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| Intellectual disability - microarray and sequencing v3.1768 | HNRNPR | Eleanor Williams commented on gene: HNRNPR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1768 | HNRNPR | Eleanor Williams Phenotypes for gene: HNRNPR were changed from Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit; Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities, OMIM:620073 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1767 | HNRNPR | Eleanor Williams Tag gene-checked was removed from gene: HNRNPR. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1562 | HNRNPR | Arina Puzriakova Tag gene-checked tag was added to gene: HNRNPR. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1056 | HNRNPR | Catherine Snow Classified gene: HNRNPR as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1056 | HNRNPR | Catherine Snow Gene: hnrnpr has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1055 | HNRNPR | Catherine Snow reviewed gene: HNRNPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 31079900, 26795593; Phenotypes: Intellectual Disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1015 | HNRNPR |
Konstantinos Varvagiannis changed review comment from: Duijkers et al. (2019 - PMID: 31079900) report on the phenotype of 4 individuals with de novo HNRNPR variants and provide additional information on a previously published case (Helbig et al, 2016 - PMID: 26795593). All 5 were unrelated. The phenotype consisted of DD (5/5 - moderate to severe in 4 for which this has been commented on), postnatal microcephaly, seizures, brachydactyly, with additional (cardiac, urogenital, etc) anomalies observed in few. Some partially overlapping facial features were also noted. 3 truncating variants as well as a missense one, all localizing within the last exon of the gene (NM_001102398.2 used as ref. although this exon is shared by all transcripts). HNRNPR encodes heterogeneous nuclear ribonucleoprotein R, which is part of the spliceosome C. The latter functions in the nucleus to process and transport mRNA. Apart from splicing hnRNPs are also involved in other levels of gene regulation (PMID: 27215579). Some hnRNPs have been found in the cytoplasm in stress granules, aggregations of protein, RNAs and stalled initiation complexes that are formed as stress response upon oxidative insult and dissipate upon cessation of this insult. Western blot in LCLs from affected individuals demonstrated the presence of the truncated protein as well as the full-length and short isoform (as expected by the variant localization). As the C-terminal part has features of a "prion-like domain" (PrLD), critical for the formation of stress granules in the case of hnRNP-related disorders, comparison of fibroblasts from affected and healthy individuals revealed abnormal persistence of these granules in affected individuals following a recovery period, despite similar formation either at basal levels or under conditions of stress. In line with a role of hnRNPs in splicing and gene regulation, RNA-Sequencing in fibroblasts from 2 affected individuals revealed abnormal splicing of some genes (eg. HOXA5, HOXB3, LHX9) and significant dysregulation of genes important for the development (upregulation of FOXG1, TBX1, several members of the HOX family and downregulation of LHX9, IRX3, etc) possibly contributing to the patient features. Helbig et al. provide details on animal studies incl.expression in neural tissues (cerebrum and cerebellum), higher levels of expression early in the development (of both R1/R2 isoforms), etc (extensive discussion in the supplement with several articles cited). HNRNPR is not associated with any phenotype in OMIM/G2P. As a result this gene can be considered for inclusion as amber (developmental outcome not commented on sufficiently despite moderate/severe DD in most). Sources: Literature; to: Duijkers et al. (2019 - PMID: 31079900) report on the phenotype of 4 individuals with de novo HNRNPR variants and provide additional information on a previously published case (Helbig et al, 2016 - PMID: 26795593). All 5 were unrelated. The phenotype consisted of DD (5/5 - moderate to severe in 4 for which this has been commented on), postnatal microcephaly, seizures, brachydactyly, with additional (cardiac, urogenital, etc) anomalies observed in few. Some partially overlapping facial features were also noted. 