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Intellectual disability

Gene: HNRNPR

Green List (high evidence)

HNRNPR (heterogeneous nuclear ribonucleoprotein R)
EnsemblGeneIds (GRCh38): ENSG00000125944
EnsemblGeneIds (GRCh37): ENSG00000125944
OMIM: 607201, Gene2Phenotype
HNRNPR is in 3 panels

2 reviews

Catherine Snow (Genomics England)

Green List (high evidence)

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 and is a confirmed DD gene in Gene2Phenotype.

All individuals had serve to moderate intellectual disability. As three of more unrelated individuals and consistent ID phenotype seen within all individuals rating as Green.
Created: 3 Oct 2019, 3:29 p.m. | Last Modified: 3 Oct 2019, 3:29 p.m.
Panel Version: 2.1055

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Intellectual Disability

Publications

Konstantinos Varvagiannis (Other)

Green List (high evidence)

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
Created: 25 Aug 2019, 8:06 p.m. | Last Modified: 25 Aug 2019, 8:10 p.m.
Panel Version: 2.1015

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
Phenotypes
  • Global developmental delay
  • Intellectual disability
  • Seizures
  • Postnatal microcephaly
  • Short digit
OMIM
607201
Clinvar variants
Variants in HNRNPR
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

3 Oct 2019, Gel status: 3

Entity classified by Genomics England curator

Catherine Snow (Genomics England)

Gene: hnrnpr has been classified as Green List (High Evidence).

25 Aug 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

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