Genetic epilepsy syndromesGene: 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.
Created: 25 Nov 2019, 8:24 p.m. | Last Modified: 25 Nov 2019, 8:24 p.m.
Panel Version: 1.428
Gene2Phenotype now records a 'confirmed' rating for HNRNPR for 'INTELLECTUAL DISABILITY'.
Created: 7 Nov 2019, 2:26 p.m. | Last Modified: 7 Nov 2019, 2:26 p.m.
Panel Version: 1.405
No disease association on OMIM. HGMD Pro mentions the Helbig paper - 1 case (26795593). The Duijkers et al, 2019 paper (31079900) - includes the variant detected in the Helbig paper along with 4 other unrelated individuals - all presenting with multisystem developmental defects including abnormalities of the brain and skeleton, dysmorphic facies, brachydactyly, seizures (in 4/5 not reported in the patient with the missense variant) and hypoplastic external genitalia. 4 diff de novo variants identified in these 5 unrelated patients - 2 fs, 1 missense, 1 nonsense all in the C-terminal region of hnRNPR.
Created: 23 Sep 2019, 1:10 p.m. | Last Modified: 23 Sep 2019, 1:10 p.m.
Panel Version: 1.336
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
HNPNR identified by Konstantinos Varvagiannis as reported in Duijkers et al. (2019 - PMID: 31079900) . Four individuals identified and one further individual who was previously reported on in PMID: 26795593. All 5 unrelated individuals found to have de novo hetrozygous mutations following trio WES, 3 truncating and one missense variant, identified in the last coding exon, individuals 2 and 3 have the same variant c.1652dupG p.(Pro552Serfs*34).
This is the first gene to phenotype reporting, no phenotypes associated in OMIM or Gene2Phenotype. A broad range of phenotypes reported and they are not consistent in all individuals. 3/5 identified as having seizures (in one of these individuals seizures are reported but not as one of the main clinical problems), a further individual had febrile seizures. Rating gene as Amber until more associations found.
Created: 10 Sep 2019, 12:37 p.m. | Last Modified: 10 Sep 2019, 12:37 p.m.
Panel Version: 1.325
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.
Created: 25 Aug 2019, 8:11 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit
Mode of inheritance for gene: HNRNPR was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Gene: hnrnpr has been classified as Green List (High Evidence).
Tag watchlist tag was added to gene: HNRNPR.
Gene: hnrnpr has been classified as Amber List (Moderate Evidence).
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