Intellectual Disability, Autosomal Dominant 30

Mendelian MONDO:0014486 Pathograph 11 Show in embeddings browser

Intellectual developmental disorder, autosomal dominant 30 (MRD30) is the monogenic ZMYND11-related neurodevelopmental disorder. ZMYND11 sits at the terminal end of chromosome 10p and is the critical gene of the 10p15.3 microdeletion syndrome; heterozygous intragenic variants reproduce that contiguous-gene phenotype on their own, which is what established the gene as the driver and defined MRD30 as a distinct entity. ZMYND11 encodes a histone reader. It recognises H3.3K36me3 - the mark deposited over the bodies of actively transcribed genes - and acts as an unconventional transcriptional co-repressor, restraining the elongation phase of RNA polymerase II. The proposed function is to suppress cryptic transcription from within gene bodies of highly expressed genes, so the protein is a brake on transcriptional noise rather than a switch on any single target. In a human pluripotent stem cell model, removing that brake has two consequences, which the published study calls bimodal regulation. ZMYND11-deficient cortical neural stem cells de-repress latent developmental pathways and produce fewer progenitors and neurons; and ZMYND11 also governs a brain-specific RNA isoform switch through the splicing regulator RBFOX2. The second arm is not independent of the first: in cortical cells the published data indicate it is indirect, mediated by raised RBFOX2 expression in the mutant rather than by ZMYND11 binding at the spliced loci, with few differentially spliced events overlapping its chromatin binding. So the disorder is a chromatin reader defect with a splicing arm downstream of it, not a pure transcriptional one. Clinically the core is intellectual disability with disproportionate expressive speech delay, behavioural abnormalities including autistic features and aggression, hypotonia, seizures, feeding difficulties and craniofacial dysmorphism. Two things about the evidence are worth flagging up front. Epilepsy is heterogeneous rather than a single syndrome, ranging from atypical benign partial epilepsy that remits spontaneously to drug-resistant generalised epilepsy, with no reproducible genotype-phenotype correlation across the gene. And the missense variants are not simply weaker loss of function: aggregate comparison suggests they carry higher rates of strabismus, hypotonia and severe intellectual disability than truncating variants, which the reporting authors read as a mechanism other than simple haploinsufficiency. That is an open question, curated here as one.

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1
Inheritance
4
Pathophys.
15
Phenotypes
2
Gaps
11
Pathograph
1
Genes
3
Medical Actions
1
Deep Research
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Heterozygous ZMYND11 variants are causative and are mostly de novo. Both intragenic loss-of-function variants and whole-gene deletion within a 10p15.3 microdeletion produce the phenotype, which is the dosage argument for haploinsufficiency as the usual mechanism.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:38397245 SUPPORT Human Clinical
"Heterozygous pathogenic variants in the ZMYND11 gene have been subsequently identified as the causes of autosomal dominant intellectual developmental disorder-30 with speech delay and behavioural abnormalities"
Names the entity and establishes heterozygous ZMYND11 variants as its cause.
PMID:34216016 SUPPORT Human Clinical
"Variants were distributed across the gene and mostly de novo with no precise genotype-phenotype correlation."
Establishes the predominantly de novo origin and the absence of a positional genotype-phenotype correlation.
PMID:34818214 SUPPORT Human Clinical
"our report contributes to expand the clinical and mutational spectrum of ZMYND11 and confirms haploinsufficiency as the underlying disease mechanism"
An intragenic deletion removing only the 5'UTR and first two exons produces the phenotype, which is the cleanest dosage argument for haploinsufficiency - it removes ZMYND11 alone without the neighbouring genes a larger 10p15.3 deletion would take.
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Discussions and Knowledge Gaps

2
Do ZMYND11 missense variants such as p.Arg600Trp act through simple haploinsufficiency, or through a distinct mechanism such as a dominant-negative effect on the reader complex?
KNOWLEDGE GAP zmynd11_missense_not_haploinsufficiency
Attached to
genetic#ZMYND11 pathophysiology#Loss of ZMYND11 H3.3K36me3 reader function
The pathophysiology node here is written as loss of reader dosage, which is well supported for truncating variants and whole-gene deletions. It may be the wrong model for missense variants. Aggregate comparison of 13 reported missense variants found higher rates of strabismus, hypotonia and severe intellectual disability than in loss-of-function carriers, and p.Arg600Trp carriers share microcephaly, broad nasal alae, short stature and cryptorchidism that are not emphasised in loss-of-function cases. A phenotype that is more severe and partly different in a missense carrier is the classic signature of a mechanism other than reduced dosage. Resolving this would change how a missense result is counselled and would determine whether the entry needs two pathophysiology branches rather than one.
Does the reduced cortical progenitor and neuron production seen in ZMYND11-deficient human pluripotent stem cell cultures correspond to a measurable cortical deficit in patients?
HUMAN MODEL MISMATCH zmynd11_corticogenesis_model_fidelity
Attached to
pathophysiology#Impaired cortical progenitor and neuron production
The entire cellular arm of this pathograph rests on one human pluripotent stem cell model. That model is human, which removes the usual species objection, but it is still an in vitro system: patients do not consistently show microcephaly, and structural brain imaging in ZMYND11 cases is described as non-specific rather than showing a reproducible cortical malformation. So the evidence that ZMYND11 loss impairs neuron production is strong in the dish and essentially unmeasured in people. Until the correspondence is established, the impaired-progenitor node should be read as a model-derived mechanism rather than a demonstrated patient finding.
Proposed experiments
Quantitative cortical morphometry in a ZMYND11 patient cohort
zmynd11_cortical_morphometry
Systematic quantitative MRI morphometry - cortical thickness, surface area and regional volumes - across a genotype-confirmed ZMYND11 cohort compared with matched controls, stratified by variant class.
Would support
pathophysiology#Impaired cortical progenitor and neuron production
Would refute
pathophysiology#Impaired cortical progenitor and neuron production
Supporting outcome
  • Reduced cortical surface area or thickness in ZMYND11 carriers relative to matched controls, with a greater deficit in missense than loss-of-function carriers.
Refuting outcome
  • Cortical morphometry indistinguishable from controls, which would place the disorder's mechanism in neuronal function rather than neuron production.
⚙

Pathophysiology

4
Loss of ZMYND11 H3.3K36me3 reader function
ZMYND11 binds H3.3K36me3 over the bodies of actively transcribed genes and acts as an unconventional co-repressor, damping the elongation phase of RNA polymerase II. A heterozygous loss-of-function allele halves that reader dosage. The proposed normal role is suppression of cryptic transcription initiating from within gene bodies of highly expressed genes, so this is loss of a brake on transcriptional noise rather than loss of a dedicated activator or repressor of specific target genes.
ZMYND11 hgnc:16966 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ZMYND11 (hgnc:16966). hgnc:16966 is a gene from the HUGO Gene Nomenclature Committee.
regulation of transcription by RNA polymerase II GO:0006357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. ↓ DECREASED
chromatin binding GO:0003682 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased chromatin binding (GO:0003682). GO:0003682 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
De-repression of latent developmental transcriptional programmes Losing the elongation brake allows normally silent developmental pathways to be expressed in cortical progenitors.
Loss of brain-specific RBFOX2-dependent splicing ZMYND11 loss also disrupts a brain-specific RNA isoform switch through the splicing regulator RBFOX2. The published study is explicit that this is not a direct chromatin-to-spliceosome effect in cortical cells: few differentially spliced events overlapped ZMYND11 chromatin binding, and the authors attribute the splicing phenotype to increased RBFOX2 expression in the mutant. The edge is therefore indirect with RBFOX2 as the named intermediate.
Show evidence (4 references)
PMID:38397245 SUPPORT Human Clinical
"ZMYND11 encodes a zinc finger MYND domain-containing protein that acts as a transcriptional co-repressor to inhibit the elongation phase of RNA polymerase II via the recognition of histone modification of the transcribed regions."
Directly states the reader and co-repressor function acting on transcriptional elongation.
PMID:28933030 SUPPORT Human Clinical
"the ZMYND11 gene has important functions in epigenetic regulation as an unconventional transcription co-repressor of highly expressed genes, possibly acting in the repression of cryptic transcription from gene bodies"
Supports the cryptic-transcription suppression model. The source itself hedges with "possibly", which is why this node is described as a proposed normal role rather than an established one.
PMID:41068108 SUPPORT In Vitro
"ZMYND11, known for its tumor suppressor function, encodes a histone-reader that recognizes sites of transcriptional elongation and acts as a co-repressor."
Independent confirmation of the reader and co-repressor function in a human stem cell system.
+ 1 more reference
De-repression of latent developmental transcriptional programmes
Cortical neural stem cells lacking ZMYND11 upregulate latent developmental pathways. The same pattern appears when other chromatin-related autism risk factors are perturbed, which positions this as a shared convergent consequence of chromatin-regulator loss rather than a ZMYND11-private effect.
neural stem cell CL:0000047 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural stem cell (CL:0000047). CL:0000047 is a cell type from the Cell Ontology.
regulation of transcription by RNA polymerase II GO:0006357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Impaired cortical progenitor and neuron production De-repressed developmental programmes impair the production of cortical progenitors and neurons.
Show evidence (1 reference)
PMID:41068108 SUPPORT In Vitro
"Similar defects are observed in other chromatin-related ASD risk genes, some of which are partially rescued by enhancing ZMYND11 function."
Supports convergence of chromatin-regulator loss on the same transcriptional and splicing consequences.
Loss of brain-specific RBFOX2-dependent splicing
Two literatures meet at this node and they do not say the same thing, so the entry states both rather than picking the tidier one. In non-neural cells, ZMYND11 couples the chromatin mark it reads directly to pre-mRNA processing: it associates with U5 snRNP spliceosome components and promotes intron retention by physically antagonising EFTUD2, and that regulation depends on its binding to H3K36me3-decorated chromatin. That is a direct, chromatin-dependent splicing role. In human cortical cells it appears not to work that way. The corticogenesis study found that ZMYND11 did not largely regulate splicing directly - few differentially spliced events overlapped its chromatin binding - and attributes the splicing phenotype instead to increased RBFOX2 expression in the mutant, making the effect indirect. The disease-relevant output is a brain-specific RNA isoform switch, and it is partially rescuable by enhancing ZMYND11 function. The incoming edge is graded INDIRECT_KNOWN_INTERMEDIATES to follow the cortical evidence, since that is the tissue this disease is about.
RNA splicing GO:0008380 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated RNA splicing (GO:0008380). GO:0008380 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Impaired cortical progenitor and neuron production Splicing dysregulation contributes, alongside transcriptional de-repression, to defective corticogenesis.
Show evidence (3 references)
PMID:25263594 SUPPORT In Vitro
"Biochemical and genetic experiments demonstrate that BS69 promotes IR by antagonizing EFTUD2 through physical interactions."
Identifies the molecular route from ZMYND11 to splicing: physical antagonism of the U5 snRNP component EFTUD2, regulating intron retention.
PMID:25263594 SUPPORT In Vitro
"We further show that regulation of IR by BS69 also depends on its binding to H3K36me3-decorated chromatin."
Establishes that the splicing function is dependent on the chromatin-reader function, which is why this node is placed downstream of reader loss.
PMID:41068108 SUPPORT In Vitro
"In addition to its role on chromatin, ZMYND11 regulates a brain-specific RNA isoform switch involving the splicing regulator RBFOX2."
Establishes the RBFOX2-dependent brain splicing programme as a ZMYND11 output.
Impaired cortical progenitor and neuron production
Reduced production of cortical progenitors and neurons is the cellular endpoint linking ZMYND11 loss to the neurodevelopmental phenotype. This node rests on a human stem cell model, not on patient brain tissue.
neural stem cell CL:0000047 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural stem cell (CL:0000047). CL:0000047 is a cell type from the Cell Ontology. neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
cerebral cortex development GO:0021987 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cerebral cortex development (GO:0021987). GO:0021987 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Intellectual disability Reduced production of cortical progenitors and neurons is the proposed cellular basis of the intellectual disability and developmental delay that define the disorder.
Seizure Epilepsy in this disorder is grouped with the other chromatin-reader epilepsies, which places the seizure phenotype downstream of the same corticogenesis defect rather than of a separate channel mechanism.
Show evidence (1 reference)
PMID:41068108 SUPPORT In Vitro
"Here, we show that mutations in ZMYND11, a newly implicated risk gene, impair human cortical progenitor and neuron production."
Establishes the cellular endpoint. This rests on a human stem cell model, which is the reason the human-model-mismatch discussion below is recorded.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Intellectual Disability, Autosomal Dominant 30 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

