Motor neuron disease (MND) is a progressive neurodegenerative disease leading to muscle weakness, paralysis, and death, on average, 27 months after symptom onset. MND is genetically heterogenous, and heritability evidence suggests that there is a genetic component underlying both inherited and sporadic MND cases. Large-scale genomics provides us with important insights into MND, yet the bioinformatic processing, management and updating of these large datasets can be complex and prohibitive.
The Macquarie University MND Research Centre’s Advanced Gene Discovery Team has developed, and continues to build upon the MMBWAP workflow, a highly modular Nextflow-based pipeline for short read WGS data. Developed in accordance with clinical best practice, the pipeline also provides detailed quality metrics to ensure high quality outputs. The workflow consists of a core analysis stream involving alignment, phasing, variant calling, and large-scale variant aggregation. Several optional analyses branches created dependant on researcher questions: comparative genomics, clinical genomics, genotyping known disease-causing genetic variation (single nucleotide variants, indels, short tandem repeats), polygenic/oligogenic inheritance, dual de novo short tandem repeat identification, and known and cryptic alternative splicing events.
Building on this foundation, we have developed a secondary pipeline (filtraAnnotate) for biological interpretation of results. filtraAnnotate steps are adaptable and customisable, based on specific research requirements for variant filtration and annotation. Integrating this with sample-matched genomic, transcriptomic and clinical data, the pipeline enhances our capacity to identify disease-associated variants, explore genetic modifiers and support translational research.
The current dataset comprises ~1,100 MND patients, including matched WGS, RNA (blood & brain), genealogical pedigrees (where available) and demographic and clinicals patient data, representing the most comprehensive collection of MND genomic data in Australia. Through continual development and integration this platform enables robust, scalable and clinically relevant genomic analyses, advancing our understanding of MND pathogenesis.