New ZNHIT3 Variants Disrupting snoRNP Assembly Cause Prenatal PEHO Syndrome with Isolated Hydrops

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• ZNHIT3 (zinc finger HIT type containing protein 3) is crucial for ribosome biogenesis and snoRNP assembly.
• Mutations in ZNHIT3 cause PEHO syndrome, a severe neurodevelopmental disorder.
• Previous studies linked ZNHIT3 variants to postnatal PEHO syndrome phenotypes.

Purpose of the Study:

• To investigate the genetic basis of isolated hydrops leading to intrauterine demise in two fetuses.
• To characterize the functional impact of novel ZNHIT3 variants.
• To extend the phenotypic spectrum of PEHO syndrome to antenatal manifestations.

Main Methods:

• Whole-genome quartet analysis to identify genetic variants.
• Human cell culture models to assess protein stability and function.
• RNA sequencing (RNA-seq) to analyze gene expression changes.
• Analysis of rRNA methylation patterns in fetal samples.

Main Results:

• Identified two novel compound heterozygous ZNHIT3 variants (c.40T>C p.Cys14Arg and c.251_254delAAGA) in affected fetuses.
• Both variants reduced cell growth, ZNHIT3 protein stability/function, snoRNA and rRNA levels, and cellular translation.
• RNA-seq revealed differential gene expression related to developmental processes and RNA binding.

Conclusions:

• Novel ZNHIT3 variants can cause severe antenatal phenotypes, including hydrops and intrauterine demise.
• The identified variants disrupt ribosome biogenesis and cellular translation through distinct molecular mechanisms.
• This study expands the known clinical and molecular spectrum of PEHO syndrome.