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Classifications

Harrison's Chapter

🔗

Mappings

MONDO

MONDO:0014336 intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

MONDO:0014336 carries OMIM:615761 as an xref, lists MRD23 and "intellectual developmental disorder, autosomal dominant 23" as exact synonyms, and asserts a causal gene relationship (RO:0004003) to HGNC:25566 (SETD5), verified with OAK before curation began. This is the NEC anchor for the entry.

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Inheritance

2

Autosomal dominant HP:0000006

The disorder is autosomal dominant. Most pathogenic SETD5 variants arise de novo, but familial transmission from a mildly affected or apparently unaffected parent is documented, so penetrance is incomplete and expressivity is variable.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:24680889 SUPPORT Human Clinical

"All mutations were compatible with de novo dominant inheritance."

The gene-discovery cohort established dominant inheritance with de novo occurrence for all seven loss-of-function variants.

PMID:27375234 SUPPORT Human Clinical

"We present the first familial case of a SETD5 mutation contributing to a phenotype of congenital heart defects and dysmorphic features, with variable expression, in two siblings and their father."

Documents vertical transmission across two generations with variable expression, consistent with autosomal dominant inheritance.

Incomplete penetrance

Penetrance of pathogenic SETD5 variants is incomplete. An apparently unaffected carrier mother and a carrier mother of normal intelligence with two affected twin sons have both been reported, and a transmitting father had only mild intellectual impairment.

Show evidence (2 references)

PMID:28881385 SUPPORT Human Clinical

"We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons."

Directly documents non-penetrant and minimally penetrant carriers.

PMID:39603091 SUPPORT Human Clinical

"Pathogenic variants in the SETD5 gene cause a neurodevelopmental disorder characterized by intellectual disability, autism, and facial dysmorphisms, with incomplete penetrance."

The largest recent multicenter cohort explicitly characterizes the condition as incompletely penetrant.

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Mechanistic Hypotheses

2

SETD5 as a Catalytic H3K36 Methyltransferase

setd5_h3k36me3_catalytic ALTERNATIVE

Evidence balance 1 support

Under this model SETD5 is a genuine SET-domain lysine methyltransferase that directly deposits H3K36me3 on active gene bodies, and haploinsufficiency causes disease by reducing that mark, desynchronizing RNA polymerase II elongation and corrupting RNA maturation and splicing.

Held as ALTERNATIVE rather than CANONICAL because the competing scaffold model is supported by independent enzymology; the two are not yet reconciled. If this model is correct, catalytic-activity restoration is conceptually a therapeutic target.

Pathograph links

SETD5 Haploinsufficiency -> Impaired H3K36 Methylation and Chromatin Regulation Reduced SETD5 dosage lowers deposition of the H3K36me3 mark on active gene bodies.

Impaired H3K36 Methylation and Chromatin Regulation -> Aberrant RNA Polymerase II Elongation and Transcriptional Infidelity Loss of the H3K36me3 mark on gene bodies desynchronizes RNA polymerase II elongation. This is the convergent hub where the catalytic and scaffold hypotheses meet: whichever molecular route is correct, transcriptional infidelity is the shared consequence.

Show evidence (1 reference)

PMID:31515109 SUPPORT Model Organism

"Notably, we demonstrated that SETD5 directly deposits H3K36me3, which is essential to allow on-time RNA elongation dynamics."

The primary experimental claim of direct catalytic H3K36me3 deposition by SETD5.

SETD5 as a Catalytically Inert Co-Repressor Scaffold

setd5_corepressor_scaffold ALTERNATIVE

Evidence balance 2 support

Under this model SETD5 lacks intrinsic methyltransferase activity and instead scaffolds a co-repressor complex containing HDAC3, NCoR, G9a, and PAF1; haploinsufficiency then acts by failure of corepressor recruitment and altered histone acetylation rather than by loss of a methyl mark. Notably, SETD5 lacks the PHD finger present in its SET-domain homologues, which is part of the enzymological argument.

Both hypotheses converge on the same downstream node - aberrant RNA polymerase II elongation and transcriptional infidelity - so the disease model is robust to the controversy even though the molecular mechanism is not settled. See the gap_setd5_catalytic_activity discussion.

Pathograph links

SETD5 Haploinsufficiency -> Impaired H3K36 Methylation and Chromatin Regulation Reduced SETD5 dosage lowers deposition of the H3K36me3 mark on active gene bodies.

Impaired H3K36 Methylation and Chromatin Regulation -> Aberrant RNA Polymerase II Elongation and Transcriptional Infidelity Loss of the H3K36me3 mark on gene bodies desynchronizes RNA polymerase II elongation. This is the convergent hub where the catalytic and scaffold hypotheses meet: whichever molecular route is correct, transcriptional infidelity is the shared consequence.

Show evidence (2 references)

PMID:36875494 SUPPORT Other

"However, there is evidence that SETD5 lacks the methyltransferase activity but scaffolds a co- repressor complex, including HDAC3, NCoR, G9a, and PAF1, which couples selective deacetylation of H3K9ac with methylation of this residue"

States the scaffold model and names the co-repressor partners; classified OTHER because it is a review synthesizing primary enzymology.

PMID:36875494 SUPPORT Other

"The yeast SET3 and SET4, Drosophila UpSET, and human MLL5 are homologous to SETD5 over their SET domains and, except for SETD5, contain a PHD ﬁnger"

Provides the comparative-domain argument that SETD5 is structurally atypical among its SET-domain homologues.

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Discussions and Knowledge Gaps

5

Should the single-gene SETD5 haploinsufficiency entity and the contiguous 3p25.3 microdeletion syndrome be modelled as one entity or two?

INTERPRETATION OPEN nec_setd5_vs_3p253_deletion

Attached to

pathophysiology#SETD5 Haploinsufficiency

dismech keeps them as two entities. SETD5 is now regarded as the principal driver of the 3p25.3 deletion neurodevelopmental phenotype - the critical region was narrowed to a 124 kb three-gene interval, and SETD5 loss of function reproduces the core features - which is a strong lumping argument. Against lumping: (i) 3p25.3 deletions vary in size and can remove THUMPD3, THUMPD3-AS1, and, in the larger 3p25-p26 deletions, many additional genes, adding features (low birth weight, microcephaly, telecanthus, cleft palate) that are not characteristic of isolated SETD5 loss of function; (ii) MONDO models them as distinct terms with distinct OMIM anchors; (iii) the diagnostic assay differs (microarray versus sequencing); and (iv) authors who deeply phenotyped both explicitly argue the overlapping chromatin disorders "still remain distinct clinical entities" and that lumping is unhelpful for families. This entry therefore scopes to the intragenic-variant entity anchored on MONDO:0014336 / OMIM:615761 / HGNC:25566, and records the deletion syndrome as a differential diagnosis. A separate consideration: Orphanet has obsoleted its own standalone term for this concept (ORPHA:404440), which shows the boundary is genuinely contested at the nosology level.

Show evidence (3 references)

PMID:32793091 SUPPORT Human Clinical

"Whilst there is significant phenotypic overlap between the above-mentioned conditions, however, they still remain distinct clinical entities. This is important for long term support to patients and families, as there are differences and subtleties in both clinical features and neurodevelopmental..."

Directly argues for keeping the overlapping SETD5 / 3p25.3-deletion / KBG entities separate, which is the split rationale adopted here.

PMID:24680889 SUPPORT Human Clinical

"The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition."

States the driver-gene relationship that motivates the lumping argument, kept visible alongside the split decision.

ORPHA:404440 PARTIAL Other

"OBSOLETE: Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency"

Orphanet has retired its standalone term for this concept in the 2025-12-09 snapshot. This is recorded as PARTIAL because obsoleting an Orphanet code is a nosology-management action whose rationale is not stated in the record; it shows the boundary is contested but does not by itself argue for lumping.

Is SETD5 itself a catalytically active histone methyltransferase, or does it act principally as a scaffold within HDAC3- and PAF1-containing complexes?

KNOWLEDGE GAP OPEN gap_setd5_catalytic_activity

Attached to

pathophysiology#Impaired H3K36 Methylation and Chromatin Regulation

The mechanism nodes in this entry deliberately avoid asserting a settled enzymatic defect. One study demonstrates that SETD5 directly deposits H3K36me3, while other groups describe the direct methyltransferase activity as debated and emphasize scaffolding through HDAC-containing complexes. The answer matters because it determines whether a catalytic-rescue therapeutic strategy is even conceptually available.

Show evidence (2 references)

PMID:37264456 SUPPORT Other

"The direct function of SETD5 as histone methyltransferase activity is debated"

States the open question directly.

PMID:31515109 SUPPORT Model Organism

"Notably, we demonstrated that SETD5 directly deposits H3K36me3, which is essential to allow on-time RNA elongation dynamics."

Presents the opposing evidence that SETD5 does deposit the mark directly.

Do the mitochondrial fragmentation and bioenergetic deficits seen in Setd5+/- mouse neural cells occur in human SETD5-haploinsufficient neurons, and where do they sit in the causal hierarchy of the human disease?

HUMAN MODEL MISMATCH OPEN mismatch_setd5_mitochondrial_hierarchy

Attached to

pathophysiology#Mitochondrial Fragmentation and Bioenergetic Deficit in Neural Cells

The mitochondrial phenotype is well characterized in mouse neural stem cells, neurons, and cortex, but has not been demonstrated in human patient-derived neural cells, and the authors explicitly state that they can only speculate about its position in the pathological hierarchy. Whether it is a driver, a parallel consequence of transcriptional dysregulation, or an epiphenomenon determines whether mitochondrial-targeted intervention is worth pursuing.

Proposed experiments

Patient-derived iPSC neural mitochondrial phenotyping

exp_setd5_patient_ipsc_mitochondrial_phenotyping

Derive iPSC neural progenitors and cortical neurons from individuals with confirmed SETD5 loss-of-function variants alongside isogenic corrected controls, and measure mitochondrial morphology, membrane potential, ATP production, and axonal/synaptic mitochondrial localization. This tests whether the mouse mitochondrial phenotype is reproduced in human SETD5-haploinsufficient neurons.

Epistasis test placing the mitochondrial defect in the causal hierarchy

exp_setd5_mitochondrial_epistasis

Determine whether restoring rDNA output (for example by TIP5 ablation, which already rescues the proliferation defect) or correcting RNA polymerase II elongation also rescues the mitochondrial phenotype. Rescue would place the mitochondrial defect downstream of transcriptional dysregulation; failure to rescue would place it in a parallel branch.

Show evidence (2 references)

PMID:37264456 SUPPORT Model Organism

"We found several defects in the mitochondrial compartment; however, we can only speculate about their position in the hierarchy of the pathological mechanisms at the basis of the disease."

The authors' own statement of the translational and causal uncertainty.

PMID:37264456 SUPPORT Model Organism

"We investigated in vitro neural stem cells as well as the brain of the Setd5 haploinsufficiency mouse model interrogating its transcriptome, analyzing mitochondrial structure, biochemical composition, and dynamics, as well as mitochondrial functionality."

Establishes that the evidence base is entirely a mouse model plus derived neural stem cells, not human patient tissue.

What determines whether a carrier of a SETD5 loss-of-function variant is severely affected, mildly affected, or clinically unaffected?

KNOWLEDGE GAP OPEN gap_setd5_penetrance_modifiers

Attached to

pathophysiology#SETD5 Haploinsufficiency

Penetrance is incomplete and expressivity is highly variable: an apparently unaffected carrier mother, a carrier mother of normal intelligence with two affected twin sons, and a transmitting father with only mild intellectual impairment have all been reported, while the same class of truncating variant produces moderate-to-severe intellectual disability in others. No modifier - genetic background, variant position, transcript usage, sex, or mosaicism - has been established. This directly affects genetic counseling and recurrence-risk communication.

Show evidence (2 references)

PMID:28881385 SUPPORT Human Clinical

"We suggest that the phenotype of SETD5 is more complex and variable than previously presented."

States the variability problem that this gap addresses.

PMID:27375234 SUPPORT Human Clinical

"Interestingly, the father demonstrated only mild intellectual impairment."

Documents a minimally affected transmitting parent within a family carrying the same variant as more severely affected children.

Is cerebrovascular imaging surveillance for moyamoya angiopathy warranted in individuals with pathogenic SETD5 variants?

KNOWLEDGE GAP OPEN gap_setd5_moyamoya_surveillance

Attached to

pathophysiology#Extra-Neural Developmental Involvement

Bilateral moyamoya angiopathy has been reported with a de novo SETD5 frameshift variant and with two rare SETD5 missense variants, but the ascertainment ran from moyamoya cohorts to variants rather than the reverse, and the authors state that the SETD5-moyamoya association still requires validation and that penetrance must be assessed before imaging can be recommended. Because moyamoya causes childhood strokes and is treatable, resolving this is clinically consequential.

Show evidence (2 references)

PMID:31474762 SUPPORT Human Clinical

"Additional studies to assess the penetrance of MMA are required before we can recommend imaging for all the patients carrying de novo variants in CHD4, CNOT3, and SETD5"

The authors explicitly frame surveillance as an unresolved question pending penetrance data.

PMID:31474762 SUPPORT Human Clinical

"These data indicate that rare variants in CHD4 and CNOT3 predispose to MMA in the presence and absence of DD; additional data are required to validate an association between SETD5 rare variants and MMA."

Distinguishes the validated CHD4/CNOT3 associations from the still-unvalidated SETD5 association.

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Pathophysiology

9

SETD5 Haploinsufficiency

Heterozygous nonsense, frameshift, and splice-disrupting SETD5 variants introduce premature termination codons whose transcripts are degraded by nonsense-mediated decay, halving functional SETD5 dosage. Whole-gene 3p25.3 microdeletions that remove one SETD5 allele converge on the same mechanism. CRISPR/Cas9 modelling of two patient intragenic variants demonstrated nonsense-mediated decay directly.

SETD5 as a Catalytic H3K36 Methyltransferase SETD5 as a Catalytically Inert Co-Repressor Scaffold

neural stem cell CL:0000047

SETD5 hgnc:25566

Downstream

Impaired H3K36 Methylation and Chromatin Regulation Reduced SETD5 dosage lowers deposition of the H3K36me3 mark on active gene bodies.

Dysregulated rDNA Expression and Reduced Translation SETD5 recruits the HDAC3 complex to the rDNA promoter; reduced SETD5 attenuates rDNA transcription.

Show evidence (3 references)

PMID:25138099 SUPPORT In Vitro

"CRISPR/Cas9 mutation modelling of the two intragenic variants demonstrated nonsense-mediated decay of the resulting transcripts, pointing to a loss-of-function (LoF) and haploinsufficiency as the common disease-causing mechanism of intragenic SETD5 sequence variants and SETD5-containing microdeletions."

Provides the direct experimental demonstration that patient variants trigger nonsense-mediated decay and therefore act by haploinsufficiency.

PMID:24680889 SUPPORT Human Clinical

"were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance."

Identifies SETD5 as the mutated gene and confirms de novo dominant occurrence of the seven truncating variants in the gene-discovery cohort.

PMID:32793091 SUPPORT Human Clinical

"In all the three patients the pathogenic mechanism of the SETD5 alteration is haploinsufficiency."

Independent clinical confirmation that both intragenic variants and a 3p25.3 deletion act through SETD5 haploinsufficiency.

Impaired H3K36 Methylation and Chromatin Regulation

SETD5 contains a SET domain and a putative PHD domain and is best characterized as depositing H3K36 methylation, though whether SETD5 itself is catalytically active as a histone methyltransferase remains debated; it also acts through HDAC-containing corepressor complexes that control chromatin accessibility. In Setd5-deficient neural stem cells, zebrafish, and mice, genome-wide H3K36me3 on active gene bodies is reduced.

SETD5 as a Catalytic H3K36 Methyltransferase SETD5 as a Catalytically Inert Co-Repressor Scaffold

neural stem cell CL:0000047

chromatin organization GO:0006325 ⚠ ABNORMAL

histone H3K36 methyltransferase activity GO:0046975 ↓ DECREASED

Downstream

Aberrant RNA Polymerase II Elongation and Transcriptional Infidelity Loss of the H3K36me3 mark on gene bodies desynchronizes RNA polymerase II elongation. This is the convergent hub where the catalytic and scaffold hypotheses meet: whichever molecular route is correct, transcriptional infidelity is the shared consequence.

Show evidence (3 references)

PMID:31515109 SUPPORT Model Organism

"Notably, we demonstrated that SETD5 directly deposits H3K36me3, which is essential to allow on-time RNA elongation dynamics."

Directly attributes H3K36me3 deposition to SETD5 and connects it to elongation kinetics.

PMID:36875494 SUPPORT Other

"SET domain-containing 5 (SETD5) is an uncharacterized member of the protein lysine methyltransferase family and is best known for its transcription machinery by methylating histone H3 on lysine 36 (H3K36)."

Review-level statement of SETD5's H3K36-directed activity; classified OTHER because it is an expert synthesis rather than primary data.

PMID:37264456 PARTIAL Other

"The direct function of SETD5 as histone methyltransferase activity is debated"

Records the explicit uncertainty about SETD5's intrinsic catalytic activity, which is why this node is framed as chromatin regulation rather than as a settled enzymatic defect.

Aberrant RNA Polymerase II Elongation and Transcriptional Infidelity

SETD5 governs RNA polymerase II dynamics through its interaction with the HDAC3 and PAF1 complexes and through the H3K36me3 mark it places on gene bodies. When SETD5 dosage falls, elongation timing is disturbed, RNA maturation and splicing are impaired, and developmental gene expression programmes are dysregulated.

neural stem cell CL:0000047

transcription by RNA polymerase II GO:0006366 ⚠ ABNORMAL regulation of gene expression GO:0010468 ⚠ ABNORMAL mRNA splicing, via spliceosome GO:0000398 ⚠ ABNORMAL

Downstream

Mitochondrial Fragmentation and Bioenergetic Deficit in Neural Cells Transcriptional aberration at mitochondria-associated genes is the proximate cause of the mitochondrial phenotype.

Impaired Neural Progenitor Proliferation and Cortical Neurogenesis Disturbed developmental gene expression impairs the proliferative dynamics of neural progenitors.

Show evidence (2 references)

PMID:30455454 SUPPORT Model Organism

"Our data additionally indicate that Setd5 regulates RNA polymerase II dynamics and gene transcription via its interaction with the Hdac3 and Paf1 complexes, findings potentially explaining the gene expression defects observed in Setd5-haploinsufficient mice."

Identifies the HDAC3/PAF1 route by which Setd5 controls RNA polymerase II dynamics and gene transcription.

PMID:31515109 SUPPORT Model Organism

"Hence, Setd5 gene loss leads to abnormal transcription, with impaired RNA maturation causing detrimental effects on gene integrity and splicing."

Directly documents transcriptional infidelity and splicing defects following Setd5 loss.

Dysregulated rDNA Expression and Reduced Translation

SETD5 positively regulates ribosomal DNA transcription by recruiting the HDAC3 complex to the rDNA promoter, removing the H4K16ac mark and its reader TIP5, a repressor of rDNA expression. SETD5 depletion attenuates rDNA expression and global translational activity, with selective loss of cyclin D1 translation; ablating TIP5 in SETD5-deficient cells rescues the phenotype, establishing the epistatic order.

neural stem cell CL:0000047

rRNA processing GO:0006364 ↓ DECREASED translational elongation GO:0006414 ↓ DECREASED

Downstream

Impaired Neural Progenitor Proliferation and Cortical Neurogenesis Reduced rDNA output and cyclin D1 translation constrain neural cell proliferation.

