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| Ataxia and cerebellar anomalies - childhood onset v9.28 | ZNHIT3 |
Ida Ertmanska gene: ZNHIT3 was added gene: ZNHIT3 was added to Ataxia and cerebellar anomalies - childhood onset. 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 |
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| Ataxia and cerebellar anomalies - childhood onset v9.26 | PCLO |
Ida Ertmanska changed review comment from: PMID: 42038819 Baneshi et al., 2025 Report of a 38-year-old Iranian female proband with mild intellectual disability, microcephaly, muscle weakness, and a history of seizures, mild ataxia, behavioral issues, toe-walking, loss of tendon reflexes, and unilateral paralysis. First febrile seizure occurred at 1 year of age. A homozygous PCLO (NM_033026: c.458TC, p. Met153Thr) variant was detected using WES. CRISPR-based cell model for PCH3 was developed (PCLO -/- HEK293T and REH-6 Cell Lines) - a significant reduction in CtBP1 mRNA expression was observed. PMID: 40661989 Lertsakulbunlue et al., 2025 Report of an 8-year-old Thai girl who presented with intractable epilepsy from 2 months of age and severe global developmental delay. Seizures were resistant to medication (control eventually achieved with 4 drugs: topiramate, levetiracetam, perampanel, and carbamazepine). WES identified compound heterozygous mutations in the PCLO gene: c.9018_9037del (p.Tyr3007Ter) and c.8456del (p.Ala2819GlufsTer2) - inherited from unaffected het parents. Brain MRI showed a thin corpus callosum, small pons, thinning of the medulla oblongata, and a hypoplastic cerebellar vermis. PMID: 30287594 Chitre et al., 2018 Cohort of 19 children from 11 UK families with Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome (7/19) or PEHO-like syndrome (12/19). Family A - 5 affected children, 2 diagnosed with PEHO syndrome and 3 with PEHO-like syndrome. All 5 harboured comp het PCLO variants: c.2703C>T, p.(Gln901*Ter) and c.7080C>G, p.(Tyr2360*Ter). Phenotype: Infantile hypotonia 5/5, profound psychomotor delay 5/5, Convulsive disorders presenting with myoclonias and infantile spasms 5/5, Atrophy of optic disc by 2 years 4/4; Progressive brain atrophy confirmed in 2 sibs. PMID: 25832664 Ahmed et al., 2015 Consanguineous Omani family with Pontocerebellar hypoplasia type 3. The 4 affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. WES identified a homozygous NM_033026.5:c.10624C>T; p.Arg3542* variant. FUNCTIONAL EVIDENCE: PMID: 32122952 Falck et al., 2020 - Pclo gt/gt rat model. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT (Pclo wt/wt ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Behavioral studies demonstrated that adult Pclo gt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Seizures were also present in the mutated rats. PCLO is associated with AR Pontocerebellar hypoplasia, type 3, 608027 in OMIM (accessed 13th Aug 2026).; to: PMID: 42038819 Baneshi et al., 2025 Report of a 38-year-old Iranian female proband with mild intellectual disability, microcephaly, muscle weakness, and a history of seizures, mild ataxia (usure on age of onset), behavioral issues, toe-walking, loss of tendon reflexes, and unilateral paralysis. First febrile seizure occurred at 1 year of age. A homozygous PCLO (NM_033026: c.458TC, p. Met153Thr) variant was detected using WES. CRISPR-based cell model for PCH3 was developed (PCLO -/- HEK293T and REH-6 Cell Lines) - a significant reduction in CtBP1 mRNA expression was observed. PMID: 40661989 Lertsakulbunlue et al., 2025 Report of an 8-year-old Thai girl who presented with intractable epilepsy from 2 months of age and severe global developmental delay. Seizures were resistant to medication (control eventually achieved with 4 drugs: topiramate, levetiracetam, perampanel, and carbamazepine). WES identified compound heterozygous mutations in the PCLO gene: c.9018_9037del (p.Tyr3007Ter) and c.8456del (p.Ala2819GlufsTer2) - inherited from unaffected het parents. Brain MRI showed a thin corpus callosum, small pons, thinning of the medulla oblongata, and a hypoplastic cerebellar vermis. PMID: 30287594 Chitre et al., 2018 Cohort of 19 children from 11 UK families with Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome (7/19) or PEHO-like syndrome (12/19). Family A - 5 affected children, 2 diagnosed with PEHO syndrome and 3 with PEHO-like syndrome. All 5 harboured comp het PCLO variants: c.2703C>T, p.(Gln901*Ter) and c.7080C>G, p.(Tyr2360*Ter). Phenotype: Infantile hypotonia 5/5, profound psychomotor delay 5/5, Convulsive disorders presenting with myoclonias and infantile spasms 5/5, Atrophy of optic disc by 2 years 4/4; Progressive brain atrophy confirmed in 2 sibs. PMID: 25832664 Ahmed et al., 2015 Consanguineous Omani family with Pontocerebellar hypoplasia type 3. The 4 affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. WES identified a homozygous NM_033026.5:c.10624C>T; p.Arg3542* variant. FUNCTIONAL EVIDENCE: PMID: 32122952 Falck et al., 2020 - Pclo gt/gt rat model. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT (Pclo wt/wt ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Behavioral studies demonstrated that adult Pclo gt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Seizures were also present in the mutated rats. PCLO is associated with AR Pontocerebellar hypoplasia, type 3, 608027 in OMIM (accessed 13th Aug 2026). |