3 truncating variants as well as a missense one, all localizing within the last exon of the gene (NM_001102398.2 used as ref. although this exon is shared by all transcripts). HNRNPR encodes heterogeneous nuclear ribonucleoprotein R, which is part of the spliceosome C. The latter functions in the nucleus to process and transport mRNA. Apart from splicing hnRNPs are also involved in other levels of gene regulation (PMID: 27215579). Some hnRNPs have been found in the cytoplasm in stress granules, aggregations of protein, RNAs and stalled initiation complexes that are formed as stress response upon oxidative insult and dissipate upon cessation of this insult. Western blot in LCLs from affected individuals demonstrated the presence of the truncated protein as well as the full-length and short isoform (as expected by the variant localization). As the C-terminal part has features of a "prion-like domain" (PrLD), critical for the formation of stress granules in the case of hnRNP-related disorders, comparison of fibroblasts from affected and healthy individuals revealed abnormal persistence of these granules in affected individuals following a recovery period, despite similar formation either at basal levels or under conditions of stress. In line with a role of hnRNPs in splicing and gene regulation, RNA-Sequencing in fibroblasts from 2 affected individuals revealed abnormal splicing of some genes (eg. HOXA5, HOXB3, LHX9) and significant dysregulation of genes important for the development (upregulation of FOXG1, TBX1, several members of the HOX family and downregulation of LHX9, IRX3, etc) possibly contributing to the patient features. Helbig et al. provide details on animal studies incl.expression in neural tissues (cerebrum and cerebellum), higher levels of expression early in the development (of both R1/R2 isoforms), etc (extensive discussion in the supplement with several articles cited). HNRNPR is not associated with any phenotype in OMIM/G2P. As a result this gene can be considered for inclusion as amber (developmental outcome not commented on sufficiently despite moderate/severe DD in most) or green. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1015 | HNRNPR |
Konstantinos Varvagiannis gene: HNRNPR was added gene: HNRNPR was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: HNRNPR was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: HNRNPR were set to 31079900; 26795593 Phenotypes for gene: HNRNPR were set to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit Penetrance for gene: HNRNPR were set to unknown Review for gene: HNRNPR was set to GREEN Added comment: Duijkers et al. (2019 - PMID: 31079900) report on the phenotype of 4 individuals with de novo HNRNPR variants and provide additional information on a previously published case (Helbig et al, 2016 - PMID: 26795593). All 5 were unrelated. The phenotype consisted of DD (5/5 - moderate to severe in 4 for which this has been commented on), postnatal microcephaly, seizures, brachydactyly, with additional (cardiac, urogenital, etc) anomalies observed in few. Some partially overlapping facial features were also noted. 3 truncating variants as well as a missense one, all localizing within the last exon of the gene (NM_001102398.2 used as ref. although this exon is shared by all transcripts). HNRNPR encodes heterogeneous nuclear ribonucleoprotein R, which is part of the spliceosome C. The latter functions in the nucleus to process and transport mRNA. Apart from splicing hnRNPs are also involved in other levels of gene regulation (PMID: 27215579). Some hnRNPs have been found in the cytoplasm in stress granules, aggregations of protein, RNAs and stalled initiation complexes that are formed as stress response upon oxidative insult and dissipate upon cessation of this insult. Western blot in LCLs from affected individuals demonstrated the presence of the truncated protein as well as the full-length and short isoform (as expected by the variant localization). As the C-terminal part has features of a "prion-like domain" (PrLD), critical for the formation of stress granules in the case of hnRNP-related disorders, comparison of fibroblasts from affected and healthy individuals revealed abnormal persistence of these granules in affected individuals following a recovery period, despite similar formation either at basal levels or under conditions of stress. In line with a role of hnRNPs in splicing and gene regulation, RNA-Sequencing in fibroblasts from 2 affected individuals revealed abnormal splicing of some genes (eg. HOXA5, HOXB3, LHX9) and significant dysregulation of genes important for the development (upregulation of FOXG1, TBX1, several members of the HOX family and downregulation of LHX9, IRX3, etc) possibly contributing to the patient features. Helbig et al. provide details on animal studies incl.expression in neural tissues (cerebrum and cerebellum), higher levels of expression early in the development (of both R1/R2 isoforms), etc (extensive discussion in the supplement with several articles cited). HNRNPR is not associated with any phenotype in OMIM/G2P. As a result this gene can be considered for inclusion as amber (developmental outcome not commented on sufficiently despite moderate/severe DD in most). Sources: Literature |
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