy may have transient developmental regression during periods of frequent seizures. Early treatment and early seizure control may be beneficial for willing outcomes in children with KCNQ2-DEE.Plain language summaryThis article reports 23 cases of children with KCNQ2-related epilepsy, including 10 new mutation sites and 2 new phenotypes. It further expands the genetic and phenotypic spectrum of KCNQ2-related epilepsy. In addition, the article summarizes the gene mutation characteristics and clinical manifestations of children with KCNQ2-related epilepsy, with the expectation of providing a certain theoretical basis for the diagnosis and treatment of such patients.

Project description:ObjectiveAlbeit the gene of PCDH19-FE was ascertained, the correlation of gene mutation, PCDH19 protein structure, and phenotype heterogeneity remained obscure. This study aimed to report a five-generation pedigree of seven female patients of PCDH19-FE and tried to explore whether two variants were correlated with PCDH19 protein structure and function alteration, and PCDH19-FE phenotype.MethodsWe analyzed the clinical data and genetic variants of a PCDH19-FE pedigree, to explore the phenotype heterogeneity of PCDH19-FE and underlying mechanisms. In addition to the clinical information of family members, next-generation sequencing was adopted to detect the variant sites of probands with validation by sanger sequencing. And the sanger sequencing was conducted in other patients in this pedigree. The biological conservation analysis and population polymorphism analysis of variants were also performed subsequently. The structure alteration of mutated PCDH19 protein was predicted by AlphaFold2.ResultsBased on a five-generation pedigree of PCDH19-FE, missense variants of c.695A>G and c.2760T>A in the PCDH19 gene were found in the heterozygous proband (V:1), which resulted in the change of amino acid 232 from Asn to Ser (p.Asn232Ser) and amino acid 920 from Asp to Glu (p.Asp920Glu) influencing PCDH19 function. The other six females in the pedigree (II:6, II:8, IV:3, IV:4, IV:5, IV:11) exhibited different clinical phenotypes but shared the same variant. Two males with the same variant have no clinical manifestations (III:3, III:10). The biological conservation analysis and population polymorphism analysis demonstrated the highly conservative characteristics of these two variants. AlphaFold2 predicted that the variant, p.Asp920Glu, led to the disappearance of the hydrogen bond between Asp at position 920 and His at position 919. Furthermore, the hydrogen bond between Asp920 and His919 also disappeared when the Asn amino acid mutated to Ser at position 232.ConclusionA strong genotype-phenotype heterogeneity was observed among female patients with the same genotype in our PCDH19-FE pedigree. And two missense variants, c.695A > G and c.2760T>A in the PCDH19 gene, have been identified in our pedigree. The c.2760T>A variant was a novel variant site probably related to the PCDH19-FE.

Dataset Information

Genetic and Phenotype Analysis of a Chinese Cohort of Infants and Children With Epilepsy.

Publications

Genetic and Phenotype Analysis of a Chinese Cohort of Infants and Children With Epilepsy.

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