ICCFGG 2022
#55 Biology across boundaries: exploring shared genetic risk factors for humans and cats with autoimmune encephalitis Sophie Binks1,2 , Hiron TK3,4, Crawford AH3, Falcone S4, Woodhall M1, Fower A1, Wallace MD3,4, Fox H1, Waters P1, Irani SR1,2, Kennedy LJ5, Pakozdy A6, Davison LJ3,4 sophie.binks@ndcn.ox.ac.uk 1Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, UK, 2Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals Foundation NHS Trust, Oxford, UK, 3Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK, 4Department of Clinical Sciences and Services, Royal Veterinary College, Herts, UK, 5Centre for Integrated Genomic Medical Research, University of Manchester, UK, 6University Clinic for Small Animals, University of Veterinary Medicine, Vienna, Austria Introduction: Autoantibodies to surface-expressed central nervous system proteins are known as a cause of autoimmune encephalitis (AE) in humans. AE caused by antibodies to the secreted protein leucine-rich glioma-inactivated 1 (LGI1-Ab-E), presents with a distinctive phenotype of seizures, memory deficits and personality change. More than 90% of humans with LGI1-Ab-E carry the major histocompatibility complex (MHC) class II allele, DRB1*07:01. Remarkably, a parallel encephalitis exists in cats, also associated with LGI1-autoantibodies and a characteristic phenotype. MHC associations remain to be explored, because of the notoriously complex and repetitive nature of the feline MHC region. Methods: The International Feline Encephalitis Study Group has screened the largest-to-date cohort of cats with suspected AE with a feline-specific LGI1-autoantibody test. Eleven deep-phenotyped autoantibody-positive cats have been selected for MHC genotyping. An in- novative new long-read sequencing approach using Oxford Nanopore Technology is being developed for feline MHC genotyping, based on initial Nanopore whole genome sequencing of one cat followed by targeted ‘ReadUntil’ sequencing of additional cats. Results and conclusions: A new Nanopore- based feline genome assembly was successfully constructed and used as the basis for ReadUntil sequencing of the feline MHC region in a pilot experiment of 2 cats (1 AE, 1 control). Using this novel technique, sequencing of a further 10 cases and 9 controls is underway to determine whether cats with LGI1-Ab-E share a particular MHC allele as is the case in human disease. This technique has the potential to provide insights into the genetic basis of other feline immune-mediated diseases and reveal cross-species genetic risk factors in AE.
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