15
Digestive 1
Feeding difficulties FREQUENT HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38397245 SUPPORT Human Clinical
"seizures, feeding difficulties and craniofacial dysmorphism, are the main symptoms associated with pathogenic variants of the ZMYND11 gene"
Lists feeding difficulties among the main symptoms.
Ear 1
Sensorineural hearing impairment VERY_RARE HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27626064 SUPPORT Human Clinical
"female with seizures, global developmental delay, sensorineural hearing loss, hypotonia, dysmorphic features"
Single-patient report. Graded PARTIAL because the same paper records a positive family history of congenital hearing impairment on both sides, so this observation does not establish hearing loss as attributable to ZMYND11.
Eye 1
Strabismus OCCASIONAL HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41820311 SUPPORT Human Clinical
"suggested higher frequencies of strabismus, hypotonia and severe intellectual disability compared with LoF variants"
Aggregate comparison across reported missense variants, supporting strabismus as part of the spectrum and enriched in the missense subgroup.
Genitourinary 1
Cryptorchidism OCCASIONAL HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41820311 SUPPORT Human Clinical
"The present patient showed global developmental delay, hypotonia, distinctive craniofacial features, microcephaly, short stature, cryptorchidism and right-sided inguinal hernia."
Case-level report of cryptorchidism in a ZMYND11 missense carrier.
Head and Neck 2
Abnormal facial shape FREQUENT HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34216016 SUPPORT Human Clinical
"Neurodevelopmental deficits were invariable. Dysmorphic features were variable."
Establishes that dysmorphism, unlike the neurodevelopmental deficit, is not invariable - so its absence does not argue against the diagnosis.
Microcephaly OCCASIONAL HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41820311 SUPPORT Human Clinical
"demonstrated consistent shared features, including microcephaly, broad nasal alae, short stature, cryptorchidism and nipple anomalies, findings that are not typically emphasized in LoF-associated cases"
Reports microcephaly as shared among p.Arg600Trp carriers and explicitly contrasts it with the loss-of-function presentation.
Immune 1
Recurrent infections OCCASIONAL HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28933030 SUPPORT Human Clinical
"genitourinary malformations and recurrent infections"
Lists recurrent infections among the recurring features of the phenotype.
Musculoskeletal 1
Hypotonia FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38397245 SUPPORT Human Clinical
"as well as hypotonia, seizures, feeding difficulties and craniofacial dysmorphism, are the main symptoms associated with pathogenic variants of the ZMYND11 gene"
Lists hypotonia among the main symptoms of ZMYND11 variants.
Nervous System 6
Intellectual disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38397245 SUPPORT Human Clinical
"Intellectual disability with speech delay and behavioural abnormalities, as well as hypotonia, seizures, feeding difficulties and craniofacial dysmorphism, are the main symptoms associated with pathogenic variants of the ZMYND11 gene."
Names intellectual disability as a core manifestation of ZMYND11 variants.
PMID:34216016 SUPPORT Human Clinical
"Neurodevelopmental deficits were invariable. Dysmorphic features were variable."
In a 20-person ZMYND11 epilepsy cohort, neurodevelopmental impairment was present in every individual, supporting VERY_FREQUENT. The contrast drawn in the same breath - dysmorphism variable, neurodevelopment not - is what makes this the load-bearing sentence for the core phenotype.
Delayed speech and language development VERY_FREQUENT HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38397245 SUPPORT Human Clinical
"autosomal dominant intellectual developmental disorder-30 with speech delay and behavioural abnormalities"
Speech delay is part of the defining description of MRD30.
Motor delay FREQUENT HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34818214 SUPPORT Human Clinical
"patients harboring 10p15.3 microdeletions or pathogenic ZMYND11 truncating variants share similar clinical features including hypotonia, intellectual disability, facial dysmorphisms, speech and motor delays, seizures, and significant behavioral problems"
Names motor delay among the shared features of the deletion syndrome and intragenic ZMYND11 variants.
Seizure FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34216016 SUPPORT Human Clinical
"Seizure prognosis ranged from spontaneous remission to drug resistant."
Establishes the wide prognostic range that makes a single epilepsy classification inappropriate here.
PMID:34216016 SUPPORT Human Clinical
"ZMYND11 is one of a small group of chromatin reader genes associated in the pathogenesis of epilepsy, and specifically ABPE."
Links the epilepsy phenotype specifically to chromatin reader loss.
Autistic behavior FREQUENT HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25217958 SUPPORT Human Clinical
"truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features"
The discovery study that linked ZMYND11 truncations to autism and aggression.
Aggressive behavior OCCASIONAL HP:0000718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aggressive behavior (HP:0000718). HP:0000718 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25217958 SUPPORT Human Clinical
"truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features"
Directly names aggression among the features associated with ZMYND11 truncations.
Growth 1
Short stature OCCASIONAL HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28933030 SUPPORT Human Clinical
"behavioural disturbances, hypotonia, seizures, low birth weight, short stature in those older than 10 years of age, genitourinary malformations and recurrent infections"
Lists short stature among the recurring features of the deletion cohort, with its age dependence.
PMID:41820311 SUPPORT Human Clinical
"demonstrated consistent shared features, including microcephaly, broad nasal alae, short stature, cryptorchidism and nipple anomalies, findings that are not typically emphasized in LoF-associated cases"
Corroborates short stature in intragenic missense carriers, independent of the contiguous-gene deletion.
🧬

Genetic Associations

1
ZMYND11 (Causative)
Gene: ZMYND11 hgnc:16966 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ZMYND11 (hgnc:16966). hgnc:16966 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:25217958 SUPPORT Human Clinical
"truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features"
The integrated CNV and sequencing study that first pinpointed ZMYND11 truncations as causal.
PMID:28933030 SUPPORT Human Clinical
"The results of our study further confirm that the ZMYND11 gene is the critical gene for the clinical phenotype of 10p15.3 microdeletion"
Establishes ZMYND11 as the driver gene of the contiguous-gene syndrome, which is the argument for MRD30 as a monogenic entity.
PMID:34818214 SUPPORT Human Clinical
"patients harboring 10p15.3 microdeletions or pathogenic ZMYND11 truncating variants share similar clinical features including hypotonia, intellectual disability, facial dysmorphisms, speech and motor delays, seizures, and significant behavioral problems"
Direct statement of the phenotypic equivalence between the deletion syndrome and intragenic ZMYND11 variants, which is what justifies curating MRD30 as one disease.
💊

Medical Actions

3
Antiseizure medication
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Seizure management follows the epilepsy syndrome rather than the genotype. Response is genuinely bimodal: some individuals remit spontaneously, others are drug resistant despite multiple agents, ketogenic diet and vagal nerve stimulation. No ZMYND11-directed or mechanism-targeted therapy exists.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34216016 SUPPORT Human Clinical
"Seizure prognosis ranged from spontaneous remission to drug resistant."
Establishes the range of treatment response, which is why no single antiseizure strategy is recommended.
Developmental and behavioural support
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Management is supportive: early intervention, speech and language therapy given the disproportionate expressive deficit, and behavioural support for autistic features and aggression.
Target Phenotypes: Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology. Autistic behavior HP:0000729 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38397245 SUPPORT Human Clinical
"Intellectual disability with speech delay and behavioural abnormalities"
Identifies the domains supportive care must address. Graded PARTIAL because the source characterises the phenotype rather than evaluating any intervention - no trial evidence for management exists in this disorder.
Genetic counselling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Most cases are de novo, so recurrence risk for parents is usually low - but not merely through gonadal mosaicism. A 10p15.3 deletion has been reported inherited from a father with mild language impairment, so parental testing is warranted rather than assumed negative, and a mildly affected parent may be identified by it. An affected individual's own transmission risk is 50%.
Show evidence (2 references)
PMID:34216016 SUPPORT Human Clinical
"Variants were distributed across the gene and mostly de novo"
Establishes that most variants are de novo - note "mostly", not "all".
PMID:39696561 SUPPORT Human Clinical
"Parental CMA analysis revealed that the 10p15.3 microdeletion was inherited from the father, who displayed mild language impairment."
A documented inherited case from a mildly affected parent. This is a materially larger recurrence risk than gonadal mosaicism and also demonstrates variable expressivity, so the counselling message cannot rest on a de novo assumption.
🔬

Diagnosis

1
Molecular genetic testing
Diagnosis is molecular. Intragenic ZMYND11 variants are found by exome or genome sequencing or by intellectual-disability and epilepsy gene panels; whole-gene deletions within a 10p15.3 microdeletion are found by chromosomal microarray, which a sequencing-only strategy can miss. Variants are classified against ACMG criteria. There is no biochemical marker and no functional assay in clinical use.
Show evidence (2 references)
PMID:34216016 SUPPORT Human Clinical
"Genetic evaluation was performed using gene panels or exome sequencing; variants were classified using American College of Medical Genetics (ACMG) criteria."
States the testing modalities and the classification framework used in the largest published series.
PMID:39696561 SUPPORT Human Clinical
"Karyotyping and chromosomal microarray analysis (CMA) was conducted to assess chromosomal abnormalities and detect copy number variations (CNVs) within the families, respectively."
Supports chromosomal microarray as the modality that detects the deletion form, which sequencing panels may not call.
📈

Progression

1
Onset and course
Onset is congenital to early childhood and the course is static rather than neurodegenerative: neurodevelopmental deficits are invariable and do not remit, while the epilepsy is the variable element, ranging from spontaneous remission to drug resistance.
Show evidence (1 reference)
PMID:34216016 SUPPORT Human Clinical
"Seizure prognosis ranged from spontaneous remission to drug resistant."
Establishes that the seizure course, unlike the neurodevelopmental one, is not fixed at onset.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population prevalence estimate exists. The disorder is known from aggregated case reports and small cohorts - the largest published series describes 20 individuals with ZMYND11-associated epilepsy, assembled through GeneMatcher, ClinVar and a rare-epilepsy network. The class is recorded as ULTRA_RARE on that basis, and this record exists to say "no estimate exists" structurally rather than to leave the section absent.
Show evidence (1 reference)
PMID:34216016 SUPPORT Human Clinical
"We obtained clinical descriptions of 16 new and nine published individuals, plus detailed case history of two children."
Shows the scale the field is working at - a landmark series assembled from 16 new and nine previously published individuals - which is what supports an ultra-rare classification in the absence of any population estimate.
{ }

Source YAML

click to show 
name: Intellectual Disability, Autosomal Dominant 30
creation_date: "2026-08-28T12:30:00Z"
category: Mendelian
description: >-
  Intellectual developmental disorder, autosomal dominant 30 (MRD30) is the
  monogenic ZMYND11-related neurodevelopmental disorder. ZMYND11 sits at the
  terminal end of chromosome 10p and is the critical gene of the 10p15.3
  microdeletion syndrome; heterozygous intragenic variants reproduce that
  contiguous-gene phenotype on their own, which is what established the gene as
  the driver and defined MRD30 as a distinct entity.

