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Novel clinical and genetic insight into CXorf56-associated intellectual disability
Intellectual disability (ID) is one of most frequent reasons for genetic consultation. The complex molecular anatomy of ID ranges from complete chromosomal imbalances to single nucleotide variant changes occurring de novo, with thousands of genes identified. This extreme genetic heterogeneity challe...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028711/ https://www.ncbi.nlm.nih.gov/pubmed/31822863 http://dx.doi.org/10.1038/s41431-019-0558-3 |
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author | Rocha, Maria Eugenia Silveira, Tainá Regina Damaceno Sasaki, Erina Sás, Daíse Moreno Lourenço, Charles Marques Kandaswamy, Krishna K. Beetz, Christian Rolfs, Arndt Bauer, Peter Reardon, Willie Bertoli-Avella, Aida M. |
author_facet | Rocha, Maria Eugenia Silveira, Tainá Regina Damaceno Sasaki, Erina Sás, Daíse Moreno Lourenço, Charles Marques Kandaswamy, Krishna K. Beetz, Christian Rolfs, Arndt Bauer, Peter Reardon, Willie Bertoli-Avella, Aida M. |
author_sort | Rocha, Maria Eugenia |
collection | PubMed |
description | Intellectual disability (ID) is one of most frequent reasons for genetic consultation. The complex molecular anatomy of ID ranges from complete chromosomal imbalances to single nucleotide variant changes occurring de novo, with thousands of genes identified. This extreme genetic heterogeneity challenges the molecular diagnosis, which mostly requires a genomic approach. CXorf56 is largely uncharacterized and was recently proposed as a candidate ID gene based on findings in a single Dutch family. Here, we describe nine cases (six males and three females) from three unrelated families. Exome sequencing and combined database analyses, identified family-specific CXorf56 variants (NM_022101.3:c.498_503del, p.(Glu167_Glu168del) and c.303_304delCTinsACCC, p.(Phe101Leufs*20)) that segregated with the ID phenotype. These variants are presumably leading to loss-of-function, which is the proposed disease mechanism. Clinically, CXorf56-related disease is a slowly progressive neurological disorder. The phenotype is more severe in hemizygote males, but might also manifests in heterozygote females, which showed skewed X-inactivation patterns in blood. Male patients might present previously unreported neurological features such as epilepsy, abnormal gait, tremor, and clonus, which extends the clinical spectrum of the disorder. In conclusion, we confirm the causative role of variants in CXorf56 for an X-linked form of intellectual disability with additional neurological features. The gene should be considered for molecular diagnostics of patients with ID, specifically when family history is suggestive of X-linked inheritance. Further work is needed to understand the role of this gene in neurodevelopment and intellectual disability. |
format | Online Article Text |
id | pubmed-7028711 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-70287112020-02-27 Novel clinical and genetic insight into CXorf56-associated intellectual disability Rocha, Maria Eugenia Silveira, Tainá Regina Damaceno Sasaki, Erina Sás, Daíse Moreno Lourenço, Charles Marques Kandaswamy, Krishna K. Beetz, Christian Rolfs, Arndt Bauer, Peter Reardon, Willie Bertoli-Avella, Aida M. Eur J Hum Genet Article Intellectual disability (ID) is one of most frequent reasons for genetic consultation. The complex molecular anatomy of ID ranges from complete chromosomal imbalances to single nucleotide variant changes occurring de novo, with thousands of genes identified. This extreme genetic heterogeneity challenges the molecular diagnosis, which mostly requires a genomic approach. CXorf56 is largely uncharacterized and was recently proposed as a candidate ID gene based on findings in a single Dutch family. Here, we describe nine cases (six males and three females) from three unrelated families. Exome sequencing and combined database analyses, identified family-specific CXorf56 variants (NM_022101.3:c.498_503del, p.(Glu167_Glu168del) and c.303_304delCTinsACCC, p.(Phe101Leufs*20)) that segregated with the ID phenotype. These variants are presumably leading to loss-of-function, which is the proposed disease mechanism. Clinically, CXorf56-related disease is a slowly progressive neurological disorder. The phenotype is more severe in hemizygote males, but might also manifests in heterozygote females, which showed skewed X-inactivation patterns in blood. Male patients might present previously unreported neurological features such as epilepsy, abnormal gait, tremor, and clonus, which extends the clinical spectrum of the disorder. In conclusion, we confirm the causative role of variants in CXorf56 for an X-linked form of intellectual disability with additional neurological features. The gene should be considered for molecular diagnostics of patients with ID, specifically when family history is suggestive of X-linked inheritance. Further work is needed to understand the role of this gene in neurodevelopment and intellectual disability. Springer International Publishing 2019-12-10 2020-03 /pmc/articles/PMC7028711/ /pubmed/31822863 http://dx.doi.org/10.1038/s41431-019-0558-3 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Rocha, Maria Eugenia Silveira, Tainá Regina Damaceno Sasaki, Erina Sás, Daíse Moreno Lourenço, Charles Marques Kandaswamy, Krishna K. Beetz, Christian Rolfs, Arndt Bauer, Peter Reardon, Willie Bertoli-Avella, Aida M. Novel clinical and genetic insight into CXorf56-associated intellectual disability |
title | Novel clinical and genetic insight into CXorf56-associated intellectual disability |
title_full | Novel clinical and genetic insight into CXorf56-associated intellectual disability |
title_fullStr | Novel clinical and genetic insight into CXorf56-associated intellectual disability |
title_full_unstemmed | Novel clinical and genetic insight into CXorf56-associated intellectual disability |
title_short | Novel clinical and genetic insight into CXorf56-associated intellectual disability |
title_sort | novel clinical and genetic insight into cxorf56-associated intellectual disability |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028711/ https://www.ncbi.nlm.nih.gov/pubmed/31822863 http://dx.doi.org/10.1038/s41431-019-0558-3 |
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