Rare Copy Number Variations and Predictors in Children With Intellectual Disability and Epilepsy
Introduction: The concurrence of intellectual disability/global developmental delay and epilepsy (ID/GDD-EP) is very common in the pediatric population. The etiologies for both conditions are complex and largely unknown. The predictors of significant copy number variations (CNVs) are known for the c...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
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Frontiers Media S.A.
2018-11-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fneur.2018.00947/full |
| _version_ | 1819048948498694144 |
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| author | Miriam Kessi Miriam Kessi Juan Xiong Juan Xiong Liwen Wu Liwen Wu Lifen Yang Lifen Yang Fang He Fang He Chen Chen Chen Chen Nan Pang Nan Pang Haolin Duan Haolin Duan Wen Zhang Wen Zhang Ahmed Arafat Ahmed Arafat Fei Yin Fei Yin Jing Peng Jing Peng |
| author_facet | Miriam Kessi Miriam Kessi Juan Xiong Juan Xiong Liwen Wu Liwen Wu Lifen Yang Lifen Yang Fang He Fang He Chen Chen Chen Chen Nan Pang Nan Pang Haolin Duan Haolin Duan Wen Zhang Wen Zhang Ahmed Arafat Ahmed Arafat Fei Yin Fei Yin Jing Peng Jing Peng |
| author_sort | Miriam Kessi |
| collection | DOAJ |
| description | Introduction: The concurrence of intellectual disability/global developmental delay and epilepsy (ID/GDD-EP) is very common in the pediatric population. The etiologies for both conditions are complex and largely unknown. The predictors of significant copy number variations (CNVs) are known for the cases with ID/GDD, but unknown for those with exclusive ID/GDD-EP. Importantly, the known predictors are largely from the same ethnic group; hence, they lack replication.Purpose: We aimed to determine and investigate the diagnostic yield of CNV tests, new causative CNVs, and the independent predictors of significant CNVs in Chinese children with unexplained ID/GDD-EP.Materials and methods: A total of 100 pediatric patients with unexplained ID/GDD-EP and 1,000 healthy controls were recruited. The American College of Medical Genetics guideline was used to classify the CNVs. Additionally, clinical information was collected and compared between those with significant and non-significant CNVs.Results: Twenty-eight percent of the patients had significant CNVs, 16% had variants of unknown significance, and 56% had non-significant CNVs. In total, 31 CNVs were identified in 28% (28/100) of cases: 25 pathogenic and 6 likely pathogenic. Eighteen known syndromes were diagnosed in 17 cases. Thirteen rare CNVs (8 novel and 5 reported in literature) were identified, of which three spanned dosage-sensitive genes: 19q13.2 deletion (ATP1A3), Xp11.4-p11.3 deletion (CASK), and 6q25.3-q25.3 deletion (ARID1B). By comparing clinical features in patients with significant CNVs against those with non-significant CNVs, a statistically significant association was found between the presence of significant CNVs and speech and language delay for those aged above 2 years and for those with facial malformations, microcephaly, congenital heart disease, fair skin, eye malformations, and mega cisterna magna. Multivariate logistic regression analysis allowed the identification of two independent significant CNV predictors, which are eye malformations and facial malformations.Conclusion: Our study supports the performance of CNV tests in pediatric patients with unexplained ID/GDD-EP, as there is high diagnostic yield, which informs genetic counseling. It adds 13 rare CNVs (8 novel), which can be accountable for both conditions. Moreover, congenital eye and facial malformations are clinical markers that can aid clinicians to understand which patients can benefit from the CNV testing and which will not, thus helping patients to avoid unnecessary and expensive tests. |
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| spelling | doaj.art-d484e8cd4ba74f51806723c2a60dc3a62022-12-21T19:05:42ZengFrontiers Media S.A.Frontiers in Neurology1664-22952018-11-01910.3389/fneur.2018.00947420241Rare Copy Number Variations and Predictors in Children With Intellectual Disability and EpilepsyMiriam Kessi0Miriam Kessi1Juan Xiong2Juan Xiong3Liwen Wu4Liwen Wu5Lifen Yang6Lifen Yang7Fang He8Fang He9Chen Chen10Chen Chen11Nan Pang12Nan Pang13Haolin Duan14Haolin Duan15Wen Zhang16Wen Zhang17Ahmed Arafat18Ahmed Arafat19Fei Yin20Fei Yin21Jing Peng22Jing Peng23Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, ChinaHunan Intellectual and Developmental Disabilities Research Center, Changsha, ChinaDepartment of Pediatrics, Xiangya Hospital, Central South University, Changsha, ChinaHunan Intellectual and Developmental Disabilities Research Center, Changsha, ChinaDepartment of Pediatrics, Xiangya Hospital, Central South University, Changsha, ChinaHunan Intellectual and Developmental Disabilities Research Center, Changsha, ChinaDepartment of Pediatrics, Xiangya Hospital, Central South University, Changsha, ChinaHunan Intellectual and Developmental Disabilities Research Center, Changsha, ChinaDepartment of Pediatrics, Xiangya Hospital, Central South University, Changsha, ChinaHunan Intellectual and Developmental Disabilities Research Center, Changsha, ChinaDepartment of Pediatrics, Xiangya Hospital, Central South