Show evidence (2 references)

PMID:32299058 SUPPORT Model Organism

"Depletion of SETD5 attenuated rDNA expression, translational activity, and neural cell proliferation, whereas ablation of TIP5 in SETD5-deficient cells rescued these effects."

Direct experimental chain from SETD5 depletion to reduced rDNA expression, translation, and proliferation, with genetic rescue establishing causality.

PMID:32299058 SUPPORT Model Organism

"Translation of cyclin D1 mRNA was specifically down-regulated in SETD5-insufficient cells."

Identifies the specific translational target linking the rDNA defect to cell-cycle progression.

Mitochondrial Fragmentation and Bioenergetic Deficit in Neural Cells

In Setd5-haploinsufficient neural stem cells, neurons, and mouse cortex, mitochondria are fragmented, mitochondrial membrane potential and ATP production are reduced, and mitochondria are mislocalized with fewer organelles in neurites and synapses. The authors explicitly caution that they cannot place this defect within the causal hierarchy of the disease.

neural stem cell CL:0000047 neuron CL:0000540

mitochondrial fission GO:0000266 ↑ INCREASED mitochondrion organization GO:0007005 ⚠ ABNORMAL

Downstream

Reduced Synaptic Density and Cortical Network Hypoconnectivity Depletion of mitochondria from neurites and synapses is a plausible but unproven contributor to the synaptic phenotype; the authors do not establish this ordering.

Show evidence (3 references)

PMID:37264456 SUPPORT Model Organism

"Low levels of SETD5 resulted in fragmented mitochondria, reduced mitochondrial membrane potential, and ATP production both in neural precursors and neurons."

Directly documents the mitochondrial structural and bioenergetic phenotype in two neural cell types.

PMID:37264456 SUPPORT Model Organism

"Mitochondria were also mislocalized in mutant neurons, with reduced organelles within neurites and synapses."

Documents mitochondrial mislocalization away from neurites and synapses, connecting the organelle defect to synaptic compartments.

PMID:37264456 PARTIAL Model Organism

"We found several defects in the mitochondrial compartment; however, we can only speculate about their position in the hierarchy of the pathological mechanisms at the basis of the disease."

The authors' own limitation statement, retained so this node is not overstated as an established causal step in human disease.

Impaired Neural Progenitor Proliferation and Cortical Neurogenesis

Setd5 haploinsufficiency impairs the proliferative dynamics of neural progenitors and produces a deficit of deep-layer cortical neurons in the developing brain, with altered expression of neurodevelopment-related genes in a specific subpopulation of fetal cortical neurons.

neural stem cell CL:0000047 cortical projection neuron CL:0000598

neural precursor cell proliferation GO:0061351 ↓ DECREASED cerebral cortex neuron differentiation GO:0021895 ⚠ ABNORMAL

Downstream

Reduced Synaptic Density and Cortical Network Hypoconnectivity Fewer and abnormally specified cortical neurons underlie the reduced synaptic density and network hypoconnectivity.

Show evidence (3 references)

PMID:30655503 SUPPORT Model Organism

"Anatomical differences were observed in Setd5+/- adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain."

Directly documents the deep-layer cortical neuron deficit arising during development.

PMID:30655503 SUPPORT Model Organism

"A specific subpopulation of fetal Setd5+/- cortical neurons showed altered gene expression of neurodevelopment-related genes."

Links the transcriptional defect to a defined fetal cortical neuron population.

PMID:31515109 SUPPORT Model Organism

"Herein, we found that Setd5 haploinsufficiency impairs the proliferative dynamics of neural progenitors and synaptic wiring of neurons, ultimately resulting in behavioral deficits in mice."

Independent confirmation of impaired neural progenitor proliferation.

Reduced Synaptic Density and Cortical Network Hypoconnectivity

Setd5-haploinsufficient cortical neurons show reduced synaptic density and neuritic outgrowth in vitro with corresponding reductions in network activity and synchrony on multielectrode arrays. In vivo, Setd5-mutant mice show enhanced long-term potentiation and abnormal expression of postsynaptic density proteins previously associated with cognition, indicating that synaptic function as well as synapse number is disturbed.

cortical neuron CL:0000540

synapse assembly GO:0007416 ↓ DECREASED neuron projection development GO:0031175 ↓ DECREASED chemical synaptic transmission GO:0007268 ⚠ ABNORMAL

Downstream

Impaired Neurodevelopment Synaptic and network-level disruption is the cellular substrate of the human neurodevelopmental phenotype.

Show evidence (3 references)

PMID:30655503 SUPPORT Model Organism

"Setd5+/- cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology."

Directly measures reduced synaptic density, neuritic outgrowth, and network activity.

PMID:30455454 SUPPORT Model Organism

"Behavioral issues are accompanied by abnormal expression of postsynaptic density proteins previously associated with cognition."

Links behavioral impairment to postsynaptic density protein dysregulation.

PMID:30455454 SUPPORT Model Organism

"Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalization, and behavioral inflexibility."

Documents altered synaptic plasticity (enhanced LTP) alongside cognitive and communication deficits.

Impaired Neurodevelopment

The convergent consequence in affected humans is impaired nervous-system development, producing global developmental delay with disproportionate speech and language impairment, intellectual disability of variable severity, autism spectrum and other psychiatric features, hypotonia, movement and gait abnormalities, and in a minority epilepsy.

neuron CL:0000540

nervous system development GO:0007399 ⚠ ABNORMAL

Downstream

Global Developmental Delay Developmental delay is the usual presenting manifestation.

Intellectual Disability Intellectual disability of mild to severe degree is a defining feature.

Delayed Speech and Language Development Speech and language are disproportionately affected.

Hypotonia Hypotonia is a frequent neurological manifestation.

Gait Disturbance Gait abnormality ranges from tip-toe to unsteady walking.

Hyperkinetic Movements Stereotypies and chorea occur in a minority.

Autistic Behavior Autism spectrum disorder is a defining behavioral feature.

Seizure Epilepsy affects a minority of individuals.

Abnormal Facial Shape A recognizable but non-specific facial gestalt accompanies the neurologic phenotype.

Show evidence (2 references)

PMID:39603091 SUPPORT Human Clinical

"Pathogenic variants in the SETD5 gene cause a neurodevelopmental disorder characterized by intellectual disability, autism, and facial dysmorphisms, with incomplete penetrance."

Establishes the human neurodevelopmental outcome of SETD5 pathogenic variants.

PMID:32793091 SUPPORT Human Clinical

"The MRD23 phenotype is characterized by ID, facial dysmorphisms, skeletal anomalies, behavioral problems and speech and language difficulties"

Summarizes the MRD23 clinical core, including the speech and language component of the neurodevelopmental phenotype.

Extra-Neural Developmental Involvement

Beyond the nervous system, SETD5 haploinsufficiency is associated with skeletal anomalies (scoliosis, kyphosis, leg-length discrepancy), congenital heart defects, gastrointestinal and abdominal-wall anomalies, inguinal hernia, and hypospadias. In the mouse, Setd5 haploinsufficiency produces abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes, offering a developmental route to the craniofacial and cardiac findings that has not been directly demonstrated in affected humans.

migratory neural crest cell CL:0000333

Downstream

Abnormal Heart Morphology Congenital heart defects occur in a minority of individuals.

Scoliosis Thoracic scoliosis is among the reported skeletal anomalies.

Feeding Difficulties Difficulty with swallowing and chewing was reported by families and physicians.

Inguinal Hernia Inguinal hernia was reported and often required early repair.

Hypospadias Hypospadias was reported and often required early repair.

Moyamoya Phenomenon Bilateral moyamoya angiopathy has been reported in an individual with a de novo SETD5 frameshift variant, but the association is not yet validated.

Show evidence (3 references)

PMID:24680889 SUPPORT Human Clinical

"Congenital heart defects, inguinal hernia, or hypospadias were also reported."

Documents the extra-neural malformations reported in the gene-discovery cohort.

PMID:24680889 SUPPORT Human Clinical

"Thoracic scoliosis, kyphosis, and lordosis were reported"

Documents the skeletal spectrum.

PMID:30455454 PARTIAL Model Organism

"Here we show that Setd5-haploinsufficient mice present developmental defects such as abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes."

Provides the neural-crest developmental hypothesis for the craniofacial and cardiac findings; PARTIAL because it is mouse data not confirmed in humans.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

40

Cardiovascular 1

Abnormal Heart Morphology OCCASIONAL Abnormal heart morphology HP:0001627

Show evidence (2 references)

PMID:24680889 SUPPORT Human Clinical

"Two children had congenital heart defects; one had a mitral valve prolapse, and the other had a ventricular septal defect with a patent ductus arteriosus"

2 of 7 (29%) had congenital heart defects, within the OCCASIONAL band (5-29%).

PMID:27375234 SUPPORT Human Clinical

"We present the first familial case of a SETD5 mutation contributing to a phenotype of congenital heart defects and dysmorphic features, with variable expression, in two siblings and their father."

Independent familial documentation of congenital heart defects.

Digestive 4

Feeding Difficulties FREQUENT Feeding difficulties HP:0011968

The frequency band is derived from the SETD5-variant column of Table 1 (5/7 = 71%). The narrative text reports the feature only qualitatively ("noted by several families and physicians"); the table supplies the count.

Show evidence (2 references)

PMID:24680889 SUPPORT Human Clinical

"Feeding problems, particularly difﬁculties with swallowing and chewing, were noted by several families and physicians."

Directly documents feeding difficulties.

PMID:24680889 SUPPORT Human Clinical

"Feeding difﬁculties 5 NA"

Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) with individuals with a 3p25 deletion (n = 4); the trailing values give 5/7 SETD5-variant individuals, with the deletion column not available.

Constipation FREQUENT Constipation HP:0002019

Show evidence (1 reference)

PMID:42468298 SUPPORT Human Clinical

"Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%)."

Reports constipation at 47%, within the FREQUENT band (30-79%).

Inguinal Hernia Inguinal hernia HP:0000023

Frequency is omitted because the reported 4/7 figure is a combined count for inguinal hernia OR hypospadias.

Show evidence (1 reference)

PMID:24680889 SUPPORT Human Clinical

"Four of the seven children had either an inguinal hernia or hypospadias repaired at a young age."

Documents inguinal hernia within the combined 4/7 count.

Abnormality of the Gastrointestinal Tract FREQUENT Abnormality of the gastrointestinal tract HP:0011024

A broad HPO term is used deliberately because the source reports the finding as an undifferentiated "gastrointestinal and/or abdominal-wall anomalies" category without naming a specific malformation. The frequency band is derived from the SETD5-variant column of Table 1 (5/7 = 71%), not from the adjacent 3p25.3-deletion column, which is out of scope for this entry.

Show evidence (1 reference)

PMID:24680889 SUPPORT Human Clinical

"Gastrointestinal and/ or abdominal-wall anomalies 51"

Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) against individuals with a 3p25 deletion (n = 4); the two trailing digits are the per-column counts, giving 5/7 SETD5-variant individuals (and 1/4 deletion individuals) with gastrointestinal and/or abdominal-wall anomalies. This replaces an earlier snippet that quoted the paper's description of the smallest-3p25-microdeletion phenotype, which is a different entity from the single-gene SETD5 disorder this entry covers.

Ear 1

Low-Set Ears FREQUENT Low-set ears HP:0000369

The frequency band is derived from the SETD5-variant column of Table 1 (5/7 = 71%). The source table scores this as a combined "low-set and/or malformed ears" category, so the HPO term is narrower than the scored feature.

Show evidence (2 references)

PMID:24680889 SUPPORT Human Clinical

"Ears tended to be large with ﬂeshy lobes, long, and low set"

Directly documents low-set ears.

PMID:24680889 SUPPORT Human Clinical

"Low-set and/or malformed ears 53"

Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) with individuals with a 3p25 deletion (n = 4); the trailing counts give 5/7 SETD5-variant individuals and 3/4 deletion individuals.

Eye 1

Visual Impairment FREQUENT Visual impairment HP:0000505

The generic HPO term is used deliberately: the survey reports "vision problems" as an undifferentiated category, and the case-level findings (ptosis, amblyopia, nystagmus, strabismus) were each single occurrences.

Show evidence (1 reference)

PMID:42468298 SUPPORT Human Clinical

"Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%)."

Reports vision problems at 51%, within the FREQUENT band (30-79%).

Genitourinary 1

Hypospadias Hypospadias HP:0000047

Frequency is omitted because the reported 4/7 figure is a combined count for inguinal hernia OR hypospadias, so neither individual anomaly can be banded.

Show evidence (1 reference)

PMID:24680889 SUPPORT Human Clinical

"Four of the seven children had either an inguinal hernia or hypospadias repaired at a young age."

Documents hypospadias within the combined 4/7 count.

Head and Neck 6

Abnormal Facial Shape VERY_FREQUENT Abnormal facial shape HP:0001999

Show evidence (2 references)

PMID:25138099 SUPPORT Human Clinical

"All six patients presented with ID and certain facial dysmorphisms, suggesting that SETD5 sequence variants contribute substantially to the microdeletion 3p25.3 phenotype."

All six molecularly confirmed patients had facial dysmorphism, supporting the VERY_FREQUENT band (80-100%).

PMID:24680889 SUPPORT Human Clinical

"The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears."

Enumerates the component craniofacial features.

Brachycephaly FREQUENT Brachycephaly HP:0000248

The frequency band is derived from the SETD5-variant column of Table 1 (3/7 = 43%). The narrative text describes the feature only qualitatively as variable; the table supplies the count.

Show evidence (2 references)

PMID:24680889 SUPPORT Human Clinical

"The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears."

Directly names brachycephaly.

PMID:24680889 SUPPORT Human Clinical

"Brachycephaly 3 NA"

Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) with individuals with a 3p25 deletion (n = 4); the trailing values give 3/7 SETD5-variant individuals, with the deletion column not available.

Prominent Forehead Prominent forehead HP:0011220

Frequency is omitted: the source describes it as a variable feature.

Show evidence (1 reference)

PMID:24680889 SUPPORT Human Clinical

"a prominent high forehead with striking eyebrows described as full, broad, straight, or with synophrys"

Directly documents the prominent high forehead.

Upslanted Palpebral Fissure VERY_FREQUENT Upslanted palpebral fissure HP:0000582

The frequency band is derived from the SETD5-variant column of Table 1 (6/7 = 86%). The source table scores this as a combined "upslanting or downslanting palpebral fissures" category, so the HPO term is narrower than the scored feature; the narrative describes the cohort's fissures as upslanting.

Show evidence (2 references)

PMID:24680889 SUPPORT Human Clinical

"The morphology around the eyes was similar with long, narrow, and upslanting palpebral ﬁssures"

Directly documents upslanting palpebral fissures.

PMID:24680889 SUPPORT Human Clinical

"Upslanting or downslanting palpebral ﬁssures 61"

Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) with individuals with a 3p25 deletion (n = 4); the trailing counts give 6/7 SETD5-variant individuals and 1/4 deletion individuals.

Depressed Nasal Bridge FREQUENT Depressed nasal bridge HP:0005280

The frequency band is derived from the SETD5-variant column of Table 1 (3/7 = 43%). The same feature occurs in 3/4 individuals with a 3p25 deletion, but that contiguous deletion syndrome is a separate entity and is not the basis for this annotation.

Show evidence (1 reference)

PMID:24680889 SUPPORT Human Clinical

"Depressed nasal bridge 3 3"

Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) with individuals with a 3p25 deletion (n = 4); the trailing counts give 3/7 SETD5-variant individuals with a depressed nasal bridge. This replaces an earlier snippet that quoted the paper's summary of the 3p25-microdeletion phenotype, which is a different entity from the single-gene SETD5 disorder.

Long Philtrum FREQUENT Long philtrum HP:0000343

The frequency band is derived from the SETD5-variant column of Table 1 (5/7 = 71%). The source table scores this as a combined "long, smooth, and/or prominent philtrum" category, so the HPO term is narrower than the scored feature.

Show evidence (1 reference)

PMID:24680889 SUPPORT Human Clinical

"Long, smooth, and/or prominent philtrum 53"

Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) with individuals with a 3p25 deletion (n = 4); the trailing counts give 5/7 SETD5-variant individuals. This replaces an earlier snippet that quoted the paper's summary of the 3p25-microdeletion phenotype, which is a different entity from the single-gene SETD5 disorder this entry covers.

Musculoskeletal 2

Hypotonia FREQUENT Hypotonia HP:0001252

Show evidence (2 references)

PMID:39603091 SUPPORT Human Clinical

"In our cohort neurological symptoms include hypotonia (39.2 %), hyperkinetic movement disorders including stereotypies and chorea (21.4 %) and gait abnormalities ranging from tip-toe or unsteady walking and alterations of fine motor skills (35.7 %)."

Reports hypotonia at 39.2%, within the FREQUENT band (30-79%).

PMID:42468298 SUPPORT Human Clinical

"Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%)."

Survey cohort reports hypotonia at 78%, also within the FREQUENT band.

Scoliosis FREQUENT Scoliosis HP:0002650

Show evidence (2 references)

PMID:24680889 SUPPORT Human Clinical

"Also, 4/7 children had skeletal abnormalities that required varying degrees of intervention. Thoracic scoliosis, kyphosis, and lordosis were reported"

4 of 7 (57%) had skeletal abnormalities including scoliosis, mapping to the FREQUENT band (30-79%).

PMID:28881385 SUPPORT Human Clinical

"The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities."

Independent cohort confirming skeletal abnormalities as a majority feature.

Nervous System 15

Global Developmental Delay VERY_FREQUENT Global developmental delay HP:0001263

Show evidence (2 references)

PMID:42468298 SUPPORT Human Clinical

"Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%)."

Developmental delay was reported in 96% of respondents, mapping to the VERY_FREQUENT band (80-100%).

PMID:28881385 SUPPORT Human Clinical

"The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities."

Independent cohort confirming developmental delay in the majority of individuals.

Intellectual Disability FREQUENT Intellectual disability HP:0001249

Show evidence (2 references)

PMID:39603091 SUPPORT Human Clinical

"Concerning the cognitive phenotype, intellectual disability or global developmental delay depending on age, ranging from mild to severe, was present in 75 % of cohort, 21.4 % exhibit borderline intellectual functioning while an individual has a normal intelligence quotient."

Reports 75% affected, mapping to the FREQUENT band (30-79%), and documents the mild-to-severe range.

PMID:42468298 SUPPORT Human Clinical

"Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%)."

An independent survey cohort reports the same 75% figure for intellectual disability.

Delayed Speech and Language Development VERY_FREQUENT Delayed speech and language development HP:0000750

Show evidence (3 references)

PMID:32793091 SUPPORT Human Clinical

"The MRD23 phenotype is characterized by ID, facial dysmorphisms, skeletal anomalies, behavioral problems and speech and language difficulties"

Speech and language difficulties are named as a defining component of the MRD23 phenotype.

PMID:40462669 SUPPORT Human Clinical

"characterized by receptive-expressive language difficulties with speech disorder and mild cognitive impairment"

Case-level documentation of the receptive-expressive language phenotype.