  ZMYND11 encodes a histone reader. It recognises H3.3K36me3 - the mark
  deposited over the bodies of actively transcribed genes - and acts as an
  unconventional transcriptional co-repressor, restraining the elongation phase
  of RNA polymerase II. The proposed function is to suppress cryptic
  transcription from within gene bodies of highly expressed genes, so the
  protein is a brake on transcriptional noise rather than a switch on any single
  target.

  In a human pluripotent stem cell model, removing that brake has two
  consequences, which the published study calls bimodal regulation.
  ZMYND11-deficient cortical neural stem cells de-repress latent developmental
  pathways and produce fewer progenitors and neurons; and ZMYND11 also governs a
  brain-specific RNA isoform switch through the splicing regulator RBFOX2. The
  second arm is not independent of the first: in cortical cells the published
  data indicate it is indirect, mediated by raised RBFOX2 expression in the
  mutant rather than by ZMYND11 binding at the spliced loci, with few
  differentially spliced events overlapping its chromatin binding. So the
  disorder is a chromatin reader defect with a splicing arm downstream of it,
  not a pure transcriptional one.

  Clinically the core is intellectual disability with disproportionate expressive
  speech delay, behavioural abnormalities including autistic features and
  aggression, hypotonia, seizures, feeding difficulties and craniofacial
  dysmorphism. Two things about the evidence are worth flagging up front.
  Epilepsy is heterogeneous rather than a single syndrome, ranging from atypical
  benign partial epilepsy that remits spontaneously to drug-resistant generalised
  epilepsy, with no reproducible genotype-phenotype correlation across the gene.
  And the missense variants are not simply weaker loss of function: aggregate
  comparison suggests they carry higher rates of strabismus, hypotonia and severe
  intellectual disability than truncating variants, which the reporting authors
  read as a mechanism other than simple haploinsufficiency. That is an open
  question, curated here as one.
disease_term:
  preferred_term: intellectual disability, autosomal dominant 30
  term:
    id: MONDO:0014486
    label: intellectual disability, autosomal dominant 30
synonyms:
- MRD30
- mental retardation, autosomal dominant 30
- autosomal dominant intellectual disability 30
- intellectual disability-expressive aphasia-facial dysmorphism syndrome caused by mutation in ZMYND11
- ZMYND11-related neurodevelopmental disorder
- autosomal dominant intellectual developmental disorder-30 with speech delay and behavioural abnormalities
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous ZMYND11 variants are causative and are mostly de novo. Both
    intragenic loss-of-function variants and whole-gene deletion within a
    10p15.3 microdeletion produce the phenotype, which is the dosage argument
    for haploinsufficiency as the usual mechanism.
  evidence:
  - reference: PMID:38397245
    reference_title: "Further Delineation of Clinical Phenotype of ZMYND11 Variants in Patients with Neurodevelopmental Dysmorphic Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous pathogenic variants in the ZMYND11 gene have been
      subsequently identified as the causes of autosomal dominant intellectual
      developmental disorder-30 with speech delay and behavioural abnormalities
    explanation: >-
      Names the entity and establishes heterozygous ZMYND11 variants as its
      cause.
  - reference: PMID:34216016
    reference_title: "ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variants were distributed across the gene and mostly de novo with no
      precise genotype-phenotype correlation.
    explanation: >-
      Establishes the predominantly de novo origin and the absence of a
      positional genotype-phenotype correlation.
  - reference: PMID:34818214
    reference_title: "Intragenic Deletion of the ZMYND11 Gene in 10p15.3 is Associated with Developmental Delay Phenotype: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      our report contributes to expand the clinical and mutational spectrum of
      ZMYND11 and confirms haploinsufficiency as the underlying disease
      mechanism
    explanation: >-
      An intragenic deletion removing only the 5'UTR and first two exons produces
      the phenotype, which is the cleanest dosage argument for haploinsufficiency
      - it removes ZMYND11 alone without the neighbouring genes a larger 10p15.3
      deletion would take.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence estimate exists. The disorder is known from
    aggregated case reports and small cohorts - the largest published series
    describes 20 individuals with ZMYND11-associated epilepsy, assembled through
    GeneMatcher, ClinVar and a rare-epilepsy network. The class is recorded as
    ULTRA_RARE on that basis, and this record exists to say "no estimate exists"
    structurally rather than to leave the section absent.
  evidence:
  - reference: PMID:34216016
    reference_title: "ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We obtained clinical descriptions of 16 new and nine published
      individuals, plus detailed case history of two children.
    explanation: >-
      Shows the scale the field is working at - a landmark series assembled from
      16 new and nine previously published individuals - which is what supports
      an ultra-rare classification in the absence of any population estimate.
progression:
- phase: Onset and course
  notes: >-
    Onset is congenital to early childhood and the course is static rather than
    neurodegenerative: neurodevelopmental deficits are invariable and do not
    remit, while the epilepsy is the variable element, ranging from spontaneous
    remission to drug resistance.
  evidence:
  - reference: PMID:34216016
    reference_title: "ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizure prognosis ranged from spontaneous remission to drug resistant.
    explanation: >-
      Establishes that the seizure course, unlike the neurodevelopmental one, is
      not fixed at onset.
diagnosis:
- name: Molecular genetic testing
  description: >-
    Diagnosis is molecular. Intragenic ZMYND11 variants are found by exome or
    genome sequencing or by intellectual-disability and epilepsy gene panels;
    whole-gene deletions within a 10p15.3 microdeletion are found by chromosomal
    microarray, which a sequencing-only strategy can miss. Variants are
    classified against ACMG criteria. There is no biochemical marker and no
    functional assay in clinical use.
  evidence:
  - reference: PMID:34216016
    reference_title: "ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic evaluation was performed using gene panels or exome sequencing;
      variants were classified using American College of Medical Genetics
      (ACMG) criteria.
    explanation: >-
      States the testing modalities and the classification framework used in the
      largest published series.
  - reference: PMID:39696561
    reference_title: "Prenatal diagnosis and molecular cytogenetic analysis of pure chromosome 10p15.3 microdeletion using chromosomal microarray analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Karyotyping and chromosomal microarray analysis (CMA) was conducted to
      assess chromosomal abnormalities and detect copy number variations (CNVs)
      within the families, respectively.
    explanation: >-
      Supports chromosomal microarray as the modality that detects the deletion
      form, which sequencing panels may not call.
pathophysiology:
- name: Loss of ZMYND11 H3.3K36me3 reader function
  biological_scale: MOLECULAR
  description: >-
    ZMYND11 binds H3.3K36me3 over the bodies of actively transcribed genes and
    acts as an unconventional co-repressor, damping the elongation phase of RNA
    polymerase II. A heterozygous loss-of-function allele halves that reader
    dosage. The proposed normal role is suppression of cryptic transcription
    initiating from within gene bodies of highly expressed genes, so this is
    loss of a brake on transcriptional noise rather than loss of a dedicated
    activator or repressor of specific target genes.
  genes:
  - preferred_term: ZMYND11
    term:
      id: hgnc:16966
      label: ZMYND11
  molecular_functions:
  - preferred_term: chromatin binding
    term:
      id: GO:0003682
      label: chromatin binding
    modifier: DECREASED
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DECREASED
  evidence:
  - reference: PMID:38397245
    reference_title: "Further Delineation of Clinical Phenotype of ZMYND11 Variants in Patients with Neurodevelopmental Dysmorphic Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ZMYND11 encodes a zinc finger MYND domain-containing protein that acts as
      a transcriptional co-repressor to inhibit the elongation phase of RNA
      polymerase II via the recognition of histone modification of the
      transcribed regions.
    explanation: >-
      Directly states the reader and co-repressor function acting on
      transcriptional elongation.
  - reference: PMID:28933030
    reference_title: "Phenotype comparison confirms ZMYND11 as a critical gene for 10p15.3 microdeletion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the ZMYND11 gene has important functions in epigenetic regulation as an
      unconventional transcription co-repressor of highly expressed genes,
      possibly acting in the repression of cryptic transcription from gene
      bodies
    explanation: >-
      Supports the cryptic-transcription suppression model. The source itself
      hedges with "possibly", which is why this node is described as a proposed
      normal role rather than an established one.
  - reference: PMID:41068108
    reference_title: "ZMYND11 functions in bimodal regulation of latent genes and brain-like splicing to safeguard corticogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ZMYND11, known for its tumor suppressor function, encodes a
      histone-reader that recognizes sites of transcriptional elongation and
      acts as a co-repressor.
    explanation: >-
      Independent confirmation of the reader and co-repressor function in a
      human stem cell system.
  - reference: PMID:25263594
    reference_title: "BS69/ZMYND11 reads and connects histone H3.3 lysine 36 trimethylation-decorated chromatin to regulated pre-mRNA processing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we show that BS69 selectively recognizes histone variant H3.3 lysine 36
      trimethylation
    explanation: >-
      The founding biochemical study identifying the specific mark ZMYND11 reads.
      It establishes selectivity for the H3.3 variant, which is what makes this a
      variant-specific reader rather than a generic H3K36me3 binder.
  downstream:
  - target: De-repression of latent developmental transcriptional programmes
    description: >-
      Losing the elongation brake allows normally silent developmental pathways
      to be expressed in cortical progenitors.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41068108
      reference_title: "ZMYND11 functions in bimodal regulation of latent genes and brain-like splicing to safeguard corticogenesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        ZMYND11-deficient cortical neural stem cells upregulate inappropriate
        developmental pathways, leading to disrupted neurogenesis.
      explanation: >-
        Direct experimental link from ZMYND11 deficiency to de-repression of
        latent programmes.
  - target: Loss of brain-specific RBFOX2-dependent splicing
    description: >-
      ZMYND11 loss also disrupts a brain-specific RNA isoform switch through the
      splicing regulator RBFOX2. The published study is explicit that this is
      not a direct chromatin-to-spliceosome effect in cortical cells: few
      differentially spliced events overlapped ZMYND11 chromatin binding, and
      the authors attribute the splicing phenotype to increased RBFOX2
      expression in the mutant. The edge is therefore indirect with RBFOX2 as
      the named intermediate.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41068108
      reference_title: "ZMYND11 functions in bimodal regulation of latent genes and brain-like splicing to safeguard corticogenesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In addition to its role on chromatin, ZMYND11 regulates a brain-specific
        RNA isoform switch involving the splicing regulator RBFOX2.
      explanation: >-
        Establishes the RBFOX2 isoform switch as an output of ZMYND11 loss.
        Note the published wording is "in addition to its role on chromatin",
        not "on histones" - the preprint said the latter, and the difference
        matters for how separable this arm is taken to be.
    - reference: PMID:41068108
      reference_title: "ZMYND11 functions in bimodal regulation of latent genes and brain-like splicing to safeguard corticogenesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we found that ZMYND11 did not largely regulate splicing, as few DAS
        events overlapped with chromatin binding.
      explanation: >-
        The authors' own negative result, and the reason this edge is graded
        INDIRECT_KNOWN_INTERMEDIATES rather than DIRECT.
- name: De-repression of latent developmental transcriptional programmes
  biological_scale: CELLULAR
  description: >-
    Cortical neural stem cells lacking ZMYND11 upregulate latent developmental
    pathways. The same pattern appears when other chromatin-related autism risk
    factors are perturbed, which positions this as a shared convergent
    consequence of chromatin-regulator loss rather than a ZMYND11-private effect.
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:41068108
    reference_title: "ZMYND11 functions in bimodal regulation of latent genes and brain-like splicing to safeguard corticogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Similar defects are observed in other chromatin-related ASD risk genes,
      some of which are partially rescued by enhancing ZMYND11 function.
    explanation: >-
      Supports convergence of chromatin-regulator loss on the same
      transcriptional and splicing consequences.
  downstream:
  - target: Impaired cortical progenitor and neuron production
    description: >-
      De-repressed developmental programmes impair the production of cortical
      progenitors and neurons.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41068108
      reference_title: "ZMYND11 functions in bimodal regulation of latent genes and brain-like splicing to safeguard corticogenesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, we show that mutations in ZMYND11, a newly implicated risk gene,
        impair human cortical progenitor and neuron production.
      explanation: >-
        Direct causal statement linking the transcriptional de-repression to
        reduced progenitor and neuron output.
- name: Loss of brain-specific RBFOX2-dependent splicing
  biological_scale: MOLECULAR
  description: >-
    Two literatures meet at this node and they do not say the same thing, so
    the entry states both rather than picking the tidier one.

