Motor neuron disease, MND, is an ultimately fatal neurodegenerative disease. Approximately 10% is hereditary (familial). MND is genetically heterogeneous, with over 20 causal and 14 associated MND genes identified to date. Mutations in these genes are the only proven cause of disease, however one third of MND families carry an unidentified mutation. These families are often small and exhibit incomplete penetrance, inhibiting traditional disease gene discovery. Using whole exome sequencing and custom bioinformatics, we employed two innovative approaches to identify novel genetic contributors to familial MND. Analysis of four MND families identified 52, 55, 66 and 112 shared variants respectively. Custom bioinformatics filtering reduced these numbers to 21, 24, 22 and 74. Having exhausted genetic analysis, we assessed the potential pathogenicity of each variant using in silico tools, including protein predictions and conservation, genic tolerance, and presence in other MND cohorts, to rank and categorise each as having a high, medium or low likelihood to cause MND. This resulted in just a handful of high priority variants for downstream in vitro analysis and confirmation of pathology. Additionally, 34 candidate genes implicated in disease by proteomic, transgenic mouse models or other genetic studies were screened through 61 probands. Five novel variants potentially causing MND were identified and processed through the above pipeline. Further, 14 known variants were found to be either over- or under-represented in MND patients. Elucidating the remaining genetic contribution to MND is crucial for enhancing our understanding of disease and inspiring downstream studies, particularly therapeutic development.