PMID:24680889 SUPPORT Human Clinical

"Language delay and/ or stammer 6N A"

Table 1 row for individuals with SETD5 LoF mutations (n = 7); the trailing characters are the per-column values, giving 6/7 (86%) SETD5-variant individuals with language delay and/or stammer and "NA" for the 3p25-deletion column. 86% falls in the VERY_FREQUENT band (80-99%), giving this frequency a quantitative anchor rather than relying only on qualitative "characterized by" wording.

Motor Delay FREQUENT Motor delay HP:0001270

The FREQUENT band is the conservative reading: the only source stating "all individuals" is a seven-person ascertained cohort, and the larger series report fine-motor and gait involvement at 35.7% rather than universal motor delay.

Show evidence (1 reference)

PMID:39603091 PARTIAL Human Clinical

"gait abnormalities ranging from tip-toe or unsteady walking and alterations of fine motor skills (35.7 %)"

Documents fine-motor and gait involvement at 35.7%; PARTIAL because the cohort reports motor-skill alterations rather than a formal motor-milestone delay.

Gait Disturbance FREQUENT Gait disturbance HP:0001288

Show evidence (2 references)

PMID:39603091 SUPPORT Human Clinical

"In our cohort neurological symptoms include hypotonia (39.2 %), hyperkinetic movement disorders including stereotypies and chorea (21.4 %) and gait abnormalities ranging from tip-toe or unsteady walking and alterations of fine motor skills (35.7 %)."

Reports gait abnormality at 35.7%, within the FREQUENT band (30-79%).

PMID:42468298 SUPPORT Human Clinical

"Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%)."

Survey cohort reports gait abnormality at 59%, also within the FREQUENT band.

Chorea Chorea HP:0002072

Frequency is omitted: the 21.4% figure is for hyperkinetic movement disorders collectively, not chorea alone.

Show evidence (1 reference)

PMID:39603091 SUPPORT Human Clinical

"hyperkinetic movement disorders including stereotypies and chorea (21.4 %)"

Directly names chorea as part of the movement phenotype.

Seizure OCCASIONAL Seizure HP:0001250

Show evidence (3 references)

PMID:39603091 SUPPORT Human Clinical

"Epilepsy was present in about 14 % of patients, including different types of seizures as epileptic spasms, focal motor, and non-motor seizures."

Reports epilepsy at about 14%, within the OCCASIONAL band (5-29%).

PMID:24680889 PARTIAL Human Clinical

"Growth parameters were within the normal range in all children, none had micro- cephaly or seizures"

Records the absence of seizures in the original seven-person cohort, which is why the frequency band rests on the later, larger series rather than on this one.

PMID:40462669 SUPPORT Human Clinical

"Our findings confirm that epilepsy may arise after SETD5 variants, with subtle clinical manifestations that may overlap with behavioral phenomena in children who also exhibit cognitive and behavioral comorbidities."

Confirms epilepsy as a genuine but sometimes clinically subtle manifestation.

Epileptic Spasm Epileptic spasm HP:0011097

Frequency is omitted: the 14% figure applies to epilepsy overall, not to epileptic spasms specifically.

Show evidence (1 reference)

PMID:39603091 SUPPORT Human Clinical

"Epilepsy was present in about 14 % of patients, including different types of seizures as epileptic spasms, focal motor, and non-motor seizures."

Directly names epileptic spasms among the observed seizure types.

Focal-Onset Seizure Focal-onset seizure HP:0007359

Frequency is omitted: the 14% figure applies to epilepsy overall.

Show evidence (2 references)

PMID:39603091 SUPPORT Human Clinical

"Epilepsy was present in about 14 % of patients, including different types of seizures as epileptic spasms, focal motor, and non-motor seizures."

Directly names focal motor and non-motor seizures.

PMID:40462669 SUPPORT Human Clinical

"Her neurologic phenotype evolved during follow-up to include focal and generalized seizures as well as an overt neurodevelopmental disorder"

Case-level documentation of focal seizures in a molecularly confirmed individual.

Autistic Behavior Autistic behavior HP:0000729

Frequency is omitted: the multicenter cohort lists autism among psychiatric comorbidities without giving a proportion in the available abstract.

Show evidence (2 references)

PMID:39603091 SUPPORT Human Clinical

"Pathogenic variants in the SETD5 gene cause a neurodevelopmental disorder characterized by intellectual disability, autism, and facial dysmorphisms, with incomplete penetrance."

Autism is part of the disorder's core clinical definition.

PMID:24680889 SUPPORT Human Clinical

"Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features."

Documents autism as a prominent feature in the gene-discovery cohort.

Behavioral Abnormalities FREQUENT Atypical behavior HP:0000708

Show evidence (2 references)

PMID:28881385 SUPPORT Human Clinical

"The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities."

States that the majority of patients have behavioral/psychiatric issues, mapping to the FREQUENT band (30-79%).

PMID:39603091 SUPPORT Human Clinical

"Other psychiatric comorbidities include autism, ADHD, psychotic disorder and other internalizing and externalizing symptoms."

Enumerates the psychiatric comorbidity spectrum.

Attention Deficit Hyperactivity Disorder Attention deficit hyperactivity disorder HP:0007018

Frequency is omitted: the cohort lists ADHD without a proportion.

Show evidence (1 reference)

PMID:39603091 SUPPORT Human Clinical

"Other psychiatric comorbidities include autism, ADHD, psychotic disorder and other internalizing and externalizing symptoms."

Directly names ADHD among psychiatric comorbidities.

Psychosis Psychosis HP:0000709

Frequency is omitted: the cohort lists psychotic disorder without a proportion.

Show evidence (1 reference)

PMID:39603091 SUPPORT Human Clinical

"Other psychiatric comorbidities include autism, ADHD, psychotic disorder and other internalizing and externalizing symptoms."

Directly names psychotic disorder among psychiatric comorbidities.

Anxiety FREQUENT Anxiety HP:0000739

Show evidence (1 reference)

PMID:42468298 SUPPORT Human Clinical

"Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%)."

Reports anxiety at 47%, within the FREQUENT band (30-79%).

Compulsive Behaviors Compulsive behaviors HP:0000722

Frequency is omitted: the source describes these as prominent in a seven-person cohort without a defensible proportion for the wider population.

Show evidence (1 reference)

PMID:24680889 SUPPORT Human Clinical

"Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features."

Directly documents obsessive-compulsive disorder and ritualized behavior.

Constitutional 1

Limb Pain Limb pain HP:0009763

Frequency is omitted despite the reported percentages: these are parent-reported survey findings that the authors themselves label as potential novel findings requiring confirmation, and they have not been replicated in a clinician-ascertained cohort.

Show evidence (1 reference)

PMID:42468298 PARTIAL Human Clinical

"Potential novel findings included high pain tolerance (43%), persistent leg pain (31%), and joint pain (27%)."

Reports persistent leg pain and joint pain, explicitly framed by the authors as potential novel findings.

Growth 2

Lower Limb Asymmetry OCCASIONAL Lower limb asymmetry HP:0100559

Frequency band is derived from the denominator stated in the same source: 2 of 7 children (29%), the top of the OCCASIONAL band (5-29%). This is concordant with the HPO annotation of HP:0100559 to OMIM:615761 at 2/7. The cohort is small, so the point estimate is unstable even though the band assignment is defensible.

Show evidence (2 references)

PMID:24680889 SUPPORT Human Clinical

"Thoracic scoliosis, kyphosis, and lordosis were reported, and two children had a signiﬁcant leg-length discrepancy (one of them also had talipes and hypoplasia of the left calf and required surgery)."

Documents leg-length discrepancy in two children of the seven-person cohort, giving both the phenotype and the 2/7 count underlying the OCCASIONAL band.

PMID:24680889 SUPPORT Human Clinical

"Skeletal anomalies, including signiﬁcant leg-length discrepancy, were a frequent ﬁnding in two individuals."

The abstract-level statement of the same finding, independently confirming the two-individual count.

Growth Delay Growth delay HP:0001510

Frequency is omitted and the evidence is explicitly conflicting: the original cohort found normal growth parameters in all children, while a later single case had severe short stature. Both evidence items are retained so the discrepancy is visible rather than smoothed over.

Show evidence (2 references)

PMID:40869907 SUPPORT Human Clinical

"A female patient with severe short stature and intellectual disability had been followed since she was 9 years old."

Documents severe short stature in an individual with a de novo SETD5 variant.

PMID:24680889 REFUTE Human Clinical

"Growth parameters were within the normal range in all children"

Directly contradicts growth impairment as a general feature; growth was normal in all seven individuals of the gene-discovery cohort.

Other 6

Hyperkinetic Movements OCCASIONAL Hyperkinetic movements HP:0002487

Show evidence (1 reference)

PMID:39603091 SUPPORT Human Clinical

"In our cohort neurological symptoms include hypotonia (39.2 %), hyperkinetic movement disorders including stereotypies and chorea (21.4 %) and gait abnormalities ranging from tip-toe or unsteady walking and alterations of fine motor skills (35.7 %)."

Reports hyperkinetic movement disorders at 21.4%, within the OCCASIONAL band (5-29%).

Motor Stereotypy Motor stereotypy HP:0000733

Frequency is omitted: the 21.4% figure covers hyperkinetic movement disorders collectively (stereotypies plus chorea), not stereotypy alone.

Show evidence (2 references)

PMID:24680889 SUPPORT Human Clinical

"Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features."

Documents hand flapping with ritualized behavior, a motor stereotypy.

PMID:39603091 SUPPORT Human Clinical

"hyperkinetic movement disorders including stereotypies and chorea (21.4 %)"

Independent cohort naming stereotypies within the hyperkinetic movement spectrum.

Synophrys FREQUENT Synophrys HP:0000664

The frequency band is derived from the SETD5-variant column of Table 1 (5/7 = 71%). The source table scores this as a combined "synophrys and/or abnormal eyebrows" category, so the HPO term is narrower than the scored feature; the narrative likewise describes the eyebrow finding as variable (full, broad, straight, or with synophrys).

Show evidence (2 references)

PMID:24680889 SUPPORT Human Clinical

"a prominent high forehead with striking eyebrows described as full, broad, straight, or with synophrys"

Directly documents synophrys among the eyebrow findings.

PMID:24680889 SUPPORT Human Clinical

"Synophrys and/or abnormal eyebrows 51"

Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) with individuals with a 3p25 deletion (n = 4); the trailing counts give 5/7 SETD5-variant individuals and 1/4 deletion individuals.

Long Nose VERY_FREQUENT Long nose HP:0003189

The frequency band is derived from the SETD5-variant column of Table 1 (7/7 = 100%). Caveat: the scored table row is the broader "abnormal nasal shape" category rather than long nose specifically, so the band applies to nasal-shape abnormality as a class; the narrative text is what identifies that shape as long, thin, and tubular in this cohort. Recorded as VERY_FREQUENT on that basis rather than left unbanded, but it is the least tightly term-matched of the Table 1 re-anchorings in this entry.

Show evidence (2 references)

PMID:24680889 SUPPORT Human Clinical

"The nose morphology was long, thin, and tubular."

Directly documents the long, thin, tubular nose.

PMID:24680889 PARTIAL Human Clinical

"Abnormal nasal shape 7 NA"

Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) with individuals with a 3p25 deletion (n = 4); the trailing values give 7/7 SETD5-variant individuals, with the deletion column not available. PARTIAL because the row scores abnormal nasal shape generally rather than long nose specifically.

Pain Insensitivity Pain insensitivity HP:0007021

Frequency is omitted: this is a parent-reported survey finding explicitly labelled by the authors as a potential novel finding requiring confirmation.

Show evidence (1 reference)

PMID:42468298 PARTIAL Human Clinical

"Potential novel findings included high pain tolerance (43%), persistent leg pain (31%), and joint pain (27%)."

Reports high pain tolerance, explicitly framed by the authors as a potential novel finding.

Moyamoya Phenomenon Moyamoya phenomenon HP:0011834

Frequency is deliberately omitted and support is PARTIAL. This is an ascertainment-inverted association (moyamoya cohort screened for variants, not SETD5 cohort screened for moyamoya), and the authors say penetrance must be assessed before imaging can be recommended.

Show evidence (2 references)

PMID:31474762 PARTIAL Human Clinical

"A de novo SETD5 haploinsufficiency variant, p.Glu661Lysfs*5 (Fig. 1), was identified in a patient diagnosed with bilateral MMA at 10 years of age with a history of developmental delay, polydactyly, and mild dysmorphic facial features"

Documents the index SETD5 moyamoya case.

PMID:31474762 PARTIAL Human Clinical

"These data indicate that rare variants in CHD4 and CNOT3 predispose to MMA in the presence and absence of DD; additional data are required to validate an association between SETD5 rare variants and MMA."

The authors explicitly caveat the SETD5-moyamoya association, which is why this phenotype is recorded as PARTIAL with no frequency.

🧬

Genetic Associations

1

SETD5 (Causative)

Gene: SETD5 hgnc:25566 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:24680889 SUPPORT Human Clinical

"we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation sequencing approach"

Establishes the ascertainment design of the cohort in which SETD5 loss of function was validated as a cause of intellectual disability.

PMID:40265665 SUPPORT Human Clinical

"In the cohort, there were 11 unique pathogenic/likely pathogenic variants in 13 individuals from 11 different families. Of these 11 unique variants, 6 were nonsense, 4 were frameshift, and one was splice site."

Quantifies the truncating-variant-dominated mutational spectrum in a registry cohort.

PMID:31474762 SUPPORT Computational

"SETD5 is intolerant to LoF variation (pLI = 1) but not missense variation (Z-score = −0.04)."

Population constraint metrics support haploinsufficiency as the mechanism and explain why missense alleles are less often pathogenic.

💊

Medical Actions

8

Developmental and Educational Support

Category: Therapeutic Action: speech and language therapy Ontology label: Speech Language Therapy NCIT:C159273

Early intervention, speech and language therapy, occupational and physical therapy, and individualized educational support address the core developmental phenotype. No disease-modifying therapy exists; management is symptomatic and anticipatory.

Target Phenotypes: Delayed speech and language development HP:0000750 Global developmental delay HP:0001263

Show evidence (2 references)

PMID:42468298 PARTIAL Human Clinical

"Findings expand the phenotypic spectrum and inform prognosis, surveillance, and management."

Supports phenotype-directed management as the current standard of care; it does not evaluate any specific intervention.

PMID:24680889 SUPPORT Human Clinical

"Older children had required special schooling because of their ID and behavioral problems, although some attended mainstream school at a young age but required educational statements and extra support."

Directly documents the educational support requirements of affected children.

Antiseizure Medication

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Standard antiseizure medication is used in the minority of individuals who develop epilepsy. No SETD5-specific agent or protocol has been established, seizure types are heterogeneous, and drug-resistant epilepsy has been reported.

Target Phenotypes: Seizure HP:0001250

Show evidence (2 references)

PMID:39603091 PARTIAL Human Clinical

"Epilepsy was present in about 14 % of patients, including different types of seizures as epileptic spasms, focal motor, and non-motor seizures."

Establishes the treatable epilepsy population and its heterogeneity; the cohort does not evaluate antiseizure medication efficacy.

PMID:40462669 PARTIAL Human Clinical

"Our findings confirm that epilepsy may arise after SETD5 variants, with subtle clinical manifestations that may overlap with behavioral phenomena in children who also exhibit cognitive and behavioral comorbidities."

Supports vigilance for subtle seizures that may be mistaken for behavioral events, which is the practical prerequisite for treating them.

Psychiatric and Behavioral Pharmacotherapy

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Psychotropic medication is used as standard neurodevelopmental care for the psychiatric and behavioral burden of this disorder - anxiety in about 47%, plus ADHD, psychotic disorder, and obsessive-compulsive/ritualized behavior. Treatment follows general psychiatric practice for the individual symptom cluster; no SETD5-specific agent, dose, or protocol has been evaluated.

Target Phenotypes: Anxiety HP:0000739 Attention deficit hyperactivity disorder HP:0007018 Psychosis HP:0000709 Compulsive behaviors HP:0000722

Show evidence (3 references)

PMID:39603091 PARTIAL Human Clinical

"Other psychiatric comorbidities include autism, ADHD, psychotic disorder and other internalizing and externalizing symptoms."

Establishes the composition of the treatable psychiatric population in a multicenter cohort. PARTIAL because the cohort characterizes the phenotype and does not evaluate any pharmacological intervention.

PMID:42468298 PARTIAL Human Clinical

"Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%)."

Quantifies anxiety at 47%, the largest single psychiatric target. PARTIAL because this is a parent-reported survey of burden, not a treatment study.

PMID:24680889 PARTIAL Human Clinical

"Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features."

Independent cohort documenting the obsessive-compulsive and ritualized-behavior component of the treatable population. PARTIAL because no intervention is reported.

Recombinant Growth Hormone Therapy

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Recombinant growth hormone was given from age 12 to a girl with a de novo SETD5 variant and severe short stature (-5.22 SDS) in an overlap phenotype spanning MRD23, Cornelia de Lange, and KBG syndromes; growth velocity increased significantly over two years. This is a single case and is not established therapy for the disorder.

Target Phenotypes: Growth delay HP:0001510

Show evidence (2 references)

PMID:40869907 PARTIAL Human Clinical

"Recombinant growth hormone therapy (rhGH) was started at the age of 12 years. After both one year (+3.16 SDS) and two years (+2.9 SDS), the growth rate significantly increased compared with the pre-therapy period."

Documents the measured growth response; PARTIAL because it is an uncontrolled single case.

PMID:40869907 PARTIAL Human Clinical

"This is the first case of a patient with overlap syndrome due to SETD5 mutation treated with rhGH."

The authors state this is the first such case, confirming that the evidence base is a single report.

Orthopedic and Skeletal Management

Category: Therapeutic Action: orthopedic surgical procedure Ontology label: Orthopedic Surgical Procedure NCIT:C16186

Skeletal anomalies including thoracic scoliosis, kyphosis, lordosis, and significant leg-length discrepancy required varying degrees of intervention in 4 of 7 individuals in the gene-discovery cohort, including surgery in one child with talipes and calf hypoplasia.

Target Phenotypes: Scoliosis HP:0002650 Lower limb asymmetry HP:0100559

Show evidence (2 references)

PMID:24680889 SUPPORT Human Clinical

"Also, 4/7 children had skeletal abnormalities that required varying degrees of intervention."

Directly documents that skeletal abnormalities required orthopedic intervention.

PMID:24680889 SUPPORT Human Clinical

"and two children had a signiﬁcant leg-length discrepancy (one of them also had talipes and hypoplasia of the left calf and required surgery)"

Documents surgical management of the limb findings.

Ophthalmologic Assessment

Category: Monitoring Action: eye examination Ontology label: Eye Examination NCIT:C38060

Vision problems affect about half of individuals, and ptosis, amblyopia, nystagmus, and strabismus have been documented, so ophthalmologic assessment is warranted.

Show evidence (1 reference)

PMID:42468298 PARTIAL Human Clinical

"Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%)."

Establishes the high burden of vision problems that motivates ophthalmologic assessment; the survey does not evaluate a surveillance protocol.

Inguinal Hernia and Hypospadias Repair

Category: Therapeutic Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Surgical repair of inguinal hernia or hypospadias was required at a young age in 4 of 7 individuals in the gene-discovery cohort.

Target Phenotypes: Inguinal hernia HP:0000023 Hypospadias HP:0000047

Show evidence (1 reference)

PMID:24680889 SUPPORT Human Clinical

"Four of the seven children had either an inguinal hernia or hypospadias repaired at a young age."

