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Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease

PURPOSE: RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease. METHODS: Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with p...

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Autores principales: Van de Sompele, Stijn, Smith, Claire, Karali, Marianthi, Corton, Marta, Van Schil, Kristof, Peelman, Frank, Cherry, Timothy, Rosseel, Toon, Verdin, Hannah, Derolez, Julien, Van Laethem, Thalia, Khan, Kamron N., McKibbin, Martin, Toomes, Carmel, Ali, Manir, Torella, Annalaura, Testa, Francesco, Jimenez, Belen, Simonelli, Francesca, De Zaeytijd, Julie, Van den Ende, Jenneke, Leroy, Bart P., Coppieters, Frauke, Ayuso, Carmen, Inglehearn, Chris F., Banfi, Sandro, De Baere, Elfride
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752271/
https://www.ncbi.nlm.nih.gov/pubmed/30377383
http://dx.doi.org/10.1038/s41436-018-0345-5
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author Van de Sompele, Stijn
Smith, Claire
Karali, Marianthi
Corton, Marta
Van Schil, Kristof
Peelman, Frank
Cherry, Timothy
Rosseel, Toon
Verdin, Hannah
Derolez, Julien
Van Laethem, Thalia
Khan, Kamron N.
McKibbin, Martin
Toomes, Carmel
Ali, Manir
Torella, Annalaura
Testa, Francesco
Jimenez, Belen
Simonelli, Francesca
De Zaeytijd, Julie
Van den Ende, Jenneke
Leroy, Bart P.
Coppieters, Frauke
Ayuso, Carmen
Inglehearn, Chris F.
Banfi, Sandro
De Baere, Elfride
author_facet Van de Sompele, Stijn
Smith, Claire
Karali, Marianthi
Corton, Marta
Van Schil, Kristof
Peelman, Frank
Cherry, Timothy
Rosseel, Toon
Verdin, Hannah
Derolez, Julien
Van Laethem, Thalia
Khan, Kamron N.
McKibbin, Martin
Toomes, Carmel
Ali, Manir
Torella, Annalaura
Testa, Francesco
Jimenez, Belen
Simonelli, Francesca
De Zaeytijd, Julie
Van den Ende, Jenneke
Leroy, Bart P.
Coppieters, Frauke
Ayuso, Carmen
Inglehearn, Chris F.
Banfi, Sandro
De Baere, Elfride
author_sort Van de Sompele, Stijn
collection PubMed
description PURPOSE: RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease. METHODS: Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members. RESULTS: Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry. CONCLUSION: This study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases.
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spelling pubmed-67522712019-09-23 Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease Van de Sompele, Stijn Smith, Claire Karali, Marianthi Corton, Marta Van Schil, Kristof Peelman, Frank Cherry, Timothy Rosseel, Toon Verdin, Hannah Derolez, Julien Van Laethem, Thalia Khan, Kamron N. McKibbin, Martin Toomes, Carmel Ali, Manir Torella, Annalaura Testa, Francesco Jimenez, Belen Simonelli, Francesca De Zaeytijd, Julie Van den Ende, Jenneke Leroy, Bart P. Coppieters, Frauke Ayuso, Carmen Inglehearn, Chris F. Banfi, Sandro De Baere, Elfride Genet Med Article PURPOSE: RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease. METHODS: Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members. RESULTS: Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry. CONCLUSION: This study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases. Nature Publishing Group US 2018-10-31 2019 /pmc/articles/PMC6752271/ /pubmed/30377383 http://dx.doi.org/10.1038/s41436-018-0345-5 Text en © The Author(s) 2018 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
Van de Sompele, Stijn
Smith, Claire
Karali, Marianthi
Corton, Marta
Van Schil, Kristof
Peelman, Frank
Cherry, Timothy
Rosseel, Toon
Verdin, Hannah
Derolez, Julien
Van Laethem, Thalia
Khan, Kamron N.
McKibbin, Martin
Toomes, Carmel
Ali, Manir
Torella, Annalaura
Testa, Francesco
Jimenez, Belen
Simonelli, Francesca
De Zaeytijd, Julie
Van den Ende, Jenneke
Leroy, Bart P.
Coppieters, Frauke
Ayuso, Carmen
Inglehearn, Chris F.
Banfi, Sandro
De Baere, Elfride
Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease
title Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease
title_full Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease
title_fullStr Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease
title_full_unstemmed Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease
title_short Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease
title_sort biallelic sequence and structural variants in rax2 are a novel cause for autosomal recessive inherited retinal disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752271/
https://www.ncbi.nlm.nih.gov/pubmed/30377383
http://dx.doi.org/10.1038/s41436-018-0345-5
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