ZNHIT3 – PEHO syndrome

PEHO syndrome (Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy) is a severe early-onset autosomal recessive encephalopathy characterized by cerebellar granule neuron loss, profound microcephaly, hypsarrhythmia, optic atrophy, and peripheral edema. The syndrome arises from biallelic variants in ZNHIT3, an evolutionarily conserved zinc finger HIT–type protein essential for small nucleolar ribonucleoprotein (snoRNP) assembly and pre-rRNA processing (PMID:28335020).

Genetic evidence includes three unrelated probands: multiple Finnish families homozygous for c.92C>T (p.Ser31Leu) founder variants, a non-Finnish individual with compound heterozygous p.Ser31Leu and c.41C>T (p.Cys14Phe) variants (PMID:31048081), and two fetuses with compound heterozygous c.40T>C (p.Cys14Arg) and c.251_254del (p.Glu84AlafsTer8) variants presenting with prenatal hydrops (PMID:39252897). All variants segregate in an autosomal recessive pattern without additional affected relatives.

Variant spectrum comprises three missense changes (p.Ser31Leu, p.Cys14Phe, p.Cys14Arg) and one frameshift (p.Glu84AlafsTer8). The recurrent Finnish founder p.Ser31Leu variant has a gnomAD heterozygote frequency <0.01% and is predicted deleterious by multiple algorithms. Biallelic LoF alleles are exceedingly rare in controls.

Functional studies demonstrate a loss-of-function mechanism: zebrafish znhit3 knockdown and CRISPR models recapitulate cerebellar atrophy, microcephaly, and edema, all rescued by wild-type but not mutant human ZNHIT3 mRNA (PMID:28335020). In vitro assays of patient-derived and engineered variants show reduced protein stability, impaired snoRNP assembly, decreased box C/D snoRNA levels, defective rRNA 2'-O-methylation, and attenuated cellular translation (PMID:39252897).

No conflicting evidence has been reported for PEHO syndrome. The concordance of genetic segregation, case reports across populations, and robust functional concordance supports a strong gene–disease relationship.

Key Take-home: Biallelic ZNHIT3 variants cause autosomal recessive PEHO syndrome via loss of snoRNP assembly and pre-rRNA processing, enabling precise molecular diagnosis and potential development of targeted therapies.

References

• Brain : a journal of neurology • 2017 • ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss. PMID:28335020
• European journal of medical genetics • 2020 • PEHO syndrome caused by compound heterozygote variants in ZNHIT3 gene. PMID:31048081
• medRxiv : the preprint server for health sciences • 2024 • New ZNHIT3 Variants Disrupting snoRNP Assembly Cause Prenatal PEHO Syndrome with Isolated Hydrops. PMID:39252897

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