Directly documents surgical repair of these anomalies.

Genetic Counseling

Category: Counseling / Informational Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counseling should cover autosomal dominant inheritance, the usual de novo occurrence, the 50% transmission risk from an affected individual, and - critically for this disorder - incomplete penetrance, since apparently unaffected and mildly affected carrier parents have been documented. Parental testing is therefore important before assuming de novo status.

Show evidence (2 references)

PMID:28881385 SUPPORT Human Clinical

"We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons."

Documents the non-penetrant carriers that make incomplete penetrance a required counseling point.

PMID:27375234 SUPPORT Human Clinical

"Family based exome sequencing combined to careful parental phenotyping may reveal a more complex clinical picture in newly recognized syndromes."

Supports careful parental phenotyping and family-based testing as part of counseling.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from SETD5 Haploinsufficiency Syndrome:

3p25.3 Microdeletion Syndrome Not Yet Curated MONDO:0018564

Overlapping Features A contiguous-gene deletion syndrome whose critical region contains THUMPD3, SETD5, and THUMPD3-AS1 within a 124 kb interval. SETD5 is regarded as the principal driver of the neurodevelopmental core, so the two entities share most clinical features - but they are separate entities because deletions can remove additional genes and are detected by a different assay.

Distinguishing Features

Molecular: an intragenic SETD5 sequence variant defines the single-gene entity; a copy-number loss at 3p25.3 defines the microdeletion syndrome. The deletion may remove THUMPD3 and THUMPD3-AS1 in addition to SETD5, and larger 3p25-p26 deletions remove substantially more.
Clinical: the larger, more distal 3p deletions add low birth weight, microcephaly, telecanthus, ptosis, micrognathia, cleft palate, and congenital heart disease - features that are not characteristic of isolated SETD5 loss of function.
Assay: chromosomal microarray detects the deletion; sequencing detects the intragenic variant. Either may be the first-line test depending on presentation.

Show evidence (3 references)

PMID:24680889 SUPPORT Human Clinical

"Deﬁning the minimum common overlap of deletions in multiple individuals has reduced the critical region for 3p25 microdeletion syndrome to three genes within a 124 kb interval."

Defines the three-gene critical region that distinguishes the contiguous-gene syndrome from the single-gene entity.

PMID:24680889 SUPPORT Human Clinical

"a clinical syndrome characterized by ID, low birth weight, microcephaly, telecanthus, ptosis, micro- gnathia, cleft palate, and congenital heart disease"

Enumerates the distal-deletion features that are not characteristic of isolated SETD5 loss of function.

PMID:24680889 SUPPORT Human Clinical

"SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in..."

States the driver-gene relationship, the basis for treating SETD5 haploinsufficiency as the principal contributor while keeping the deletion syndrome a separate entity.

KBG Syndrome MONDO:0007846

Overlapping Features ANKRD11-related KBG syndrome shares intellectual disability, developmental delay, behavioral features, and a partly overlapping facial appearance with SETD5 haploinsufficiency, and individuals with SETD5 variants have been referred with suspected KBG syndrome. The two remain distinct clinical entities.

Distinguishing Features

Gene: ANKRD11 (KBG) versus SETD5. The proteins physically interact and both engage HDAC3, which is the likely reason for the phenotypic convergence.
Hand anomalies characteristic of KBG syndrome were absent in two of three SETD5 patients referred with suspected KBG, and expert review did not find a satisfactory KBG facial resemblance.

Show evidence (3 references)

PMID:32793091 SUPPORT Human Clinical

"Whilst there is significant phenotypic overlap between the above-mentioned conditions, however, they still remain distinct clinical entities."

Directly supports keeping SETD5 haploinsufficiency, KBG syndrome, and 3p25.3 deletion syndrome as separate entities despite overlap.

PMID:32793091 SUPPORT Human Clinical

"Of note, two out of the three patients do not show hand anomalies consistent with KBGS, which are good diagnostic clues for differential diagnosis"

Identifies hand anomalies as the discriminating clinical clue.

PMID:32793091 SUPPORT In Vitro

"Interestingly, the ANKRD11 and SETD5 proteins physically interact at the molecular level as demonstrated by spectrometry assays performed in mouse embryonic stem cells and mouse neural progenitor cells"

Provides the molecular basis for the phenotypic overlap between the two disorders.

Cornelia de Lange Syndrome MONDO:0016033

Overlapping Features SETD5 variants have been reported in individuals ascertained with Cornelia de Lange-overlapping phenotypes, driven largely by the shared eyebrow findings (synophrys, full broad eyebrows) and developmental delay.

Distinguishing Features

Gene: the cohesin-pathway genes (NIPBL and others) versus SETD5; the overlap has led to SETD5 being grouped with the "cohesin-related" syndromes.

Show evidence (2 references)

PMID:32793091 SUPPORT Human Clinical

"Currently, mutations in both SETD5 and ANKRD11 genes have been identified in patients with Cornelia de Lange (CdL) syndrome overlapping phenotypes, resulting in the terminology of “cohesin-related” syndromes"

Documents the Cornelia de Lange-overlapping presentations that make CdL a relevant differential.

PMID:40869907 SUPPORT Human Clinical

"SEDT5 gene variants have been described in patients with KBG and Cornelia de Lange (CdL) syndromes."

Independent confirmation that SETD5 variants present as KBG- and CdL-overlapping phenotypes.

SETD1B-Related Neurodevelopmental Disorder MONDO:0033559

Overlapping Features A paralogue-adjacent chromatin disorder that is a named-entity-confusion hazard rather than a close clinical mimic. SETD1B-NDD is caused by heterozygous SETD1B (HGNC:29187, 12q24.31) loss-of-function variants and is dominated by epilepsy, including myoclonic absences, in most affected individuals.

Distinguishing Features

Gene and locus: SETD1B at 12q24.31 versus SETD5 at 3p25.3; different HGNC IDs (HGNC:29187 versus HGNC:25566) and different MONDO/OMIM entities (MONDO:0033559/OMIM:619000 versus MONDO:0014336/OMIM:615761).
Seizures occur in most individuals with SETD1B-NDD but in only about 14% of the SETD5 multicenter cohort, so epilepsy burden is a useful clinical discriminator.

Show evidence (1 reference)

PMID:39603091 SUPPORT Human Clinical

"Epilepsy was present in about 14 % of patients, including different types of seizures as epileptic spasms, focal motor, and non-motor seizures."

Establishes the low SETD5 epilepsy burden that distinguishes it from the epilepsy-dominated SETD1B disorder; the SETD1B side of the comparison is curated in the separate SETD1B-Related_Neurodevelopmental_Disorder entry.

{ }

Source YAML

click to show

name: SETD5 Haploinsufficiency Syndrome
creation_date: "2026-07-31T18:30:00Z"
category: Mendelian
synonyms:
- intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency
- MRD23
- intellectual developmental disorder, autosomal dominant 23
- autosomal dominant intellectual disability 23
- SETD5-related neurodevelopmental disorder
- SETD5 disorder
description: >-
  Intellectual disability-facial dysmorphism syndrome due to SETD5
  haploinsufficiency (MRD23; OMIM 615761) is an autosomal dominant
  neurodevelopmental disorder caused by heterozygous loss-of-function variants in
  SETD5 (HGNC:25566), which encodes a SET domain-containing chromatin regulator at
  3p25.3. Truncating variants trigger nonsense-mediated decay, so haploinsufficiency
  is the disease mechanism. The core phenotype is global developmental delay with
  disproportionate speech and language impairment, intellectual disability of
  variable severity, autism spectrum and other behavioral or psychiatric features,
  hypotonia and gait abnormality, and a recognizable but non-specific facial gestalt
  (prominent high forehead, full or synophrys-like eyebrows, long tubular nose,
  upslanting palpebral fissures, large low-set ears, long philtrum, thin upper lip).
  Skeletal anomalies, congenital heart defects, gastrointestinal and genitourinary
  anomalies, and epilepsy occur in a minority. Penetrance is incomplete and
  expressivity is variable, including mildly affected or apparently unaffected
  transmitting parents.

