Genomic Variability in the Survival Motor Neuron Genes ( and ): Implications for Spinal Muscular Atrophy Phenotype and Therapeutics Development.

Spinal muscular atrophy (SMA) is a leading genetic cause of infant death worldwide that is characterized by loss of spinal motor neurons leading to muscle weakness and atrophy. SMA results from the loss of () gene but retention of its paralog . The copy numbers of and are variable within the human population with copy number inversely correlating with SMA severity. Current therapeutic options for SMA focus on increasing expression and alternative splicing so as to increase the amount of SMN protein. Recent work has demonstrated that not all , or genes are equivalent and there is a high degree of genomic heterogeneity with respect to the genes. Because SMA is now an actionable disease with being the primary target, it is imperative to have a comprehensive understanding of this genomic heterogeneity with respect to hybrid - genes generated by gene conversion events as well as partial deletions of the genes. This review will describe this genetic heterogeneity in SMA and its impact on disease phenotype as well as therapeutic efficacy.