Homozygous TREM2 c.549del; p.(Leu184Serfs*5) variant causing Nasu‐Hakola disease in three siblings in a consanguineous Iraqi family: Case report and review of literature

Abstract

Abstract Background The Triggering Receptor Expressed on Myeloid Cells 2 protein (TREM2) plays a crucial role in various biological processes, including osteoclast differentiation, and disease‐associated microglia (DAM) activation to regulate neuroinflammation, and phagocytosis in the brain. Genetic variations in TREM2 are implicated in neurodegenerative disorders, such as Nasu‐hakola disease (NHD), characterized by bone lesions, neuropsychiatric disorders, and early‐onset dementia. Methods We studied 3 siblings with suspected NHD. Whole‐exome sequencing was conducted on the proband to identify the possible genetic cause(s) and by Sanger sequencing to validate the identified variants in the two other affected siblings, a healthy sister, and the parents. Results We identified a novel homozygous deletion (c.549del; p.(Leu184Serfs*5)) in TREM2. Our literature review reveals 16 TREM2 mutations causing early‐onset dementia and bone lesions. Conclusion These findings, alongside previous research, elucidate the clinical spectrum of TREM2‐related diseases, aiding accurate diagnosis and patient care. This knowledge is vital for understanding TREM2‐dependent DAM and its involvement in the pathogenesis of neurodevelopmental disorders which can help to develop targeted therapies and improve outcomes for TREM2‐affected individuals.

Keywords

• disease‐associated microglia (DAM)
• genetic variations
• Nasu‐Hakola disease (NHD)
• neurodegenerative disorders
• TREM2
• whole‐exome sequencing (WES)