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| Early onset or syndromic epilepsy v9.65 | PCLO | Ida Ertmanska changed review comment from: Comment on list classification: There are now at least 3 unrelated families reported in literature with biallelic PCLO variants and early-onset epilepsy. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now at least 3 unrelated families reported in literature with biallelic PCLO variants and early-onset epilepsy. There is a supportive rat model showing that pclo knock-out results in reduced brain size, impaired motor coordination, and seizures. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.65 | 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 Pclogt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. 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, 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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| Early onset or syndromic epilepsy v9.65 | PCLO | Ida Ertmanska edited their review of gene: PCLO: Changed publications to: 25832664, 30287594, 32122952, 40661989, 42038819 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.65 | 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. 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, 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 Pclogt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. PCLO is associated with AR Pontocerebellar hypoplasia, type 3, 608027 in OMIM (accessed 13th Aug 2026). |
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| Early onset or syndromic epilepsy v9.65 | PCLO | Ida Ertmanska Phenotypes for gene: PCLO were changed from to Pontocerebellar hypoplasia, type 3, OMIM:608027; PEHO syndrome, MONDO:0009841; progressive encephalopathy with edema, hypsarrhythmia and optic atrophy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.64 | PCLO | Ida Ertmanska Publications for gene: PCLO were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.63 | PCLO | Ida Ertmanska Mode of inheritance for gene: PCLO was changed from to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.62 | PCLO | Ida Ertmanska Classified gene: PCLO as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.62 | PCLO | Ida Ertmanska Added comment: Comment on list classification: There are now at least 3 unrelated families reported in literature with biallelic PCLO variants and early-onset epilepsy. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.62 | PCLO | Ida Ertmanska Gene: pclo has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.61 | PCLO | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: PCLO. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.61 | PCLO | Ida Ertmanska reviewed gene: PCLO: Rating: GREEN; Mode of pathogenicity: None; Publications: 25832664, 30287594, 40661989, 42038819; Phenotypes: Pontocerebellar hypoplasia, type 3, OMIM:608027, PEHO syndrome, MONDO:0009841, progressive encephalopathy with edema, hypsarrhythmia and optic atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v4.178 | PCLO | Sarah Leigh Classified gene: PCLO as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v4.178 | PCLO | Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be Amber on this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v4.178 | PCLO | Sarah Leigh Gene: pclo has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v4.144 | PCLO | Dmitrijs Rots reviewed gene: PCLO: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.191 | PCLO | Rebecca Foulger Source Wessex and West Midlands GLH was added to PCLO. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.190 | PCLO | Rebecca Foulger Source NHS GMS was added to PCLO. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.189 | PCLO | Rebecca Foulger reviewed gene: PCLO: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.188 | PCLO | Tracy Lester reviewed gene: PCLO: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ?Pontocerebellar hypoplasia, type 3, 608027; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.1529 | PCLO | Sarah Leigh Marked gene: PCLO as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.1529 | PCLO | Sarah Leigh Added comment: Comment when marking as ready: Based on reviewers' comments. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.1529 | PCLO | Sarah Leigh Gene: pclo has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy | PCLO | Zornitza Stark reviewed gene: PCLO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy | PCLO | Sarah Leigh Added gene to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||