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The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2)
Hypomagnesemia, seizures, and intellectual disability (HSMR) syndrome is a rare disorder caused by mutations in the cyclin M2 (CNNM2) gene. Due to the limited number of cases, extensive phenotype analyses of these patients have not been performed, hindering early recognition of patients. In this stu...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248058/ https://www.ncbi.nlm.nih.gov/pubmed/33600043 http://dx.doi.org/10.1002/humu.24182 |
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author | Franken, Gijs A. C. Müller, Dominik Mignot, Cyril Keren, Boris Lévy, Jonathan Tabet, Anne‐Claude Germanaud, David Tejada, María‐Isabel Kroes, Hester Y. Nievelstein, Rutger A. J. Brimble, Elise Ruzhnikov, Maria Claverie‐Martin, Felix Szczepańska, Maria Ćuk, Martin Latta, Femke Konrad, Martin Martínez‐Cruz, Luis A. Bindels, René J. M. Hoenderop, Joost G. J. Schlingmann, Karl‐Peter de Baaij, Jeroen H. F. |
author_facet | Franken, Gijs A. C. Müller, Dominik Mignot, Cyril Keren, Boris Lévy, Jonathan Tabet, Anne‐Claude Germanaud, David Tejada, María‐Isabel Kroes, Hester Y. Nievelstein, Rutger A. J. Brimble, Elise Ruzhnikov, Maria Claverie‐Martin, Felix Szczepańska, Maria Ćuk, Martin Latta, Femke Konrad, Martin Martínez‐Cruz, Luis A. Bindels, René J. M. Hoenderop, Joost G. J. Schlingmann, Karl‐Peter de Baaij, Jeroen H. F. |
author_sort | Franken, Gijs A. C. |
collection | PubMed |
description | Hypomagnesemia, seizures, and intellectual disability (HSMR) syndrome is a rare disorder caused by mutations in the cyclin M2 (CNNM2) gene. Due to the limited number of cases, extensive phenotype analyses of these patients have not been performed, hindering early recognition of patients. In this study, we established the largest cohort of HSMR to date, aiming to improve recognition and diagnosis of this complex disorder. Eleven novel variants in CNNM2 were identified in nine single sporadic cases and in two families with suspected HSMR syndrome. (25)Mg(2+) uptake assays demonstrated loss‐of‐function in seven out of nine variants in CNNM2. Interestingly, the pathogenic mutations resulted in decreased plasma membrane expression. The phenotype of those affected by pathogenic CNNM2 mutations was compared with five previously reported cases of HSMR. All patients suffered from hypomagnesemia (0.44–0.72 mmol/L), which could not be fully corrected by Mg(2+) supplementation. The majority of patients (77%) experienced generalized seizures and exhibited mild to moderate intellectual disability and speech delay. Moreover, severe obesity was present in most patients (89%). Our data establish hypomagnesemia, seizures, intellectual disability, and obesity as hallmarks of HSMR syndrome. The assessment of these major features offers a straightforward tool for the clinical diagnosis of HSMR. |
format | Online Article Text |
id | pubmed-8248058 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82480582021-07-02 The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2) Franken, Gijs A. C. Müller, Dominik Mignot, Cyril Keren, Boris Lévy, Jonathan Tabet, Anne‐Claude Germanaud, David Tejada, María‐Isabel Kroes, Hester Y. Nievelstein, Rutger A. J. Brimble, Elise Ruzhnikov, Maria Claverie‐Martin, Felix Szczepańska, Maria Ćuk, Martin Latta, Femke Konrad, Martin Martínez‐Cruz, Luis A. Bindels, René J. M. Hoenderop, Joost G. J. Schlingmann, Karl‐Peter de Baaij, Jeroen H. F. Hum Mutat Research Articles Hypomagnesemia, seizures, and intellectual disability (HSMR) syndrome is a rare disorder caused by mutations in the cyclin M2 (CNNM2) gene. Due to the limited number of cases, extensive phenotype analyses of these patients have not been performed, hindering early recognition of patients. In this study, we established the largest cohort of HSMR to date, aiming to improve recognition and diagnosis of this complex disorder. Eleven novel variants in CNNM2 were identified in nine single sporadic cases and in two families with suspected HSMR syndrome. (25)Mg(2+) uptake assays demonstrated loss‐of‐function in seven out of nine variants in CNNM2. Interestingly, the pathogenic mutations resulted in decreased plasma membrane expression. The phenotype of those affected by pathogenic CNNM2 mutations was compared with five previously reported cases of HSMR. All patients suffered from hypomagnesemia (0.44–0.72 mmol/L), which could not be fully corrected by Mg(2+) supplementation. The majority of patients (77%) experienced generalized seizures and exhibited mild to moderate intellectual disability and speech delay. Moreover, severe obesity was present in most patients (89%). Our data establish hypomagnesemia, seizures, intellectual disability, and obesity as hallmarks of HSMR syndrome. The assessment of these major features offers a straightforward tool for the clinical diagnosis of HSMR. John Wiley and Sons Inc. 2021-03-01 2021-04 /pmc/articles/PMC8248058/ /pubmed/33600043 http://dx.doi.org/10.1002/humu.24182 Text en © 2021 The Authors. Human Mutation published by Wiley Periodicals LLC https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles Franken, Gijs A. C. Müller, Dominik Mignot, Cyril Keren, Boris Lévy, Jonathan Tabet, Anne‐Claude Germanaud, David Tejada, María‐Isabel Kroes, Hester Y. Nievelstein, Rutger A. J. Brimble, Elise Ruzhnikov, Maria Claverie‐Martin, Felix Szczepańska, Maria Ćuk, Martin Latta, Femke Konrad, Martin Martínez‐Cruz, Luis A. Bindels, René J. M. Hoenderop, Joost G. J. Schlingmann, Karl‐Peter de Baaij, Jeroen H. F. The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2) |
title | The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2) |
title_full | The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2) |
title_fullStr | The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2) |
title_full_unstemmed | The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2) |
title_short | The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2) |
title_sort | phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin m2 (cnnm2) |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248058/ https://www.ncbi.nlm.nih.gov/pubmed/33600043 http://dx.doi.org/10.1002/humu.24182 |
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