Abstract
Abstract
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.
Funder
the National Human Genome Research Institute of the National Institutes of Health (NIH/NHGRI) Center of Excellence in Genomic Science (CEGS) Initiative
General University Hospital in Prague
Charles University
One Brave Idea
Canada Excellence Research Chairs, Government of Canada
Canadian Institutes of Health Research
Canada Foundation for Innovation
Czech Health Research Council
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics,Molecular Biology,Molecular Medicine
Cited by
40 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献