    In non-neural cells, ZMYND11 couples the chromatin mark it reads directly to
    pre-mRNA processing: it associates with U5 snRNP spliceosome components and
    promotes intron retention by physically antagonising EFTUD2, and that
    regulation depends on its binding to H3K36me3-decorated chromatin. That is a
    direct, chromatin-dependent splicing role.

    In human cortical cells it appears not to work that way. The corticogenesis
    study found that ZMYND11 did not largely regulate splicing directly - few
    differentially spliced events overlapped its chromatin binding - and
    attributes the splicing phenotype instead to increased RBFOX2 expression in
    the mutant, making the effect indirect. The disease-relevant output is a
    brain-specific RNA isoform switch, and it is partially rescuable by
    enhancing ZMYND11 function.

    The incoming edge is graded INDIRECT_KNOWN_INTERMEDIATES to follow the
    cortical evidence, since that is the tissue this disease is about.
  biological_processes:
  - preferred_term: RNA splicing
    term:
      id: GO:0008380
      label: RNA splicing
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:25263594
    reference_title: "BS69/ZMYND11 reads and connects histone H3.3 lysine 36 trimethylation-decorated chromatin to regulated pre-mRNA processing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Biochemical and genetic experiments demonstrate that BS69 promotes IR by
      antagonizing EFTUD2 through physical interactions.
    explanation: >-
      Identifies the molecular route from ZMYND11 to splicing: physical
      antagonism of the U5 snRNP component EFTUD2, regulating intron retention.
  - reference: PMID:25263594
    reference_title: "BS69/ZMYND11 reads and connects histone H3.3 lysine 36 trimethylation-decorated chromatin to regulated pre-mRNA processing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We further show that regulation of IR by BS69 also depends on its binding
      to H3K36me3-decorated chromatin.
    explanation: >-
      Establishes that the splicing function is dependent on the chromatin-reader
      function, which is why this node is placed downstream of reader loss.
  - reference: PMID:41068108
    reference_title: "ZMYND11 functions in bimodal regulation of latent genes and brain-like splicing to safeguard corticogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In addition to its role on chromatin, ZMYND11 regulates a brain-specific
      RNA isoform switch involving the splicing regulator RBFOX2.
    explanation: >-
      Establishes the RBFOX2-dependent brain splicing programme as a ZMYND11
      output.
  downstream:
  - target: Impaired cortical progenitor and neuron production
    description: >-
      Splicing dysregulation contributes, alongside transcriptional
      de-repression, to defective corticogenesis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41068108
      reference_title: "ZMYND11 functions in bimodal regulation of latent genes and brain-like splicing to safeguard corticogenesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Similar defects are observed in other chromatin-related ASD risk genes,
        some of which are partially rescued by enhancing ZMYND11 function.
      explanation: >-
        Supports splicing dysregulation as part of the corticogenesis phenotype.
        Graded PARTIAL because the source establishes co-occurrence and partial
        rescue rather than isolating the splicing arm's independent contribution
        to progenitor loss.
- name: Impaired cortical progenitor and neuron production
  biological_scale: TISSUE
  description: >-
    Reduced production of cortical progenitors and neurons is the cellular
    endpoint linking ZMYND11 loss to the neurodevelopmental phenotype. This node
    rests on a human stem cell model, not on patient brain tissue.
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: cerebral cortex development
    term:
      id: GO:0021987
      label: cerebral cortex development
    modifier: DECREASED
  evidence:
  - reference: PMID:41068108
    reference_title: "ZMYND11 functions in bimodal regulation of latent genes and brain-like splicing to safeguard corticogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we show that mutations in ZMYND11, a newly implicated risk gene,
      impair human cortical progenitor and neuron production.
    explanation: >-
      Establishes the cellular endpoint. This rests on a human stem cell model,
      which is the reason the human-model-mismatch discussion below is recorded.
  downstream:
  - target: Intellectual disability
    description: >-
      Reduced production of cortical progenitors and neurons is the proposed
      cellular basis of the intellectual disability and developmental delay that
      define the disorder.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41068108
      reference_title: "ZMYND11 functions in bimodal regulation of latent genes and brain-like splicing to safeguard corticogenesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, we show that mutations in ZMYND11, a newly implicated risk gene,
        impair human cortical progenitor and neuron production.
      explanation: >-
        Graded PARTIAL deliberately. The cellular deficit
        is measured in a dish and the clinical phenotype is measured in people;
        no study connects the two in the same individuals. The edge is typed
        INDIRECT_UNKNOWN_INTERMEDIATES because nothing is established between
        the progenitor deficit and the cognitive outcome, and it is what the
        HUMAN_MODEL_MISMATCH discussion below is about.
  - target: Seizure
    description: >-
      Epilepsy in this disorder is grouped with the other chromatin-reader
      epilepsies, which places the seizure phenotype downstream of the same
      corticogenesis defect rather than of a separate channel mechanism.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34216016
      reference_title: "ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ZMYND11 is one of a small group of chromatin reader genes associated in
        the pathogenesis of epilepsy, and specifically ABPE.
      explanation: >-
        Places ZMYND11 epilepsy in the chromatin-reader class. Graded PARTIAL
        because class membership is not a demonstrated causal route from
        progenitor loss to seizures - the same paper says the epileptogenic
        mechanism "may be linked to interaction with histone H3.3", which is
        itself a proposal.
phenotypes:
- category: Neurodevelopmental
  name: Intellectual disability
  frequency: VERY_FREQUENT
  description: >-
    Intellectual disability is the core feature. In the epilepsy cohort it was
    mild to moderate in 16 of 20 individuals and severe in 4 of 20.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:38397245
    reference_title: "Further Delineation of Clinical Phenotype of ZMYND11 Variants in Patients with Neurodevelopmental Dysmorphic Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intellectual disability with speech delay and behavioural abnormalities,
      as well as hypotonia, seizures, feeding difficulties and craniofacial
      dysmorphism, are the main symptoms associated with pathogenic variants of
      the ZMYND11 gene.
    explanation: >-
      Names intellectual disability as a core manifestation of ZMYND11 variants.
  - reference: PMID:34216016
    reference_title: "ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodevelopmental deficits were invariable. Dysmorphic features were
      variable.
    explanation: >-
      In a 20-person ZMYND11 epilepsy cohort, neurodevelopmental impairment was
      present in every individual, supporting VERY_FREQUENT. The contrast drawn
      in the same breath - dysmorphism variable, neurodevelopment not - is what
      makes this the load-bearing sentence for the core phenotype.
- category: Neurodevelopmental
  name: Delayed speech and language development
  frequency: VERY_FREQUENT
  description: >-
    Speech delay is disproportionate and is written into the disorder's own
    name, which distinguishes the ZMYND11 phenotype from generic developmental
    delay.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:38397245
    reference_title: "Further Delineation of Clinical Phenotype of ZMYND11 Variants in Patients with Neurodevelopmental Dysmorphic Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      autosomal dominant intellectual developmental disorder-30 with speech
      delay and behavioural abnormalities
    explanation: >-
      Speech delay is part of the defining description of MRD30.
- category: Neurodevelopmental
  name: Motor delay
  frequency: FREQUENT
  description: >-
    Motor delay accompanies the speech delay and is named in the same
    description of the shared 10p15.3 deletion and ZMYND11-variant phenotype.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:34818214
    reference_title: "Intragenic Deletion of the ZMYND11 Gene in 10p15.3 is Associated with Developmental Delay Phenotype: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients harboring 10p15.3 microdeletions or pathogenic ZMYND11 truncating
      variants share similar clinical features including hypotonia, intellectual
      disability, facial dysmorphisms, speech and motor delays, seizures, and
      significant behavioral problems
    explanation: >-
      Names motor delay among the shared features of the deletion syndrome and
      intragenic ZMYND11 variants.
- category: Neurological
  name: Seizure
  frequency: FREQUENT
  description: >-
    Epilepsy in ZMYND11 disorder is heterogeneous rather than a single syndrome.
    Among 20 individuals it split into atypical benign partial or idiopathic
    focal epilepsy, generalised epilepsies and infantile epileptic
    encephalopathy, and an unclassified group; prognosis ranged from spontaneous
    remission to drug resistance.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:34216016
    reference_title: "ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizure prognosis ranged from spontaneous remission to drug resistant.
    explanation: >-
      Establishes the wide prognostic range that makes a single epilepsy
      classification inappropriate here.
  - reference: PMID:34216016
    reference_title: "ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ZMYND11 is one of a small group of chromatin reader genes associated in
      the pathogenesis of epilepsy, and specifically ABPE.
    explanation: >-
      Links the epilepsy phenotype specifically to chromatin reader loss.
- category: Behavioral
  name: Autistic behavior
  frequency: FREQUENT
  description: >-
    Autistic features are prominent, and a ZMYND11 splice variant was originally
    found in autism without intellectual disability or obvious dysmorphism -
    evidence that the behavioural phenotype can occur without the syndromic one.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:25217958
    reference_title: "Refining analyses of copy number variation identifies specific genes associated with developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      truncations of ZMYND11 in individuals with autism, aggression and complex
      neuropsychiatric features
    explanation: >-
      The discovery study that linked ZMYND11 truncations to autism and
      aggression.
- category: Behavioral
  name: Aggressive behavior
  frequency: OCCASIONAL
  description: >-
    Aggression was one of the features that distinguished the original
    ZMYND11-truncation cohort from other developmental delay cases.
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:25217958
    reference_title: "Refining analyses of copy number variation identifies specific genes associated with developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      truncations of ZMYND11 in individuals with autism, aggression and complex
      neuropsychiatric features
    explanation: >-
      Directly names aggression among the features associated with ZMYND11
      truncations.
- category: Neurological
  name: Hypotonia
  frequency: FREQUENT
  description: >-
    Hypotonia is a consistent early feature and is reported at higher frequency
    in missense than in loss-of-function variant carriers.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:38397245
    reference_title: "Further Delineation of Clinical Phenotype of ZMYND11 Variants in Patients with Neurodevelopmental Dysmorphic Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      as well as hypotonia, seizures, feeding difficulties and craniofacial
      dysmorphism, are the main symptoms associated with pathogenic variants of
      the ZMYND11 gene
    explanation: >-
      Lists hypotonia among the main symptoms of ZMYND11 variants.
- category: Craniofacial
  name: Abnormal facial shape
  frequency: FREQUENT
  description: >-
    Craniofacial dysmorphism is characteristic but explicitly variable - present
    in only 12 of 20 individuals in the epilepsy cohort - so its absence does not
    argue against the diagnosis.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:34216016
    reference_title: "ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodevelopmental deficits were invariable. Dysmorphic features were
      variable.
    explanation: >-
      Establishes that dysmorphism, unlike the neurodevelopmental deficit, is
      not invariable - so its absence does not argue against the diagnosis.
- category: Gastrointestinal
  name: Feeding difficulties
  frequency: FREQUENT
  description: >-
    Feeding difficulties are among the recurring features of the ZMYND11
    phenotype.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:38397245
    reference_title: "Further Delineation of Clinical Phenotype of ZMYND11 Variants in Patients with Neurodevelopmental Dysmorphic Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      seizures, feeding difficulties and craniofacial dysmorphism, are the main
      symptoms associated with pathogenic variants of the ZMYND11 gene
    explanation: >-
      Lists feeding difficulties among the main symptoms.
- category: Growth
  name: Short stature
  frequency: OCCASIONAL
  description: >-
    Short stature is reported in the 10p15.3 deletion literature, notably in
    those older than 10 years, and independently in carriers of the recurrent
    p.Arg600Trp missense variant - so unlike recurrent infections it is
    corroborated outside the deletion cohort.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:28933030
    reference_title: "Phenotype comparison confirms ZMYND11 as a critical gene for 10p15.3 microdeletion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      behavioural disturbances, hypotonia, seizures, low birth weight, short
      stature in those older than 10 years of age, genitourinary malformations
      and recurrent infections
    explanation: >-
      Lists short stature among the recurring features of the deletion cohort,
      with its age dependence.
  - reference: PMID:41820311
    reference_title: "ZMYND11 p.Arg600Trp variant associated with a distinctive neurodevelopmental phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      demonstrated consistent shared features, including microcephaly, broad
      nasal alae, short stature, cryptorchidism and nipple anomalies, findings
      that are not typically emphasized in LoF-associated cases
    explanation: >-
      Corroborates short stature in intragenic missense carriers, independent of
      the contiguous-gene deletion.
- category: Ophthalmological
  name: Strabismus
  frequency: OCCASIONAL
  description: >-
    Strabismus is reported at higher frequency among missense than
    loss-of-function variant carriers.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:41820311
    reference_title: "ZMYND11 p.Arg600Trp variant associated with a distinctive neurodevelopmental phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      suggested higher frequencies of strabismus, hypotonia and severe
      intellectual disability compared with LoF variants
    explanation: >-
      Aggregate comparison across reported missense variants, supporting
      strabismus as part of the spectrum and enriched in the missense subgroup.
- category: Genitourinary
  name: Cryptorchidism
  frequency: OCCASIONAL
  description: >-
    Genitourinary malformations including cryptorchidism recur in the 10p15.3
    deletion and ZMYND11 variant literature.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:41820311
    reference_title: "ZMYND11 p.Arg600Trp variant associated with a distinctive neurodevelopmental phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present patient showed global developmental delay, hypotonia,
      distinctive craniofacial features, microcephaly, short stature,
      cryptorchidism and right-sided inguinal hernia.
    explanation: >-
      Case-level report of cryptorchidism in a ZMYND11 missense carrier.
- category: Neurological
  name: Microcephaly
  frequency: OCCASIONAL
  description: >-
    Microcephaly is reported in individual ZMYND11 cases, including two
    independent carriers of the recurrent p.Arg600Trp variant, and is not a
    consistent feature of loss-of-function cases.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:41820311
    reference_title: "ZMYND11 p.Arg600Trp variant associated with a distinctive neurodevelopmental phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      demonstrated consistent shared features, including microcephaly, broad
      nasal alae, short stature, cryptorchidism and nipple anomalies, findings
      that are not typically emphasized in LoF-associated cases
    explanation: >-
      Reports microcephaly as shared among p.Arg600Trp carriers and explicitly
      contrasts it with the loss-of-function presentation.
- category: Auditory
  name: Sensorineural hearing impairment
  frequency: VERY_RARE
  description: >-
    Sensorineural hearing loss is a single-case observation in a ZMYND11
    missense carrier and is recorded here as an isolated report, not an
    established feature. The reporting authors themselves note a family history
    of hearing impairment in that patient, so an independent cause is possible.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:27626064
    reference_title: "A de novo missense mutation in ZMYND11 is associated with global developmental delay, seizures, and hypotonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      female with seizures, global developmental delay, sensorineural hearing
      loss, hypotonia, dysmorphic features
    explanation: >-
      Single-patient report. Graded PARTIAL because the same paper records a
      positive family history of congenital hearing impairment on both sides,
      so this observation does not establish hearing loss as attributable to
      ZMYND11.
- category: Immunological
  name: Recurrent infections
  frequency: OCCASIONAL
  description: >-
    Recurrent infections are listed among the more frequent additional symptoms
    in a 10p15.3-deletion cohort. Attribution caveat: unlike the core
    neurodevelopmental features, this one is not independently reported in
    intragenic ZMYND11 variant carriers, and no immunological mechanism is known
    for ZMYND11. It may belong to the contiguous-gene deletion rather than to
    MRD30, and is retained here flagged rather than dropped because the deletion
    cohort is a legitimate observation about the shared phenotype.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:28933030
    reference_title: "Phenotype comparison confirms ZMYND11 as a critical gene for 10p15.3 microdeletion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      genitourinary malformations and recurrent infections
    explanation: >-
      Lists recurrent infections among the recurring features of the phenotype.
genetic:
- name: ZMYND11
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: ZMYND11
    term:
      id: hgnc:16966
      label: ZMYND11
  evidence:
  - reference: PMID:25217958
    reference_title: "Refining analyses of copy number variation identifies specific genes associated with developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      truncations of ZMYND11 in individuals with autism, aggression and complex
      neuropsychiatric features
    explanation: >-
      The integrated CNV and sequencing study that first pinpointed ZMYND11
      truncations as causal.
  - reference: PMID:28933030
    reference_title: "Phenotype comparison confirms ZMYND11 as a critical gene for 10p15.3 microdeletion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The results of our study further confirm that the ZMYND11 gene is the
      critical gene for the clinical phenotype of 10p15.3 microdeletion
    explanation: >-
      Establishes ZMYND11 as the driver gene of the contiguous-gene syndrome,
      which is the argument for MRD30 as a monogenic entity.
  - reference: PMID:34818214
    reference_title: "Intragenic Deletion of the ZMYND11 Gene in 10p15.3 is Associated with Developmental Delay Phenotype: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients harboring 10p15.3 microdeletions or pathogenic ZMYND11 truncating
      variants share similar clinical features including hypotonia, intellectual
      disability, facial dysmorphisms, speech and motor delays, seizures, and
      significant behavioral problems
    explanation: >-
      Direct statement of the phenotypic equivalence between the deletion
      syndrome and intragenic ZMYND11 variants, which is what justifies curating
      MRD30 as one disease.
  notes: >-
    Variant origin. Most reported pathogenic variants are de novo, but not all:
    a 10p15.3 microdeletion has been shown to be inherited from a father with
    mild language impairment. variant_origin is therefore deliberately left
    unset rather than asserted as DE_NOVO, because both origins occur and the
    difference is what a counselling conversation turns on.

