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

• DOI: 10.1186/s13073-020-0711-1
• Publication Date: 2020-01-30T13:03:13Z
• Authors: Song Sun; Jochen Weile; Marta Verby; Yingzhou Wu; Yang Wang; Atina G. Cote; Iosifina Fotiadou; Julia Kitaygorodsky; Marc Vidal; Jasper Rine; Pavel Ješina; Viktor Kožich; Frederick P. Roth
• Keywords: 0301 basic medicine; Saccharomyces cerevisiae Proteins; Genotype; Clinical Sciences; Mutation, Missense; 610; Cystathionine beta-Synthase; Saccharomyces cerevisiae; QH426-470; Medical Genetics and Genomics; 03 medical and health sciences; Genetics; 2.1 Biological and endogenous factors; Humans; Genetic Testing; Aetiology; Medicinsk genetik; Prevention; Research; Genetic Complementation Test; R; Medicinsk genetik och genomik; 3. Good health; Phenotype; Mutation; Medicine; Homocystinuria; Missense; Medical Genetics; Biotechnology

AbstractBackgroundFor 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.MethodsDamagingCBSvariants can be detected based on their failure to restore growth in yeast cells lacking the yeast orthologCYS4. 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.ResultsOur CBS variant effect map far exceeds the performance of computational predictors of disease variants. Map scores correlated strongly with both disease severity (Spearman’sϱ = 0.9) and human clinical response to vitamin B6(ϱ = 0.93).ConclusionsWe 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.