Human Gene Module / Chromosome X / HNRNPH2

HNRNPH2heterogeneous nuclear ribonucleoprotein H2

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
5 / 21
Rare Variants / Common Variants
41 / 0
Aliases
HNRNPH2, FTP3,  HNRPH',  HNRPH2,  hnRNPH'
Associated Syndromes
-
Chromosome Band
Xq22.1
Associated Disorders
SCZ, DD/NDD, ADHD, ID, EPS, ASD
Relevance to Autism

A rare, non-synonymous SNP in the HNRNPH2 gene was first identified in an individual with autism in Piton et al., 2011. Six unrelated females with a common neurodevelopmental phenotype involving developmental delay/intellectual disability were found to have de novo predicted deleterious missense variants in the HNRNPH2 gene; three of these six female patients were diagnosed with ASD (Bain et al., 2016).

Molecular Function

This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has three repeats of quasi-RRM domains that binds to RNAs.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to HNRNPH2 (21 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation A UV-responsive internal ribosome entry site enhances serine hydroxymethyltransferase 1 expression for DNA damage repair Fox JT , et al. (2009) No -
2 Primary Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia Piton A , et al. (2010) Yes SCZ
3 Recent Recommendation Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females Bain JM , et al. (2016) No ASD, epilepsy/seizures, ADHD
4 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
5 Support - Harmsen S et al. (2019) No DD
6 Support - Demos M et al. (2019) Yes -
7 Support Two additional males with X-linked, syndromic mental retardation carry de novo mutations in HNRNPH2 Jepsen WM , et al. (2019) No -
8 Support - Somashekar PH et al. (2020) No DD, ID, epilepsy/seizures, stereotypy
9 Support - Peron A et al. (2020) No DD, ID, stereotypy
10 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
11 Support - Brunet T et al. (2021) No -
12 Support - Bain JM et al. (2021) No ASD, ADHD, epilepsy/seizures
13 Support - Taşkıran EZ et al. (2021) No -
14 Support - Gillentine MA et al. (2021) No DD, epilepsy/seizures
15 Support - Mahjani B et al. (2021) Yes -
16 Support - Kreienkamp HJ et al. (2022) No ASD or autistic behavior, stereotypy, epilepsy/sei
17 Support - Bartolomaeus T et al. (2023) No -
18 Recent Recommendation - Korff A et al. (2023) No -
19 Support - Purvi Majethia et al. (2024) No -
20 Support - Axel Schmidt et al. (2024) No -
21 Highly Cited Heterogeneous nuclear ribonucleoproteins H, H', and F are members of a ubiquitously expressed subfamily of related but distinct proteins encoded by genes mapping to different chromosomes Honor B , et al. (1995) No -
Rare Variants   (41)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.617G>A p.Arg206Gln missense_variant Unknown - - 31164858 Demos M et al. (2019)
c.340C>T p.Arg114Trp missense_variant De novo - - 33728377 Bain JM et al. (2021)
c.616C>G p.Arg206Gly missense_variant De novo - - 33728377 Bain JM et al. (2021)
c.616C>T p.Arg206Trp missense_variant De novo - - 33728377 Bain JM et al. (2021)
c.617G>A p.Arg206Gln missense_variant De novo - - 33728377 Bain JM et al. (2021)
c.617G>T p.Arg206Leu missense_variant De novo - - 33728377 Bain JM et al. (2021)
c.626C>T p.Pro209Leu missense_variant De novo - - 33728377 Bain JM et al. (2021)
c.629A>G p.Tyr210Cys missense_variant De novo - - 33728377 Bain JM et al. (2021)
c.634A>G p.Arg212Gly missense_variant De novo - - 33728377 Bain JM et al. (2021)
c.635G>C p.Arg212Thr missense_variant De novo - - 33728377 Bain JM et al. (2021)
c.638C>T p.Pro213Leu missense_variant De novo - - 33728377 Bain JM et al. (2021)
c.1019A>T p.Asp340Val missense_variant De novo - - 33728377 Bain JM et al. (2021)
c.616C>T p.Arg206Trp missense_variant De novo - - 27545675 Bain JM , et al. (2016)
c.617G>A p.Arg206Gln missense_variant De novo - - 27545675 Bain JM , et al. (2016)
c.626C>T p.Pro209Leu missense_variant De novo - - 27545675 Bain JM , et al. (2016)
c.595C>T p.Arg199Ter stop_gained Unknown - - 34907471 Kreienkamp HJ et al. (2022)
c.617G>A p.Ala206Gln missense_variant De novo - - 30887513 Harmsen S et al. (2019)
c.583T>C p.Tyr195His missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.340C>T p.Arg114Trp missense_variant De novo - - 31236915 Jepsen WM , et al. (2019)
c.616C>T p.Arg206Trp missense_variant De novo - - 31236915 Jepsen WM , et al. (2019)
c.616C>T p.Arg206Trp missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.85C>T p.Arg29Cys missense_variant De novo - Unknown 33619735 Brunet T et al. (2021)
c.616C>T p.Ala206Trp missense_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.616C>T p.Arg206Trp missense_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.617G>A p.Arg206Gln missense_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.629A>G p.Tyr210Cys missense_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.629A>G p.Tyr210Cys missense_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.635G>C p.Arg212Thr missense_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.617G>T p.Arg206Leu missense_variant De novo - Simplex 31943778 Peron A et al. (2020)
c.422T>A p.Met141Lys missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.629A>G p.Tyr210Cys missense_variant De novo - - 38374498 Purvi Majethia et al. (2024)
c.422T>A p.Met141Lys missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.616C>T p.Arg206Trp missense_variant De novo - - 33739554 Taşkıran EZ et al. (2021)
c.1188G>C p.Met396Ile missense_variant Familial Maternal - 20479760 Piton A , et al. (2010)
c.85C>T p.Arg29Cys missense_variant De novo - Simplex 34907471 Kreienkamp HJ et al. (2022)
c.340C>T p.Arg114Trp missense_variant De novo - Simplex 34907471 Kreienkamp HJ et al. (2022)
c.616C>T p.Arg206Trp missense_variant De novo - Simplex 37460657 Bartolomaeus T et al. (2023)
c.1110dup p.Ala371CysfsTer24 frameshift_variant Familial Maternal - 34907471 Kreienkamp HJ et al. (2022)
c.918_919dup p.Asn307IlefsTer10 frameshift_variant Familial Maternal - 34907471 Kreienkamp HJ et al. (2022)
c.562C>T p.Arg188Ter stop_gained De novo - Multiplex (monozygotic twins) 34907471 Kreienkamp HJ et al. (2022)
c.616C>T p.Ala206Trp missense_variant De novo (germline mosaicism) - Multiplex 31670473 Somashekar PH et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

