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| White matter disorders and cerebral calcification - childhood onset v8.10 | POLR3K |
Achchuthan Shanmugasundram changed review comment from: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp) variant in POLR3K gene, with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control. PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant. This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053).; to: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp) variant in POLR3K gene, with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control. PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype (onset was in late childhood/ adolescence). This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant. This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053). |
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| White matter disorders and cerebral calcification - childhood onset v8.10 | POLR3K |
Achchuthan Shanmugasundram changed review comment from: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp), with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control. PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant. This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053).; to: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp) variant in POLR3K gene, with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control. PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant. This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053). |
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| White matter disorders and cerebral calcification - childhood onset v8.7 | POLR3K |
Achchuthan Shanmugasundram changed review comment from: PMID:40225923 (2024) reported a single female patient compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant.; to: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp), with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control. PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant. This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053). |
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| White matter disorders and cerebral calcification - childhood onset v1.181 | POLR3B | Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, 614381; Pol III-Related Leukodystrophy; General Leukodystrophy & Mitochondrial Leukoencephalopathy to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v0.11 | POLR3B |
Ellen McDonagh gene: POLR3B was added gene: POLR3B was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert Review Green Mode of inheritance for gene: POLR3B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POLR3B were set to 25655951 Phenotypes for gene: POLR3B were set to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, 614381; Pol III-Related Leukodystrophy; General Leukodystrophy & Mitochondrial Leukoencephalopathy |
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