    Variant classes and what separates them. Most reported pathogenic variants
    are truncating or whole-gene deletions and are consistent with
    haploinsufficiency. Missense variants are rarer and may not be a weaker
    version of the same thing: aggregate comparison of 13 reported missense
    variants found higher frequencies of strabismus, hypotonia and severe
    intellectual disability than in loss-of-function carriers, and the recurrent
    c.1798C>T p.Arg600Trp variant is associated with microcephaly, broad nasal
    alae, short stature, cryptorchidism and nipple anomalies that are not
    emphasised in loss-of-function cases. Variants are distributed across the
    gene with no reproducible positional genotype-phenotype correlation, so
    variant position should not be used prognostically.
treatments:
- name: Antiseizure medication
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Seizure management follows the epilepsy syndrome rather than the genotype.
    Response is genuinely bimodal: some individuals remit spontaneously, others
    are drug resistant despite multiple agents, ketogenic diet and vagal nerve
    stimulation. No ZMYND11-directed or mechanism-targeted therapy exists.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:34216016
    reference_title: "ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizure prognosis ranged from spontaneous remission to drug resistant.
    explanation: >-
      Establishes the range of treatment response, which is why no single
      antiseizure strategy is recommended.
- name: Developmental and behavioural support
  therapeutic_modality: BEHAVIORAL
  description: >-
    Management is supportive: early intervention, speech and language therapy
    given the disproportionate expressive deficit, and behavioural support for
    autistic features and aggression.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  - preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:38397245
    reference_title: "Further Delineation of Clinical Phenotype of ZMYND11 Variants in Patients with Neurodevelopmental Dysmorphic Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intellectual disability with speech delay and behavioural abnormalities
    explanation: >-
      Identifies the domains supportive care must address. Graded PARTIAL
      because the source characterises the phenotype rather than evaluating any
      intervention - no trial evidence for management exists in this disorder.
- name: Genetic counselling
  therapeutic_modality: BEHAVIORAL
  description: >-
    Most cases are de novo, so recurrence risk for parents is usually low - but
    not merely through gonadal mosaicism. A 10p15.3 deletion has been reported
    inherited from a father with mild language impairment, so parental testing
    is warranted rather than assumed negative, and a mildly affected parent may
    be identified by it. An affected individual's own transmission risk is 50%.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:34216016
    reference_title: "ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variants were distributed across the gene and mostly de novo
    explanation: >-
      Establishes that most variants are de novo - note "mostly", not "all".
  - reference: PMID:39696561
    reference_title: "Prenatal diagnosis and molecular cytogenetic analysis of pure chromosome 10p15.3 microdeletion using chromosomal microarray analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Parental CMA analysis revealed that the 10p15.3 microdeletion was
      inherited from the father, who displayed mild language impairment.
    explanation: >-
      A documented inherited case from a mildly affected parent. This is a
      materially larger recurrence risk than gonadal mosaicism and also
      demonstrates variable expressivity, so the counselling message cannot rest
      on a de novo assumption.
discussions:
- discussion_id: zmynd11_missense_not_haploinsufficiency
  kind: KNOWLEDGE_GAP
  attaches_to:
  - genetic#ZMYND11
  - pathophysiology#Loss of ZMYND11 H3.3K36me3 reader function
  prompt: >-
    Do ZMYND11 missense variants such as p.Arg600Trp act through simple
    haploinsufficiency, or through a distinct mechanism such as a
    dominant-negative effect on the reader complex?
  rationale: >-
    The pathophysiology node here is written as loss of reader dosage, which is
    well supported for truncating variants and whole-gene deletions. It may be
    the wrong model for missense variants. Aggregate comparison of 13 reported
    missense variants found higher rates of strabismus, hypotonia and severe
    intellectual disability than in loss-of-function carriers, and p.Arg600Trp
    carriers share microcephaly, broad nasal alae, short stature and
    cryptorchidism that are not emphasised in loss-of-function cases. A
    phenotype that is more severe and partly different in a missense carrier is
    the classic signature of a mechanism other than reduced dosage. Resolving
    this would change how a missense result is counselled and would determine
    whether the entry needs two pathophysiology branches rather than one.
- discussion_id: zmynd11_corticogenesis_model_fidelity
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Impaired cortical progenitor and neuron production
  prompt: >-
    Does the reduced cortical progenitor and neuron production seen in
    ZMYND11-deficient human pluripotent stem cell cultures correspond to a
    measurable cortical deficit in patients?
  rationale: >-
    The entire cellular arm of this pathograph rests on one human pluripotent
    stem cell model. That model is human, which removes the usual species
    objection, but it is still an in vitro system: patients do not consistently
    show microcephaly, and structural brain imaging in ZMYND11 cases is
    described as non-specific rather than showing a reproducible cortical
    malformation. So the evidence that ZMYND11 loss impairs neuron production is
    strong in the dish and essentially unmeasured in people. Until the
    correspondence is established, the impaired-progenitor node should be read
    as a model-derived mechanism rather than a demonstrated patient finding.
  proposed_experiments:
  - experiment_id: zmynd11_cortical_morphometry
    name: Quantitative cortical morphometry in a ZMYND11 patient cohort
    description: >-
      Systematic quantitative MRI morphometry - cortical thickness, surface area
      and regional volumes - across a genotype-confirmed ZMYND11 cohort compared
      with matched controls, stratified by variant class.
    would_support:
    - pathophysiology#Impaired cortical progenitor and neuron production
    supporting_outcome:
    - >-
      Reduced cortical surface area or thickness in ZMYND11 carriers relative to
      matched controls, with a greater deficit in missense than
      loss-of-function carriers.
    would_refute:
    - pathophysiology#Impaired cortical progenitor and neuron production
    refuting_outcome:
    - >-
      Cortical morphometry indistinguishable from controls, which would place
      the disorder's mechanism in neuronal function rather than neuron
      production.
notes: >-
  Cross-references. OMIM #616083 and ORPHA:178469 name the same entity and are
  recorded here in prose only. That is not an oversight: DiseaseMappings carries
  icd10cm, icd11f, mondo and ncit slots and has no omim or orpha slot, so there
  is no structural home for either identifier on a Disease entry. They stay
  un-queryable until the schema gains one.

