This systematic review focuses on different genetic mutations identified in studies on natural short sleepers, who would not be ill-defined as one type of sleep-related disorder. The reviewed literature is from databases such as PubMed PMC, Scopus, and ResearchGate. Due to the rare prevalence, the number of studies conducted on natural short sleepers is limited. Hence, searching the search of databases was done without any date restriction and included animal studies, since mouse and fly models share similarities with human sleep behaviors. Of the 12 articles analyzed, four conducted two types of studies, animal and human (cross-sectional or randomized-controlled studies), to testify the effects of human mutant genes in familial natural short sleepers via transgenic mouse or fly models. The remaining eight articles mainly focused on one type of study each: animal study (four articles), cross-sectional study (two articles), review (one article), and case report (one article). Hence, those articles brought different perspectives on the natural short sleep phenomenon by identifying intrinsic factors like , , , and mutant genes. Natural short sleep traits in either point-mutations or single null mutations in those genes have been examined and confirmed its intrinsic nature in affected individuals without any related health concerns. Finally, this review added a potential limitation in these studies, mainly highlighting intrinsic causes since one case study reported an extrinsically triggered short sleep behavior in an older man without any family history. The overall result of the review study suggests that the molecular mechanisms tuned by identified sleep genes can give some potential points of therapeutic intervention in future studies.