  Entity scope (NEC boundary, see `discussions`): this entry covers the single-gene
  SETD5 disorder caused by an intragenic SETD5 sequence variant. It is deliberately
  kept distinct from (i) the contiguous 3p25.3/3p- microdeletion syndrome, in which
  SETD5 is regarded as the principal driver of the neurodevelopmental core but where
  additional deleted genes can contribute, and (ii) the paralogue-adjacent chromatin
  disorders it is most often confused with - SETD2 (Luscan-Lumish syndrome), SETD1A,
  SETD1B, and the physically neighbouring SETBP1 (Schinzel-Giedion syndrome and
  SETBP1 haploinsufficiency disorder) - which are separate gene-disease entities and
  are handled here only as differential diagnoses.
disease_term:
  preferred_term: intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency
  term:
    id: MONDO:0014336
    label: intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency
parents:
- Neurodevelopmental Disorder
- Genetic Disease
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      A monogenic neurodevelopmental disorder whose core manifestations
      (developmental delay, intellectual disability, hypotonia, movement and gait
      abnormality, epilepsy) are neurologic.
    evidence:
    - reference: PMID:39603091
      reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Pathogenic variants in the SETD5 gene cause a neurodevelopmental disorder characterized by intellectual disability, autism, and facial dysmorphisms, with incomplete penetrance.
      explanation: >-
        Defines the condition as a neurodevelopmental disorder, supporting
        classification under Harrison's neurologic disorders.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Autosomal dominant Mendelian disorder caused by heterozygous
      loss-of-function SETD5 variants acting through haploinsufficiency.
    evidence:
    - reference: PMID:25138099
      reference_title: Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        pointing to a loss-of-function (LoF) and haploinsufficiency as the common disease-causing mechanism of intragenic SETD5 sequence variants and SETD5-containing microdeletions
      explanation: >-
        Establishes the Mendelian loss-of-function/haploinsufficiency genetic basis.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014336
      label: intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0014336 carries OMIM:615761 as an xref, lists MRD23 and "intellectual
      developmental disorder, autosomal dominant 23" as exact synonyms, and asserts a
      causal gene relationship (RO:0004003) to HGNC:25566 (SETD5), verified with OAK
      before curation began. This is the NEC anchor for the entry.
references:
- reference: PMID:24680889
  title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
- reference: PMID:25138099
  title: Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome.
- reference: PMID:28881385
  title: "Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance."
- reference: PMID:39603091
  title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
- reference: PMID:42468298
  title: Expanding the Phenotype of SETD5-Related Disorder Through a Facebook Support Group.
- reference: PMID:40265665
  title: Expansion of the Genotypic and Phenotypic Spectrum of SETD5 Disorder Using Data From the National Brain Gene Registry.
- reference: PMID:31515109
  title: SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring.
- reference: PMID:30455454
  title: Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition.
- reference: PMID:32299058
  title: The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression.
- reference: PMID:37264456
  title: SETD5 haploinsufficiency affects mitochondrial compartment in neural cells.
- reference: PMID:30655503
  title: Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.
- reference: PMID:31474762
  title: "The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy."
- reference: PMID:32793091
  title: SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome.
- reference: PMID:27375234
  title: SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression.
- reference: PMID:36875494
  title: "Structure, activity and function of the lysine methyltransferase SETD5."
- reference: PMID:40869907
  title: "Two Years of Growth Hormone Therapy in a Child with Severe Short Stature Due to Overlap Syndrome with a Novel SETD5 Gene Mutation: Case Report and Review of the Literature."
- reference: PMID:40462669
  title: A Novel Epilepsy Phenotype in a Young Girl With a Pathogenic SETD5 Gene Variant.
notes: >-
  No GeneReviews chapter exists for SETD5 haploinsufficiency syndrome, for MRD23, or
  for 3p25.3 microdeletion syndrome; PubMed searches for
  "SETD5 GeneReviews[All Fields]" and for GeneReviews restricted to SETD5/3p25.3
  returned zero records on 2026-07-31. The phenotype baseline therefore rests on the
  two large clinical series (PMID:39603091, PMID:28881385), the National Brain Gene
  Registry cohort (PMID:40265665), the support-group survey (PMID:42468298), and the
  original gene-discovery reports (PMID:24680889, PMID:25138099) rather than on an
  expert-curated chapter. Orphanet has obsoleted its standalone entry for this
  concept (ORPHA:404440), which is a nosology signal - not a statement that the
  single-gene entity is invalid - and is discussed under `discussions`.
inheritance:
- name: Autosomal dominant
  description: >-
    The disorder is autosomal dominant. Most pathogenic SETD5 variants arise de novo,
    but familial transmission from a mildly affected or apparently unaffected parent
    is documented, so penetrance is incomplete and expressivity is variable.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All mutations were compatible with de novo dominant inheritance.
    explanation: >-
      The gene-discovery cohort established dominant inheritance with de novo
      occurrence for all seven loss-of-function variants.
  - reference: PMID:27375234
    reference_title: SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present the first familial case of a SETD5 mutation contributing to a phenotype of congenital heart defects and dysmorphic features, with variable expression, in two siblings and their father.
    explanation: >-
      Documents vertical transmission across two generations with variable
      expression, consistent with autosomal dominant inheritance.
- name: Incomplete penetrance
  description: >-
    Penetrance of pathogenic SETD5 variants is incomplete. An apparently unaffected
    carrier mother and a carrier mother of normal intelligence with two affected twin
    sons have both been reported, and a transmitting father had only mild
    intellectual impairment.
  evidence:
  - reference: PMID:28881385
    reference_title: "Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons.
    explanation: >-
      Directly documents non-penetrant and minimally penetrant carriers.
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic variants in the SETD5 gene cause a neurodevelopmental disorder characterized by intellectual disability, autism, and facial dysmorphisms, with incomplete penetrance.
    explanation: >-
      The largest recent multicenter cohort explicitly characterizes the condition as
      incompletely penetrant.
mechanistic_hypotheses:
- hypothesis_group_id: setd5_h3k36me3_catalytic
  hypothesis_label: SETD5 as a Catalytic H3K36 Methyltransferase
  status: ALTERNATIVE
  description: >-
    Under this model SETD5 is a genuine SET-domain lysine methyltransferase that
    directly deposits H3K36me3 on active gene bodies, and haploinsufficiency causes
    disease by reducing that mark, desynchronizing RNA polymerase II elongation and
    corrupting RNA maturation and splicing.
  notes: >-
    Held as ALTERNATIVE rather than CANONICAL because the competing scaffold model is
    supported by independent enzymology; the two are not yet reconciled. If this model
    is correct, catalytic-activity restoration is conceptually a therapeutic target.
  evidence:
  - reference: PMID:31515109
    reference_title: SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Notably, we demonstrated that SETD5 directly deposits H3K36me3, which is essential to allow on-time RNA elongation dynamics.
    explanation: >-
      The primary experimental claim of direct catalytic H3K36me3 deposition by SETD5.
- hypothesis_group_id: setd5_corepressor_scaffold
  hypothesis_label: SETD5 as a Catalytically Inert Co-Repressor Scaffold
  status: ALTERNATIVE
  description: >-
    Under this model SETD5 lacks intrinsic methyltransferase activity and instead
    scaffolds a co-repressor complex containing HDAC3, NCoR, G9a, and PAF1;
    haploinsufficiency then acts by failure of corepressor recruitment and altered
    histone acetylation rather than by loss of a methyl mark. Notably, SETD5 lacks the
    PHD finger present in its SET-domain homologues, which is part of the
    enzymological argument.
  notes: >-
    Both hypotheses converge on the same downstream node - aberrant RNA polymerase II
    elongation and transcriptional infidelity - so the disease model is robust to the
    controversy even though the molecular mechanism is not settled. See the
    gap_setd5_catalytic_activity discussion.
  evidence:
  - reference: PMID:36875494
    reference_title: "Structure, activity and function of the lysine methyltransferase SETD5."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, there is evidence that SETD5 lacks the methyltransferase activity but scaffolds a co- repressor complex, including HDAC3, NCoR, G9a, and PAF1, which couples selective deacetylation of H3K9ac with methylation of this residue
    explanation: >-
      States the scaffold model and names the co-repressor partners; classified OTHER
      because it is a review synthesizing primary enzymology.
  - reference: PMID:36875494
    reference_title: "Structure, activity and function of the lysine methyltransferase SETD5."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The yeast SET3 and SET4, Drosophila UpSET, and human MLL5 are homologous to SETD5 over their SET domains and, except for SETD5, contain a PHD ﬁnger
    explanation: >-
      Provides the comparative-domain argument that SETD5 is structurally atypical
      among its SET-domain homologues.
pathophysiology:
- name: SETD5 Haploinsufficiency
  biological_scale: MOLECULAR
  description: >-
    Heterozygous nonsense, frameshift, and splice-disrupting SETD5 variants introduce
    premature termination codons whose transcripts are degraded by nonsense-mediated
    decay, halving functional SETD5 dosage. Whole-gene 3p25.3 microdeletions that
    remove one SETD5 allele converge on the same mechanism. CRISPR/Cas9 modelling of
    two patient intragenic variants demonstrated nonsense-mediated decay directly.
  genes:
  - preferred_term: SETD5
    term:
      id: hgnc:25566
      label: SETD5
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  evidence:
  - reference: PMID:25138099
    reference_title: Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CRISPR/Cas9 mutation modelling of the two intragenic variants demonstrated nonsense-mediated decay of the resulting transcripts, pointing to a loss-of-function (LoF) and haploinsufficiency as the common disease-causing mechanism of intragenic SETD5 sequence variants and SETD5-containing microdeletions.
    explanation: >-
      Provides the direct experimental demonstration that patient variants trigger
      nonsense-mediated decay and therefore act by haploinsufficiency.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance.
    explanation: >-
      Identifies SETD5 as the mutated gene and confirms de novo dominant occurrence
      of the seven truncating variants in the gene-discovery cohort.
  - reference: PMID:32793091
    reference_title: SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all the three patients the pathogenic mechanism of the SETD5 alteration is haploinsufficiency.
    explanation: >-
      Independent clinical confirmation that both intragenic variants and a 3p25.3
      deletion act through SETD5 haploinsufficiency.
  downstream:
  - target: Impaired H3K36 Methylation and Chromatin Regulation
    description: >-
      Reduced SETD5 dosage lowers deposition of the H3K36me3 mark on active gene
      bodies.
    hypothesis_groups:
    - setd5_h3k36me3_catalytic
    - setd5_corepressor_scaffold
    evidence:
    - reference: PMID:31515109
      reference_title: SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mechanistically, Setd5 inactivation in neural stem cells, zebrafish, and mice equally affects genome-wide levels of H3K36me3 on active gene bodies.
      explanation: >-
        Directly links Setd5 loss to a genome-wide reduction of the H3K36me3 mark
        across three model systems.
  - target: Dysregulated rDNA Expression and Reduced Translation
    description: >-
      SETD5 recruits the HDAC3 complex to the rDNA promoter; reduced SETD5 attenuates
      rDNA transcription.
    evidence:
    - reference: PMID:32299058
      reference_title: The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        SETD5 recruited the HDAC3 complex to the rDNA promoter, resulting in removal of the histone mark H4K16ac and its reader protein TIP5, a repressor of rDNA expression.
      explanation: >-
        Establishes the direct SETD5-HDAC3-TIP5 route from SETD5 dosage to rDNA
        promoter regulation.
- name: Impaired H3K36 Methylation and Chromatin Regulation
  biological_scale: MOLECULAR
  description: >-
    SETD5 contains a SET domain and a putative PHD domain and is best characterized as
    depositing H3K36 methylation, though whether SETD5 itself is catalytically active
    as a histone methyltransferase remains debated; it also acts through
    HDAC-containing corepressor complexes that control chromatin accessibility. In
    Setd5-deficient neural stem cells, zebrafish, and mice, genome-wide H3K36me3 on
    active gene bodies is reduced.
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  molecular_functions:
  - preferred_term: histone H3K36 methyltransferase activity
    term:
      id: GO:0046975
      label: histone H3K36 methyltransferase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31515109
    reference_title: SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Notably, we demonstrated that SETD5 directly deposits H3K36me3, which is essential to allow on-time RNA elongation dynamics.
    explanation: >-
      Directly attributes H3K36me3 deposition to SETD5 and connects it to elongation
      kinetics.
  - reference: PMID:36875494
    reference_title: "Structure, activity and function of the lysine methyltransferase SETD5."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SET domain-containing 5 (SETD5) is an uncharacterized member of the protein lysine methyltransferase family and is best known for its transcription machinery by methylating histone H3 on lysine 36 (H3K36).
    explanation: >-
      Review-level statement of SETD5's H3K36-directed activity; classified OTHER
      because it is an expert synthesis rather than primary data.
  - reference: PMID:37264456
    reference_title: SETD5 haploinsufficiency affects mitochondrial compartment in neural cells.
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      The direct function of SETD5 as histone methyltransferase activity is debated
    explanation: >-
      Records the explicit uncertainty about SETD5's intrinsic catalytic activity,
      which is why this node is framed as chromatin regulation rather than as a
      settled enzymatic defect.
  downstream:
  - target: Aberrant RNA Polymerase II Elongation and Transcriptional Infidelity
    description: >-
      Loss of the H3K36me3 mark on gene bodies desynchronizes RNA polymerase II
      elongation. This is the convergent hub where the catalytic and scaffold
      hypotheses meet: whichever molecular route is correct, transcriptional
      infidelity is the shared consequence.
    hypothesis_groups:
    - setd5_h3k36me3_catalytic
    - setd5_corepressor_scaffold
    evidence:
    - reference: PMID:31515109
      reference_title: SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Hence, Setd5 gene loss leads to abnormal transcription, with impaired RNA maturation causing detrimental effects on gene integrity and splicing.
      explanation: >-
        Directly connects the chromatin defect to abnormal transcription and splicing.
- name: Aberrant RNA Polymerase II Elongation and Transcriptional Infidelity
  biological_scale: MOLECULAR
  description: >-
    SETD5 governs RNA polymerase II dynamics through its interaction with the HDAC3
    and PAF1 complexes and through the H3K36me3 mark it places on gene bodies. When
    SETD5 dosage falls, elongation timing is disturbed, RNA maturation and splicing
    are impaired, and developmental gene expression programmes are dysregulated.
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  biological_processes:
  - preferred_term: transcription by RNA polymerase II
    term:
      id: GO:0006366
      label: transcription by RNA polymerase II
    modifier: ABNORMAL
  - preferred_term: regulation of gene expression
    term:
      id: GO:0010468
      label: regulation of gene expression
    modifier: ABNORMAL
  - preferred_term: "mRNA splicing, via spliceosome"
    term:
      id: GO:0000398
      label: "mRNA splicing, via spliceosome"
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30455454
    reference_title: Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our data additionally indicate that Setd5 regulates RNA polymerase II dynamics and gene transcription via its interaction with the Hdac3 and Paf1 complexes, findings potentially explaining the gene expression defects observed in Setd5-haploinsufficient mice.
    explanation: >-
      Identifies the HDAC3/PAF1 route by which Setd5 controls RNA polymerase II
      dynamics and gene transcription.
  - reference: PMID:31515109
    reference_title: SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Hence, Setd5 gene loss leads to abnormal transcription, with impaired RNA maturation causing detrimental effects on gene integrity and splicing.
    explanation: >-
      Directly documents transcriptional infidelity and splicing defects following
      Setd5 loss.
  downstream:
  - target: Mitochondrial Fragmentation and Bioenergetic Deficit in Neural Cells
    description: >-
      Transcriptional aberration at mitochondria-associated genes is the proximate
      cause of the mitochondrial phenotype.
    evidence:
    - reference: PMID:37264456
      reference_title: SETD5 haploinsufficiency affects mitochondrial compartment in neural cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mitochondrial impairment is facilitated by transcriptional aberrations originated by the decrease of the SETD5 enzyme.
      explanation: >-
        Explicitly places the mitochondrial defect downstream of SETD5-driven
        transcriptional aberration.
  - target: Impaired Neural Progenitor Proliferation and Cortical Neurogenesis
    description: >-
      Disturbed developmental gene expression impairs the proliferative dynamics of
      neural progenitors.
    evidence:
    - reference: PMID:31515109
      reference_title: SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Herein, we found that Setd5 haploinsufficiency impairs the proliferative dynamics of neural progenitors and synaptic wiring of neurons, ultimately resulting in behavioral deficits in mice.
      explanation: >-
        Directly links the transcriptional defect to impaired neural progenitor
        proliferation.
- name: Dysregulated rDNA Expression and Reduced Translation
  biological_scale: MOLECULAR
  description: >-
    SETD5 positively regulates ribosomal DNA transcription by recruiting the HDAC3
    complex to the rDNA promoter, removing the H4K16ac mark and its reader TIP5, a
    repressor of rDNA expression. SETD5 depletion attenuates rDNA expression and
    global translational activity, with selective loss of cyclin D1 translation;
    ablating TIP5 in SETD5-deficient cells rescues the phenotype, establishing the
    epistatic order.
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  biological_processes:
  - preferred_term: rRNA processing
    term:
      id: GO:0006364
      label: rRNA processing
    modifier: DECREASED
  - preferred_term: translational elongation
    term:
      id: GO:0006414
      label: translational elongation
    modifier: DECREASED
  evidence:
  - reference: PMID:32299058
    reference_title: The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Depletion of SETD5 attenuated rDNA expression, translational activity, and neural cell proliferation, whereas ablation of TIP5 in SETD5-deficient cells rescued these effects.
    explanation: >-
      Direct experimental chain from SETD5 depletion to reduced rDNA expression,
      translation, and proliferation, with genetic rescue establishing causality.
  - reference: PMID:32299058
    reference_title: The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Translation of cyclin D1 mRNA was specifically down-regulated in SETD5-insufficient cells.
    explanation: >-
      Identifies the specific translational target linking the rDNA defect to
      cell-cycle progression.
  downstream:
  - target: Impaired Neural Progenitor Proliferation and Cortical Neurogenesis
    description: >-
      Reduced rDNA output and cyclin D1 translation constrain neural cell
      proliferation.
    evidence:
    - reference: PMID:32299058
      reference_title: The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our results thus suggest that SETD5 positively regulates rDNA expression via an HDAC3-mediated epigenetic mechanism and that such regulation is essential for translation of cyclin D1 mRNA and neural cell proliferation.
      explanation: >-
        States the authors' conclusion that the rDNA-cyclin D1 axis is essential for
        neural cell proliferation.
- name: Mitochondrial Fragmentation and Bioenergetic Deficit in Neural Cells
  biological_scale: CELLULAR
  description: >-
    In Setd5-haploinsufficient neural stem cells, neurons, and mouse cortex,
    mitochondria are fragmented, mitochondrial membrane potential and ATP production
    are reduced, and mitochondria are mislocalized with fewer organelles in neurites
    and synapses. The authors explicitly caution that they cannot place this defect
    within the causal hierarchy of the disease.
  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: mitochondrial fission
    term:
      id: GO:0000266
      label: mitochondrial fission
    modifier: INCREASED
  - preferred_term: mitochondrion organization
    term:
      id: GO:0007005
      label: mitochondrion organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37264456
    reference_title: SETD5 haploinsufficiency affects mitochondrial compartment in neural cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Low levels of SETD5 resulted in fragmented mitochondria, reduced mitochondrial membrane potential, and ATP production both in neural precursors and neurons.
    explanation: >-
      Directly documents the mitochondrial structural and bioenergetic phenotype in
      two neural cell types.
  - reference: PMID:37264456
    reference_title: SETD5 haploinsufficiency affects mitochondrial compartment in neural cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mitochondria were also mislocalized in mutant neurons, with reduced organelles within neurites and synapses.
    explanation: >-
      Documents mitochondrial mislocalization away from neurites and synapses,
      connecting the organelle defect to synaptic compartments.
  - reference: PMID:37264456
    reference_title: SETD5 haploinsufficiency affects mitochondrial compartment in neural cells.
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found several defects in the mitochondrial compartment; however, we can only speculate about their position in the hierarchy of the pathological mechanisms at the basis of the disease.
    explanation: >-
      The authors' own limitation statement, retained so this node is not overstated
      as an established causal step in human disease.
  downstream:
  - target: Reduced Synaptic Density and Cortical Network Hypoconnectivity
    description: >-
      Depletion of mitochondria from neurites and synapses is a plausible but
      unproven contributor to the synaptic phenotype; the authors do not establish
      this ordering.
    evidence:
    - reference: PMID:37264456
      reference_title: SETD5 haploinsufficiency affects mitochondrial compartment in neural cells.
      supports: PARTIAL
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mitochondria were also mislocalized in mutant neurons, with reduced organelles within neurites and synapses.
      explanation: >-
        Supports the anatomical co-localization of the mitochondrial and synaptic
        defects while leaving the causal direction explicitly unresolved.
- name: Impaired Neural Progenitor Proliferation and Cortical Neurogenesis
  biological_scale: CELLULAR
  description: >-
    Setd5 haploinsufficiency impairs the proliferative dynamics of neural progenitors
    and produces a deficit of deep-layer cortical neurons in the developing brain,
    with altered expression of neurodevelopment-related genes in a specific
    subpopulation of fetal cortical neurons.
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  - preferred_term: cortical projection neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: neural precursor cell proliferation
    term:
      id: GO:0061351
      label: neural precursor cell proliferation
    modifier: DECREASED
  - preferred_term: cerebral cortex neuron differentiation
    term:
      id: GO:0021895
      label: cerebral cortex neuron differentiation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30655503
    reference_title: Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Anatomical differences were observed in Setd5+/- adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain.
    explanation: >-
      Directly documents the deep-layer cortical neuron deficit arising during
      development.
  - reference: PMID:30655503
    reference_title: Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      A specific subpopulation of fetal Setd5+/- cortical neurons showed altered gene expression of neurodevelopment-related genes.
    explanation: >-
      Links the transcriptional defect to a defined fetal cortical neuron population.
  - reference: PMID:31515109
    reference_title: SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Herein, we found that Setd5 haploinsufficiency impairs the proliferative dynamics of neural progenitors and synaptic wiring of neurons, ultimately resulting in behavioral deficits in mice.
    explanation: >-
      Independent confirmation of impaired neural progenitor proliferation.
  downstream:
  - target: Reduced Synaptic Density and Cortical Network Hypoconnectivity
    description: >-
      Fewer and abnormally specified cortical neurons underlie the reduced synaptic
