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Genetic Diagnosis Spectrum and Multigenic Burden of Exome-Level Rare Variants in a Childhood Epilepsy Cohort

Childhood epilepsy is a considerably heterogeneous neurological condition with a high worldwide incidence. Genetic diagnosis of childhood epilepsy provides the most accurate pathogenetic evidence; however, a large proportion of highly suspected cases remain undiagnosed. Accumulation of rare variants...

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Autores principales: Yao, Ruen, Zhou, Yunqing, Tang, Jie, Li, Niu, Yu, Tingting, He, Yingzhong, Wang, Cuijin, Wang, Jiwen, Wang, Jian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8725238/
https://www.ncbi.nlm.nih.gov/pubmed/34992632
http://dx.doi.org/10.3389/fgene.2021.782419
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author Yao, Ruen
Zhou, Yunqing
Tang, Jie
Li, Niu
Yu, Tingting
He, Yingzhong
Wang, Cuijin
Wang, Jiwen
Wang, Jian
author_facet Yao, Ruen
Zhou, Yunqing
Tang, Jie
Li, Niu
Yu, Tingting
He, Yingzhong
Wang, Cuijin
Wang, Jiwen
Wang, Jian
author_sort Yao, Ruen
collection PubMed
description Childhood epilepsy is a considerably heterogeneous neurological condition with a high worldwide incidence. Genetic diagnosis of childhood epilepsy provides the most accurate pathogenetic evidence; however, a large proportion of highly suspected cases remain undiagnosed. Accumulation of rare variants at the exome level as a multigenic burden contributing to childhood epilepsy should be further evaluated. In this retrospective analysis, exome-level sequencing was used to depict the mutation spectra of 294 childhood epilepsy patients from Shanghai Children’s Medical Center, Department of Neurology. Furthermore, variant information from exome sequencing data was analyzed apart from monogenic diagnostic purposes to elucidate the possible multigenic burden of rare variants related to epilepsy pathogenesis. Exome sequencing reached a diagnostic rate of 30.61% and identified six genes not currently listed in the epilepsy-associated gene list. A multigenic burden study revealed a three-fold possibility that deleterious missense mutations in ion channel and synaptic genes in the undiagnosed cohort may contribute to the genetic risk of childhood epilepsy, whereas variants in the gene categories of cell growth, metabolic, and regulatory function showed no significant difference. Our study provides a comprehensive overview of the genetic diagnosis of a Chinese childhood epilepsy cohort and provides novel insights into the genetic background of these patients. Harmful missense mutations in genes related to ion channels and synapses are most likely to produce a multigenic burden in childhood epilepsy.
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spelling pubmed-87252382022-01-05 Genetic Diagnosis Spectrum and Multigenic Burden of Exome-Level Rare Variants in a Childhood Epilepsy Cohort Yao, Ruen Zhou, Yunqing Tang, Jie Li, Niu Yu, Tingting He, Yingzhong Wang, Cuijin Wang, Jiwen Wang, Jian Front Genet Genetics Childhood epilepsy is a considerably heterogeneous neurological condition with a high worldwide incidence. Genetic diagnosis of childhood epilepsy provides the most accurate pathogenetic evidence; however, a large proportion of highly suspected cases remain undiagnosed. Accumulation of rare variants at the exome level as a multigenic burden contributing to childhood epilepsy should be further evaluated. In this retrospective analysis, exome-level sequencing was used to depict the mutation spectra of 294 childhood epilepsy patients from Shanghai Children’s Medical Center, Department of Neurology. Furthermore, variant information from exome sequencing data was analyzed apart from monogenic diagnostic purposes to elucidate the possible multigenic burden of rare variants related to epilepsy pathogenesis. Exome sequencing reached a diagnostic rate of 30.61% and identified six genes not currently listed in the epilepsy-associated gene list. A multigenic burden study revealed a three-fold possibility that deleterious missense mutations in ion channel and synaptic genes in the undiagnosed cohort may contribute to the genetic risk of childhood epilepsy, whereas variants in the gene categories of cell growth, metabolic, and regulatory function showed no significant difference. Our study provides a comprehensive overview of the genetic diagnosis of a Chinese childhood epilepsy cohort and provides novel insights into the genetic background of these patients. Harmful missense mutations in genes related to ion channels and synapses are most likely to produce a multigenic burden in childhood epilepsy. Frontiers Media S.A. 2021-12-21 /pmc/articles/PMC8725238/ /pubmed/34992632 http://dx.doi.org/10.3389/fgene.2021.782419 Text en Copyright © 2021 Yao, Zhou, Tang, Li, Yu, He, Wang, Wang and Wang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Yao, Ruen
Zhou, Yunqing
Tang, Jie
Li, Niu
Yu, Tingting
He, Yingzhong
Wang, Cuijin
Wang, Jiwen
Wang, Jian
Genetic Diagnosis Spectrum and Multigenic Burden of Exome-Level Rare Variants in a Childhood Epilepsy Cohort
title Genetic Diagnosis Spectrum and Multigenic Burden of Exome-Level Rare Variants in a Childhood Epilepsy Cohort
title_full Genetic Diagnosis Spectrum and Multigenic Burden of Exome-Level Rare Variants in a Childhood Epilepsy Cohort
title_fullStr Genetic Diagnosis Spectrum and Multigenic Burden of Exome-Level Rare Variants in a Childhood Epilepsy Cohort
title_full_unstemmed Genetic Diagnosis Spectrum and Multigenic Burden of Exome-Level Rare Variants in a Childhood Epilepsy Cohort
title_short Genetic Diagnosis Spectrum and Multigenic Burden of Exome-Level Rare Variants in a Childhood Epilepsy Cohort
title_sort genetic diagnosis spectrum and multigenic burden of exome-level rare variants in a childhood epilepsy cohort
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8725238/
https://www.ncbi.nlm.nih.gov/pubmed/34992632
http://dx.doi.org/10.3389/fgene.2021.782419
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