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| Ataxia and cerebellar anomalies - childhood onset v8.56 | JKAMP |
Ida Ertmanska gene: JKAMP was added gene: JKAMP was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature Mode of inheritance for gene: JKAMP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: JKAMP were set to 41643666 Phenotypes for gene: JKAMP were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: JKAMP was set to GREEN Added comment: PMID: 41643666 Chacon-Millan et al., 2026 Report of 14 affected individuals from 10 unrelated families with biallelic JKAMP variants and a neurodevelopmental disorder. Individuals came from European and Arab backgrounds; age range 18mo - 25yrs. Several frameshift, missense and splice variants reported (homozygous and compound heterozygous states). Phenotype spectrum: moderate-profound neurodevelopmental delay and ID (14/14), neurodevelopmental regression (5/14), early onset epilepsy (14/14, median age of onset 6.5 months), hypotonia (13/14), microcephaly (5/14, severity not stated), various ocular manifestations (5/14), genitourinary malformations (3/14), and other (less common). MRI findings: cortical and or cerebral atrophy (11/14), delayed myelination (6/14). Additional functional evidence: Knockout jkamp-/- zebrafish were generated using CRISPR. Roughly half of the knockout fish had a mild phenotype, and half a 'severe' phenotype - similar to variable severity seen in patient cohort. Morphant phenotype consisted of smaller eyes and heads, and reduced expression of a myelin marker mbpa, partially recapitulating the human phenotype. JKAMP is not yet linked to a disease entity in OMIM, Gene2Phenotype, or ClinGen (resources accessed 10th Feb 2026). Sources: Literature |
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| Ataxia and cerebellar anomalies - childhood onset v8.5 | CRNKL1 |
Achchuthan Shanmugasundram gene: CRNKL1 was added gene: CRNKL1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature Mode of inheritance for gene: CRNKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013 Phenotypes for gene: CRNKL1 were set to complex neurodevelopmental disorder, MONDO:0100038 Review for gene: CRNKL1 was set to GREEN Added comment: There are 10 unrelated patents identified with de novo missense variants in the spliceosomal component CRNKL1, where nine of them harboured one of the two missense variants affecting the same amino acid residue, Arg 267 (p.Arg267Cys & p.Arg267His), while the tenth patient harboured a different variant (p.Arg301Gly). All affected individuals share a common and specific phenotype: profound pre- and post-natal microcephaly (8 of 10 patients), with pontocerebellar hypoplasia (9 patients), seizures (8 patients), and severe intellectual disability (8 patients). Microinjection of mRNA encoding Crnkl1 variant into a zebrafish model caused a severe lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA sequencing analysis of injected zebrafish embryos showed broad transcriptomic changes, with altered expression of neuronal and cell cycle genes. This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype. Sources: Literature |
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| Ataxia and cerebellar anomalies - childhood onset v3.30 | SPR | Eleanor Williams Tag Q2_21_rating was removed from gene: SPR. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v3.30 | SPR | Eleanor Williams reviewed gene: SPR: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v3.29 | SPR |
Eleanor Williams Source Expert Review Green was added to SPR. Source NHS GMS was added to SPR. Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| Ataxia and cerebellar anomalies - childhood onset v2.116 | SPR | Ivone Leong Classified gene: SPR as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v2.116 | SPR | Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v2.116 | SPR | Ivone Leong Gene: spr has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v2.115 | SPR | Ivone Leong Tag Q2_21_rating tag was added to gene: SPR. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v2.115 | SPR | Ivone Leong Phenotypes for gene: SPR were changed from Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, MIM# 612716 to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v2.12 | SPR |
Zornitza Stark gene: SPR was added gene: SPR was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list Mode of inheritance for gene: SPR was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SPR were set to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, MIM# 612716 Review for gene: SPR was set to GREEN gene: SPR was marked as current diagnostic Added comment: Complex movement disorder, dystonia predominant, but ataxia described in some individuals. Most individuals have had bi-allelic variants identified, uncertain whether there is an association with mono-allelic variants. Sources: Expert list |
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