      density and network hypoconnectivity.
    evidence:
    - reference: PMID:30655503
      reference_title: Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Setd5+/- cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology.
      explanation: >-
        Documents the synaptic and network consequences measured in the same model.
- name: Reduced Synaptic Density and Cortical Network Hypoconnectivity
  biological_scale: CELLULAR
  description: >-
    Setd5-haploinsufficient cortical neurons show reduced synaptic density and
    neuritic outgrowth in vitro with corresponding reductions in network activity and
    synchrony on multielectrode arrays. In vivo, Setd5-mutant mice show enhanced
    long-term potentiation and abnormal expression of postsynaptic density proteins
    previously associated with cognition, indicating that synaptic function as well as
    synapse number is disturbed.
  cell_types:
  - preferred_term: cortical neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: synapse assembly
    term:
      id: GO:0007416
      label: synapse assembly
    modifier: DECREASED
  - preferred_term: neuron projection development
    term:
      id: GO:0031175
      label: neuron projection development
    modifier: DECREASED
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30655503
    reference_title: Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Setd5+/- cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology.
    explanation: >-
      Directly measures reduced synaptic density, neuritic outgrowth, and network
      activity.
  - reference: PMID:30455454
    reference_title: Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Behavioral issues are accompanied by abnormal expression of postsynaptic density proteins previously associated with cognition.
    explanation: >-
      Links behavioral impairment to postsynaptic density protein dysregulation.
  - reference: PMID:30455454
    reference_title: Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalization, and behavioral inflexibility.
    explanation: >-
      Documents altered synaptic plasticity (enhanced LTP) alongside cognitive and
      communication deficits.
  downstream:
  - target: Impaired Neurodevelopment
    description: >-
      Synaptic and network-level disruption is the cellular substrate of the human
      neurodevelopmental phenotype.
    evidence:
    - reference: PMID:30655503
      reference_title: Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.
      supports: PARTIAL
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our data converge on a picture of abnormal neurodevelopment driven by Setd5 haploinsufficiency, consistent with a highly penetrant risk factor.
      explanation: >-
        Supports the mouse-to-human inference while keeping it explicitly a
        model-organism extrapolation.
- name: Impaired Neurodevelopment
  biological_scale: TISSUE
  description: >-
    The convergent consequence in affected humans is impaired nervous-system
    development, producing global developmental delay with disproportionate speech and
    language impairment, intellectual disability of variable severity, autism spectrum
    and other psychiatric features, hypotonia, movement and gait abnormalities, and in
    a minority epilepsy.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic variants in the SETD5 gene cause a neurodevelopmental disorder characterized by intellectual disability, autism, and facial dysmorphisms, with incomplete penetrance.
    explanation: >-
      Establishes the human neurodevelopmental outcome of SETD5 pathogenic variants.
  - reference: PMID:32793091
    reference_title: SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The MRD23 phenotype is characterized by ID, facial dysmorphisms, skeletal anomalies, behavioral problems and speech and language difficulties
    explanation: >-
      Summarizes the MRD23 clinical core, including the speech and language component
      of the neurodevelopmental phenotype.
  downstream:
  - target: Global Developmental Delay
    description: Developmental delay is the usual presenting manifestation.
    evidence:
    - reference: PMID:42468298
      reference_title: Expanding the Phenotype of SETD5-Related Disorder Through a Facebook Support Group.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%).
      explanation: >-
        Quantifies developmental delay as the most common reported feature.
  - target: Intellectual Disability
    description: Intellectual disability of mild to severe degree is a defining feature.
    evidence:
    - reference: PMID:39603091
      reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Concerning the cognitive phenotype, intellectual disability or global developmental delay depending on age, ranging from mild to severe, was present in 75 % of cohort, 21.4 % exhibit borderline intellectual functioning while an individual has a normal intelligence quotient.
      explanation: >-
        Quantifies intellectual disability and its severity range in the multicenter
        cohort.
  - target: Delayed Speech and Language Development
    description: Speech and language are disproportionately affected.
    evidence:
    - reference: PMID:32793091
      reference_title: SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The MRD23 phenotype is characterized by ID, facial dysmorphisms, skeletal anomalies, behavioral problems and speech and language difficulties
      explanation: >-
        Directly names speech and language difficulties in the MRD23 clinical core.
  - target: Hypotonia
    description: Hypotonia is a frequent neurological manifestation.
    evidence:
    - reference: PMID:39603091
      reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In our cohort neurological symptoms include hypotonia (39.2 %), hyperkinetic movement disorders including stereotypies and chorea (21.4 %) and gait abnormalities ranging from tip-toe or unsteady walking and alterations of fine motor skills (35.7 %).
      explanation: >-
        Quantifies hypotonia in the multicenter cohort.
  - target: Gait Disturbance
    description: Gait abnormality ranges from tip-toe to unsteady walking.
    evidence:
    - reference: PMID:39603091
      reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In our cohort neurological symptoms include hypotonia (39.2 %), hyperkinetic movement disorders including stereotypies and chorea (21.4 %) and gait abnormalities ranging from tip-toe or unsteady walking and alterations of fine motor skills (35.7 %).
      explanation: >-
        Quantifies gait abnormality in the multicenter cohort.
  - target: Hyperkinetic Movements
    description: Stereotypies and chorea occur in a minority.
    evidence:
    - reference: PMID:39603091
      reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In our cohort neurological symptoms include hypotonia (39.2 %), hyperkinetic movement disorders including stereotypies and chorea (21.4 %) and gait abnormalities ranging from tip-toe or unsteady walking and alterations of fine motor skills (35.7 %).
      explanation: >-
        Quantifies hyperkinetic movement disorders in the multicenter cohort.
  - target: Autistic Behavior
    description: Autism spectrum disorder is a defining behavioral feature.
    evidence:
    - reference: PMID:24680889
      reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features.
      explanation: >-
        Documents autism among the prominent behavioral features.
  - target: Seizure
    description: Epilepsy affects a minority of individuals.
    evidence:
    - reference: PMID:39603091
      reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Epilepsy was present in about 14 % of patients, including different types of seizures as epileptic spasms, focal motor, and non-motor seizures.
      explanation: >-
        Quantifies epilepsy and its seizure types in the multicenter cohort.
  - target: Abnormal Facial Shape
    description: A recognizable but non-specific facial gestalt accompanies the neurologic phenotype.
    evidence:
    - reference: PMID:24680889
      reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears.
      explanation: >-
        Enumerates the craniofacial features of the syndrome.
- name: Extra-Neural Developmental Involvement
  biological_scale: ORGANISM
  description: >-
    Beyond the nervous system, SETD5 haploinsufficiency is associated with skeletal
    anomalies (scoliosis, kyphosis, leg-length discrepancy), congenital heart defects,
    gastrointestinal and abdominal-wall anomalies, inguinal hernia, and hypospadias.
    In the mouse, Setd5 haploinsufficiency produces abnormal brain-to-body weight
    ratios and neural crest defect-associated phenotypes, offering a developmental
    route to the craniofacial and cardiac findings that has not been directly
    demonstrated in affected humans.
  cell_types:
  - preferred_term: migratory neural crest cell
    term:
      id: CL:0000333
      label: migratory neural crest cell
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital heart defects, inguinal hernia, or hypospadias were also reported.
    explanation: >-
      Documents the extra-neural malformations reported in the gene-discovery cohort.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thoracic scoliosis, kyphosis, and lordosis were reported
    explanation: >-
      Documents the skeletal spectrum.
  - reference: PMID:30455454
    reference_title: Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition.
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here we show that Setd5-haploinsufficient mice present developmental defects such as abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes.
    explanation: >-
      Provides the neural-crest developmental hypothesis for the craniofacial and
      cardiac findings; PARTIAL because it is mouse data not confirmed in humans.
  downstream:
  - target: Abnormal Heart Morphology
    description: Congenital heart defects occur in a minority of individuals.
    evidence:
    - reference: PMID:27375234
      reference_title: SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We present the first familial case of a SETD5 mutation contributing to a phenotype of congenital heart defects and dysmorphic features, with variable expression, in two siblings and their father.
      explanation: >-
        Independent documentation of congenital heart defects segregating with a
        SETD5 variant.
  - target: Scoliosis
    description: Thoracic scoliosis is among the reported skeletal anomalies.
    evidence:
    - reference: PMID:24680889
      reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thoracic scoliosis, kyphosis, and lordosis were reported
      explanation: >-
        Directly documents scoliosis.
  - target: Feeding Difficulties
    description: Difficulty with swallowing and chewing was reported by families and physicians.
    evidence:
    - reference: PMID:24680889
      reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Feeding problems, particularly difﬁculties with swallowing and chewing, were noted by several families and physicians.
      explanation: >-
        Directly documents feeding difficulties.
  - target: Inguinal Hernia
    description: Inguinal hernia was reported and often required early repair.
    evidence:
    - reference: PMID:24680889
      reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Congenital heart defects, inguinal hernia, or hypospadias were also reported.
      explanation: >-
        Directly names inguinal hernia among reported anomalies.
  - target: Hypospadias
    description: Hypospadias was reported and often required early repair.
    evidence:
    - reference: PMID:24680889
      reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Congenital heart defects, inguinal hernia, or hypospadias were also reported.
      explanation: >-
        Directly names hypospadias among reported anomalies.
  - target: Moyamoya Phenomenon
    description: >-
      Bilateral moyamoya angiopathy has been reported in an individual with a de novo
      SETD5 frameshift variant, but the association is not yet validated.
    evidence:
    - reference: PMID:31474762
      reference_title: "The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A de novo SETD5 haploinsufficiency variant, p.Glu661Lysfs*5 (Fig. 1), was identified in a patient diagnosed with bilateral MMA at 10 years of age with a history of developmental delay, polydactyly, and mild dysmorphic facial features
      explanation: >-
        Documents the index case; PARTIAL because the same paper states that
        additional data are needed to validate the SETD5-moyamoya association.
phenotypes:
- category: Developmental
  name: Global Developmental Delay
  description: >
    Global developmental delay is the usual presenting manifestation and the most
    frequently reported feature, affecting speech and language most prominently but
    also motor and adaptive domains.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:42468298
    reference_title: Expanding the Phenotype of SETD5-Related Disorder Through a Facebook Support Group.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%).
    explanation: >-
      Developmental delay was reported in 96% of respondents, mapping to the
      VERY_FREQUENT band (80-100%).
  - reference: PMID:28881385
    reference_title: "Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities.
    explanation: >-
      Independent cohort confirming developmental delay in the majority of
      individuals.
- category: Cognitive
  name: Intellectual Disability
  description: >
    Intellectual disability (or, in younger children, global developmental delay)
    ranges from mild to severe. In the multicenter cohort 75% had intellectual
    disability or global developmental delay, 21.4% had borderline intellectual
    functioning, and one individual had a normal IQ. The original gene-discovery
    cohort was ascertained for moderate-to-severe intellectual disability, so severity
    estimates are ascertainment-sensitive.
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Concerning the cognitive phenotype, intellectual disability or global developmental delay depending on age, ranging from mild to severe, was present in 75 % of cohort, 21.4 % exhibit borderline intellectual functioning while an individual has a normal intelligence quotient.
    explanation: >-
      Reports 75% affected, mapping to the FREQUENT band (30-79%), and documents the
      mild-to-severe range.
  - reference: PMID:42468298
    reference_title: Expanding the Phenotype of SETD5-Related Disorder Through a Facebook Support Group.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%).
    explanation: >-
      An independent survey cohort reports the same 75% figure for intellectual
      disability.
- category: Developmental
  name: Delayed Speech and Language Development
  description: >
    Speech and language delay is disproportionately severe relative to other domains
    and was present in all individuals in the gene-discovery cohort. Receptive and
    expressive language difficulties with speech disorder have been documented in
    molecularly confirmed individuals.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:32793091
    reference_title: SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The MRD23 phenotype is characterized by ID, facial dysmorphisms, skeletal anomalies, behavioral problems and speech and language difficulties
    explanation: >-
      Speech and language difficulties are named as a defining component of the MRD23
      phenotype.
  - reference: PMID:40462669
    reference_title: A Novel Epilepsy Phenotype in a Young Girl With a Pathogenic SETD5 Gene Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by receptive-expressive language difficulties with speech disorder and mild cognitive impairment
    explanation: >-
      Case-level documentation of the receptive-expressive language phenotype.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Language delay and/ or stammer 6N A
    explanation: >-
      Table 1 row for individuals with SETD5 LoF mutations (n = 7); the trailing
      characters are the per-column values, giving 6/7 (86%) SETD5-variant individuals
      with language delay and/or stammer and "NA" for the 3p25-deletion column. 86%
      falls in the VERY_FREQUENT band (80-99%), giving this frequency a quantitative
      anchor rather than relying only on qualitative "characterized by" wording.
- category: Developmental
  name: Motor Delay
  description: >
    Motor developmental delay accompanies the speech and language delay and was noted
    in all individuals in the gene-discovery cohort.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  notes: >-
    The FREQUENT band is the conservative reading: the only source stating "all
    individuals" is a seven-person ascertained cohort, and the larger series report
    fine-motor and gait involvement at 35.7% rather than universal motor delay.
  evidence:
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      gait abnormalities ranging from tip-toe or unsteady walking and alterations of fine motor skills (35.7 %)
    explanation: >-
      Documents fine-motor and gait involvement at 35.7%; PARTIAL because the cohort
      reports motor-skill alterations rather than a formal motor-milestone delay.
- category: Neurologic
  name: Hypotonia
  description: >
    Hypotonia is among the most common neurological findings, reported in 39.2% of the
    multicenter cohort and 78% of support-group survey respondents.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In our cohort neurological symptoms include hypotonia (39.2 %), hyperkinetic movement disorders including stereotypies and chorea (21.4 %) and gait abnormalities ranging from tip-toe or unsteady walking and alterations of fine motor skills (35.7 %).
    explanation: >-
      Reports hypotonia at 39.2%, within the FREQUENT band (30-79%).
  - reference: PMID:42468298
    reference_title: Expanding the Phenotype of SETD5-Related Disorder Through a Facebook Support Group.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%).
    explanation: >-
      Survey cohort reports hypotonia at 78%, also within the FREQUENT band.
- category: Neurologic
  name: Gait Disturbance
  description: >
    Gait abnormalities range from tip-toe or unsteady walking to alterations of fine
    motor skills, reported in 35.7% of the multicenter cohort and 59% of survey
    respondents.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In our cohort neurological symptoms include hypotonia (39.2 %), hyperkinetic movement disorders including stereotypies and chorea (21.4 %) and gait abnormalities ranging from tip-toe or unsteady walking and alterations of fine motor skills (35.7 %).
    explanation: >-
      Reports gait abnormality at 35.7%, within the FREQUENT band (30-79%).
  - reference: PMID:42468298
    reference_title: Expanding the Phenotype of SETD5-Related Disorder Through a Facebook Support Group.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%).
    explanation: >-
      Survey cohort reports gait abnormality at 59%, also within the FREQUENT band.
- category: Neurologic
  name: Hyperkinetic Movements
  description: >
    Hyperkinetic movement disorders including stereotypies and chorea affect about one
    in five individuals.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hyperkinetic movements
    term:
      id: HP:0002487
      label: Hyperkinetic movements
  evidence:
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In our cohort neurological symptoms include hypotonia (39.2 %), hyperkinetic movement disorders including stereotypies and chorea (21.4 %) and gait abnormalities ranging from tip-toe or unsteady walking and alterations of fine motor skills (35.7 %).
    explanation: >-
      Reports hyperkinetic movement disorders at 21.4%, within the OCCASIONAL band
      (5-29%).
- category: Neurologic
  name: Motor Stereotypy
  description: >
    Motor stereotypies, including hand flapping with ritualized behavior, are part of
    the hyperkinetic movement spectrum and were prominent in the gene-discovery
    cohort.
  notes: >-
    Frequency is omitted: the 21.4% figure covers hyperkinetic movement disorders
    collectively (stereotypies plus chorea), not stereotypy alone.
  phenotype_term:
    preferred_term: Motor stereotypy
    term:
      id: HP:0000733
      label: Motor stereotypy
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features.
    explanation: >-
      Documents hand flapping with ritualized behavior, a motor stereotypy.
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hyperkinetic movement disorders including stereotypies and chorea (21.4 %)
    explanation: >-
      Independent cohort naming stereotypies within the hyperkinetic movement
      spectrum.
- category: Neurologic
  name: Chorea
  description: >
    Chorea is reported within the hyperkinetic movement spectrum of the disorder.
  notes: >-
    Frequency is omitted: the 21.4% figure is for hyperkinetic movement disorders
    collectively, not chorea alone.
  phenotype_term:
    preferred_term: Chorea
    term:
      id: HP:0002072
      label: Chorea
  evidence:
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hyperkinetic movement disorders including stereotypies and chorea (21.4 %)
    explanation: >-
      Directly names chorea as part of the movement phenotype.
- category: Neurologic
  name: Seizure
  description: >
    Epilepsy affects a minority of individuals, with heterogeneous seizure types
    including epileptic spasms and focal motor and non-motor seizures. Notably, none
    of the seven individuals in the original gene-discovery cohort had seizures,
    whereas 14% of the later multicenter cohort did - the seizure phenotype emerged
    only as the cohort broadened.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epilepsy was present in about 14 % of patients, including different types of seizures as epileptic spasms, focal motor, and non-motor seizures.
    explanation: >-
      Reports epilepsy at about 14%, within the OCCASIONAL band (5-29%).
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Growth parameters were within the normal range in all children, none had micro- cephaly or seizures
    explanation: >-
      Records the absence of seizures in the original seven-person cohort, which is
      why the frequency band rests on the later, larger series rather than on this
      one.
  - reference: PMID:40462669
    reference_title: A Novel Epilepsy Phenotype in a Young Girl With a Pathogenic SETD5 Gene Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings confirm that epilepsy may arise after SETD5 variants, with subtle clinical manifestations that may overlap with behavioral phenomena in children who also exhibit cognitive and behavioral comorbidities.
    explanation: >-
      Confirms epilepsy as a genuine but sometimes clinically subtle manifestation.
- category: Neurologic
  name: Epileptic Spasm
  description: >
    Epileptic spasms are one of the seizure types reported in the multicenter cohort.
  notes: >-
    Frequency is omitted: the 14% figure applies to epilepsy overall, not to
    epileptic spasms specifically.
  phenotype_term:
    preferred_term: Epileptic spasm
    term:
      id: HP:0011097
      label: Epileptic spasm
  evidence:
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epilepsy was present in about 14 % of patients, including different types of seizures as epileptic spasms, focal motor, and non-motor seizures.
    explanation: >-
      Directly names epileptic spasms among the observed seizure types.
- category: Neurologic
  name: Focal-Onset Seizure
  description: >
    Focal motor and non-motor seizures are reported, and focal seizures have been
    documented in individual cases alongside generalized seizures.
  notes: >-
    Frequency is omitted: the 14% figure applies to epilepsy overall.
  phenotype_term:
    preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epilepsy was present in about 14 % of patients, including different types of seizures as epileptic spasms, focal motor, and non-motor seizures.
    explanation: >-
      Directly names focal motor and non-motor seizures.
  - reference: PMID:40462669
    reference_title: A Novel Epilepsy Phenotype in a Young Girl With a Pathogenic SETD5 Gene Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her neurologic phenotype evolved during follow-up to include focal and generalized seizures as well as an overt neurodevelopmental disorder
    explanation: >-
      Case-level documentation of focal seizures in a molecularly confirmed
      individual.
- category: Behavioral
  name: Autistic Behavior
  description: >
    Autism spectrum disorder or autism-like behaviors are a defining component of the
    phenotype and are named in the disorder's core clinical definition.
  diagnostic: true
  notes: >-
    Frequency is omitted: the multicenter cohort lists autism among psychiatric
    comorbidities without giving a proportion in the available abstract.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic variants in the SETD5 gene cause a neurodevelopmental disorder characterized by intellectual disability, autism, and facial dysmorphisms, with incomplete penetrance.
    explanation: >-
      Autism is part of the disorder's core clinical definition.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features.
    explanation: >-
      Documents autism as a prominent feature in the gene-discovery cohort.
- category: Behavioral
  name: Behavioral Abnormalities
  description: >
    Behavioral and psychiatric issues beyond autism affect the majority of individuals
    and include ADHD, psychotic disorder, and other internalizing and externalizing
    symptoms.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:28881385
    reference_title: "Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities.
    explanation: >-
      States that the majority of patients have behavioral/psychiatric issues,
      mapping to the FREQUENT band (30-79%).
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other psychiatric comorbidities include autism, ADHD, psychotic disorder and other internalizing and externalizing symptoms.
    explanation: >-
      Enumerates the psychiatric comorbidity spectrum.
- category: Behavioral
  name: Attention Deficit Hyperactivity Disorder
  description: >
    ADHD is reported among the psychiatric comorbidities of the disorder.
  notes: >-
    Frequency is omitted: the cohort lists ADHD without a proportion.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other psychiatric comorbidities include autism, ADHD, psychotic disorder and other internalizing and externalizing symptoms.
    explanation: >-
      Directly names ADHD among psychiatric comorbidities.
- category: Behavioral
  name: Psychosis
  description: >
    Psychotic disorder is reported among the psychiatric comorbidities, an unusual and
    clinically important finding in a childhood-onset neurodevelopmental disorder.
  notes: >-
    Frequency is omitted: the cohort lists psychotic disorder without a proportion.
