Human Gene Module / Chromosome 1 / HNRNPU

HNRNPUheterogeneous nuclear ribonucleoprotein U

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
5 / 17
Rare Variants / Common Variants
58 / 0
Aliases
HNRNPU, EIEE54-AS1,  HNRPU,  SAF-A,  SAFA,  U21.1,  hnRNP U,  pp120, HNRNPU
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Chromosome Band
1q44
Associated Disorders
EP, DD/NDD, ID, EPS, ASD
Relevance to Autism

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017).

Molecular Function

This gene encodes a member of a family of proteins that bind nucleic acids and function in the formation of ribonucleoprotein complexes in the nucleus with heterogeneous nuclear RNA (hnRNA). The encoded protein has affinity for both RNA and DNA, and binds scaffold-attached region (SAR) DNA. Mutations in this gene have been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBase
Reports related to HNRNPU (17 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Carvill GL , et al. (2013) No ID, epilepsy/seizures
2 Support De novo mutations in epileptic encephalopathies. Epi4K Consortium , et al. (2013) No ID, epilepsy/seizures, ASD
3 Support De novo mutations in moderate or severe intellectual disability. Hamdan FF , et al. (2014) No ID, epilepsy/seizures, autistic features
4 Support Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients. de Kovel CG , et al. (2016) No ID, epilepsy/seizures
5 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
6 Recent Recommendation Heterozygous HNRNPU variants cause early onset epilepsy and severe intellectual disability. Bramswig NC , et al. (2017) No -
7 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) Yes -
8 Primary Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
9 Support Clinical and molecular characterization of de novo loss of function variants in HNRNPU. Leduc MS , et al. (2017) No ASD
10 Support De novo mutations in HNRNPU result in a neurodevelopmental syndrome. Yates TM , et al. (2017) No Epilepsy/seizures, ASD
11 Support HRPU-2, a Homolog of Mammalian hnRNP U, Regulates Synaptic Transmission by Controlling the Expression of SLO-2 Potassium Channel in Caenorhabditis ... Liu P , et al. (2017) No -
12 Support An episode of acute encephalopathy with biphasic seizures and late reduced diffusion followed by hemiplegia and intractable epilepsy observed in a ... Shimada S , et al. (2018) No Epilepsy/seizures, DD, ID, autistic behavior, ster
13 Support Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability. Borlot F , et al. (2019) No Autistic features
14 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
15 Support Clinical findings of 21 previously unreported probands with HNRNPU-related syndrome and comprehensive literature review Durkin A et al. (2020) No -
16 Support Clinical and genetic characteristics of patients with Doose syndrome Hinokuma N et al. (2020) No -
17 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
Rare Variants   (58)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo NA - 31273778 Borlot F , et al. (2019)
- - copy_number_gain Unknown - - 28393272 Bramswig NC , et al. (2017)
c.1681C>T p.Gln561Ter stop_gained De novo NA - 33004838 Wang T et al. (2020)
c.1714C>T p.Arg572Ter stop_gained De novo NA - 33004838 Wang T et al. (2020)
c.1852C>T p.Gln618Ter stop_gained De novo NA - 33004838 Wang T et al. (2020)
c.67C>T p.Arg23Ter stop_gained Unknown - - 28554332 Bowling KM , et al. (2017)
c.1060+1G>A - splice_site_variant De novo NA - 28944577 Yates TM , et al. (2017)
c.508C>T p.Gln170Ter stop_gained De novo NA - 31452935 Feliciano P et al. (2019)
c.523C>T p.Gln175Ter stop_gained De novo NA - 28393272 Bramswig NC , et al. (2017)
c.817C>T p.Gln273Ter stop_gained De novo NA - 28393272 Bramswig NC , et al. (2017)
c.1744-2del - splice_site_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.67C>T p.Arg23Ter stop_gained De novo NA Simplex 32319732 Durkin A et al. (2020)
c.692-1G>A - splice_site_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.418G>A p.Glu140Lys missense_variant De novo NA - 28944577 Yates TM , et al. (2017)
c.619C>T p.Gln207Ter stop_gained De novo NA Simplex 32319732 Durkin A et al. (2020)
c.1686+1G>C - splice_site_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.2365C>T p.Arg789Ter stop_gained De novo NA Multiplex 33004838 Wang T et al. (2020)
