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Paediatric disorders - additional genes v8.13 ZNHIT3 Ida Ertmanska Tag founder-effect tag was added to gene: ZNHIT3.
Paediatric disorders - additional genes v8.13 ZNHIT3 Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence)
Paediatric disorders - additional genes v8.13 ZNHIT3 Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including childhood-onset cerebellar atrophy, optic atrophy, oedema, microcephaly, infantile spasms, and profound developmental delay. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation similar to reported patients. Hence, this gene can be promoted to Green at the next update.
Paediatric disorders - additional genes v8.13 ZNHIT3 Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v8.12 ZNHIT3 Ida Ertmanska gene: ZNHIT3 was added
gene: ZNHIT3 was added to Paediatric disorders - additional genes. Sources: Literature
Q3_26_promote_green tags were added to gene: ZNHIT3.
Mode of inheritance for gene: ZNHIT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNHIT3 were set to 28335020; 31048081; 39252897; 40178020
Phenotypes for gene: ZNHIT3 were set to PEHO syndrome, OMIM:260565; PEHO syndrome, MONDO:0009841
Review for gene: ZNHIT3 was set to GREEN
Added comment: 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). Brain MRI showed cerebral, cerebellar and brainstem atrophy and thin corpus callosum. 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.
Sources: Literature