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MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia

BACKGROUND: Despite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders. OBJECTIVE: The objective of this study was to identify and characterize...

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Autores principales: Reid, Kimberley M., Spaull, Robert, Salian, Smrithi, Barwick, Katy, Meyer, Esther, Zhen, Juan, Hirata, Hiromi, Sheipouri, Diba, Benkerroum, Hind, Gorman, Kathleen M., Papandreou, Apostolos, Simpson, Michael A., Hirano, Yoshinobu, Farabella, Irene, Topf, Maya, Grozeva, Detelina, Carss, Keren, Smith, Martin, Pall, Hardev, Lunt, Peter, De Gressi, Susanna, Kamsteeg, Erik‐Jan, Haack, Tobias B., Carr, Lucinda, Guerreiro, Rita, Bras, Jose, Maher, Eamonn R., Scott, Richard H., Vandenberg, Robert J., Raymond, F. Lucy, Chong, Wui K., Sudhakar, Sniya, Mankad, Kshitij, Reith, Maarten E., Campeau, Philippe M., Harvey, Robert J., Kurian, Manju A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9796674/
https://www.ncbi.nlm.nih.gov/pubmed/35876425
http://dx.doi.org/10.1002/mds.29147
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author Reid, Kimberley M.
Spaull, Robert
Salian, Smrithi
Barwick, Katy
Meyer, Esther
Zhen, Juan
Hirata, Hiromi
Sheipouri, Diba
Benkerroum, Hind
Gorman, Kathleen M.
Papandreou, Apostolos
Simpson, Michael A.
Hirano, Yoshinobu
Farabella, Irene
Topf, Maya
Grozeva, Detelina
Carss, Keren
Smith, Martin
Pall, Hardev
Lunt, Peter
De Gressi, Susanna
Kamsteeg, Erik‐Jan
Haack, Tobias B.
Carr, Lucinda
Guerreiro, Rita
Bras, Jose
Maher, Eamonn R.
Scott, Richard H.
Vandenberg, Robert J.
Raymond, F. Lucy
Chong, Wui K.
Sudhakar, Sniya
Mankad, Kshitij
Reith, Maarten E.
Campeau, Philippe M.
Harvey, Robert J.
Kurian, Manju A.
author_facet Reid, Kimberley M.
Spaull, Robert
Salian, Smrithi
Barwick, Katy
Meyer, Esther
Zhen, Juan
Hirata, Hiromi
Sheipouri, Diba
Benkerroum, Hind
Gorman, Kathleen M.
Papandreou, Apostolos
Simpson, Michael A.
Hirano, Yoshinobu
Farabella, Irene
Topf, Maya
Grozeva, Detelina
Carss, Keren
Smith, Martin
Pall, Hardev
Lunt, Peter
De Gressi, Susanna
Kamsteeg, Erik‐Jan
Haack, Tobias B.
Carr, Lucinda
Guerreiro, Rita
Bras, Jose
Maher, Eamonn R.
Scott, Richard H.
Vandenberg, Robert J.
Raymond, F. Lucy
Chong, Wui K.
Sudhakar, Sniya
Mankad, Kshitij
Reith, Maarten E.
Campeau, Philippe M.
Harvey, Robert J.
Kurian, Manju A.
author_sort Reid, Kimberley M.
collection PubMed
description BACKGROUND: Despite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders. OBJECTIVE: The objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts. METHODS: Candidate genes identified by autozygosity mapping and whole‐exome sequencing were characterized using cellular and vertebrate model systems. RESULTS: Homozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27‐related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell‐surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L‐proline transporter–G396S RNA. Lastly, patient fibroblasts displayed reduced cell‐surface expression of glycophosphatidylinositol‐anchored proteins linked to MPPE1 dysfunction. CONCLUSIONS: We report a family harboring a homozygous MED27 variant with additional loss‐of‐function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
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spelling pubmed-97966742023-01-04 MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia Reid, Kimberley M. Spaull, Robert Salian, Smrithi Barwick, Katy Meyer, Esther Zhen, Juan Hirata, Hiromi Sheipouri, Diba Benkerroum, Hind Gorman, Kathleen M. Papandreou, Apostolos Simpson, Michael A. Hirano, Yoshinobu Farabella, Irene Topf, Maya Grozeva, Detelina Carss, Keren Smith, Martin Pall, Hardev Lunt, Peter De Gressi, Susanna Kamsteeg, Erik‐Jan Haack, Tobias B. Carr, Lucinda Guerreiro, Rita Bras, Jose Maher, Eamonn R. Scott, Richard H. Vandenberg, Robert J. Raymond, F. Lucy Chong, Wui K. Sudhakar, Sniya Mankad, Kshitij Reith, Maarten E. Campeau, Philippe M. Harvey, Robert J. Kurian, Manju A. Mov Disord Regular Issue Articles BACKGROUND: Despite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders. OBJECTIVE: The objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts. METHODS: Candidate genes identified by autozygosity mapping and whole‐exome sequencing were characterized using cellular and vertebrate model systems. RESULTS: Homozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27‐related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell‐surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L‐proline transporter–G396S RNA. Lastly, patient fibroblasts displayed reduced cell‐surface expression of glycophosphatidylinositol‐anchored proteins linked to MPPE1 dysfunction. CONCLUSIONS: We report a family harboring a homozygous MED27 variant with additional loss‐of‐function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society John Wiley & Sons, Inc. 2022-07-25 2022-10 /pmc/articles/PMC9796674/ /pubmed/35876425 http://dx.doi.org/10.1002/mds.29147 Text en © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Regular Issue Articles
Reid, Kimberley M.
Spaull, Robert
Salian, Smrithi
Barwick, Katy
Meyer, Esther
Zhen, Juan
Hirata, Hiromi
Sheipouri, Diba
Benkerroum, Hind
Gorman, Kathleen M.
Papandreou, Apostolos
Simpson, Michael A.
Hirano, Yoshinobu
Farabella, Irene
Topf, Maya
Grozeva, Detelina
Carss, Keren
Smith, Martin
Pall, Hardev
Lunt, Peter
De Gressi, Susanna
Kamsteeg, Erik‐Jan
Haack, Tobias B.
Carr, Lucinda
Guerreiro, Rita
Bras, Jose
Maher, Eamonn R.
Scott, Richard H.
Vandenberg, Robert J.
Raymond, F. Lucy
Chong, Wui K.
Sudhakar, Sniya
Mankad, Kshitij
Reith, Maarten E.
Campeau, Philippe M.
Harvey, Robert J.
Kurian, Manju A.
MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia
title MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia
title_full MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia
title_fullStr MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia
title_full_unstemmed MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia
title_short MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia
title_sort med27, slc6a7, and mppe1 variants in a complex neurodevelopmental disorder with severe dystonia
topic Regular Issue Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9796674/
https://www.ncbi.nlm.nih.gov/pubmed/35876425
http://dx.doi.org/10.1002/mds.29147
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