Optic neuropathy

Gene: ZNHIT3

I don't know

Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including optic atrophy. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation, though optic atrophy is not specifically mentioned. Hence, this gene can only be rated Amber on Optic neuropathy with the current evidence. It was tagged for promotion to Green on Paediatric disorders - additional genes, to ensure inclusion on R27.

Created: 14 Aug 2026, 2:20 p.m. | Last Modified: 14 Aug 2026, 2:30 p.m.

Panel Version: 6.51

PMID: 39252897 Rahman et al., 2024 - PRE-PRINT
Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants.
Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells.

PMID: 31048081 Õunap et al., 2019
Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each.
She had severe muscular hypotonia, profound developmental delay, seizures (onset at 10 months), hypotonia, feeding difficulties, limb edema, and absent visual fixation, diagnosed with blindness at 17 months (pale and small disks, and temporal disk pallor noted). Progressive microcephaly also noted: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.

PMID: 28335020 Anttonen et al., 2017
Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features.
All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported.
Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability.

Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant.

FUNCTIONAL EVIDENCE:
PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development.

Created: 14 Aug 2026, 10:35 a.m. | Last Modified: 14 Aug 2026, 1:56 p.m.

Panel Version: 6.47

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
PEHO syndrome, OMIM:260565; PEHO syndrome, MONDO:0009841

Publications

• 28335020
• 31048081
• 39252897
• 40178020

Red List (low evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) 260565

Publications

• 28335020