FB2026_03 , released September 17, 2026
Human Disease Model Report: intellectual disability, autosomal dominant 75
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General Information
Name
intellectual disability, autosomal dominant 75
FlyBase ID
FBhh0001537
Disease Ontology Term
Parent Disease
OMIM
INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 75; MRD75
Overview

This report describes intellectual disability, syndromic, autosomal dominant 75, a newly identified neurodevelopmental disorder postulated to be associated with heterozygous de novo missense variants of the DHX9 gene. DHX9 encodes an RNA helicase that appears to function as a transcriptional regulator. There is a single orthologous gene in Drosophila, mle, but the Drosophila gene has not been used in this disease model.

Multiple UAS constructs of the human Hsap\DHX9 gene have been introduced into flies, including wild-type and variants implicated in human disease. See the 'Disease-Implicated Variants' table below. Expression of wild-type Hsap\DHX9 protein in the fly visual system results in a rough eye phenotype; expression of the variant proteins has minimal effect, supporting the hypothesis that they are loss-of-function mutations. Assessments of transcript and protein levels suggest that the variant DHX9:p.Gly414Arg protein is more susceptible to degradation after translation.

[updated Mar. 2025 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: intellectual disability, autosomal dominant
Symptoms and phenotype

Intellectual disability is characterized by impairments in intellectual functioning and adaptive behavior; symptoms must be present before a child becomes 18 years old (http://medical-dictionary.thefreedictionary.com/mental+retardation; 2016.01.19).

(FlyBase Curators, 2013-)

Intellectual disability can be subdivided into syndromic forms, characterized by cognitive impairment accompanied by dysmorphic features, malformations or neurological abnormalities, and nonsyndromic forms, characterized by cognitive impairment without additional features (Basel-Vanagaite, 2008; DOI: 10.1002/9780470015902.a0021454).

(FlyBase Curators, 2013-)
Specific Disease Summary: intellectual disability, autosomal dominant 75
OMIM report

[INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 75; MRD75](https://omim.org/entry/620988)

Human gene(s) implicated

[DExH-BOX HELICASE 9; DHX9](https://omim.org/entry/603115)

Symptoms and phenotype

Autosomal dominant intellectual developmental disorder-75 (MRD75) is a neurodevelopmental disorder with highly variable severity and features. Affected individuals have developmental delay and most have mild to severely impaired intellectual development, often accompanied by neuropsychiatric disorders. Additional more variable features may include hypotonia, seizures, nonspecific dysmorphic features, poor overall growth with small head circumference, abnormal brain imaging, and heart disease (Calame et al., 2023; pubmed:37467750). [from MIM:620988; 2025.03.08]

(OMIM, 2013-)

The single patient described presented with short stature, intellectual disability, and ventricular non-compaction cardiomyopathy (Yamada et al., 2023; pubmed:37369308; FBrf0257121).

(FlyBase Curators, 2013-)
Genetics

Autosomal dominant intellectual developmental disorder-75 (MRD75) is caused by heterozygous mutation in the DHX9 gene. [from MIM:620988; 2025.03.08]

(OMIM, 2013-)

The variant DHX9:p.Gly414Arg was identified in the described patient. A second variant in the DXH9 gene, DHX9:p.Arg1052Gln , has been identified in a patient with autism (Yamada et al., 2023; pubmed:37369308; FBrf0257121).

(FlyBase Curators, 2013-)
Cellular phenotype and pathology
Molecular information

DHX9 encodes a member of the DEAD/DExH-box-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. The DHX9 protein localizes to both the nucleus and the cytoplasm and functions as a transcriptional regulator. [Gene Cards, DHX9; 2023.09.18]

(FlyBase Curators, 2013-)
External links
Disease synonyms
DHX9-related disorder
intellectual developmental disorder, autosomal dominant 75
intellectual disability, syndromic, autosomal dominant 75
MRD75
neurodevelopmental disorder, DHX9-related
neurodeveopmental disorder with developmental delay, dysmorphic facial features, hypotonia, and failure to thrive
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
Symbol / Name
DHX9; DExH-box helicase 9
D. melanogaster ortholog (based on DIOPT)
Dmel\mle
(DIOPT, 2013-)
Comments on ortholog(s)

