Bi-allelicNIT1variants cause small vessel disease with movement disorders and massive non-lobar intracerebral haemorrhage

Abstract Highly penetrant monogenic causes of intracerebral haemorrhage are rare, and are almost exclusively hereditary cerebral amyloid angiopathies caused by heterozygous pathogenic variants in the APP gene. Here, we identified a novel genetic cause of mid-adult onset non-lobar ICH, caused by bi-allelic pathogenic variants in the NIT1 gene. The seven identified patients from five unrelated pedigrees presented with movement disorders, slowly progressive cognitive decline, ischemic strokes and psychiatric disturbances. All patients shared a striking neuroimaging phenotype with a honeycomb appearance of the basal ganglia due to an extremely high burden of enlarged perivascular spaces. Two patients were deceased, due to mid-adult massive non-lobar intracerebral haemorrhage. Small cerebral arteries showed strongly abnormal morphology, with thickening of the media and numerous large electron dense deposits located between the media and adventitia. Patients were homozygous for the NIT1 c.727C>T; p.Arg243Trp variant or compound heterozygous for the NIT1 c.727C>T; p.Arg243Trp and c.198_199del, p.Ala68* variant. Urine analysis showed increased levels of deaminated gluthatione, consistent with loss of NIT1 function in both homozygous and compound heterozygous patients. Based on NIT1 carrier frequencies in UK Biobank and gnomAD, an estimated minimum of 4500 individuals worldwide are affected with this novel, autosomal recessively inherited cause of intracerebral haemorrhage, which we term NIT1-small vessel disease.