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Truncated DNM1 variant underlines developmental delay and epileptic encephalopathy
BACKGROUND: Developmental and epileptic encephalopathies (DEEs) signify a group of heterogeneous neurodevelopmental disorder associated with early-onset seizures accompanied by developmental delay, hypotonia, mild to severe intellectual disability, and developmental regression. Variants in the DNM1...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10601988/ https://www.ncbi.nlm.nih.gov/pubmed/37900685 http://dx.doi.org/10.3389/fped.2023.1266376 |
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author | Afsar, Tayyaba Huang, Xiaoyun Shah, Abid Ali Abbas, Safdar Bano, Shazia Mahmood, Arif Hu, Junjian Razak, Suhail Umair, Muhammad |
author_facet | Afsar, Tayyaba Huang, Xiaoyun Shah, Abid Ali Abbas, Safdar Bano, Shazia Mahmood, Arif Hu, Junjian Razak, Suhail Umair, Muhammad |
author_sort | Afsar, Tayyaba |
collection | PubMed |
description | BACKGROUND: Developmental and epileptic encephalopathies (DEEs) signify a group of heterogeneous neurodevelopmental disorder associated with early-onset seizures accompanied by developmental delay, hypotonia, mild to severe intellectual disability, and developmental regression. Variants in the DNM1 gene have been associated with autosomal dominant DEE type 31A and autosomal recessive DEE type 31B. METHODS: In the current study, a consanguineous Pakistani family consisting of a proband (IV-2) was clinically evaluated and genetically analyzed manifesting in severe neurodevelopmental phenotypes. WES followed by Sanger sequencing was performed to identify the disease-causing variant. Furthermore, 3D protein modeling and dynamic simulation of wild-type and mutant proteins along with reverse transcriptase (RT)–based mRNA expression were checked using standard methods. RESULTS: Data analysis of WES revealed a novel homozygous non-sense variant (c.1402G>T; p. Glu468*) in exon 11 of the DNM1 gene that was predicted as pathogenic class I. Variants in the DNM1 gene have been associated with DEE types 31A and B. Different bioinformatics prediction tools and American College of Medical Genetics guidelines were used to verify the identified variant. Sanger sequencing was used to validate the disease-causing variant. Our approach validated the pathogenesis of the variant as a cause of heterogeneous neurodevelopmental disorders. In addition, 3D protein modeling showed that the mutant protein would lose most of the amino acids and might not perform the proper function if the surveillance non-sense-mediated decay mechanism was skipped. Molecular dynamics analysis showed varied trajectories of wild-type and mutant DNM1 proteins in terms of root mean square deviation, root mean square fluctuation and radius of gyration. Similarly, RT-qPCR revealed a substantial reduction of the DNM1 gene in the index patient. CONCLUSION: Our finding further confirms the association of homozygous, loss-of-function variants in DNM1 associated with DEE type 31B. The study expands the genotypic and phenotypic spectrum of pathogenic DNM1 variants related to DNM1-associated pathogenesis. |
format | Online Article Text |
id | pubmed-10601988 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-106019882023-10-27 Truncated DNM1 variant underlines developmental delay and epileptic encephalopathy Afsar, Tayyaba Huang, Xiaoyun Shah, Abid Ali Abbas, Safdar Bano, Shazia Mahmood, Arif Hu, Junjian Razak, Suhail Umair, Muhammad Front Pediatr Pediatrics BACKGROUND: Developmental and epileptic encephalopathies (DEEs) signify a group of heterogeneous neurodevelopmental disorder associated with early-onset seizures accompanied by developmental delay, hypotonia, mild to severe intellectual disability, and developmental regression. Variants in the DNM1 gene have been associated with autosomal dominant DEE type 31A and autosomal recessive DEE type 31B. METHODS: In the current study, a consanguineous Pakistani family consisting of a proband (IV-2) was clinically evaluated and genetically analyzed manifesting in severe neurodevelopmental phenotypes. WES followed by Sanger sequencing was performed to identify the disease-causing variant. Furthermore, 3D protein modeling and dynamic simulation of wild-type and mutant proteins along with reverse transcriptase (RT)–based mRNA expression were checked using standard methods. RESULTS: Data analysis of WES revealed a novel homozygous non-sense variant (c.1402G>T; p. Glu468*) in exon 11 of the DNM1 gene that was predicted as pathogenic class I. Variants in the DNM1 gene have been associated with DEE types 31A and B. Different bioinformatics prediction tools and American College of Medical Genetics guidelines were used to verify the identified variant. Sanger sequencing was used to validate the disease-causing variant. Our approach validated the pathogenesis of the variant as a cause of heterogeneous neurodevelopmental disorders. In addition, 3D protein modeling showed that the mutant protein would lose most of the amino acids and might not perform the proper function if the surveillance non-sense-mediated decay mechanism was skipped. Molecular dynamics analysis showed varied trajectories of wild-type and mutant DNM1 proteins in terms of root mean square deviation, root mean square fluctuation and radius of gyration. Similarly, RT-qPCR revealed a substantial reduction of the DNM1 gene in the index patient. CONCLUSION: Our finding further confirms the association of homozygous, loss-of-function variants in DNM1 associated with DEE type 31B. The study expands the genotypic and phenotypic spectrum of pathogenic DNM1 variants related to DNM1-associated pathogenesis. Frontiers Media S.A. 2023-10-09 /pmc/articles/PMC10601988/ /pubmed/37900685 http://dx.doi.org/10.3389/fped.2023.1266376 Text en © 2023 Afsar, Huang, Shah, Abbas, Bano, Mahmood, Hu, Razak and Umair. 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) (https://creativecommons.org/licenses/by/4.0/) . 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 | Pediatrics Afsar, Tayyaba Huang, Xiaoyun Shah, Abid Ali Abbas, Safdar Bano, Shazia Mahmood, Arif Hu, Junjian Razak, Suhail Umair, Muhammad Truncated DNM1 variant underlines developmental delay and epileptic encephalopathy |
title | Truncated DNM1 variant underlines developmental delay and epileptic encephalopathy |
title_full | Truncated DNM1 variant underlines developmental delay and epileptic encephalopathy |
title_fullStr | Truncated DNM1 variant underlines developmental delay and epileptic encephalopathy |
title_full_unstemmed | Truncated DNM1 variant underlines developmental delay and epileptic encephalopathy |
title_short | Truncated DNM1 variant underlines developmental delay and epileptic encephalopathy |
title_sort | truncated dnm1 variant underlines developmental delay and epileptic encephalopathy |
topic | Pediatrics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10601988/ https://www.ncbi.nlm.nih.gov/pubmed/37900685 http://dx.doi.org/10.3389/fped.2023.1266376 |
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