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Novel Variant Expands the Clinical Spectrum of CUX2-Associated Developmental and Epileptic Encephalopathies

Developmental and epileptic encephalopathies (DEE) caused by heterozygous deleterious variants in Cut Like Homeobox2 (CUX2) is rare. To the best of our knowledge the only variant associated with a phenotype in this gene is the de novo missense variant c.1768G > A, p.Glu590Lys; however, further ad...

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Autores principales: Zhang, Feng, Li, Fuwei, Chen, Fujian, Huang, Jinrong, Luo, Qiong, Du, Xilong, Zhou, Jiapeng, Gu, Weiyue, Xu, Kaishou
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9283828/
https://www.ncbi.nlm.nih.gov/pubmed/35846140
http://dx.doi.org/10.3389/fgene.2022.808181
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author Zhang, Feng
Li, Fuwei
Chen, Fujian
Huang, Jinrong
Luo, Qiong
Du, Xilong
Zhou, Jiapeng
Gu, Weiyue
Xu, Kaishou
author_facet Zhang, Feng
Li, Fuwei
Chen, Fujian
Huang, Jinrong
Luo, Qiong
Du, Xilong
Zhou, Jiapeng
Gu, Weiyue
Xu, Kaishou
author_sort Zhang, Feng
collection PubMed
description Developmental and epileptic encephalopathies (DEE) caused by heterozygous deleterious variants in Cut Like Homeobox2 (CUX2) is rare. To the best of our knowledge the only variant associated with a phenotype in this gene is the de novo missense variant c.1768G > A, p.Glu590Lys; however, further additional research is needed to characterize the relationship between disease and variants in this gene. In this study, we reported a patient from a non-consanguineous Chinese family presenting with epilepsy, developmental delay, and speech delay. Additionally, the patient responded well to levetiracetam, and at his last follow-up (5.5 years old), he had discontinued antiepileptic drug treatment and remained seizure-free for 6 months. To identify possible causative variants, trio-whole exome sequencing was performed. We identified a novel de novo missense CUX2 c.2834C > T, p. Thr945Met variant in the patient. Based on clinical and genetics information associated with the bioinformatics analyses, we hypothesized that this variant was the cause of the reported phenotype. AlphaFold and SWISS-MODEL homology modeling servers were used to predict the three-dimensional (3D) structure of CUX2 protein. Predictions based on the 3D-structure modeling indicated that the p.Thr945Met substitution was likely to alter the DNA-binding specificities and affect protein function. On the basis of clinical characteristics and genetic analysis, we presented one case diagnosed with DEE67. Our finding expanded the clinical and molecular spectrum of CUX2 variants.
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spelling pubmed-92838282022-07-16 Novel Variant Expands the Clinical Spectrum of CUX2-Associated Developmental and Epileptic Encephalopathies Zhang, Feng Li, Fuwei Chen, Fujian Huang, Jinrong Luo, Qiong Du, Xilong Zhou, Jiapeng Gu, Weiyue Xu, Kaishou Front Genet Genetics Developmental and epileptic encephalopathies (DEE) caused by heterozygous deleterious variants in Cut Like Homeobox2 (CUX2) is rare. To the best of our knowledge the only variant associated with a phenotype in this gene is the de novo missense variant c.1768G > A, p.Glu590Lys; however, further additional research is needed to characterize the relationship between disease and variants in this gene. In this study, we reported a patient from a non-consanguineous Chinese family presenting with epilepsy, developmental delay, and speech delay. Additionally, the patient responded well to levetiracetam, and at his last follow-up (5.5 years old), he had discontinued antiepileptic drug treatment and remained seizure-free for 6 months. To identify possible causative variants, trio-whole exome sequencing was performed. We identified a novel de novo missense CUX2 c.2834C > T, p. Thr945Met variant in the patient. Based on clinical and genetics information associated with the bioinformatics analyses, we hypothesized that this variant was the cause of the reported phenotype. AlphaFold and SWISS-MODEL homology modeling servers were used to predict the three-dimensional (3D) structure of CUX2 protein. Predictions based on the 3D-structure modeling indicated that the p.Thr945Met substitution was likely to alter the DNA-binding specificities and affect protein function. On the basis of clinical characteristics and genetic analysis, we presented one case diagnosed with DEE67. Our finding expanded the clinical and molecular spectrum of CUX2 variants. Frontiers Media S.A. 2022-07-01 /pmc/articles/PMC9283828/ /pubmed/35846140 http://dx.doi.org/10.3389/fgene.2022.808181 Text en Copyright © 2022 Zhang, Li, Chen, Huang, Luo, Du, Zhou, Gu and Xu. 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
Zhang, Feng
Li, Fuwei
Chen, Fujian
Huang, Jinrong
Luo, Qiong
Du, Xilong
Zhou, Jiapeng
Gu, Weiyue
Xu, Kaishou
Novel Variant Expands the Clinical Spectrum of CUX2-Associated Developmental and Epileptic Encephalopathies
title Novel Variant Expands the Clinical Spectrum of CUX2-Associated Developmental and Epileptic Encephalopathies
title_full Novel Variant Expands the Clinical Spectrum of CUX2-Associated Developmental and Epileptic Encephalopathies
title_fullStr Novel Variant Expands the Clinical Spectrum of CUX2-Associated Developmental and Epileptic Encephalopathies
title_full_unstemmed Novel Variant Expands the Clinical Spectrum of CUX2-Associated Developmental and Epileptic Encephalopathies
title_short Novel Variant Expands the Clinical Spectrum of CUX2-Associated Developmental and Epileptic Encephalopathies
title_sort novel variant expands the clinical spectrum of cux2-associated developmental and epileptic encephalopathies
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9283828/
https://www.ncbi.nlm.nih.gov/pubmed/35846140
http://dx.doi.org/10.3389/fgene.2022.808181
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