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| Optic neuropathy v6.51 | ZNHIT3 | Ida Ertmanska changed review comment from: 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.; to: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.51 | ZNHIT3 | Ida Ertmanska Tag founder-effect tag was added to gene: ZNHIT3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.51 | ZNHIT3 | Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.51 | 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 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.51 | ZNHIT3 | Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.50 | ZNHIT3 | Ida Ertmanska edited their review of gene: ZNHIT3: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.50 | ZNHIT3 | Ida Ertmanska Phenotypes for gene: ZNHIT3 were changed from Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) 260565 to Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy; PEHO syndrome, OMIM:260565; PEHO syndrome, MONDO:0009841 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.49 | ZNHIT3 | Ida Ertmanska Publications for gene: ZNHIT3 were set to 28335020 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.48 | ZNHIT3 | Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.48 | ZNHIT3 | Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.47 | ZNHIT3 | Ida Ertmanska edited their review of gene: ZNHIT3: Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.47 | ZNHIT3 |
Ida Ertmanska changed review comment from: 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 progressive microcephaly: 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.; to: 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. |
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| Optic neuropathy v6.47 | ZNHIT3 | Ida Ertmanska edited their review of gene: ZNHIT3: Changed publications to: 28335020, 31048081, 39252897, 40178020 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.47 | ZNHIT3 |
Ida Ertmanska changed review comment from: 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. 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). Unaffected parents het for a variant each. She had progressive microcephaly: 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.; to: 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 progressive microcephaly: 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. |
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| Optic neuropathy v6.47 | ZNHIT3 | Ida Ertmanska edited their review of gene: ZNHIT3: Changed phenotypes to: PEHO syndrome, OMIM:260565, PEHO syndrome, MONDO:0009841 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.47 | ZNHIT3 | Ida Ertmanska edited their review of gene: ZNHIT3: Changed publications to: 31048081, 39252897 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.47 | ZNHIT3 |
Ida Ertmanska changed review comment from: 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). Unaffected parents het for a variant each. She had progressive microcephaly: 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.; to: 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. 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). Unaffected parents het for a variant each. She had progressive microcephaly: 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. |
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| Optic neuropathy v6.47 | ZNHIT3 |
Ida Ertmanska changed review comment from: PMID: 31048081 Õunap et al., 2019 Report of a female patient (non-Finnish) 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). Unaffected parents het for a variant each. She had progressive microcephaly: 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.; to: 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). Unaffected parents het for a variant each. She had progressive microcephaly: 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. |
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| Optic neuropathy v6.47 | ZNHIT3 | Ida Ertmanska reviewed gene: ZNHIT3: Rating: AMBER; Mode of pathogenicity: None; Publications: 31048081; Phenotypes: PEHO syndrome, OMIM:260565; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v1.95 | ZNHIT3 | Ivone Leong Phenotypes for gene: ZNHIT3 were changed from to Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) 260565 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v1.94 | ZNHIT3 | Ivone Leong Publications for gene: ZNHIT3 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v1.93 | ZNHIT3 | Ivone Leong Mode of inheritance for gene: ZNHIT3 was changed from to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v1.28 | ZNHIT3 | Tom Cullup reviewed gene: ZNHIT3: Rating: RED; Mode of pathogenicity: ; Publications: 28335020; Phenotypes: Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) 260565; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v1.27 | ZNHIT3 |
Ivone Leong gene: ZNHIT3 was added gene: ZNHIT3 was added to Optic neuropathy. Sources: London North GLH,Expert Review Red Mode of inheritance for gene: ZNHIT3 was set to |
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