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

Multidimensional functional mapping of MYBPC3 variants (saturation base editing at the native locus, long-read splicing assay, iPSC-cardiomyocyte phenotypes); reduced cMyBP-C abundance is a key driver.

Variants in MYBPC3 account for a large share of hypertrophic cardiomyopathy (HCM), but many remain classified as VUS. The authors deploy a multidimensional functional mapping strategy combining saturation base editing at the native MYBPC3 locus, a massively parallel long-read splicing assay and measurement of HCM-relevant phenotypes in iPSC-derived cardiomyocytes. Integrating these data shows that reduced cMyBP-C abundance is a key driver of phenotypes, and identifies splice-disrupting variants as well as novel mechanisms for missense variants. Bayesian estimates of variant effect enable reclassification of clinical variants.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Exactly the kind of large-scale functional work that advances VUS reclassification for a common gene like MYBPC3: the data are generated in the right cell type (iPSC cardiomyocytes) and at the native locus, not on an artificial reporter system. In the exome/genome era, it is these functional maps, more than adding genes, that unlock interpretation. It remains to be seen how this integrates into ACMG frameworks and transfers to other protein domains.

Analysis by Dr Thibaut Benquey