Ultra-rare variants in LAMA2 are risk factors for frontotemporal dementia and motor neuron disease.

There is overlap between frontotemporal dementia (FTD) and motor neuron disease (MND) in terms of genetics, neuroimaging and clinical phenotypes. We aimed to identify in three patient cohorts, ultra-rare variants (frequency ≤ 0.00002) in genes whose mutations are associated with white matter dysfunction, and to examine impact of these variants on protein function in vitro, and neuroimaging and lipid profiles in vivo. Next generation sequencing (NGS) of N = 289 patients with clinical FTD recruited through two dementia research clinics identified ultra-rare variants in established leukodystrophy genes, including ARSA. Further, novel and ultra-rare loss-of-function and missense variants in LAMA2 increased risk of disease in three independent cohorts, including N = 598 MND and N = 14 logopenic variant primary progressive aphasia (lvPPA) patients (maximum odds ratio (OR) of 3.05, P = 0.0357 for FTD cohort, OR of 9.57, P = 0.0233 for lvPPA cohort, and 1.78, P = 0.0250 for MND cohort). An in vitro transfection assay demonstrated a loss-of-secretion phenotype in the subset of LAMA2 ultra-rare missense variants where the full-length proteins were translated but not secreted into growth media. LAMA2 ultra-rare variant carriers have a distinctive serum lipidomics profile compared with sporadic cases and cognitively normal controls. Finally, LAMA2 ultra-rare variants were associated with white matter changes in brain regions relevant to disease process. Our results broaden the phenotypes associated with LAMA2 from muscular dystrophies to include FTD, lvPPA and MND; and our data provide convergent evidence for the role of ultra-rare variants in LAMA2 as risk factors.