c.1089G>A p.Trp363Ter stop_gained De novo NA Simplex 32319732 Durkin A et al. (2020)
c.1450C>T p.Arg484Ter stop_gained De novo NA Simplex 32319732 Durkin A et al. (2020)
c.1801C>T p.Arg601Ter stop_gained De novo NA Simplex 32319732 Durkin A et al. (2020)
c.960G>A p.Trp320Ter stop_gained De novo NA Simplex 28944577 Yates TM , et al. (2017)
c.1089G>A p.Trp363Ter stop_gained De novo NA Simplex 28815871 Leduc MS , et al. (2017)
c.1714C>T p.Arg572Ter stop_gained De novo NA Simplex 28815871 Leduc MS , et al. (2017)
c.511C>T p.Gln171Ter stop_gained De novo NA Simplex 25356899 Hamdan FF , et al. (2014)
c.970A>G p.Arg324Gly missense_variant De novo NA - 28393272 Bramswig NC , et al. (2017)
c.1088G>A p.Trp363Ter stop_gained De novo NA Multiplex 32319732 Durkin A et al. (2020)
c.1132T>C p.Ser378Pro missense_variant De novo NA - 28393272 Bramswig NC , et al. (2017)
c.359C>T p.Pro120Leu missense_variant De novo NA Simplex 28714951 Lim ET , et al. (2017)
c.469G>C p.Gly157Arg missense_variant De novo NA Simplex 28714951 Lim ET , et al. (2017)
c.334dup p.Ala112GlyfsTer33 frameshift_variant De novo NA - 33004838 Wang T et al. (2020)
c.1211A>G p.Asp404Gly missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1507C>T p.Pro522Ser missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.2167+35_*4156del p.? copy_number_loss De novo NA Simplex 32319732 Durkin A et al. (2020)
c.878A>G p.Tyr293Cys missense_variant De novo NA Simplex 32913952 Hinokuma N et al. (2020)
c.2357G>A p.Trp786Ter stop_gained Unknown Not maternal - 23708187 Carvill GL , et al. (2013)
c.1687-4_1692del - splice_site_variant De novo NA - 23934111 Epi4K Consortium , et al. (2013)
c.1050_1051del p.Thr351LysfsTer4 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.837_839del p.Glu279del inframe_deletion De novo NA Simplex 32319732 Durkin A et al. (2020)
c.23del p.Val8GlufsTer4 frameshift_variant De novo NA Simplex 28944577 Yates TM , et al. (2017)
c.1755dup p.Val586CysfsTer7 frameshift_variant De novo NA - 27652284 de Kovel CG , et al. (2016)
c.1641del p.Asp548IlefsTer5 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.76del p.Ser26LeufsTer35 frameshift_variant De novo NA Simplex 29858110 Shimada S , et al. (2018)
c.1681del p.Gln561SerfsTer45 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.1836del p.Tyr613IlefsTer11 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.1571dup p.Lys525GlufsTer25 frameshift_variant De novo NA Simplex 28944577 Yates TM , et al. (2017)
c.1664del p.Leu555ArgfsTer51 frameshift_variant De novo NA Simplex 28944577 Yates TM , et al. (2017)
c.706_707del p.Glu236ThrfsTer6 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.847_857del p.Phe283SerfsTer5 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.395_401del p.Asn132ThrfsTer63 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.454_466del p.Ala152ThrfsTer41 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.712_715del p.Lys238AlafsTer100 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.1925_1926del p.Leu642ProfsTer5 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.2083_2084del p.Ser695TrpfsTer6 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.651_660del p.Gly218AlafsTer118 frameshift_variant De novo NA Simplex 28815871 Leduc MS , et al. (2017)
c.2270_2271del p.Pro757ArgfsTer7 frameshift_variant De novo NA Simplex 28815871 Leduc MS , et al. (2017)
c.706_707del p.Glu236ThrfsTer6 frameshift_variant De novo NA Not simplex 32319732 Durkin A et al. (2020)
c.1756_1757insGT p.Val586GlyfsTer2 frameshift_variant Unknown Not maternal - 33004838 Wang T et al. (2020)
c.1367_1368insGA p.Phe456LeufsTer8 frameshift_variant De novo NA Simplex 28944577 Yates TM , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017). Mutations in the HNRNPU gene have also been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391) (Carvill et al., 2013; Epi4K Consortium; Epilepsy Phenome/Genome Project 2013; Hamdan et al., 2014; de Kovel et al., 2016; Bramswig et al., 2017; Leduc et al., 2017; Yates et al., 2017); a diagnosis of autism or autistic features have been observed in several patients with this disorder in Epi4K Consortium; Epilepsy Phenome/Genome Project 2013, Bramswig et al., 2017, Leduc et al., 2017, and Yates et al., 2017.