  Naming. The entry is filed under the MONDO label for MONDO:0014486. The
  literature increasingly calls this "ZMYND11-related neurodevelopmental
  disorder", which is carried as a synonym; the OMIM name MRD30 and ORPHA 178469
  refer to the same entity.

  Relationship to 10p15.3 microdeletion syndrome. These are not two diseases.
  ZMYND11 is the critical gene of the terminal 10p deletion, and intragenic
  ZMYND11 variants reproduce that phenotype, which is why the monogenic disorder
  was carved out. A deletion patient may have additional features from the other
  deleted genes, so the deletion syndrome is the broader phenotype and MRD30 is
  its ZMYND11-attributable core.

  Frequency grading. FrequencyEnum values here are graded from cohort
  descriptions rather than counted proportions, because the two largest series
  report features narratively. Where a proportion is given it is stated in the
  phenotype description; where it is not, the enum value is a reading of
  narrative language and should be treated accordingly.
📚

References & Deep Research

Deep Research

1
OpenScientist ▸
1. Disease Information
openscientist-autonomous 18 citations 2026-08-28T12:39:39.253210

1. Disease Information

MRD30 is a Mendelian, monogenic neurodevelopmental disorder in the intellectual-disability spectrum. It is defined molecularly by haploinsufficiency of ZMYND11 and represents the "pure gene" counterpart of the 10p15.3 microdeletion syndrome, in which ZMYND11 is the critical dosage-sensitive gene (PMID: 34216016).

Key identifiers (F014):

Resource Identifier
OMIM #616083 (Intellectual developmental disorder, autosomal dominant 30; MRD30)
MONDO MONDO:0014486
Gene (HGNC) ZMYND11, HGNC:29316
NCBI Gene 10778
UniProt Q15326
Locus 10p15.3
Gene aliases BS69, BRAM1

Synonyms / alternative names (F014): ZMYND11-related intellectual disability; ZMYND11-related neurodevelopmental disorder; ZMYND11-related syndromic intellectual disability; MRD30; and — for the deletion form — 10p15.3 microdeletion syndrome (of which ZMYND11 is the critical gene).

Information source type: The knowledge base for MRD30 is derived from aggregated case reports and small cohorts plus functional/mechanistic studies (patient-derived iPSC/cortical organoid, mouse ESC/MEF, and zebrafish models), not from population-scale EHR datasets (PMID: 34216016). Suggested ontology mapping: MONDO:0014486.

2. Etiology

Disease causal factors (F014): MRD30 etiology is exclusively genetic. It is caused by heterozygous loss-of-function or deleterious variants in ZMYND11 (nonsense, frameshift, canonical splice-site, missense, whole-gene or intragenic deletions) or by 10p15.3 deletions that remove ZMYND11. There are no established environmental, lifestyle, toxic, occupational, or infectious causal or risk factors, and no known protective factors or gene–environment interactions.

Genetic risk factors: The only risk factor is carriage of a pathogenic ZMYND11 variant. ZMYND11 is a highly loss-of-function–intolerant, dosage-sensitive gene; heterozygous LoF is sufficient to cause disease, and pathogenic LoF alleles are essentially absent from population controls (gnomAD) (F013). Variants are distributed across the gene with no precise genotype–phenotype correlation, though missense and LoF classes show partially distinct phenotypic emphases (see Section 4) (PMID: 34216016; PMID: 41820311).

Environmental / lifestyle / infectious factors: None identified or applicable (F014). No CTD/toxicogenomic, NHANES-type lifestyle, or infectious-agent associations are established for this monogenic disorder.

Gene–environment interactions: None reported.

3. Phenotypes

The MRD30 core phenotype is a syndromic neurodevelopmental disorder. Across cohorts, affected individuals show hypotonia, intellectual disability/global developmental delay, facial dysmorphism, speech and motor delay, seizures, and significant behavioral problems (including autism spectrum disorder, ADHD, and aggression) (PMID: 34818214; F003).

"patients harboring 10p15.3 microdeletions or pathogenic ZMYND11 truncating variants share similar clinical features including hypotonia, intellectual disability, facial dysmorphisms, speech and motor delays, seizures, and significant behavioral problems" (PMID: 34818214)

Epilepsy subtypes (F003). In a cohort of ~20 individuals, ZMYND11-associated epilepsy fell into three groups:

Epilepsy group n Notes
(i) Atypical benign partial epilepsy (ABPE) / idiopathic focal epilepsy 8 Centrotemporal features
(ii) Generalised epilepsies / infantile epileptic encephalopathy 4 More severe end
(iii) Unclassified 8 —

"Individuals with ZMYND11 associated epilepsy fell into three groups: (i) atypical benign partial epilepsy or idiopathic focal epilepsy (n = 8); (ii) generalised epilepsies/infantile epileptic encephalopathy (n = 4); (iii) unclassified (n = 8)" (PMID: 34216016)

Phenotype characteristics. Onset is congenital to early childhood. "Neurodevelopmental deficits were invariable. Dysmorphic features were variable." (PMID: 34216016) — i.e., near-complete penetrance for the neurodevelopmental core, with variable expressivity of dysmorphism and epilepsy. Seizure progression ranges from spontaneous remission to drug-resistant. Individual reports additionally document sensorineural hearing loss, ataxic gait, a happy disposition (Angelman-like), and rarer features such as eosinophilic esophagitis and severe allergies.

"seizures, global developmental delay, sensorineural hearing loss, hypotonia, dysmorphic features, and other features including a happy disposition and ataxic gait similar to Angelman syndrome" (PMID: 27626064)

Suggested HPO terms:

Phenotype HPO term Frequency / severity
Intellectual disability / global developmental delay HP:0001249 / HP:0001263 Invariable (near-100%); mild–severe
Hypotonia HP:0001252 Common
Seizures HP:0001250 Variable subset; remission to drug-resistant
Delayed speech and language development HP:0000750 Common
Motor delay HP:0001270 Common
Autism spectrum disorder / behavioral abnormality HP:0000729 / HP:0000708 Common
Facial dysmorphism HP:0001999 Variable
Sensorineural hearing impairment HP:0000407 Reported (subset)
Strabismus HP:0000486 Enriched in missense variants
Ataxic gait HP:0002066 Reported
Aggressive behavior HP:0000718 Reported

Quality-of-life impact. Disease-specific EQ-5D/SF-36 data are not available for this ultra-rare disorder. By clinical extrapolation, lifelong intellectual disability, communication impairment, behavioral difficulties, and (in a subset) epilepsy substantially affect daily functioning, independence, and caregiver burden.

4. Genetic / Molecular Information

Causal gene (F001, F014): ZMYND11 (zinc finger MYND-type containing 11; alias BS69/BRAM1), 10p15.3; HGNC:29316; NCBI Gene 10778; UniProt Q15326; OMIM disease #616083.

Variant spectrum and classification (F006, F008, F013). Most reported MRD30 patients carry loss-of-function variants — nonsense, frameshift, canonical splice-site, and whole/partial-gene deletions. Missense variants are rarer (~13 reported) and their mechanistic characteristics are less defined. Variants are classified per ACMG/AMP criteria and are distributed across the gene with no precise genotype–phenotype correlation.

"Most previously reported patients harbor loss-of-function (LoF) variants, whereas missense variants are rare and their clinical and mechanistic characteristics remain insufficiently defined" (PMID: 41820311)

Missense vs. LoF genotype–phenotype (F006). Aggregate analysis of the 13 reported missense variants (including recurrent c.1798C>T, p.Arg600Trp) suggests higher frequencies of strabismus, hypotonia, and severe intellectual disability than LoF variants, plus associations with microcephaly, broad nasal alae, short stature, cryptorchidism, and nipple anomalies.

"Aggregate analysis of reported 13 missense variants suggested higher frequencies of strabismus, hypotonia and severe intellectual disability compared with LoF variants" (PMID: 41820311)

Allele frequency / origin. Pathogenic ZMYND11 LoF alleles are essentially absent from population databases (gnomAD), consistent with strong LoF constraint. Variants are germline (not somatic in the disease context) and mostly de novo, with rare inherited cases (F013).

Functional consequences (F001). The unifying mechanism is loss of function / haploinsufficiency. An intragenic deletion removing only the 5′UTR + first two exons produced the same phenotype, confirming that reduced dosage — rather than a dominant-negative product — drives disease.

"our report contributes to expand the clinical and mutational spectrum of ZMYND11 and confirms haploinsufficiency as the underlying disease mechanism" (PMID: 34818214)

Dosage sensitivity / chromatinopathy overlap (F006). ZMYND11 is dosage-sensitive; its perturbation has also been linked to Cornelia de Lange Syndrome (CdLS)-like phenotypes, placing MRD30 within the broader family of chromatinopathies. Adult presentations may include movement disorders. Independently, ZMYND11 LoF is an FDR-significant schizophrenia risk gene (PMID: 40753099).

"ZMYND11, a dosage-sensitive gene, has been associated with Cornelia de Lange Syndrome (CdLS)-like phenotypes, and its haploinsufficiency is linked to 10p15.3 microdeletion syndrome" (PMID: 42003802)

Modifier genes. None specifically established for pure MRD30. In the contiguous-deletion form, co-deleted neighbors (DIP2C, GATA3) modify the phenotype (Section 10).

Epigenetic information. ZMYND11's own function is epigenetic (H3.3K36me3 reading); no disease-specific DNA-methylation episignature has been definitively established, though its role in chromatin regulation makes an episignature plausible (a knowledge gap).

Chromosomal abnormalities (F008, F010). 10p15.3 deletions (detected by CMA/karyotype/FISH), ring chromosome 10, inv dup del(10p), and complex rearrangements involving 10p can remove ZMYND11 and cause the deletion form of the disorder.

Suggested ontology terms: Gene product — UniProt Q15326; molecular function — GO:0035064 (methylated histone binding), GO:0003682 (chromatin binding).

5. Environmental Information

Not applicable. MRD30 is a monogenic disorder with no established environmental, lifestyle, or infectious contributors (F014). No toxin, radiation, pollution, occupational-exposure, dietary, or pathogen association is documented. This section is included for completeness and is explicitly negative.

6. Mechanism / Pathophysiology

Domain architecture and histone-reader function (F002, F004)

ZMYND11/BS69 contains tandemly arranged PHD, Bromo, and PWWP chromatin-recognition modules plus a C-terminal MYND zinc-finger domain. Together these read the histone variant mark H3.3K36me3.

"BS69 (also called ZMYND11) contains tandemly arranged PHD, BROMO, and PWWP domains, which are chromatin recognition modalities. Here, we show that BS69 selectively recognizes histone variant H3.3 lysine 36 trimethylation (H3.3K36me3) via its chromatin-binding domains." (PMID: 25263594)

ZMYND11 was originally identified as a specific reader for H3.3K36me3 and a candidate tumor suppressor; some oncogenic H3.3 mutations abrogate the H3.3K36me3/BS69 interaction, underscoring its functional importance.

"two recent studies identified BS69/ZMYND11, which was proposed to be a candidate tumor suppressor, as a specific reader for a modified form of H3.3 (H3.3K36me3)" (PMID: 25453099)

The chromatin-reader function connects directly to epilepsy pathogenesis: "ZMYND11 is one of a small group of chromatin reader genes associated in the pathogenesis of epilepsy, and specifically ABPE" (PMID: 34216016).

