新致病性 ZNHIT3 变异导致胎儿水肿与致死，破坏 snoRNP 组装

ZNHIT3 is a conserved assembly factor required for biogenesis of box C/D small nucleolar ribonucleoprotein (snoRNP) complexes, which are key players in ribosome biogenesis. Pathogenic variants in ZNHIT3 cause Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic Atrophy (PEHO) syndrome, a severe neurodevelopmental disorder typically recognized postnatally. Here, we describe two fetuses from a single family who developed isolated hydrops in the early second trimester of pregnancy, resulting in intrauterine demise. Whole-genome quartet sequencing identified two new ZNHIT3 variants, c.40T > C; p.(Cys14Arg) and c.251_254del; p.(Glu84Alafs*8), inherited from healthy parents that present as compound heterozygous alleles in both fetuses. Functional studies using a ZNHIT3 knockdown-rescue system in HEK293T cells demonstrated impaired proliferation and increased apoptosis and revealed distinct molecular consequences for the two variants. One variant produced a stable ZNHIT3 protein lacking the region required for interaction with NUFIP1 and efficient box C/D snoRNP assembly, whereas the second variant reduced ZNHIT3 protein abundance. Both variants impaired snoRNP assembly, reduced the abundance of select box C/D snoRNAs, and caused site-specific losses of ribosomal RNA (rRNA) 2′-O-methylation. These defects were accompanied by changes in ribosome biogenesis and reduced translational output. Together, our findings expand the phenotypic spectrum associated with ZNHIT3 deficiency to include severe antenatal disease and demonstrate that impaired box C/D snoRNP assembly and rRNA modification represent convergent molecular consequences of pathogenic ZNHIT3 variants.