New pathogenic ZNHIT3 variants causing fetal hydrops and lethality disrupt snoRNP assembly
6 affiliations
- 1Department of Biochemistry, Emory University School of Medicine , Atlanta, GA 30322 ,
- 2Génétique du développement, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP) , 75019 Paris ,
- 3INSERM UMR 1141, Paris-Cité University , NeuroDiderot, Paris 75019 ,
- 4Department of Human Genetics, Emory University School of Medicine , Atlanta, GA 30322 ,
- 5Université de Lorraine, SMP IBSLor, Biopôle , 9 Avenue de la Forêt de Haye, 54505 Vandoeuvre-les-Nancy ,
- 6Université de Lorraine, UMR7365 IMoPA, CNRS, Biopôle , 9 Avenue de la Forêt de Haye, 54505 Vandoeuvre-les-Nancy ,
Abstract
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.
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BibTeX
@article{rahman2026pathogenic,
title = {{New pathogenic ZNHIT3 variants causing fetal hydrops and lethality disrupt snoRNP assembly}},
author = {Md Lutfur Rahman and Adeline A Bonnard and Lyse Ruaud and Fabien Guimiot and Ines Defer and Feng Wang and Virginie Marchand and Yuri Motorin and Bing Yao and Séverine Drunat and Homa Ghalei},
journal = {Nucleic Acids Research},
year = {2026},
month = nov,
doi = {10.1093/nar/gkag1024},
url = {https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1024/9013030},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - New pathogenic ZNHIT3 variants causing fetal hydrops and lethality disrupt snoRNP assembly
AU - Md Lutfur Rahman
AU - Adeline A Bonnard
AU - Lyse Ruaud
AU - Fabien Guimiot
AU - Ines Defer
AU - Feng Wang
AU - Virginie Marchand
AU - Yuri Motorin
AU - Bing Yao
AU - Séverine Drunat
AU - Homa Ghalei
PY - 2026
DA - 2026/11/05
JO - Nucleic Acids Research
DO - 10.1093/nar/gkag1024
UR - https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1024/9013030
AB - 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.
SN - 0305-1048
SN - 1362-4962
ER -