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.

4/1/2021
1
icon
1

Score remained at 1

Description

A rare, non-synonymous SNP in the HNRNPH2 gene was first identified in an individual with autism in Piton et al., 2011. Six unrelated females with a common neurodevelopmental phenotype involving developmental delay/intellectual disability were found to have de novo predicted deleterious missense variants in the HNRNPH2 gene; three of these six female patients were diagnosed with ASD (Bain et al., 2016).

Reports Added
[Bain type of X-linked syndromic mental retardation in boys2019] [Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-Onset Epilepsy2019] [Bain type of X-linked syndromic mental retardation in a male with a pathogenic variant in HNRNPH22020] [Missense variants in the Arg206 residue of HNRNPH2: Further evidence of causality and expansion of the phenotype2020] [Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020] [Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental Disorder2021] [Diagnostic yield of whole-exome sequencing in non-syndromic intellectual disability2021] [Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders2021]
1/1/2021
1
icon
1

Score remained at 1

Description

A rare, non-synonymous SNP in the HNRNPH2 gene was first identified in an individual with autism in Piton et al., 2011. Six unrelated females with a common neurodevelopmental phenotype involving developmental delay/intellectual disability were found to have de novo predicted deleterious missense variants in the HNRNPH2 gene; three of these six female patients were diagnosed with ASD (Bain et al., 2016).

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
10/1/2019
4
icon
1

Decreased from 4 to 1

New Scoring Scheme
Description

A rare, non-synonymous SNP in the HNRNPH2 gene was first identified in an individual with autism in Piton et al., 2011. Six unrelated females with a common neurodevelopmental phenotype involving developmental delay/intellectual disability were found to have de novo predicted deleterious missense variants in the HNRNPH2 gene; three of these six female patients were diagnosed with ASD (Bain et al., 2016).

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

A rare, non-synonymous SNP in the HNRNPH2 gene was first identified in an individual with autism in Piton et al., 2011. Six unrelated females with a common neurodevelopmental phenotype involving developmental delay/intellectual disability were found to have de novo predicted deleterious missense variants in the HNRNPH2 gene; three of these six female patients were diagnosed with ASD (Bain et al., 2016).

Reports Added
[Two additional males with X-linked, syndromic mental retardation carry de novo mutations in HNRNPH2.2019]
10/1/2016
5
icon
4

Decreased from 5 to 4

Description

A rare, non-synonymous SNP in the HNRNPH2 gene was first identified in an individual with autism in Piton et al., 2011. Six unrelated females with a common neurodevelopmental phenotype involving developmental delay/intellectual disability were found to have de novo predicted deleterious missense variants in the HNRNPH2 gene; three of these six female patients were diagnosed with ASD (Bain et al., 2016).

Reports Added
[Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females.2016]
7/1/2014
No data
icon
5

Increased from No data to 5

Description

A rare, non-synonymous SNP in the HNRNPH2 gene was identified in an individual with autism (Piton et al., 2011).

4/1/2014
No data
icon
5

Increased from No data to 5

Description

A rare, non-synonymous SNP in the HNRNPH2 gene was identified in an individual with autism (Piton et al., 2011).

Krishnan Probability Score

Score 0.49504368952014

Ranking 3246/25841 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 0.86828424043336

Ranking 3478/18225 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 0.9236170662671

Ranking 9815/18665 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
Larsen Cumulative Evidence Score

Score 0

Ranking 448/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.45822334137896

Ranking 848/20870 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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