  phenotype_term:
    preferred_term: Psychosis
    term:
      id: HP:0000709
      label: Psychosis
  evidence:
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other psychiatric comorbidities include autism, ADHD, psychotic disorder and other internalizing and externalizing symptoms.
    explanation: >-
      Directly names psychotic disorder among psychiatric comorbidities.
- category: Behavioral
  name: Anxiety
  description: >
    Anxiety was reported by 47% of support-group survey respondents.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:42468298
    reference_title: Expanding the Phenotype of SETD5-Related Disorder Through a Facebook Support Group.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%).
    explanation: >-
      Reports anxiety at 47%, within the FREQUENT band (30-79%).
- category: Behavioral
  name: Compulsive Behaviors
  description: >
    Obsessive-compulsive disorder and ritualized behavior were prominent in the
    gene-discovery cohort.
  notes: >-
    Frequency is omitted: the source describes these as prominent in a seven-person
    cohort without a defensible proportion for the wider population.
  phenotype_term:
    preferred_term: Compulsive behaviors
    term:
      id: HP:0000722
      label: Compulsive behaviors
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features.
    explanation: >-
      Directly documents obsessive-compulsive disorder and ritualized behavior.
- category: Craniofacial
  name: Abnormal Facial Shape
  description: >
    A recognizable but non-specific facial gestalt comprising brachycephaly, a
    prominent high forehead with full/broad eyebrows or synophrys, a long thin tubular
    nose, long narrow upslanting palpebral fissures, and large fleshy low-set ears.
    Facial dysmorphism is part of the disorder's core clinical definition, but it was
    not sufficient for clinicians to recognize the syndrome prospectively - all cases
    were genotype-driven.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:25138099
    reference_title: Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All six patients presented with ID and certain facial dysmorphisms, suggesting that SETD5 sequence variants contribute substantially to the microdeletion 3p25.3 phenotype.
    explanation: >-
      All six molecularly confirmed patients had facial dysmorphism, supporting the
      VERY_FREQUENT band (80-100%).
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears.
    explanation: >-
      Enumerates the component craniofacial features.
- category: Craniofacial
  name: Brachycephaly
  description: >
    Brachycephaly is part of the reported craniofacial gestalt, recorded in 3 of the 7
    individuals carrying intragenic SETD5 loss-of-function variants in the
    gene-discovery cohort.
  frequency: FREQUENT
  notes: >-
    The frequency band is derived from the SETD5-variant column of Table 1 (3/7 = 43%).
    The narrative text describes the feature only qualitatively as variable; the table
    supplies the count.
  phenotype_term:
    preferred_term: Brachycephaly
    term:
      id: HP:0000248
      label: Brachycephaly
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears.
    explanation: >-
      Directly names brachycephaly.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brachycephaly 3 NA
    explanation: >-
      Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) with
      individuals with a 3p25 deletion (n = 4); the trailing values give 3/7
      SETD5-variant individuals, with the deletion column not available.
- category: Craniofacial
  name: Prominent Forehead
  description: >
    A prominent high forehead is a consistent element of the facial gestalt.
  notes: >-
    Frequency is omitted: the source describes it as a variable feature.
  phenotype_term:
    preferred_term: Prominent forehead
    term:
      id: HP:0011220
      label: Prominent forehead
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a prominent high forehead with striking eyebrows described as full, broad, straight, or with synophrys
    explanation: >-
      Directly documents the prominent high forehead.
- category: Craniofacial
  name: Synophrys
  description: >
    Full, broad, straight eyebrows or frank synophrys are among the more distinctive
    facial features and contribute to the phenotypic overlap with Cornelia de Lange
    syndrome.
  frequency: FREQUENT
  notes: >-
    The frequency band is derived from the SETD5-variant column of Table 1 (5/7 = 71%).
    The source table scores this as a combined "synophrys and/or abnormal eyebrows"
    category, so the HPO term is narrower than the scored feature; the narrative
    likewise describes the eyebrow finding as variable (full, broad, straight, or with
    synophrys).
  phenotype_term:
    preferred_term: Synophrys
    term:
      id: HP:0000664
      label: Synophrys
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a prominent high forehead with striking eyebrows described as full, broad, straight, or with synophrys
    explanation: >-
      Directly documents synophrys among the eyebrow findings.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Synophrys and/or abnormal eyebrows 51
    explanation: >-
      Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) with
      individuals with a 3p25 deletion (n = 4); the trailing counts give 5/7
      SETD5-variant individuals and 1/4 deletion individuals.
- category: Craniofacial
  name: Upslanted Palpebral Fissure
  description: >
    Long, narrow, upslanting palpebral fissures are a recurrent periorbital finding,
    recorded in 6 of the 7 individuals carrying intragenic SETD5 loss-of-function
    variants in the gene-discovery cohort.
  frequency: VERY_FREQUENT
  notes: >-
    The frequency band is derived from the SETD5-variant column of Table 1 (6/7 = 86%).
    The source table scores this as a combined "upslanting or downslanting palpebral
    fissures" category, so the HPO term is narrower than the scored feature; the
    narrative describes the cohort's fissures as upslanting.
  phenotype_term:
    preferred_term: Upslanted palpebral fissure
    term:
      id: HP:0000582
      label: Upslanted palpebral fissure
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The morphology around the eyes was similar with long, narrow, and upslanting palpebral ﬁssures
    explanation: >-
      Directly documents upslanting palpebral fissures.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Upslanting or downslanting palpebral ﬁssures 61
    explanation: >-
      Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) with
      individuals with a 3p25 deletion (n = 4); the trailing counts give 6/7
      SETD5-variant individuals and 1/4 deletion individuals.
- category: Craniofacial
  name: Long Nose
  description: >
    A long, thin, tubular nose is a characteristic nasal morphology, and abnormal nasal
    shape was scored in all 7 individuals carrying intragenic SETD5 loss-of-function
    variants in the gene-discovery cohort.
  frequency: VERY_FREQUENT
  notes: >-
    The frequency band is derived from the SETD5-variant column of Table 1
    (7/7 = 100%). Caveat: the scored table row is the broader "abnormal nasal shape"
    category rather than long nose specifically, so the band applies to nasal-shape
    abnormality as a class; the narrative text is what identifies that shape as long,
    thin, and tubular in this cohort. Recorded as VERY_FREQUENT on that basis rather
    than left unbanded, but it is the least tightly term-matched of the Table 1
    re-anchorings in this entry.
  phenotype_term:
    preferred_term: Long nose
    term:
      id: HP:0003189
      label: Long nose
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The nose morphology was long, thin, and tubular.
    explanation: >-
      Directly documents the long, thin, tubular nose.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Abnormal nasal shape 7 NA
    explanation: >-
      Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) with
      individuals with a 3p25 deletion (n = 4); the trailing values give 7/7
      SETD5-variant individuals, with the deletion column not available. PARTIAL
      because the row scores abnormal nasal shape generally rather than long nose
      specifically.
- category: Craniofacial
  name: Low-Set Ears
  description: >
    Ears tend to be large with fleshy lobes, long, and low set, recorded in 5 of the 7
    individuals carrying intragenic SETD5 loss-of-function variants in the
    gene-discovery cohort.
  frequency: FREQUENT
  notes: >-
    The frequency band is derived from the SETD5-variant column of Table 1 (5/7 = 71%).
    The source table scores this as a combined "low-set and/or malformed ears"
    category, so the HPO term is narrower than the scored feature.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ears tended to be large with ﬂeshy lobes, long, and low set
    explanation: >-
      Directly documents low-set ears.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Low-set and/or malformed ears 53
    explanation: >-
      Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) with
      individuals with a 3p25 deletion (n = 4); the trailing counts give 5/7
      SETD5-variant individuals and 3/4 deletion individuals.
- category: Craniofacial
  name: Depressed Nasal Bridge
  description: >
    A depressed nasal bridge was recorded in 3 of the 7 individuals carrying intragenic
    SETD5 loss-of-function variants in the gene-discovery cohort.
  frequency: FREQUENT
  notes: >-
    The frequency band is derived from the SETD5-variant column of Table 1 (3/7 = 43%).
    The same feature occurs in 3/4 individuals with a 3p25 deletion, but that contiguous
    deletion syndrome is a separate entity and is not the basis for this annotation.
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Depressed nasal bridge 3 3
    explanation: >-
      Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) with
      individuals with a 3p25 deletion (n = 4); the trailing counts give 3/7
      SETD5-variant individuals with a depressed nasal bridge. This replaces an
      earlier snippet that quoted the paper's summary of the 3p25-microdeletion
      phenotype, which is a different entity from the single-gene SETD5 disorder.
- category: Craniofacial
  name: Long Philtrum
  description: >
    A long, smooth, or prominent philtrum is a recurrent midface finding, recorded in
    5 of the 7 individuals carrying intragenic SETD5 loss-of-function variants in the
    gene-discovery cohort.
  frequency: FREQUENT
  notes: >-
    The frequency band is derived from the SETD5-variant column of Table 1 (5/7 = 71%).
    The source table scores this as a combined "long, smooth, and/or prominent
    philtrum" category, so the HPO term is narrower than the scored feature.
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Long, smooth, and/or prominent philtrum 53
    explanation: >-
      Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) with
      individuals with a 3p25 deletion (n = 4); the trailing counts give 5/7
      SETD5-variant individuals. This replaces an earlier snippet that quoted the
      paper's summary of the 3p25-microdeletion phenotype, which is a different
      entity from the single-gene SETD5 disorder this entry covers.
- category: Digestive
  name: Feeding Difficulties
  description: >
    Difficulties with swallowing and chewing were noted by several families and
    physicians in the gene-discovery cohort.
  frequency: FREQUENT
  notes: >-
    The frequency band is derived from the SETD5-variant column of Table 1 (5/7 = 71%).
    The narrative text reports the feature only qualitatively ("noted by several
    families and physicians"); the table supplies the count.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Feeding problems, particularly difﬁculties with swallowing and chewing, were noted by several families and physicians.
    explanation: >-
      Directly documents feeding difficulties.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Feeding difﬁculties 5 NA
    explanation: >-
      Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) with
      individuals with a 3p25 deletion (n = 4); the trailing values give 5/7
      SETD5-variant individuals, with the deletion column not available.
- category: Digestive
  name: Constipation
  description: >
    Constipation was reported by 47% of support-group survey respondents.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:42468298
    reference_title: Expanding the Phenotype of SETD5-Related Disorder Through a Facebook Support Group.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%).
    explanation: >-
      Reports constipation at 47%, within the FREQUENT band (30-79%).
- category: Eye
  name: Visual Impairment
  description: >
    Vision problems were reported by 51% of support-group survey respondents; mild
    ptosis, unilateral amblyopia, nystagmus, and strabismus were each described in
    single individuals in the gene-discovery cohort.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  notes: >-
    The generic HPO term is used deliberately: the survey reports "vision problems"
    as an undifferentiated category, and the case-level findings (ptosis, amblyopia,
    nystagmus, strabismus) were each single occurrences.
  evidence:
  - reference: PMID:42468298
    reference_title: Expanding the Phenotype of SETD5-Related Disorder Through a Facebook Support Group.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%).
    explanation: >-
      Reports vision problems at 51%, within the FREQUENT band (30-79%).
- category: Musculoskeletal
  name: Scoliosis
  description: >
    Thoracic scoliosis, kyphosis, and lordosis were reported, with 4 of 7 children in
    the gene-discovery cohort having skeletal abnormalities requiring varying degrees
    of intervention.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Also, 4/7 children had skeletal abnormalities that required varying degrees of intervention. Thoracic scoliosis, kyphosis, and lordosis were reported
    explanation: >-
      4 of 7 (57%) had skeletal abnormalities including scoliosis, mapping to the
      FREQUENT band (30-79%).
  - reference: PMID:28881385
    reference_title: "Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities.
    explanation: >-
      Independent cohort confirming skeletal abnormalities as a majority feature.
- category: Musculoskeletal
  name: Lower Limb Asymmetry
  description: >
    Significant leg-length discrepancy was present in 2 of the 7 children in the
    gene-discovery cohort, in one case together with talipes and hypoplasia of the
    left calf requiring surgery. It is the sibling skeletal finding to the scoliosis /
    kyphosis / lordosis reported in the same cohort and contributes to the same
    orthopedic management need.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Lower limb asymmetry
    term:
      id: HP:0100559
      label: Lower limb asymmetry
  notes: >-
    Frequency band is derived from the denominator stated in the same source: 2 of 7
    children (29%), the top of the OCCASIONAL band (5-29%). This is concordant with
    the HPO annotation of HP:0100559 to OMIM:615761 at 2/7. The cohort is small, so
    the point estimate is unstable even though the band assignment is defensible.
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thoracic scoliosis, kyphosis, and lordosis were reported, and two children had a signiﬁcant leg-length discrepancy (one of them also had talipes and hypoplasia of the left calf and required surgery).
    explanation: >-
      Documents leg-length discrepancy in two children of the seven-person cohort,
      giving both the phenotype and the 2/7 count underlying the OCCASIONAL band.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skeletal anomalies, including signiﬁcant leg-length discrepancy, were a frequent ﬁnding in two individuals.
    explanation: >-
      The abstract-level statement of the same finding, independently confirming the
      two-individual count.
- category: Musculoskeletal
  name: Limb Pain
  description: >
    Persistent leg pain (31%) and joint pain (27%) were identified as potential novel
    findings in the support-group survey and are not captured in the clinician-derived
    literature.
  notes: >-
    Frequency is omitted despite the reported percentages: these are parent-reported
    survey findings that the authors themselves label as potential novel findings
    requiring confirmation, and they have not been replicated in a clinician-ascertained
    cohort.
  phenotype_term:
    preferred_term: Limb pain
    term:
      id: HP:0009763
      label: Limb pain
  evidence:
  - reference: PMID:42468298
    reference_title: Expanding the Phenotype of SETD5-Related Disorder Through a Facebook Support Group.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Potential novel findings included high pain tolerance (43%), persistent leg pain (31%), and joint pain (27%).
    explanation: >-
      Reports persistent leg pain and joint pain, explicitly framed by the authors as
      potential novel findings.
- category: Neurologic
  name: Pain Insensitivity
  description: >
    High pain tolerance was reported by 43% of support-group survey respondents, a
    potential novel finding for this disorder.
  notes: >-
    Frequency is omitted: this is a parent-reported survey finding explicitly labelled
    by the authors as a potential novel finding requiring confirmation.
  phenotype_term:
    preferred_term: Pain insensitivity
    term:
      id: HP:0007021
      label: Pain insensitivity
  evidence:
  - reference: PMID:42468298
    reference_title: Expanding the Phenotype of SETD5-Related Disorder Through a Facebook Support Group.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Potential novel findings included high pain tolerance (43%), persistent leg pain (31%), and joint pain (27%).
    explanation: >-
      Reports high pain tolerance, explicitly framed by the authors as a potential
      novel finding.
- category: Cardiovascular
  name: Abnormal Heart Morphology
  description: >
    Congenital heart defects occur in a minority; mitral valve prolapse and a
    ventricular septal defect with patent ductus arteriosus were each seen once in the
    gene-discovery cohort, and congenital heart defects segregated with a SETD5
    variant in the reported familial case.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two children had congenital heart defects; one had a mitral valve prolapse, and the other had a ventricular septal defect with a patent ductus arteriosus
    explanation: >-
      2 of 7 (29%) had congenital heart defects, within the OCCASIONAL band (5-29%).
  - reference: PMID:27375234
    reference_title: SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present the first familial case of a SETD5 mutation contributing to a phenotype of congenital heart defects and dysmorphic features, with variable expression, in two siblings and their father.
    explanation: >-
      Independent familial documentation of congenital heart defects.
- category: Genitourinary
  name: Hypospadias
  description: >
    Hypospadias occurred in the gene-discovery cohort; 4 of 7 children had either an
    inguinal hernia or hypospadias repaired at a young age.
  notes: >-
    Frequency is omitted because the reported 4/7 figure is a combined count for
    inguinal hernia OR hypospadias, so neither individual anomaly can be banded.
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four of the seven children had either an inguinal hernia or hypospadias repaired at a young age.
    explanation: >-
      Documents hypospadias within the combined 4/7 count.
- category: Musculoskeletal
  name: Inguinal Hernia
  description: >
    Inguinal hernia occurred in the gene-discovery cohort; 4 of 7 children had either
    an inguinal hernia or hypospadias repaired at a young age.
  notes: >-
    Frequency is omitted because the reported 4/7 figure is a combined count for
    inguinal hernia OR hypospadias.
  phenotype_term:
    preferred_term: Inguinal hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four of the seven children had either an inguinal hernia or hypospadias repaired at a young age.
    explanation: >-
      Documents inguinal hernia within the combined 4/7 count.
- category: Digestive
  name: Abnormality of the Gastrointestinal Tract
  description: >
    Gastrointestinal and abdominal-wall anomalies were reported in 5 of the 7
    individuals in the gene-discovery cohort carrying intragenic SETD5 loss-of-function
    variants.
  frequency: FREQUENT
  notes: >-
    A broad HPO term is used deliberately because the source reports the finding as an
    undifferentiated "gastrointestinal and/or abdominal-wall anomalies" category
    without naming a specific malformation. The frequency band is derived from the
    SETD5-variant column of Table 1 (5/7 = 71%), not from the adjacent 3p25.3-deletion
    column, which is out of scope for this entry.
  phenotype_term:
    preferred_term: Abnormality of the gastrointestinal tract
    term:
      id: HP:0011024
      label: Abnormality of the gastrointestinal tract
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gastrointestinal and/ or abdominal-wall anomalies 51
    explanation: >-
      Table 1 row comparing individuals with SETD5 LoF mutations (n = 7) against
      individuals with a 3p25 deletion (n = 4); the two trailing digits are the
      per-column counts, giving 5/7 SETD5-variant individuals (and 1/4 deletion
      individuals) with gastrointestinal and/or abdominal-wall anomalies. This
      replaces an earlier snippet that quoted the paper's description of the
      smallest-3p25-microdeletion phenotype, which is a different entity from the
      single-gene SETD5 disorder this entry covers.
- category: Cardiovascular
  name: Moyamoya Phenomenon
  description: >
    Bilateral moyamoya angiopathy has been reported in an individual with a de novo
    SETD5 frameshift variant and in two further individuals with rare SETD5 missense
    variants. The authors of the index report state explicitly that additional data
    are required to validate the association.
  notes: >-
    Frequency is deliberately omitted and support is PARTIAL. This is an
    ascertainment-inverted association (moyamoya cohort screened for variants, not
    SETD5 cohort screened for moyamoya), and the authors say penetrance must be
    assessed before imaging can be recommended.
  phenotype_term:
    preferred_term: Moyamoya phenomenon
    term:
      id: HP:0011834
      label: Moyamoya phenomenon
  evidence:
  - reference: PMID:31474762
    reference_title: "The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A de novo SETD5 haploinsufficiency variant, p.Glu661Lysfs*5 (Fig. 1), was identified in a patient diagnosed with bilateral MMA at 10 years of age with a history of developmental delay, polydactyly, and mild dysmorphic facial features
    explanation: >-
      Documents the index SETD5 moyamoya case.
  - reference: PMID:31474762
    reference_title: "The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data indicate that rare variants in CHD4 and CNOT3 predispose to MMA in the presence and absence of DD; additional data are required to validate an association between SETD5 rare variants and MMA.
    explanation: >-
      The authors explicitly caveat the SETD5-moyamoya association, which is why this
      phenotype is recorded as PARTIAL with no frequency.
- category: Growth
  name: Growth Delay
  description: >
    Growth was normal in all seven individuals of the gene-discovery cohort, but
    severe short stature has been reported in an individual with a de novo SETD5
    variant and an overlap phenotype spanning MRD23, Cornelia de Lange, and KBG
    syndromes.
  notes: >-
    Frequency is omitted and the evidence is explicitly conflicting: the original
    cohort found normal growth parameters in all children, while a later single case
    had severe short stature. Both evidence items are retained so the discrepancy is
    visible rather than smoothed over.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:40869907
    reference_title: "Two Years of Growth Hormone Therapy in a Child with Severe Short Stature Due to Overlap Syndrome with a Novel SETD5 Gene Mutation: Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A female patient with severe short stature and intellectual disability had been followed since she was 9 years old.
    explanation: >-
      Documents severe short stature in an individual with a de novo SETD5 variant.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Growth parameters were within the normal range in all children
    explanation: >-
      Directly contradicts growth impairment as a general feature; growth was normal
      in all seven individuals of the gene-discovery cohort.
genetic:
- name: SETD5
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: SETD5
    term:
      id: hgnc:25566
      label: SETD5
  notes: >-
    Heterozygous germline loss-of-function variants (nonsense, frameshift, splice
    site) in SETD5 at 3p25.3 cause the disorder through haploinsufficiency. MONDO
    asserts RO:0004003 from MONDO:0014336 to HGNC:25566 (SETD5); this was verified
    with OAK before curation as the NEC anchor. SETD5 is intolerant to loss-of-function
    variation (pLI = 1) but not to missense variation, which is why LoF alleles rather
    than missense alleles dominate the pathogenic spectrum. In the National Brain Gene
    Registry cohort, 6 of 11 unique variants were nonsense, 4 frameshift, and 1 splice
    site.
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation sequencing approach
    explanation: >-
      Establishes the ascertainment design of the cohort in which SETD5 loss of
      function was validated as a cause of intellectual disability.
  - reference: PMID:40265665
    reference_title: Expansion of the Genotypic and Phenotypic Spectrum of SETD5 Disorder Using Data From the National Brain Gene Registry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the cohort, there were 11 unique pathogenic/likely pathogenic variants in 13 individuals from 11 different families. Of these 11 unique variants, 6 were nonsense, 4 were frameshift, and one was splice site.
    explanation: >-
      Quantifies the truncating-variant-dominated mutational spectrum in a registry
      cohort.
  - reference: PMID:31474762
    reference_title: "The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      SETD5 is intolerant to LoF variation (pLI = 1) but not missense variation (Z-score = −0.04).
    explanation: >-
      Population constraint metrics support haploinsufficiency as the mechanism and
      explain why missense alleles are less often pathogenic.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Diagnosis rests on identification of a heterozygous pathogenic SETD5 sequence
    variant, typically by trio exome sequencing performed for unexplained
    developmental delay or intellectual disability. Because the facial gestalt is
    non-specific, diagnosis is genotype-driven rather than gestalt-driven.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:25138099