University, Changsha, ChinaHunan Intellectual and Developmental Disabilities Research Center, Changsha, ChinaDepartment of Pediatrics, Xiangya Hospital, Central South University, Changsha, ChinaHunan Intellectual and Developmental Disabilities Research Center, Changsha, ChinaDepartment of Pediatrics, Xiangya Hospital, Central South University, Changsha, ChinaHunan Intellectual and Developmental Disabilities Research Center, Changsha, ChinaDepartment of Pediatrics, Xiangya Hospital, Central South University, Changsha, ChinaHunan Intellectual and Developmental Disabilities Research Center, Changsha, ChinaDepartment of Pediatrics, Xiangya Hospital, Central South University, Changsha, ChinaHunan Intellectual and Developmental Disabilities Research Center, Changsha, ChinaDepartment of Pediatrics, Xiangya Hospital, Central South University, Changsha, ChinaHunan Intellectual and Developmental Disabilities Research Center, Changsha, ChinaDepartment of Pediatrics, Xiangya Hospital, Central South University, Changsha, ChinaHunan Intellectual and Developmental Disabilities Research Center, Changsha, ChinaIntroduction: The concurrence of intellectual disability/global developmental delay and epilepsy (ID/GDD-EP) is very common in the pediatric population. The etiologies for both conditions are complex and largely unknown. The predictors of significant copy number variations (CNVs) are known for the cases with ID/GDD, but unknown for those with exclusive ID/GDD-EP. Importantly, the known predictors are largely from the same ethnic group; hence, they lack replication.Purpose: We aimed to determine and investigate the diagnostic yield of CNV tests, new causative CNVs, and the independent predictors of significant CNVs in Chinese children with unexplained ID/GDD-EP.Materials and methods: A total of 100 pediatric patients with unexplained ID/GDD-EP and 1,000 healthy controls were recruited. The American College of Medical Genetics guideline was used to classify the CNVs. Additionally, clinical information was collected and compared between those with significant and non-significant CNVs.Results: Twenty-eight percent of the patients had significant CNVs, 16% had variants of unknown significance, and 56% had non-significant CNVs. In total, 31 CNVs were identified in 28% (28/100) of cases: 25 pathogenic and 6 likely pathogenic. Eighteen known syndromes were diagnosed in 17 cases. Thirteen rare CNVs (8 novel and 5 reported in literature) were identified, of which three spanned dosage-sensitive genes: 19q13.2 deletion (ATP1A3), Xp11.4-p11.3 deletion (CASK), and 6q25.3-q25.3 deletion (ARID1B). By comparing clinical features in patients with significant CNVs against those with non-significant CNVs, a statistically significant association was found between the presence of significant CNVs and speech and language delay for those aged above 2 years and for those with facial malformations, microcephaly, congenital heart disease, fair skin, eye malformations, and mega cisterna magna. Multivariate logistic regression analysis allowed the identification of two independent significant CNV predictors, which are eye malformations and facial malformations.Conclusion: Our study supports the performance of CNV tests in pediatric patients with unexplained ID/GDD-EP, as there is high diagnostic yield, which informs genetic counseling. It adds 13 rare CNVs (8 novel), which can be accountable for both conditions. Moreover, congenital eye and facial malformations are clinical markers that can aid clinicians to understand which patients can benefit from the CNV testing and which will not, thus helping patients to avoid unnecessary and expensive tests.https://www.frontiersin.org/article/10.3389/fneur.2018.00947/fullintellectual disabilityglobal developmental delay and epilepsycopy number variationsindependent predictorsclinical markers |
| spellingShingle | Miriam Kessi Miriam Kessi Juan Xiong Juan Xiong Liwen Wu Liwen Wu Lifen Yang Lifen Yang Fang He Fang He Chen Chen Chen Chen Nan Pang Nan Pang Haolin Duan Haolin Duan Wen Zhang Wen Zhang Ahmed Arafat Ahmed Arafat Fei Yin Fei Yin Jing Peng Jing Peng Rare Copy Number Variations and Predictors in Children With Intellectual Disability and Epilepsy Frontiers in Neurology intellectual disability global developmental delay and epilepsy copy number variations independent predictors clinical markers |
| title | Rare Copy Number Variations and Predictors in Children With Intellectual Disability and Epilepsy |
| title_full | Rare Copy Number Variations and Predictors in Children With Intellectual Disability and Epilepsy |
| title_fullStr | Rare Copy Number Variations and Predictors in Children With Intellectual Disability and Epilepsy |
| title_full_unstemmed | Rare Copy Number Variations and Predictors in Children With Intellectual Disability and Epilepsy |
| title_short | Rare Copy Number Variations and Predictors in Children With Intellectual Disability and Epilepsy |
| title_sort | rare copy number variations and predictors in children with intellectual disability and epilepsy |
| topic | intellectual disability global developmental delay and epilepsy copy number variations independent predictors clinical markers |
| url | https://www.frontiersin.org/article/10.3389/fneur.2018.00947/full |
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