A novel splice‐site mutation in CHMP2B associated with frontotemporal dementia: The first report from China and literature review

Abstract Background Frontotemporal dementia (FTD) has genetic heterogeneity, and the endosomal ESCRTIII‐complex subunit CHMP2B variant is a rare cause of FTD. The mutations in CHMP2B were first identified in a large Danish pedigree with autosomal dominant FTD, and have also been found in several individuals from Belgium, France, the United States, and Türkiye. In the Chinese population, cases of CHMP2B variant‐associated FTD have never been reported. Methods The spectrum of clinical symptoms and the genetic analysis of the presented patient were identified and investigated. Besides this case, we assessed previously reported cases with CHMP2B gene mutations. Results This study presents a Chinese patient harboring a novel heterozygous A‐to‐T variant (NM_014043:c.532‐2A>T) in CHMP2B with a phenotype compatible with FTD. Although previous reports suggested cases of CHMP2B variant‐associated FTD initially presented with personality changes and stereotypical movements at the age of 50, this case was characterized by psychosis involving delusion of persecution, auditory hallucination, and suspiciousness at the earlier onset age of 44. Minigene splicing assay revealed that the splice‐site variant could result in the retention of intron 5. Conclusion This is the first case of CHMP2B variant‐associated FTD reported in the Chinese population. The novel c.532‐2A>T variant in the acceptor splice site of exon 6 retaining intron 5 was predicted to cause truncated protein and protein conformation changes. This discovery may expand the genetic and phenotypic spectrum of CHMP2B variant‐associated FTD.