Genetic resiliency associated with dominant lethal <i>TPM1</i> mutation causing atrial septal defect with high heritability.

Abstract

Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe disease in healthy individuals. Here, we report the unexpected recovery of a rare dominant lethal mutation in <i>TPM1</i>, a sarcomeric actin-binding protein, in eight individuals with large atrial septal defect (ASD) in a five-generation pedigree. Mice with <i>Tpm1</i> mutation exhibit early embryonic lethality with disrupted myofibril assembly and no heartbeat. However, patient-induced pluripotent-stem-cell-derived cardiomyocytes show normal beating with mild myofilament defect, indicating disease suppression. A variant in <i>TLN2</i>, another myofilament actin-binding protein, is identified as a candidate suppressor. Mouse CRISPR knock-in (KI) of both the <i>TLN2</i> and <i>TPM1</i> variants rescues heart beating, with near-term fetuses exhibiting large ASD. Thus, the role of <i>TPM1</i> in ASD pathogenesis unfolds with suppression of its embryonic lethality by protective <i>TLN2</i> variant. These findings provide evidence that genetic resiliency can arise with genetic suppression of a deleterious mutation.