One to one: 1 human gene to 1 Drosophila gene; multiple related genes exist in both species.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Dmel\mle
    Gene Snapshot
    maleless (mle) encodes a helicase and a member of the Male-Specific-Lethal dosage compensation complex, which increases male X chromosome transcription approximately two-fold. mle homozygous mutant males die as larvae, while females are viable. [Date last reviewed: 2019-03-14]
    Molecular function (GO)
    Cellular component (GO)
    Gene Groups / Pathways
    Comments on ortholog(s)

    High-scoring ortholog of human DHX9 (1 Drosophila to 1 human); multiple related genes exist in both species.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    H. sapiens (Human)
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (32 groups)
      mle
      RNA-protein
      Interacting group
      Assay
      References
      mle - hpRNA:LINR-2
      anti tag coimmunoprecipitation, full identification by RNA sequencing
      (Müller et al., 2020)
      mle - lncRNA:roX1
      nucleic acid uv cross-linking assay, anti bait coimmunoprecipitation, full identification by DNA sequencing, proximity ligation assay, fluorescence microscopy, anti tag coimmunoprecipitation, full identification by RNA sequencing, pull down, western blot, clip, quantitative reverse transcription pcr
      (Müller et al., 2020, Valsecchi et al., 2018, Lindehell et al., 2015, Quinn et al., 2014, Ilik et al., 2013, Maenner et al., 2013)
      mle - lncRNA:roX2
      nucleic acid uv cross-linking assay, tandem affinity purification, nucleotide sequence identification, anti tag coimmunoprecipitation, full identification by RNA sequencing, anti bait coimmunoprecipitation, full identification by DNA sequencing, pull down, anti tag western blot, quantitative reverse transcription pcr, filter trap assay, chemical footprinting, enzymatic footprinting, autoradiography, primer specific pcr, electrophoretic mobility shift assay, western blot, nuclear magnetic resonance, reverse transcription pcr, filter binding, clip, isothermal titration calorimetry, molecular weight estimation by bromide staining, x-ray crystallography, affinity chromatography technology, proximity ligation assay, fluorescence microscopy, fluorescence polarization spectroscopy, predetermined participant, enzymatic study
      (Müller et al., 2020, Ankush Jagtap et al., 2019, Lv et al., 2019, Valsecchi et al., 2018, Ilik et al., 2017, Lindehell et al., 2015, Prabu et al., 2015, Militti et al., 2014, Ilik et al., 2013, Maenner et al., 2013, Hallacli et al., 2012, Izzo et al., 2008, Buscaino et al., 2003, Akhtar et al., 2000, Meller et al., 2000)
      mle - mt:ND1
      anti tag coimmunoprecipitation, full identification by RNA sequencing
      (Müller et al., 2020)
      mle - mt:ND2
      anti tag coimmunoprecipitation, full identification by RNA sequencing
      (Müller et al., 2020)
      mle - para
      anti tag coimmunoprecipitation, full identification by RNA sequencing
      (Müller et al., 2020)
      mle - RpS29
      anti bait coimmunoprecipitation, full identification by RNA sequencing, nucleic acid uv cross-linking assay, tandem affinity purification, nucleotide sequence identification
      (Müller et al., 2020, Ilik et al., 2017)
      mle - rudhira
      anti tag coimmunoprecipitation, full identification by RNA sequencing
      (Müller et al., 2020)
      mle - Srp54
      nucleic acid uv cross-linking assay, autoradiography, anti bait coimmunoprecipitation
      (Kennedy et al., 1998)
      mle - U2af50
      nucleic acid uv cross-linking assay, autoradiography, anti bait coimmunoprecipitation
      (Kennedy et al., 1998)
      protein-protein
      Interacting group
      Assay
      References
      mle
      two hybrid, anti tag coimmunoprecipitation, anti tag western blot
      (Tikhonova et al., 2024, Izzo et al., 2008, Copps et al., 1998)
      mle - Bap170
      anti bait coimmunoprecipitation, western blot
      (Nikolenko et al., 2021)
      mle - brm
      anti bait coimmunoprecipitation, western blot
      (Nikolenko et al., 2021)
      mle - Clamp
      proximity ligation assay, fluorescence microscopy, two hybrid, anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation
