Genetic Resiliency Associated With Dominant Lethal <i>TPM1</i> Mutation Causing Atrial Septal Defect With High Heritability

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 a rare dominant lethal mutation TPM1, sarcomeric actin-binding protein, 8 individuals with atrial septal defect (ASD) 5-generation pedigree. Mice TPM1 exhibited early embryonic lethality disrupted myofibril assembly and no heartbeat. However, patient induced pluripotent stem cell derived cardiomyocytes showed normal beating mild myofilament defect, indicating suppression. A variant TLN2, another was identified as candidate suppressor. Mouse CRISRP knockin both TLN2/TPM1 variants rescued heart beating, near term fetuses exhibiting ASD. Thus, role ASD pathogenesis unfolded suppression its by TLN2 protective variant. These findings provide evidence that genetic resiliency can arise deleterious mutation.