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Early onset or syndromic epilepsy v2.607 HNRNPR Eleanor Williams commented on gene: HNRNPR
Early onset or syndromic epilepsy v2.607 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
Early onset or syndromic epilepsy v2.606 HNRNPR Eleanor Williams Tag gene-checked was removed from gene: HNRNPR.
Early onset or syndromic epilepsy v2.518 HNRNPR Arina Puzriakova Tag gene-checked tag was added to gene: HNRNPR.
Early onset or syndromic epilepsy v2.0 HNRNPR Louise Daugherty Tag watchlist was removed from gene: HNRNPR.
Early onset or syndromic epilepsy v2.0 HNRNPR Louise Daugherty commented on gene: HNRNPR
Early onset or syndromic epilepsy v1.430 HNRNPR Rebecca Foulger Mode of inheritance for gene: HNRNPR was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.429 HNRNPR Rebecca Foulger Classified gene: HNRNPR as Green List (high evidence)
Early onset or syndromic epilepsy v1.429 HNRNPR Rebecca Foulger Gene: hnrnpr has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.428 HNRNPR Rebecca Foulger commented on gene: HNRNPR: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Although obvious dysmoprhism is associated with the phenotype, it meets the criteria for a Green rating. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.405 HNRNPR Rebecca Foulger commented on gene: HNRNPR
Early onset or syndromic epilepsy v1.336 HNRNPR Helen Lord reviewed gene: HNRNPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 26795593, 31079900; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.326 HNRNPR Catherine Snow Tag watchlist tag was added to gene: HNRNPR.
Early onset or syndromic epilepsy v1.326 HNRNPR Catherine Snow Classified gene: HNRNPR as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.326 HNRNPR Catherine Snow Gene: hnrnpr has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.325 HNRNPR Catherine Snow reviewed gene: HNRNPR: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.256 HNRNPR Konstantinos Varvagiannis gene: HNRNPR was added
gene: HNRNPR was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: HNRNPR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 AMBER
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 (4/5), 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 (seizures in 4/5) or green.
Sources: Literature