      (Tikhonova et al., 2024, Lindehell et al., 2015)
      mle - e(y)2
      anti bait coimmunoprecipitation, western blot
      (Nikolenko et al., 2019)
      mle - foxo
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      (Vinayagam et al., 2016)
      mle - gig
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      (Vinayagam et al., 2016)
      mle - Hrb87F
      anti tag coimmunoprecipitation, western blot, Identification by mass spectrometry
      (Cugusi et al., 2015)
      mle - MEP-1
      anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation
      (Cugusi et al., 2015)
      mle - Mi-2
      anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, Identification by mass spectrometry
      (Cugusi et al., 2015)
      mle - mof
      anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot, proximity ligation assay, fluorescence microscopy
      (Aleman et al., 2021, Schunter et al., 2017, Lindehell et al., 2015, Buscaino et al., 2003, Akhtar et al., 2000)
      mle - msl-1
      anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, proximity ligation assay, fluorescence microscopy
      (Lindehell et al., 2015, Cugusi et al., 2013, Ilik et al., 2013, Kadlec et al., 2011, Morra et al., 2008, Smith et al., 2000, Copps et al., 1998)
      mle - msl-2
      proximity ligation assay, fluorescence microscopy, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation
      (Lindehell et al., 2015, Maenner et al., 2013, Li et al., 2008, Copps et al., 1998)
      mle - msl-3
      anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, peptide massfingerprinting, proximity ligation assay, fluorescence microscopy
      (Zee et al., 2016, Lindehell et al., 2015, Alekseyenko et al., 2014, Cugusi et al., 2013, Buscaino et al., 2003, Akhtar et al., 2000, Copps et al., 1998)
      mle - Pep
      anti tag coimmunoprecipitation, western blot, Identification by mass spectrometry
      (Cugusi et al., 2015)
      mle - Pi3K21B
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      (Vinayagam et al., 2016)
      mle - Polr2A
      pull down, western blot
      (Aratani et al., 2008)
      mle - polybromo
      anti bait coimmunoprecipitation, western blot
      (Nikolenko et al., 2021)
      mle - simj
      anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation
      (Cugusi et al., 2015)
      mle - Top2
      proximity ligation assay, fluorescence microscopy, anti tag coimmunoprecipitation, western blot
      (Lindehell et al., 2015, Cugusi et al., 2013)
      mle - Tsc1
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      (Vinayagam et al., 2016)
      mle - Unr
      anti bait coimmunoprecipitation, western blot
      (Militti et al., 2014)
      Alleles Reported to Model Human Disease (Disease Ontology) (5 alleles)
      Hsap\DHX9
      Models Based on Experimental Evidence ( 2 )
      Modifiers Based on Experimental Evidence ( 1 )
      mle
      Models Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Evidence
      References
      mlenap-ts1
      model of  epilepsy
      CEA
      (Fergestad et al., 2006)
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      mleGD1488
      exacerbates  spinocerebellar ataxia 31
      modeled by Zzzz\UGGAAW.UAS
      (Ishiguro et al., 2017)
      Alleles Representing Disease-Implicated Variants
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Related mammalian, viral, bacterial, or synthetic transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Hsap\DHX9UAS.Tag:MYC
      P{UAS-hDHX9.MYC}
      Hsap\DHX9G414R.UAS.Tag:MYC
      P{UAS-hDHX9.G414R.MYC}
      Hsap\DHX9R1052Q.UAS.Tag:MYC
      P{UAS-hDHX9.R1052Q.MYC}
      Hsap\DHX9UAS.cFa
      P{UAS-hDHX9.F}
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      mleGD1488
      P{GD1488}
      w1118; P{GD1488}v19691
      mleHMS00182
      P{TRiP.HMS00182}
      y1 sc* v1 sev21; P{TRiP.HMS00182}attP2/TM3, Sb1
      mleVSH330190
      P{VSH330190}
      P{VSH330190}attP40
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      mle9
      loss of function allele
      gamma ray
      mle9 cn1 bw1/CyO
      mlenap-ts1
      ethyl methanesulfonate
      mle1
      amorphic allele - molecular evidence
      spontaneous
      y1 w1 Nspl-1/Dp(1;Y)BarS; mle1/SM1
      References (7)