RT Journal Article SR Electronic T1 Frontotemporal dementia presentation in patients with heterozygous p.H157Y variant of TREM2 JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2022-108627 DO 10.1136/jmg-2022-108627 A1 Natalia Ogonowski A1 Hernando Santamaria-Garcia A1 Sandra Baez A1 Andrea Lopez A1 Andrés Laserna A1 Elkin Garcia-Cifuentes A1 Paola Ayala-Ramirez A1 Ignacio Zarante A1 Fernando Suarez-Obando A1 Pablo Reyes A1 Marcelo Kauffman A1 Nick Cochran A1 Michael Schulte A1 Daniel W Sirkis A1 Salvatore Spina A1 Jennifer S Yokoyama A1 Bruce L Miller A1 Kenneth S Kosik A1 Diana Matallana A1 Agustín Ibáñez YR 2023 UL http://jmg.bmj.com/content/early/2023/02/22/jmg-2022-108627.abstract AB Background The triggering receptor expressed on myeloid cell 2 (TREM2) is a major regulator of neuroinflammatory processes in neurodegeneration. To date, the p.H157Y variant of TREM2 has been reported only in patients with Alzheimer’s disease. Here, we report three patients with frontotemporal dementia (FTD) from three unrelated families with heterozygous p.H157Y variant of TREM2: two patients from Colombian families (study 1) and a third Mexican origin case from the USA (study 2).Methods To determine if the p.H157Y variant might be associated with a specific FTD presentation, we compared in each study the cases with age-matched, sex-matched and education-matched groups—a healthy control group (HC) and a group with FTD with neither TREM2 mutations nor family antecedents (Ng-FTD and Ng-FTD-MND).Results The two Colombian cases presented with early behavioural changes, greater impairments in general cognition and executive function compared with both HC and Ng-FTD groups. These patients also exhibited brain atrophy in areas characteristic of FTD. Furthermore, TREM2 cases showed increased atrophy compared with Ng-FTD in frontal, temporal, parietal, precuneus, basal ganglia, parahippocampal/hippocampal and cerebellar regions. The Mexican case presented with FTD and motor neuron disease (MND), showing grey matter reduction in basal ganglia and thalamus, and extensive TDP-43 type B pathology.Conclusion In all TREM2 cases, multiple atrophy peaks overlapped with the maximum peaks of TREM2 gene expression in crucial brain regions including frontal, temporal, thalamic and basal ganglia areas. These results provide the first report of an FTD presentation potentially associated with the p.H157Y variant with exacerbated neurocognitive impairments.Data are available upon reasonable request.