End-truncated LAMB1 causes a hippocampal memory defect and a leukoencephalopathy.

OBJECTIVE The majority of patients with a familial cerebral small vessel disease (CSVD) referred for molecular screening do not show pathogenic variants in known genes. In this study, we aimed to identify novel CSVD causal genes. METHODS We performed a gene-based collapsing test of rare protein truncating variants identified in exome data of 258 unrelated CSVD patients of an ethnically matched control cohort and of two publicly available large-scale databases, gnomAD and TOPMed. Western blotting was used to investigate variants functional consequences. Clinical and MRI features of mutated patients were characterized. RESULTS We showed that LAMB1 truncating variants escaping nonsense-mediated mRNA decay are strongly overrepresented in CSVD patients, reaching genome-wide significance (p < 5 x10-8 ). Using two antibodies recognizing the N-and C-terminal parts of LAMB1, we showed that truncated forms of LAMB1 are expressed in patients' endogenous fibroblasts and are trapped in the cytosol. These variants are associated with a novel phenotype characterized by the association of a hippocampal type episodic memory defect and a diffuse vascular leukoencephalopathy. INTERPRETATION These findings are important for diagnosis and clinical care, to avoid unnecessary and sometimes invasive investigations, and also from a mechanistic point of view to understand the role of extracellular matrix proteins in neuronal homeostasis. This article is protected by copyright. All rights reserved.