Score Delta: Score remained at 4S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2020
4S
icon
4S

Score remained at 4S

Description

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017). Mutations in the HNRNPU gene have also been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391) (Carvill et al., 2013; Epi4K Consortium; Epilepsy Phenome/Genome Project 2013; Hamdan et al., 2014; de Kovel et al., 2016; Bramswig et al., 2017; Leduc et al., 2017; Yates et al., 2017); a diagnosis of autism or autistic features have been observed in several patients with this disorder in Epi4K Consortium; Epilepsy Phenome/Genome Project 2013, Bramswig et al., 2017, Leduc et al., 2017, and Yates et al., 2017.

Reports Added
[Clinical and genetic characteristics of patients with Doose syndrome2020] [Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
4/1/2020
4S
icon
4S

Score remained at 4S

Description

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017). Mutations in the HNRNPU gene have also been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391) (Carvill et al., 2013; Epi4K Consortium; Epilepsy Phenome/Genome Project 2013; Hamdan et al., 2014; de Kovel et al., 2016; Bramswig et al., 2017; Leduc et al., 2017; Yates et al., 2017); a diagnosis of autism or autistic features have been observed in several patients with this disorder in Epi4K Consortium; Epilepsy Phenome/Genome Project 2013, Bramswig et al., 2017, Leduc et al., 2017, and Yates et al., 2017.

Reports Added
[Clinical findings of 21 previously unreported probands with HNRNPU-related syndrome and comprehensive literature review2020]
10/1/2019
4S
icon
1

Decreased from 4S to 1

New Scoring Scheme
Description

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017). Mutations in the HNRNPU gene have also been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391) (Carvill et al., 2013; Epi4K Consortium; Epilepsy Phenome/Genome Project 2013; Hamdan et al., 2014; de Kovel et al., 2016; Bramswig et al., 2017; Leduc et al., 2017; Yates et al., 2017); a diagnosis of autism or autistic features have been observed in several patients with this disorder in Epi4K Consortium; Epilepsy Phenome/Genome Project 2013, Bramswig et al., 2017, Leduc et al., 2017, and Yates et al., 2017.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017). Mutations in the HNRNPU gene have also been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391) (Carvill et al., 2013; Epi4K Consortium; Epilepsy Phenome/Genome Project 2013; Hamdan et al., 2014; de Kovel et al., 2016; Bramswig et al., 2017; Leduc et al., 2017; Yates et al., 2017); a diagnosis of autism or autistic features have been observed in several patients with this disorder in Epi4K Consortium; Epilepsy Phenome/Genome Project 2013, Bramswig et al., 2017, Leduc et al., 2017, and Yates et al., 2017.

Reports Added
[Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability.2019]
7/1/2018
4.4 + S
icon
4S

Decreased from 4.4 + S to 4S

Description

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017). Mutations in the HNRNPU gene have also been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391) (Carvill et al., 2013; Epi4K Consortium; Epilepsy Phenome/Genome Project 2013; Hamdan et al., 2014; de Kovel et al., 2016; Bramswig et al., 2017; Leduc et al., 2017; Yates et al., 2017); a diagnosis of autism or autistic features have been observed in several patients with this disorder in Epi4K Consortium; Epilepsy Phenome/Genome Project 2013, Bramswig et al., 2017, Leduc et al., 2017, and Yates et al., 2017.

Reports Added
[An episode of acute encephalopathy with biphasic seizures and late reduced diffusion followed by hemiplegia and intractable epilepsy observed in a ...2018]
4/1/2018
4S
icon
4.4 + S

Decreased from 4S to 4.4 + S

Description

4S

Reports Added
[HRPU-2, a Homolog of Mammalian hnRNP U, Regulates Synaptic Transmission by Controlling the Expression of SLO-2 Potassium Channel in Caenorhabditis ...2017]
7/1/2017
icon
4S

Increased from to 4S

Description

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017). Mutations in the HNRNPU gene have also been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391) (Carvill et al., 2013; Epi4K Consortium; Epilepsy Phenome/Genome Project 2013; Hamdan et al., 2014; de Kovel et al., 2016; Bramswig et al., 2017; Leduc et al., 2017); a diagnosis of autism or autistic features have been observed in several patients with this disorder.

Krishnan Probability Score

Score 0.57111211166452

Ranking 825/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99990332258243

Ranking 673/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.7919757025084

Ranking 2076/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.38266856349508

Ranking 1654/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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