Scaled Multidimensional Assays of Variant Effect Identify Sequence-Function Relationships in Hypertrophic Cardiomyopathy.

Multidimensional mapping of variant effects (MAVE) of MYBPC3: saturation base editing at the native locus, long-read RNA sequencing splicing assay, and phenotyping in iPSC-derived cardiomyocytes

The authors developed a scaled multidimensional mapping strategy to assess the functional impact of variants across a critical domain of MYBPC3, a major hypertrophic cardiomyopathy gene where many variants remain of uncertain significance. The approach combines saturation base editing at the native locus, a long-read RNA sequencing splicing assay, and measurements of HCM-relevant phenotypes (cMyBP-C abundance, hypertrophic signaling, proteasome function) in human iPSC-derived cardiomyocytes. The massively parallel splicing assay identified novel splice-disrupting variants, and integration of assays showed decreased cMyBP-C abundance is a key driver of phenotype. Bayesian estimates of variant effects enable reclassification of clinical variants.

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An elegant demonstration of multidimensional MAVE applied to a clinically high-stakes cardiac gene, in the relevant cell type (iPSC cardiomyocytes). The direct diagnostic contribution is VUS reclassification, though here at the scale of a protein domain rather than the whole gene. Anchoring on real cellular phenotypes and long-read RNA sequencing for splicing strengthens functional credibility; transfer to routine clinical interpretation will require formalized ACMG integration.

Analysis by Dr Thibaut Benquey