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