Coupling chromatin to transcription and splicing (F004)

Beyond elongation control, ZMYND11 couples the H3K36me3 chromatin state to pre-mRNA processing, mainly regulating intron retention (IR) by antagonizing the U5 snRNP spliceosome component EFTUD2; this depends on binding H3K36me3-decorated chromatin.

"BS69 mainly regulates intron retention (IR)... BS69 promotes IR by antagonizing EFTUD2 through physical interactions. We further show that regulation of IR by BS69 also depends on its binding to H3K36me3-decorated chromatin." (PMID: 25263594)

More recent data show ZMYND11 also localizes to gene promoters and regulates transcription initiation:

"ZMYND11 deficiency reduces the pausing index of Pol II, H3.3, and H3K36me3, indicating impaired transcription initiation" (PMID: 42262664)

Neurodevelopmental convergence (F005, F007)

In human cortical models, ZMYND11 mutations impair cortical progenitor and neuron production; ZMYND11-deficient neural stem cells upregulate inappropriate developmental pathways, disrupting neurogenesis, and ZMYND11 controls a brain-specific RNA isoform switch involving RBFOX2.

"mutations in ZMYND11, a newly implicated risk gene, impair human cortical progenitor and neuron production" (PMID: 41068108) "ZMYND11-deficient cortical neural stem cells upregulate inappropriate developmental pathways, leading to disrupted neurogenesis" (PMID: 41068108) "ZMYND11 regulates a brain-specific RNA isoform switch involving the splicing regulator RBFOX2" (PMID: 41068108)

A complementary mechanistic axis: ZMYND11 restrains the histone methyltransferase KMT2A (MLL1) to enable a neuronal developmental program (PMID: 41279818), linking MRD30 to the KMT2A/COMPASS chromatin-modifier network implicated in neurodevelopmental disorders.

Causal chain (upstream → downstream)

ZMYND11 haploinsufficiency (heterozygous LoF / 10p15.3 deletion)
│
▼
Reduced reading of H3.3K36me3 on gene bodies & promoters
│
├─► Impaired Pol II elongation control + reduced Pol II pausing (initiation)
├─► Loss of EFTUD2 antagonism → aberrant intron retention / mis-splicing
├─► Disrupted RBFOX2-dependent brain-specific isoform switch
└─► Loss of restraint on KMT2A → de-repression of latent developmental genes
│
▼
Cortical neural stem cells activate inappropriate developmental programs
│
▼
Impaired cortical progenitor & neuron production (disrupted corticogenesis)
│
▼
Intellectual disability, developmental delay, seizures, behavioral problems

Cell types & compartments: neural stem/progenitor cells and cortical neurons (CL:0000047 neural stem cell; CL:0000679 glutamatergic neuron); subcellular localization is the nucleus/chromatin (GO:0005634 nucleus; GO:0000785 chromatin).

Suggested GO biological processes: GO:0006357 (regulation of transcription by RNA Pol II), GO:0008380 (RNA splicing), GO:0006397 (mRNA processing), GO:0021987 (cerebral cortex development), GO:0022008 (neurogenesis).

Immune, metabolic, oxidative-stress mechanisms: Not central to MRD30 pathophysiology. (Co-deleted DIP2C perturbs sphingolipid metabolism/myelination in the deletion syndrome — Section 10 — but this is not ZMYND11-intrinsic.)

7. Anatomical Structures Affected

Primary organ / system (F005, F010): the brain / central nervous system (nervous system) — specifically the developing cerebral cortex (UBERON:0000955 brain; UBERON:0000956 cerebral cortex).

Tissue and cell level: nervous tissue; neural stem/progenitor cells and cortical neurons (CL:0000047, CL:0000679).

Subcellular level: nucleus and chromatin (GO:0005634, GO:0000785).

Secondary / contiguous-deletion involvement (F010): In larger 10p15.3 deletions, additional organs are affected because neighboring genes are co-deleted — heart (congenital heart defects, via DIP2C), kidney, parathyroid (hypoparathyroidism, via GATA3/DGS2), skeleton (short stature, hand/foot malformation, butterfly vertebrae, scoliosis), inner ear (sensorineural deafness), and rarely the GI tract (refractory gastroparesis). Some patients show cerebellar/posterior-fossa malformations (ring chromosome 10 cases).

"Recurrent 10p15.3 microdeletion syndrome is a rare multisystem disorder characterized by abnormal facial features, global developmental delay (DD)/intellectual disability (ID), short stature, hand/foot malformation, and congenital heart defects (CHDs)" (PMID: 40915331)

Lateralization: CNS involvement is bilateral/diffuse (a developmental, not focal-lesion, disorder), though focal epileptiform (e.g., centrotemporal) EEG features occur.

8. Temporal Development

Onset (F011): Congenital to early childhood — neonatal hypotonia and infantile developmental delay are typical; onset pattern is chronic/insidious, not acute.

Progression (F011): The disorder is chronic and lifelong and the neurodevelopmental deficit is largely static (non-neurodegenerative) rather than progressive. Neurodevelopmental deficits are essentially invariable (fully penetrant).

"Seizure prognosis ranged from spontaneous remission to drug resistant. Neurodevelopmental deficits were invariable." (PMID: 34216016)

Course patterns / adult evolution (F011): Epilepsy course is variable (episodic/remitting to drug-resistant). A distinct subset develops or worsens a movement disorder (dystonia/ataxia/tremor) in adulthood, prompting adult neurological referral and underscoring the need for lifelong surveillance.

"displayed a movement disorder (dystonia/ataxia/tremor) which manifested for the first time, or worsened, in the adulthood" (PMID: 35172867)

Critical periods: Cortical neurogenesis (fetal/early-postnatal) is the key vulnerable window, consistent with the corticogenesis defect and congenital onset (F005). Prenatal presentations are nonspecific (Section 10).

9. Inheritance and Population

Epidemiology (F013): MRD30 is ultra-rare; only on the order of dozens of individuals are reported worldwide (e.g., a 2021 study assembled 20 individuals with epilepsy). No population prevalence or incidence estimate is established.

Inheritance (F008, F013): Autosomal dominant. Pathogenic variants mostly arise de novo; rare inherited cases from mildly/variably affected parents demonstrate incomplete penetrance and variable expressivity.

"Variants were distributed across the gene and mostly de novo with no precise genotype-phenotype correlation." (PMID: 34216016) "Parental CMA analysis revealed that the 10p15.3 microdeletion was inherited from the father, who displayed mild language impairment" (PMID: 39696561)

Penetrance / expressivity: Neurodevelopmental deficits are near-fully penetrant; dysmorphism, epilepsy, and additional features are variably expressed. Germline mosaicism is plausible for de novo cases but not specifically quantified.

Founder effects / consanguinity / carrier frequency: No founder effect described; consanguinity is not relevant (dominant, mostly de novo). Carrier frequency in the healthy population is effectively negligible given strong LoF constraint (gnomAD).

Demographics (F013): Reported in both sexes with no clear sex predilection and across diverse populations; no ethnic or geographic clustering is established.

10. Diagnostics

Recommended approach (F008). Diagnosis is molecular. Point/truncating ZMYND11 variants are detected by whole-exome or whole-genome sequencing or by epilepsy/intellectual-disability gene panels, with variants classified per ACMG/AMP criteria. 10p15.3 deletions are detected by chromosomal microarray analysis (CMA), karyotyping, and FISH; prenatally by amniocentesis + CMA.

"Genetic evaluation was performed using gene panels or exome sequencing; variants were classified using American College of Medical Genetics (ACMG) criteria" (PMID: 34216016)

Test Utility in MRD30
WES / WGS High — detects intragenic point/truncating variants (first-line for ID/epilepsy)
Epilepsy/ID gene panels High — targeted detection of ZMYND11 variants
Chromosomal microarray (CMA) Detects 10p15.3 deletions and contiguous-gene involvement
Karyotype / FISH Detects ring chr10, inv dup del(10p), translocations involving 10p
Prenatal (amniocentesis + CMA) Detects deletions; correlate with ultrasound

Prenatal / fetal features (F008). Nonspecific: increased nuchal translucency (first trimester), fetal growth restriction (third trimester), and skeletal anomalies (butterfly vertebrae, scoliosis).

"Two cases were diagnosed in the first trimester because of increased nuchal translucency (NT). Three had normal routine first-trimester and second-trimester ultrasound scans, and were diagnosed because of fetal growth restriction (FGR)" (PMID: 42362275)

Ancillary tests. EEG (for epilepsy classification, including centrotemporal/ABPE patterns), brain MRI (may show cerebellar/posterior-fossa anomalies in some deletion/ring-chromosome cases), and audiology/ophthalmology assessments for hearing loss and strabismus. No specific blood/urine biomarker or enzyme assay exists.

Differential diagnosis. Angelman syndrome (happy disposition, ataxic gait, hypotonia — overlap noted in individual reports; PMID: 27626064), other chromatinopathies including Cornelia de Lange-like presentations (PMID: 42003802), and — for contiguous deletions — HDR/Barakat syndrome (via GATA3) and DiGeorge-region disorders.

Distinguishing pure MRD30 from the contiguous-deletion syndrome (F010). Pure ZMYND11 disruption (point variants or small intragenic deletions) causes the core neurodevelopmental phenotype only. Larger deletions add features from co-deleted neighbors: DIP2C (congenital heart defects, short stature, hand/foot malformation, abnormal myelination/sphingolipid metabolism) and, for larger terminal deletions, GATA3 + DiGeorge critical region 2 (DGS2) → hypoparathyroidism, sensorineural deafness, renal abnormalities (HDR/Barakat-like).

"We identified Disco Interacting Protein 2 Homolog C (DIP2C) as a putative candidate gene underlying CHDs" (PMID: 40915331) "includes the ZMYND11 and GATA3 genes and a partial critical region of the DiGeorge syndrome 2 gene (DGS2)" (PMID: 34049562)

Screening / cascade testing. Once a familial variant is identified, targeted cascade testing of at-risk relatives is appropriate given documented inherited/variably expressed cases. No population newborn screening exists.

11. Outcome / Prognosis

Survival / mortality (F011). MRD30 is not associated with reduced life expectancy in the reported literature; it is a static neurodevelopmental disorder rather than a lethal or neurodegenerative one. No disease-specific mortality rate is established.

Morbidity / function. The principal burden is lifelong intellectual disability and developmental disability, with communication impairment, behavioral difficulties (ASD/ADHD/aggression), and — in a subset — epilepsy and adult movement disorders contributing to functional impairment and caregiver dependence. Formal disability/QoL metrics (ICF, EQ-5D, PROMIS) have not been reported for this rare disorder.

Disease course / complications. Complications include drug-resistant epilepsy (subset), adult-onset/worsening movement disorder, sensorineural hearing loss, and — in contiguous deletions — cardiac, renal, endocrine, and GI complications. Recovery to normal cognition does not occur; developmental gains are achievable with early intervention.

Prognostic factors (F006, F011). Variant class appears prognostically relevant: missense variants (e.g., p.Arg600Trp) associate with more severe intellectual disability, strabismus, and hypotonia. Seizure severity/drug-resistance and the presence of contiguous-gene deletions also influence prognosis. No validated molecular prognostic biomarker exists.

12. Treatment

No disease-specific or curative therapy exists (F012). Management is symptomatic and multidisciplinary, following general neurodevelopmental-disorder care:

Domain Intervention Suggested NCIT concept
Epilepsy Antiseizure medications (ASMs); recognize drug-resistant subset NCIT:C264 (Anticonvulsant Agent)
Development Early developmental intervention NCIT:C15275 (Rehabilitation Therapy)
Motor / hypotonia Physical & occupational therapy NCIT:C15242 / NCIT:C15226
Speech / language Speech-language therapy NCIT:C15275
Behavior (ASD/ADHD/aggression) Behavioral & educational support NCIT:C15319 (Behavioral Therapy)
Sensory Vision (strabismus) & hearing surveillance/treatment —
Contiguous deletions Cardiac, renal, parathyroid/endocrine, skeletal evaluation & management —

"Seizure prognosis ranged from spontaneous remission to drug resistant." (PMID: 34216016) — justifies individualized antiseizure management including recognition of drug-resistant epilepsy.

