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

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064165%3A_____%2F20%3A10411410" target="_blank" >RIV/00064165:_____/20:10411410 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11110/20:10411410
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=faCcI6uilN" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=faCcI6uilN</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1186/s13073-020-0711-1" target="_blank" >10.1186/s13073-020-0711-1</a>

Result language
angličtina
Original language name
A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase
Original language 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 B6 (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.
Czech name
—
Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
10600 - Biological sciences

Project
<a href="/en/project/NV19-01-00307" target="_blank" >NV19-01-00307: Etiology of severely disturbed sulfur amino acid metabolism: a basis for targeted diagnosis and personalized treatment in the Czech Republic</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year
2020
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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