Variable phenotypic manifestations of two splice-site variants in DNAJB2: insights from two families and a systematic...

DNAJB2 encodes an HSP40 co‑chaperone involved in protein quality control and maintenance of neuronal proteostasis. Pathogenic variants in this gene, typically inherited in an autosomal recessive manner, cause hereditary motor neuropathy (HMN), Charcot-Marie-Tooth disease (CMT), and other neuromuscular disorders. In this study, we report two unrelated families harboring two distinct splice-site variants within the same intron of DNAJB2: one affecting the acceptor site and the other the donor site, identified in patients presenting with HMN and CMT, respectively. We also performed a systematic review of previously reported variants to further investigate phenotypic variabilities and likely genotype-phenotype correlations. Whole‑exome sequencing (WES) was performed for probands with clinical diagnosis of hereditary neuropathy. Identified variants were confirmed by Sanger sequencing, and co‑segregation analysis was conducted within the families. A systematic review was performed following PRISMA 2020 guidelines using PubMed, Scopus, and Google Scholar databases (January 2000-May 2026). WES identified a known variant, c.446‑1 G > C, in one proband and a novel one, c.445+1del, in another. Clinically, the first patient showed an HMN phenotype, whereas the second presented with an axonal CMT (CMT2). In total, 25 distinct DNAJB2 variants were identified across 46 families in the literature, with most occurring in the homozygous state. Our study expands the mutational spectrums of this gene, and the systematic evaluation of DNAJB2-related cases demonstrates the marked clinical heterogeneity but not a significant genotype-phenotype correlation.