Emerging / experimental directions (F012). Cellular studies indicate that defects seen in ZMYND11-deficient and related chromatin-ASD-gene models can be partially rescued by enhancing ZMYND11 function, hinting at future targeted approaches — but nothing is clinically available.

"Similar defects are observed in other chromatin-related ASD risk genes, some of which are partially rescued by enhancing ZMYND11 function" (PMID: 41068108)

Pharmacogenomics / gene / cell / RNA therapy: No approved targeted, gene-, cell-, or RNA-based therapy; no MRD30-specific pharmacogenomic guidance. There are no registered disease-specific interventional trials at the time of this review.

13. Prevention

Because MRD30 is a monogenic disorder with no environmental component, prevention is limited to genetic risk management (F013, F014):

  • Primary prevention: Not applicable in the classical sense (no modifiable environmental risk). For families with a known variant, genetic counseling, prenatal diagnosis, and preimplantation genetic testing (PGT) can inform reproductive decisions.
  • Secondary prevention: Early molecular diagnosis (WES/WGS/CMA) enables early developmental intervention and surveillance for epilepsy, hearing, and vision problems.
  • Tertiary prevention: Proactive management of complications — antiseizure therapy, adult neurological surveillance for movement disorders, and organ-specific monitoring in contiguous-deletion cases.
  • Genetic counseling: Given that most variants are de novo but inherited/variably expressed cases occur, recurrence-risk counseling should account for variable expressivity, incomplete penetrance, and possible parental mosaicism; cascade testing follows identification of a familial variant.

No immunization, behavioral, or public-health/environmental prevention is applicable.

14. Other Species / Natural Disease

  • Taxonomy / orthologs (F009): ZMYND11 is evolutionarily conserved; functional orthologs are studied in mouse (Zmynd11) and zebrafish (bs69/zmynd11). Human gene NCBI Gene 10778.
  • Natural disease in animals: No naturally occurring companion-animal or wildlife disease is described (OMIA has no established entry for a natural ZMYND11 disorder). This is a research-modeled, not a naturally recognized veterinary, condition.
  • Comparative biology: Disease mechanisms (H3.3K36me3 reading, transcription/splicing control, developmental-signaling regulation) are conserved. In zebrafish, Mga modulates Bmpr1a activity by antagonizing Bs69, providing an in-vivo developmental-signaling (BMP) context (PMID: 30324105).
  • Transmission / zoonosis: Not applicable (genetic disorder).

15. Model Organisms

Available models (F009):

System Model Key finding PMID
Human iPSC / cortical organoid ZMYND11-deficient cortical NSCs Impaired progenitor/neuron production; de-repressed latent genes; RBFOX2 splicing switch 41068108
Mouse ESC / MEF Zmynd11 deficiency Impaired transcription initiation; reduced Pol II pausing index 42262664
Zebrafish bs69 (Mga–Bmpr1a axis) In-vivo BMP developmental-signaling model 30324105
Mouse (neighboring Dip2c) Het/hom Dip2c mutants Dosage-sensitive cognitive impairment, hyperlocomotion, abnormal sphingolipid metabolism/myelination 41054236
Zebrafish (neighboring dip2ca) dip2ca knockdown Craniofacial and cardiac defects 40915331

"heterozygous mutant mice displayed only mild cognitive impairment, recapitulating the dosage-sensitive phenotype observed in human 10p15.3 microdeletion syndrome" (PMID: 41054236) — dosage-sensitive model for the neighboring 10p15.3 gene DIP2C.

Phenotype recapitulation & limitations. Human iPSC/cortical-organoid models faithfully reproduce the corticogenesis defect and molecular signatures (latent-gene de-repression, RBFOX2 splicing) and are the most disease-relevant system. Mouse ESC/MEF models capture the transcription/chromatin mechanism. Limitations: no published constitutive Zmynd11 knockout mouse fully modeling the MRD30 behavioral/seizure phenotype was identified; zebrafish/mouse Dip2c models inform the contiguous-deletion (not pure-ZMYND11) phenotype. Genetic-model types available: cellular knockout/deficiency and organoid systems; a humanized or conditional neuronal knockout mouse would be a valuable addition.

Applications & resources: Cortical organoids for mechanism and drug-rescue screening; ESC/MEF for chromatin/transcription assays; zebrafish for developmental signaling. Resources: MGI (Zmynd11), ZFIN (bs69/zmynd11), Cellosaurus (patient iPSC lines).

Mechanistic Model / Interpretation

MRD30 is best understood as a chromatinopathy of transcriptional–splicing coupling in the developing cortex. A single functional dose of ZMYND11 is insufficient for normal reading of the H3.3K36me3 mark deposited on active gene bodies. The immediate consequence is dysregulated RNA Pol II behavior (elongation control plus initiation/pausing) and loss of the ZMYND11–EFTUD2 balance that governs intron retention. Layered on top, ZMYND11 normally restrains KMT2A and enforces a brain-specific RBFOX2 isoform switch. When ZMYND11 is halved, latent developmental gene programs are inappropriately activated, cortical neural stem cells fail to execute proper neurogenesis, and the mature cortex is built from too few, mis-specified neurons — producing intellectual disability, developmental delay, epilepsy, and behavioral phenotypes. Because the insult is developmental and completed early, the clinical disorder is static rather than degenerative, explaining its lifelong-but-stable natural history (with a distinct adult movement-disorder subset).

Two "concentric" clinical entities emerge from the same locus:

  ┌──────────────────────── 10p15.3 deletion (large terminal) ─────────────────────┐
  │  + GATA3/DGS2  → hypoparathyroidism, deafness, renal (HDR/Barakat-like)         │
  │  ┌──────────────── 10p15.3 microdeletion (recurrent) ─────────────────────┐     │
  │  │  + DIP2C → CHD, short stature, hand/foot malformation, myelination      │     │
  │  │  ┌──────────── Pure ZMYND11 loss = MRD30 (core) ───────────────┐        │     │
  │  │  │  ID/DD, hypotonia, seizures, dysmorphism, behavior           │        │     │
  │  │  └──────────────────────────────────────────────────────────────┘        │     │
  │  └──────────────────────────────────────────────────────────────────────────┘     │
  └──────────────────────────────────────────────────────────────────────────────────┘

This nested model is the single most clinically actionable synthesis: the size and gene content of the lesion predict which additional organ systems require evaluation, while the ZMYND11 core drives the neurodevelopmental phenotype in every case.

Evidence Base

PMID Title (abbrev.) Role
34818214 Intragenic ZMYND11 deletion / DD Confirms haploinsufficiency mechanism; deletion–truncating phenotypic equivalence
34216016 ZMYND11 epilepsies + NDD (cohort ~20) Critical-gene status; epilepsy subtypes; de novo predominance; diagnostic methods; penetrance
25263594 BS69/ZMYND11 reads H3.3K36me3, regulates splicing Domain architecture; H3.3K36me3 reader; EFTUD2/intron-retention
25453099 Histone H3.3 and cancer reader connection Reader specificity; tumor-suppressor context
42262664 ZMYND11 at promoters / initiation Transcription initiation & Pol II pausing role
41068108 ZMYND11 safeguards corticogenesis Corticogenesis defect; latent-gene de-repression; RBFOX2; partial rescue
41279818 ZMYND11 restrains KMT2A KMT2A restraint enabling neuronal program
41820311 p.Arg600Trp / missense phenotype Missense-vs-LoF genotype–phenotype
42003802 7p dup + 10p del chromatinopathy Dosage sensitivity; CdLS-like overlap
27626064 De novo missense; DD/seizures/hypotonia Individual multisystem phenotype; Angelman-like features
35172867 NDD in adulthood — movement disorder Adult-onset/worsening movement disorder
39696561 Prenatal pure 10p15.3 deletion Inherited case, variable expressivity
42362275 Prenatal 10p15.3 (5 cases) Nonspecific prenatal features (NT, FGR)
40915331 DIP2C and CHD in 10p15.3 Attributes CHD to co-deleted DIP2C
41054236 Dip2c deficiency / sphingolipids in mice Dosage-sensitive mouse model (neighboring gene)
34049562 Large 10p15.3p13 deletion GATA3/DGS2 co-deletion adds endocrine/renal/hearing features
30324105 Mga–Bmpr1a–Bs69 in zebrafish Zebrafish developmental-signaling model
40753099 Schizophrenia exome risk genes ZMYND11 LoF as FDR-significant SCZ risk gene

Evidence source types: human clinical (case reports/small cohorts), in vitro/iPSC (human cortical organoids), model organism (mouse ESC/MEF, zebrafish), and computational/genetic (exome burden). No population EHR or randomized-trial evidence exists for this ultra-rare disorder.

Limitations and Knowledge Gaps

  1. Small evidence base. All clinical knowledge derives from case reports and small cohorts (dozens of patients). No prevalence/incidence estimate, no natural-history registry, and no controlled trials exist.
  2. No population-scale or QoL data. Formal disability, EQ-5D/SF-36/PROMIS, and long-term functional-outcome metrics are unreported.
  3. Genotype–phenotype resolution is coarse. Missense-vs-LoF differences are suggested from aggregate analysis of only ~13 missense variants; larger, systematically phenotyped cohorts are needed.
  4. No definitive disease-specific episignature or biomarker has been validated, despite ZMYND11's chromatin role.
  5. Model gap. No published constitutive/conditional Zmynd11-knockout mouse fully recapitulating the MRD30 behavioral/seizure phenotype was identified; much mouse evidence pertains to the neighboring gene DIP2C.
  6. Contiguous-gene confounding. Deletion-based literature mixes ZMYND11 effects with those of DIP2C, GATA3, and DGS2, complicating attribution — mitigated only by pure-variant/intragenic-deletion cases.
  7. No therapeutics. Rescue-by-enhancement is a cellular observation only, with no translational pathway yet.

Proposed Follow-up Experiments / Actions

  1. Assemble an international MRD30 registry with standardized deep phenotyping (HPO-coded), variant-class stratification, and longitudinal follow-up to establish penetrance, expressivity, and prognostic factors quantitatively.
  2. Systematic genotype–phenotype study contrasting LoF vs. missense (especially recurrent p.Arg600Trp) with functional assays of reader capacity, EFTUD2 antagonism, and KMT2A restraint.
  3. Test for a DNA-methylation episignature in patient blood to enable a diagnostic biomarker and VUS reclassification.
  4. Generate a conditional neuronal Zmynd11 mouse (and validate against patient cortical organoids) to model behavior, seizures, and to serve as a preclinical rescue platform.
  5. Mechanistic dissection of the RBFOX2 splicing switch and KMT2A axis in patient neurons, with multi-omics (RNA-seq intron-retention analysis, CUT&RUN for H3.3K36me3/ZMYND11, Pol II ChIP).
  6. Pursue "enhance-ZMYND11-function" or downstream-node therapeutic screens (e.g., modulating KMT2A/COMPASS activity or splicing) in cortical organoids to identify actionable targets.
  7. Standardize clinical care pathways distinguishing pure MRD30 from contiguous-deletion syndrome, specifying which patients need cardiac (DIP2C), renal/parathyroid/audiologic (GATA3/DGS2) evaluation, and lifelong adult neurological surveillance for movement disorders.

Report compiled from 14 confirmed findings across 5 investigation iterations and 28 reviewed publications. Ontology suggestions provided for MONDO, HPO, GO, CL, UBERON, and NCIT to support knowledge-base ingestion.

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