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

Kód výsledku v IS VaVaI

RIV/00064165:_____/20:10411410 - isvavai.cz

Nalezeny alternativní kódy

RIV/00216208:11110/20:10411410

Výsledek na webu

https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=faCcI6uilN

DOI - Digital Object Identifier

10.1186/s13073-020-0711-1

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10600 - Biological sciences

Projekt

NV19-01-00307: Etiologie závažných poruch metabolismu sirných aminokyselin: využití pro cílenou diagnostiku a personalizovanou léčbu v České republice

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Genome Medicine

ISSN

1756-994X

e-ISSN

—

Svazek periodika

12

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

18

Strana od-do

13

Kód UT WoS článku

000512015600001

EID výsledku v databázi Scopus

2-s2.0-85078712884