Human Gene Module / Chromosome 1 / DHX9

DHX9DExH-box helicase 9

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
24 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
1q25.3
Associated Disorders
-
Relevance to Autism

Yamada et al., 2023 demonstrated that two de novo missense variants in the DHX9 gene (a p.Arg1052Gln variant that was previously reported in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014, and a p.Gly414Arg variant that was identified in a novel patient presenting with developmental delay/intellectual disability, undergrowth, and ventricular non-compaction cardiomyopathy) resulted in aberrant localization and loss-of-function effects in transgenic Drosophila lines. In the same report, the authors also found that mice heterozygous for a p.Gly416Arg variant, which corresponded to the p.Gly414Arg variant, displayed reduced body weight, reduced emotionality, and cardiac conduction abnormalities (prolonged PR interval). Additional de novo variants in the DHX9 gene, including a de novo loss-of-function variant, have been identified in ASD probands from simplex families from the MSSNG cohort (Zhou et al., 2022), while a paternally-inherited DHX9 missense variant with a CADD score of 31 was identified in a Chinese ASD proband from the ACGC cohort (Guo et al., 2018). Calame et al., 2023 described 20 individuals with rare monoallelic DHX9 variants presenting with either a neurodevelopmental disorder characterized by developmental delay/intellectual disability, neuropsychiatric disorders (including autism spectrum disorder), seizures, axial hypotonia, and dysmorphic features, or Charcot-Marie-Tooth disease; subsequent functional studies demonstrated that DHX9 variants disrupted cellular localization and helicase activity and increased R-loops and double-stranded DNA breaks, while a Dhx9 -/- mice was shown to exhibit behavioral and neurological abnormalities in this report.

Molecular Function

This gene encodes a member of the DEAH-containing family of RNA helicases. The encoded protein is an enzyme that catalyzes the ATP-dependent unwinding of double-stranded RNA and DNA-RNA complexes. This protein localizes to both the nucleus and the cytoplasm and functions as a transcriptional regulator. This protein may also be involved in the expression and nuclear export of retroviral RNAs. Alternate splicing results in multiple transcript variants.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DHX9 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
3 Support - Zhou X et al. (2022) Yes -
4 Primary - Yamada M et al. (2023) Yes -
5 Recent Recommendation - Calame DG et al. (2023) No ASD, epilepsy/seizures, Charcot-Marie-Tooth diseas
Rare Variants   (24)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.674-1G>A - splice_site_variant Unknown - Unknown 37467750 Calame DG et al. (2023)
c.685C>T p.Arg229Ter stop_gained De novo - Simplex 37467750 Calame DG et al. (2023)
c.2786+1G>T - splice_site_variant Unknown - Simplex 37467750 Calame DG et al. (2023)
c.627-4dup - splice_region_variant De novo - Simplex 37467750 Calame DG et al. (2023)
c.359A>G p.Lys120Arg missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3787C>T p.Gln1263Ter stop_gained Unknown - Simplex 37467750 Calame DG et al. (2023)
c.2290C>T p.Arg764Ter stop_gained Unknown - Multiplex 37467750 Calame DG et al. (2023)
c.2746G>A p.Val916Ile missense_variant Familial Paternal - 30564305 Guo H , et al. (2018)
c.1240G>A p.Gly414Arg missense_variant De novo - Simplex 37369308 Yamada M et al. (2023)
c.422G>A p.Arg141Gln missense_variant De novo - Simplex 37467750 Calame DG et al. (2023)
c.3417T>C p.Ser1139%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1232G>A p.Gly411Glu missense_variant De novo - Simplex 37467750 Calame DG et al. (2023)
c.1417G>A p.Val473Ile missense_variant De novo - Simplex 37467750 Calame DG et al. (2023)
c.1822T>G p.Cys608Gly missense_variant De novo - Simplex 37467750 Calame DG et al. (2023)
c.2281C>T p.Arg761Trp missense_variant De novo - Simplex 37467750 Calame DG et al. (2023)
c.2282G>A p.Arg761Gln missense_variant De novo - Simplex 37467750 Calame DG et al. (2023)
c.2510G>C p.Arg837Thr missense_variant Unknown - Simplex 37467750 Calame DG et al. (2023)
c.2537A>G p.Asp846Gly missense_variant De novo - Simplex 37467750 Calame DG et al. (2023)
c.3488A>G p.Lys1163Arg missense_variant De novo - Simplex 37467750 Calame DG et al. (2023)
c.3497G>C p.Arg1166Pro missense_variant De novo - Simplex 37467750 Calame DG et al. (2023)
c.3763G>A p.Ala1255Thr missense_variant Unknown - Simplex 37467750 Calame DG et al. (2023)
c.3155G>A p.Arg1052Gln missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.157_158insT p.Asn53IlefsTer2 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2078_2079del p.Glu693GlyfsTer7 frameshift_variant De novo - Simplex 37467750 Calame DG et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

Score Delta: Score remained at 3S

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

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."

7/1/2023
icon
3S

Increased from to 3S

Krishnan Probability Score

Score 0.48509526598834

Ranking 7424/25841 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 0.99999998615466

Ranking 142/18225 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 0.81706497296366

Ranking 2541/18665 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 0.36592080283928

Ranking 1831/20870 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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