Human Gene Module / Chromosome 4 / HNRNPD

HNRNPDheterogeneous nuclear ribonucleoprotein D

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
14 / 0
Aliases
HNRNPD, AUF1,  AUF1A,  HNRPD,  P37,  hnRNPD0
Associated Syndromes
-
Chromosome Band
4q21.22
Associated Disorders
DD/NDD, ADHD, EPS
Relevance to Autism

A de novo splice-site variant in the HNRNPD gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A de novo frameshift variant in this gene was subsequently identified in a proband from the 2017 Deciphering Developmental Disorders study; while the original report did not describe the clinical presentation of this proband, Gillentine et al., 2021 subsequently reported that he presented with autism spectrum disorder. Gillentine et al., 2021 reported ten previously unreported individuals with likely gene-disruptive (LGD) variants in HNRNPD, including an ASD proband from the SPARK cohort; in total, four of the novel patients in this report presented with autism spectrum disorder and had de novo LGD variants in HNRNPD.

Molecular Function

This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are nucleic acid 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 two repeats of quasi-RRM domains that bind to RNAs. It localizes to both the nucleus and the cytoplasm. This protein is implicated in the regulation of mRNA stability.

External Links
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SFARI Genomic Platforms
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Reports related to HNRNPD (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes ADHD, DD, epilepsy/seizures
2 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) Yes -
3 Support - Kaplanis J et al. (2020) No -
4 Recent Recommendation - Gillentine MA et al. (2021) Yes ADHD, epilepsy/seizures
5 Support - Zhou X et al. (2022) Yes -
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.233+1919G>A - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.103C>T p.Gln35Ter stop_gained De novo - - 33874999 Gillentine MA et al. (2021)
c.233+3_233+6del - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.*30+1G>A - splice_site_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.381_384del p.Lys127AsnfsTer5 frameshift_variant De novo - - 28135719 et al. (2017)
c.691del p.Ser231ValfsTer5 frameshift_variant De novo - - 33057194 Kaplanis J et al. (2020)
c.286del p.Glu96AsnfsTer6 frameshift_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.196del p.Ala66ArgfsTer17 frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.303del p.Phe101LeufsTer5 frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.417del p.Glu140AsnfsTer4 frameshift_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.418del p.Glu140AsnfsTer4 frameshift_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.104_105del p.Gln35ArgfsTer34 frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.536_537del p.Glu179AlafsTer3 frameshift_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.332_333del p.Lys111ArgfsTer11 frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
icon
2S

Increased from to 2S

Krishnan Probability Score

Score 0.49939157596347

Ranking 2162/25841 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 0.95734418540436

Ranking 2571/18225 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 0.23577558072635

Ranking 133/18665 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 0.62975862142503

Ranking 35/20870 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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