Bi-allelic NIT1 variants cause small vessel disease with movement disorders and massive non-lobar intracerebral haemorrhage

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 massive non-lobar intracerebral haemorrhage at age 47 and 60, respectively. 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Netherlands Organisation for Health Research and Development (ZonMW grant no 91717325 and 09150161910010) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study has been approved by the Medical Ethics Committee Leiden The Hague Delft (P21.013) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors