Genetic mutations occur when nucleotide sequences in an organism are altered. These mutations lead to not only observable phenotypic influences in an individual, but also alterations that are undetectable phenotypically. The sources for these mutations can be errors during replication, spontaneous mutations, and chemical and physical mutagens (UV and ionizing radiation, heat).  Silencers, being encoded in the genome, are susceptible to such alterations which, in many cases, can lead to severe phenotypical and functional abnormalities. In general terms, mutations in silencer elements or regions could lead to either the inhibition of the silencers action or to the persisting repression of a necessary gene. This can then lead to the expression or suppression of an undesired phenotype which may affect the normal functionality of certain systems in the organism. Among the many silencer elements and proteins, REST/NSRF is an important silencer factor that has a variety of impacts, not only in neural aspects of development. In fact, in many cases, REST/NSRF acts in conjunction with RE-1/NRSE to repress and influence non-neuronal cells. Its effects range from frogs (Xenopus laevis) to humans, with innumerous effects in phenotype and also in development. In Xenopus laevis, REST/NRSF malfunction or damage has been associated to abnormal ectodermal patterning during development and significant consequences in neural tube, cranial ganglia, and eye development. In humans, a deficiency in the REST/NSRF silencer element has been correlated to Huntingtons disease due to the decrease in the transcription of BDNF.
Furthermore, ongoing studies indicate that NRSE is involved in the regulation of the ANP gene, which when over expressed, can lead to ventricular hypertrophy. Mutations in the Polycomb-group (PcG) complexes also presented significant modifications in physiological systems of organisms. Hence, modification in silencer elements and sequences can result in either devastating or unnoticeable changes.