A rare homozygous mutation in TYROBP resulting in early-onset dementia with bone cysts

Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by progressive dementia and multiple bone cysts. The known pathogenic genes include TYRO protein tyrosine kinase binding protein (TYROBP) on chromosome 19q13.1 and triggering receptor expressed on myeloid cells 2 (TREM2) on chromosome 6p21.1. Until now, no case related to TYROBP gene mutation has been reported in the Chinese population. We report a 39-year-old Chinese Han patient who presented with early-onset dementia and cystic bone lesions. Brain magnetic resonance imaging showed extensive cerebral atrophy with ventricular enlargement and diffuse, symmetric white matter lesions. Whole-exome sequencing identified a nonsense mutation, c.214C > T (p.Arg72Ter), in the TYROBP gene. Minigene experiments suggested that this variant may partially affect TYROBP splicing, providing supplementary transcript-level evidence for NHD. This is the first genetically confirmed case of NHD associated with a homozygous TYROBP c.214C > T (p.Arg72Ter) variant in the Chinese population. Our findings expand the mutation spectrum of NHD and provide new reference evidence for its molecular diagnosis and genetic counseling.