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A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase

BACKGROUND: For the majority of rare clinical missense variants, pathogenicity status cannot currently be classified. Classical homocystinuria, characterized by elevated homocysteine in plasma and urine, is caused by variants in the cystathionine beta-synthase (CBS) gene, most of which are rare. Wit...

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Autores principales: Sun, Song, Weile, Jochen, Verby, Marta, Wu, Yingzhou, Wang, Yang, Cote, Atina G., Fotiadou, Iosifina, Kitaygorodsky, Julia, Vidal, Marc, Rine, Jasper, Ješina, Pavel, Kožich, Viktor, Roth, Frederick P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993387/
https://www.ncbi.nlm.nih.gov/pubmed/32000841
http://dx.doi.org/10.1186/s13073-020-0711-1
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author Sun, Song
Weile, Jochen
Verby, Marta
Wu, Yingzhou
Wang, Yang
Cote, Atina G.
Fotiadou, Iosifina
Kitaygorodsky, Julia
Vidal, Marc
Rine, Jasper
Ješina, Pavel
Kožich, Viktor
Roth, Frederick P.
author_facet Sun, Song
Weile, Jochen
Verby, Marta
Wu, Yingzhou
Wang, Yang
Cote, Atina G.
Fotiadou, Iosifina
Kitaygorodsky, Julia
Vidal, Marc
Rine, Jasper
Ješina, Pavel
Kožich, Viktor
Roth, Frederick P.
author_sort Sun, Song
collection PubMed
description BACKGROUND: For the majority of rare clinical missense variants, pathogenicity status cannot currently be classified. Classical homocystinuria, characterized by elevated homocysteine in plasma and urine, is caused by variants in the cystathionine beta-synthase (CBS) gene, most of which are rare. With early detection, existing therapies are highly effective. METHODS: Damaging CBS variants can be detected based on their failure to restore growth in yeast cells lacking the yeast ortholog CYS4. This assay has only been applied reactively, after first observing a variant in patients. Using saturation codon-mutagenesis, en masse growth selection, and sequencing, we generated a comprehensive, proactive map of CBS missense variant function. RESULTS: Our CBS variant effect map far exceeds the performance of computational predictors of disease variants. Map scores correlated strongly with both disease severity (Spearman’s ϱ = 0.9) and human clinical response to vitamin B(6) (ϱ = 0.93). CONCLUSIONS: We demonstrate that highly multiplexed cell-based assays can yield proactive maps of variant function and patient response to therapy, even for rare variants not previously seen in the clinic.
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spelling pubmed-69933872020-02-04 A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase Sun, Song Weile, Jochen Verby, Marta Wu, Yingzhou Wang, Yang Cote, Atina G. Fotiadou, Iosifina Kitaygorodsky, Julia Vidal, Marc Rine, Jasper Ješina, Pavel Kožich, Viktor Roth, Frederick P. Genome Med Research BACKGROUND: For the majority of rare clinical missense variants, pathogenicity status cannot currently be classified. Classical homocystinuria, characterized by elevated homocysteine in plasma and urine, is caused by variants in the cystathionine beta-synthase (CBS) gene, most of which are rare. With early detection, existing therapies are highly effective. METHODS: Damaging CBS variants can be detected based on their failure to restore growth in yeast cells lacking the yeast ortholog CYS4. This assay has only been applied reactively, after first observing a variant in patients. Using saturation codon-mutagenesis, en masse growth selection, and sequencing, we generated a comprehensive, proactive map of CBS missense variant function. RESULTS: Our CBS variant effect map far exceeds the performance of computational predictors of disease variants. Map scores correlated strongly with both disease severity (Spearman’s ϱ = 0.9) and human clinical response to vitamin B(6) (ϱ = 0.93). CONCLUSIONS: We demonstrate that highly multiplexed cell-based assays can yield proactive maps of variant function and patient response to therapy, even for rare variants not previously seen in the clinic. BioMed Central 2020-01-30 /pmc/articles/PMC6993387/ /pubmed/32000841 http://dx.doi.org/10.1186/s13073-020-0711-1 Text en © The Author(s). 2020 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Sun, Song
Weile, Jochen
Verby, Marta
Wu, Yingzhou
Wang, Yang
Cote, Atina G.
Fotiadou, Iosifina
Kitaygorodsky, Julia
Vidal, Marc
Rine, Jasper
Ješina, Pavel
Kožich, Viktor
Roth, Frederick P.
A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase
title A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase
title_full A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase
title_fullStr A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase
title_full_unstemmed A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase
title_short A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase
title_sort proactive genotype-to-patient-phenotype map for cystathionine beta-synthase
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993387/
https://www.ncbi.nlm.nih.gov/pubmed/32000841
http://dx.doi.org/10.1186/s13073-020-0711-1
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