Poster Presentation 47th Lorne Genome Conference 2026

Characterising mitochondrial haplogroups and clinical features in Australian sporadic motor neuron disease (133327)

Sandrine Chan Moi Fat 1 , Zoe Zussa 1 , Andrew Smith 1 , Longfei Wang 2 3 , Melanie Bahlo 2 3 , Lyndal Henden 1 , Kelly Williams 1
  1. Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
  2. Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
  3. Genetics and Gene Regulation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

Motor neuron disease (MND) is a fatal neurodegenerative disorder with heterogeneous clinical presentation. While pathogenic gene mutations are the only confirmed cause, they explain fewer than 10% of cases. Mitochondrial dysfunction has emerged as a key contributor to MND pathogenesis. Mitochondria contain their own genome (mtDNA), which is maternally inherited, and can be classified into haplogroups to reflect common maternal lineages. This characterises an Australian sporadic MND cohort using clinical features and mitochondrial haplogroups, whilst establishing a pipeline for more advanced mtDNA analyses in MND.

We analysed 563 Australian sporadic MND patients with whole-genome sequencing and matched clinical data. Haplogroups were assigned using Hi-MC1, with sub-haplogroups (H1, H2, H3) consolidated into parent haplogroups (H) and rare haplogroups represented in less than five individuals grouped as “Other”. Associations between haplogroups and clinical features were tested using Chi-squared (site of onset: bulbar vs spinal) and Kruskal-Wallis (age at onset and disease duration) tests. Our pipeline is currently being expanded to include additional mtDNA features, including estimation of mtDNA copy number using MitoCN2 and identification of heteroplasmic variants using MitoHPC3.

Our cohort consisted of 402 spinal-onset and 161 bulbar-onset MND cases, with a mean age at onset of 60.7 years and mean disease duration of 3.6 years. The haplogroup distribution was consistent with previously reported European populations, with haplogroups H (31.3%), U (7.7%), and J (6.1%) being the most prevalent4. No significant statistical associations were observed between mitochondrial haplogroup and site of disease onset (p = 0.29), age at onset (p = 0.50) or disease duration (p = 0.57).

Our findings suggest that mtDNA haplogroup alone does not appear to drive clinical variability in our cohort. Ongoing work will examine whether combined mitochondrial features, mtDNA copy number, and heteroplasmy, might affect disease expression and progression, offering deeper insight into mitochondrial contributions to MND.

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