The Popeye domain containing 1 (POPDC1) gene encodes a plasma membrane-localized cAMP binding protein. Despite its essential role in regulating the structure and function of cardiac and skeletal muscle in animal models, this gene has never been associated with human cardiac and muscular diseases. We describe a homozygous missense variant (c.602C>T, p.S201F) in POPDC1, identified by whole exome sequencing, in a family-of-four with cardiac arrhythmia and mild limb girdle muscular dystrophy (LGMD). This very rare allele variation was absent in databases, and segregated with the phenotype. Further screening in 104 unrelated patients affected with cardiac rhythm disturbance and mild limb girdle myopathy or high CK resulted negative for other homozygous/compound heterozygous variations, which is consistent with a very rare, family-specific mutation. In skeletal muscle biopsies of two patients, the membrane levels of POPDC1^S201F and of the related POPDC2 protein were reduced suggesting impaired membrane trafficking. The mutant protein displayed a 50% reduction in cAMP affinity and displayed deregulation of TREK-1 ion channel gating when injected into Xenopus oocytes. Forced expression of POPDC1^S201F in HL-1 cells increased hyperpolarization and upstroke velocity of the action potential. The homologous mutation in zebrafish (popdc1^S191F) displayed heart and skeletal muscle phenotypes, which resembled those observed in patients and also affected membrane trafficking. In addition, we showed that POPDC1 interacts with Caveolin 3, acting on membrane compartmentalization and with dystrophin and dysferlin, underlining the common functional circuits these proteins are involved in. Our study therefore identifies POPDC1 as a novel disease gene causing a very rare autosomal recessive cardiac arrhythmia and mild limb girdle muscular dystrophy. POPDC1 expands the heterogeneous genetic landscape of LGMDs with heart disturbances and opens novel pathways underling these complex genetic disorders. We are currently searching  for mutations in POPDC1 gene in other LGMD phenotypes in order to evaluate its causative role also as possible disease modifier.