    reference_title: Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To identify further genes involved in ID, we performed WES in 250 patients with unexplained ID and their unaffected parents and included exomes of 51 previously sequenced child-parents trios in the analysis.
    explanation: >-
      Documents trio exome sequencing as the diagnostic modality that identifies
      SETD5 variants in unexplained intellectual disability.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prior to mutation analysis, the clinical features alone were not sufﬁcient or consistent for clinicians to delineate this syndrome. In none of the individuals we report was a 3p25 microdeletion syndrome clinically suspected.
    explanation: >-
      Establishes that clinical gestalt is insufficient and that molecular testing is
      the necessary diagnostic route.
- name: Chromosomal Microarray Analysis
  description: >-
    Chromosomal microarray detects the 3p25.3 microdeletions that remove SETD5 and is
    complementary to sequencing; a deletion involving THUMPD3, SETD5, and THUMPD3-AS1
    yields the same haploinsufficiency mechanism as an intragenic variant.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: >-
    A deletion encompassing SETD5 at 3p25.3 supports the diagnosis; the boundary
    between the single-gene entity and the contiguous-gene syndrome depends on which
    additional genes the deletion removes.
  evidence:
  - reference: PMID:32793091
    reference_title: SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Array CGH analyses identified in P1 a pathogenic deletion at 3p25.3, involving the THUMPD3, SETD5, and THUMPD3-AS1 genes.
    explanation: >-
      Documents array CGH detection of the SETD5-containing 3p25.3 deletion.
  - reference: PMID:25138099
    reference_title: Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromosomal microarray diagnostics further identified four de novo non-recurrent microdeletions encompassing SETD5.
    explanation: >-
      Documents microarray identification of SETD5-encompassing deletions.
- name: DNA Methylation Episignature Testing
  description: >-
    Genome-wide DNA methylation profiling of peripheral blood using the clinically
    validated EpiSign assay resolves two problems that sequencing alone does not.
    First, it reclassifies SETD5 variants of uncertain significance: in a 400-person
    routine diagnostic neurodevelopmental cohort, methylation profiles supported the
    pathogenicity of variants previously called VUS and were diagnostically concordant
    with SETD5 among the disease-associated genes. Second, it addresses the KBG /
    Cornelia de Lange / SETD5 differential curated in `differential_diagnoses` below -
    although not by cleanly separating the entities, because SETD5 truncating variants
    match a combined KBGS_MRD23 episignature shared with ANKRD11-related KBG syndrome,
    reflecting the same ANKRD11-SETD5-HDAC3 convergence recorded in the KBG Syndrome
    and Cornelia de Lange Syndrome differentials. Disorder-specific secondary
    episignatures and MDS clustering are needed on top of the combined classifier to
    assign a case to one syndrome or the other.
  diagnosis_term:
    preferred_term: DNA methylation episignature (EpiSign) testing
    term:
      id: NCIT:C63328
      label: DNA Methylation Analysis
  results: >-
    A blood methylation profile matching the combined KBGS_MRD23 episignature supports
    the pathogenicity of a SETD5 sequence variant of uncertain significance. A
    non-matching profile does not exclude the diagnosis: three ANKRD11/SETD5 VUS in the
    same cohort showed no episignature concordant with KBGS_MRD23, and one ANKRD11
    truncating carrier was also episignature-negative.
  notes: >-
    The two general EpiSign catalogue papers suggested for this entry
    (PMID:32109418, the 42-syndrome episignature mapping study, and PMID:34906459,
    the chromatinopathy EpiSign cohort) do not name SETD5 or MRD23 anywhere in their
    cached abstracts, so neither can be cited for the SETD5-specific claim.
    PMID:32109418 is cited here only for the general principle that blood
    episignatures are used to interpret ambiguous genetic test results;
    PMID:34906459 is not cited at all. The SETD5-specific evidence comes from
    PMID:41957673, whose cached record is full text rather than abstract-only.
  evidence:
  - reference: PMID:41957673
    reference_title: "Chromatinopathies: clinically overlapping disorders, revealing novel variants and their DNA methylation signatures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      methylation profiles supported the pathogenicity of several variants previously classified as VUS and demonstrated diagnostic concordance with known disease-associated genes including ANKRD11, SETD5, KMT2A, KDM5C, CHD8, and others.
    explanation: >-
      Names SETD5 explicitly among the genes for which EpiSign methylation profiling
      was diagnostically concordant and supported reclassification of variants
      previously called VUS - the reclassification use case for this disorder.
  - reference: PMID:41957673
    reference_title: "Chromatinopathies: clinically overlapping disorders, revealing novel variants and their DNA methylation signatures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all other identified individuals with truncating variants inANKRD11andSETD5matched the established combined episignatures associated with both syndromes, KBGS_MRD23. Despite the range of MVPs in the positive cases shown in Fig.2, additional MDS clustering plots and disorder specific secondary episignatures for KBGS and MRD23 were used to add confidence to our final reporting.
    explanation: >-
      Establishes that the SETD5 episignature is a combined KBGS_MRD23 classifier
      shared with ANKRD11/KBG syndrome, and that secondary disorder-specific
      episignatures are required to resolve the KBG-versus-SETD5 differential. The
      gene symbols run together in the cached full text because the source marks them
      up in italics; the snippet is quoted byte-exactly.
  - reference: PMID:41957673
    reference_title: "Chromatinopathies: clinically overlapping disorders, revealing novel variants and their DNA methylation signatures."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three variants inANKRD11andSETD5,classified as VUS did not show episignatures concordant with KBGS_MRD23 (Table1).
    explanation: >-
      Bounds the test's negative predictive value: an episignature-negative result does
      not reclassify or exclude a SETD5 VUS. PARTIAL because the report does not
      establish a sensitivity figure for SETD5 specifically.
  - reference: PMID:32109418
    reference_title: Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results.
    explanation: >-
      Establishes the general clinical-utility principle for blood episignature testing
      in Mendelian neurodevelopmental disorders. PARTIAL and deliberately scoped: this
      abstract does not name SETD5 or MRD23, so it supports the modality but not the
      SETD5-specific claim, which rests on PMID:41957673.
differential_diagnoses:
- name: 3p25.3 Microdeletion Syndrome
  disease_term:
    preferred_term: 3p25.3 microdeletion syndrome
    term:
      id: MONDO:0018564
      label: 3p25.3 microdeletion syndrome
  description: >-
    A contiguous-gene deletion syndrome whose critical region contains THUMPD3, SETD5,
    and THUMPD3-AS1 within a 124 kb interval. SETD5 is regarded as the principal
    driver of the neurodevelopmental core, so the two entities share most clinical
    features - but they are separate entities because deletions can remove additional
    genes and are detected by a different assay.
  distinguishing_features:
  - >-
    Molecular: an intragenic SETD5 sequence variant defines the single-gene entity;
    a copy-number loss at 3p25.3 defines the microdeletion syndrome. The deletion may
    remove THUMPD3 and THUMPD3-AS1 in addition to SETD5, and larger 3p25-p26 deletions
    remove substantially more.
  - >-
    Clinical: the larger, more distal 3p deletions add low birth weight, microcephaly,
    telecanthus, ptosis, micrognathia, cleft palate, and congenital heart disease -
    features that are not characteristic of isolated SETD5 loss of function.
  - >-
    Assay: chromosomal microarray detects the deletion; sequencing detects the
    intragenic variant. Either may be the first-line test depending on presentation.
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deﬁning the minimum common overlap of deletions in multiple individuals has reduced the critical region for 3p25 microdeletion syndrome to three genes within a 124 kb interval.
    explanation: >-
      Defines the three-gene critical region that distinguishes the contiguous-gene
      syndrome from the single-gene entity.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a clinical syndrome characterized by ID, low birth weight, microcephaly, telecanthus, ptosis, micro- gnathia, cleft palate, and congenital heart disease
    explanation: >-
      Enumerates the distal-deletion features that are not characteristic of isolated
      SETD5 loss of function.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition.
    explanation: >-
      States the driver-gene relationship, the basis for treating SETD5
      haploinsufficiency as the principal contributor while keeping the deletion
      syndrome a separate entity.
- name: KBG Syndrome
  disease_term:
    preferred_term: KBG syndrome
    term:
      id: MONDO:0007846
      label: KBG syndrome
  description: >-
    ANKRD11-related KBG syndrome shares intellectual disability, developmental delay,
    behavioral features, and a partly overlapping facial appearance with SETD5
    haploinsufficiency, and individuals with SETD5 variants have been referred with
    suspected KBG syndrome. The two remain distinct clinical entities.
  distinguishing_features:
  - >-
    Gene: ANKRD11 (KBG) versus SETD5. The proteins physically interact and both engage
    HDAC3, which is the likely reason for the phenotypic convergence.
  - >-
    Hand anomalies characteristic of KBG syndrome were absent in two of three SETD5
    patients referred with suspected KBG, and expert review did not find a satisfactory
    KBG facial resemblance.
  evidence:
  - reference: PMID:32793091
    reference_title: SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whilst there is significant phenotypic overlap between the above-mentioned conditions, however, they still remain distinct clinical entities.
    explanation: >-
      Directly supports keeping SETD5 haploinsufficiency, KBG syndrome, and 3p25.3
      deletion syndrome as separate entities despite overlap.
  - reference: PMID:32793091
    reference_title: SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of note, two out of the three patients do not show hand anomalies consistent with KBGS, which are good diagnostic clues for differential diagnosis
    explanation: >-
      Identifies hand anomalies as the discriminating clinical clue.
  - reference: PMID:32793091
    reference_title: SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Interestingly, the ANKRD11 and SETD5 proteins physically interact at the molecular level as demonstrated by spectrometry assays performed in mouse embryonic stem cells and mouse neural progenitor cells
    explanation: >-
      Provides the molecular basis for the phenotypic overlap between the two
      disorders.
- name: Cornelia de Lange Syndrome
  disease_term:
    preferred_term: Cornelia de Lange syndrome
    term:
      id: MONDO:0016033
      label: Cornelia de Lange syndrome
  description: >-
    SETD5 variants have been reported in individuals ascertained with Cornelia de
    Lange-overlapping phenotypes, driven largely by the shared eyebrow findings
    (synophrys, full broad eyebrows) and developmental delay.
  distinguishing_features:
  - >-
    Gene: the cohesin-pathway genes (NIPBL and others) versus SETD5; the overlap has
    led to SETD5 being grouped with the "cohesin-related" syndromes.
  evidence:
  - reference: PMID:32793091
    reference_title: SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Currently, mutations in both SETD5 and ANKRD11 genes have been identified in patients with Cornelia de Lange (CdL) syndrome overlapping phenotypes, resulting in the terminology of “cohesin-related” syndromes
    explanation: >-
      Documents the Cornelia de Lange-overlapping presentations that make CdL a
      relevant differential.
  - reference: PMID:40869907
    reference_title: "Two Years of Growth Hormone Therapy in a Child with Severe Short Stature Due to Overlap Syndrome with a Novel SETD5 Gene Mutation: Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SEDT5 gene variants have been described in patients with KBG and Cornelia de Lange (CdL) syndromes.
    explanation: >-
      Independent confirmation that SETD5 variants present as KBG- and CdL-overlapping
      phenotypes.
- name: SETD1B-Related Neurodevelopmental Disorder
  disease_term:
    preferred_term: SETD1B-related neurodevelopmental disorder
    term:
      id: MONDO:0033559
      label: intellectual developmental disorder with seizures and language delay
  description: >-
    A paralogue-adjacent chromatin disorder that is a named-entity-confusion hazard
    rather than a close clinical mimic. SETD1B-NDD is caused by heterozygous SETD1B
    (HGNC:29187, 12q24.31) loss-of-function variants and is dominated by epilepsy,
    including myoclonic absences, in most affected individuals.
  distinguishing_features:
  - >-
    Gene and locus: SETD1B at 12q24.31 versus SETD5 at 3p25.3; different HGNC IDs
    (HGNC:29187 versus HGNC:25566) and different MONDO/OMIM entities
    (MONDO:0033559/OMIM:619000 versus MONDO:0014336/OMIM:615761).
  - >-
    Seizures occur in most individuals with SETD1B-NDD but in only about 14% of the
    SETD5 multicenter cohort, so epilepsy burden is a useful clinical discriminator.
  evidence:
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epilepsy was present in about 14 % of patients, including different types of seizures as epileptic spasms, focal motor, and non-motor seizures.
    explanation: >-
      Establishes the low SETD5 epilepsy burden that distinguishes it from the
      epilepsy-dominated SETD1B disorder; the SETD1B side of the comparison is
      curated in the separate SETD1B-Related_Neurodevelopmental_Disorder entry.
prevalence:
- population: Individuals ascertained for unexplained intellectual disability
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population prevalence estimate exists for this disorder. The only quantitative
    figures in the literature are diagnostic yields within intellectual-disability
    cohorts: 7/996 (0.7%) in the UK10K targeted-sequencing cohort and 2/301 (0.7%) in
    an exome cohort. These are yields conditional on ascertainment for intellectual
    disability, not population rates, and are deliberately not converted into a
    rate_per_100000.
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID.
    explanation: >-
      Gives the 0.7% diagnostic yield in the 996-person intellectual-disability
      cohort described in the same abstract.
  - reference: PMID:25138099
    reference_title: Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present report of two SETD5 LoF variants in 301 patients demonstrates a prevalence of 0.7% and thus SETD5 variants as a relatively frequent cause of ID.
    explanation: >-
      Independently replicates the 0.7% yield in a separate exome cohort.
treatments:
- name: Developmental and Educational Support
  description: >-
    Early intervention, speech and language therapy, occupational and physical
    therapy, and individualized educational support address the core developmental
    phenotype. No disease-modifying therapy exists; management is symptomatic and
    anticipatory.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  notes: >-
    There is no GeneReviews management chapter for this disorder, so the evidence
    below establishes the treatable phenotype targets rather than an evaluated
    intervention protocol. The specific therapy modalities named here are standard
    neurodevelopmental care, not SETD5-specific recommendations.
  evidence:
  - reference: PMID:42468298
    reference_title: Expanding the Phenotype of SETD5-Related Disorder Through a Facebook Support Group.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Findings expand the phenotypic spectrum and inform prognosis, surveillance, and management.
    explanation: >-
      Supports phenotype-directed management as the current standard of care; it does
      not evaluate any specific intervention.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Older children had required special schooling because of their ID and behavioral problems, although some attended mainstream school at a young age but required educational statements and extra support.
    explanation: >-
      Directly documents the educational support requirements of affected children.
- name: Antiseizure Medication
  description: >-
    Standard antiseizure medication is used in the minority of individuals who develop
    epilepsy. No SETD5-specific agent or protocol has been established, seizure types
    are heterogeneous, and drug-resistant epilepsy has been reported.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  notes: >-
    No therapeutic_agent is recorded because no specific drug has been evaluated for
    this disorder; naming one would overstate the evidence.
  evidence:
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epilepsy was present in about 14 % of patients, including different types of seizures as epileptic spasms, focal motor, and non-motor seizures.
    explanation: >-
      Establishes the treatable epilepsy population and its heterogeneity; the cohort
      does not evaluate antiseizure medication efficacy.
  - reference: PMID:40462669
    reference_title: A Novel Epilepsy Phenotype in a Young Girl With a Pathogenic SETD5 Gene Variant.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings confirm that epilepsy may arise after SETD5 variants, with subtle clinical manifestations that may overlap with behavioral phenomena in children who also exhibit cognitive and behavioral comorbidities.
    explanation: >-
      Supports vigilance for subtle seizures that may be mistaken for behavioral
      events, which is the practical prerequisite for treating them.
- name: Psychiatric and Behavioral Pharmacotherapy
  description: >-
    Psychotropic medication is used as standard neurodevelopmental care for the
    psychiatric and behavioral burden of this disorder - anxiety in about 47%, plus
    ADHD, psychotic disorder, and obsessive-compulsive/ritualized behavior. Treatment
    follows general psychiatric practice for the individual symptom cluster; no
    SETD5-specific agent, dose, or protocol has been evaluated.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  - preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  - preferred_term: Psychosis
    term:
      id: HP:0000709
      label: Psychosis
  - preferred_term: Compulsive behaviors
    term:
      id: HP:0000722
      label: Compulsive behaviors
  notes: >-
    No therapeutic_agent is recorded because no drug has been evaluated in this
    disorder; naming one would overstate the evidence. This follows the same
    convention as the Antiseizure Medication entry. The evidence below is PARTIAL
    throughout and establishes only the size and composition of the treatable
    psychiatric population - none of the cited studies measures the efficacy, safety,
    or comparative effectiveness of any psychotropic drug in SETD5 haploinsufficiency,
    and one source notes that subtle seizures can be mistaken for behavioral
    phenomena, so a psychiatric attribution should not be assumed before
    neurological evaluation.
  evidence:
  - reference: PMID:39603091
    reference_title: Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other psychiatric comorbidities include autism, ADHD, psychotic disorder and other internalizing and externalizing symptoms.
    explanation: >-
      Establishes the composition of the treatable psychiatric population in a
      multicenter cohort. PARTIAL because the cohort characterizes the phenotype and
      does not evaluate any pharmacological intervention.
  - reference: PMID:42468298
    reference_title: Expanding the Phenotype of SETD5-Related Disorder Through a Facebook Support Group.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%).
    explanation: >-
      Quantifies anxiety at 47%, the largest single psychiatric target. PARTIAL because
      this is a parent-reported survey of burden, not a treatment study.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features.
    explanation: >-
      Independent cohort documenting the obsessive-compulsive and ritualized-behavior
      component of the treatable population. PARTIAL because no intervention is
      reported.
- name: Recombinant Growth Hormone Therapy
  description: >-
    Recombinant growth hormone was given from age 12 to a girl with a de novo SETD5
    variant and severe short stature (-5.22 SDS) in an overlap phenotype spanning
    MRD23, Cornelia de Lange, and KBG syndromes; growth velocity increased
    significantly over two years. This is a single case and is not established therapy
    for the disorder.
  action_category: THERAPEUTIC
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  notes: >-
    Evidence strength is deliberately low. This is n=1, uncontrolled, and short
    stature was normal in all seven individuals of the original SETD5 cohort, so this
    is not generalizable guidance. It is recorded because it is the only reported
    pharmacological intervention with a measured outcome in this disorder.
  evidence:
  - reference: PMID:40869907
    reference_title: "Two Years of Growth Hormone Therapy in a Child with Severe Short Stature Due to Overlap Syndrome with a Novel SETD5 Gene Mutation: Case Report and Review of the Literature."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recombinant growth hormone therapy (rhGH) was started at the age of 12 years. After both one year (+3.16 SDS) and two years (+2.9 SDS), the growth rate significantly increased compared with the pre-therapy period.
    explanation: >-
      Documents the measured growth response; PARTIAL because it is an uncontrolled
      single case.
  - reference: PMID:40869907
    reference_title: "Two Years of Growth Hormone Therapy in a Child with Severe Short Stature Due to Overlap Syndrome with a Novel SETD5 Gene Mutation: Case Report and Review of the Literature."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is the first case of a patient with overlap syndrome due to SETD5 mutation treated with rhGH.
    explanation: >-
      The authors state this is the first such case, confirming that the evidence base
      is a single report.
- name: Orthopedic and Skeletal Management
  description: >-
    Skeletal anomalies including thoracic scoliosis, kyphosis, lordosis, and
    significant leg-length discrepancy required varying degrees of intervention in 4 of
    7 individuals in the gene-discovery cohort, including surgery in one child with
    talipes and calf hypoplasia.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_phenotypes:
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  - preferred_term: Lower limb asymmetry
    term:
      id: HP:0100559
      label: Lower limb asymmetry
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Also, 4/7 children had skeletal abnormalities that required varying degrees of intervention.
    explanation: >-
      Directly documents that skeletal abnormalities required orthopedic intervention.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and two children had a signiﬁcant leg-length discrepancy (one of them also had talipes and hypoplasia of the left calf and required surgery)
    explanation: >-
      Documents surgical management of the limb findings.
- name: Ophthalmologic Assessment
  description: >-
    Vision problems affect about half of individuals, and ptosis, amblyopia,
    nystagmus, and strabismus have been documented, so ophthalmologic assessment is
    warranted.
  action_category: MONITORING
  treatment_term:
    preferred_term: eye examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  evidence:
  - reference: PMID:42468298
    reference_title: Expanding the Phenotype of SETD5-Related Disorder Through a Facebook Support Group.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%).
    explanation: >-
      Establishes the high burden of vision problems that motivates ophthalmologic
      assessment; the survey does not evaluate a surveillance protocol.
- name: Inguinal Hernia and Hypospadias Repair
  description: >-
    Surgical repair of inguinal hernia or hypospadias was required at a young age in 4
    of 7 individuals in the gene-discovery cohort.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Inguinal hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  - preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four of the seven children had either an inguinal hernia or hypospadias repaired at a young age.
    explanation: >-
      Directly documents surgical repair of these anomalies.
- name: Genetic Counseling
  description: >-
    Counseling should cover autosomal dominant inheritance, the usual de novo
    occurrence, the 50% transmission risk from an affected individual, and - critically
    for this disorder - incomplete penetrance, since apparently unaffected and mildly
    affected carrier parents have been documented. Parental testing is therefore
    important before assuming de novo status.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:28881385
    reference_title: "Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons.
    explanation: >-
      Documents the non-penetrant carriers that make incomplete penetrance a required
      counseling point.
  - reference: PMID:27375234
    reference_title: SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Family based exome sequencing combined to careful parental phenotyping may reveal a more complex clinical picture in newly recognized syndromes.
    explanation: >-
      Supports careful parental phenotyping and family-based testing as part of
      counseling.
animal_models:
- species: Mouse
  genotype: Setd5 heterozygous null (Setd5+/-)
  description: >-
    The Setd5 null mouse is embryonic lethal; the heterozygote is viable and is the
    principal model. It reproduces cognitive impairment, behavioral inflexibility,
    delayed ultrasonic vocalization ontogeny, altered social recognition, hyperactivity,
    reduced synaptic density and cortical network hypoconnectivity, a deep-layer
    cortical neuron deficit, MRI-detectable brain anatomical differences, neural crest
    defect-associated phenotypes, and mitochondrial fragmentation with reduced ATP
    production.
  genes:
  - preferred_term: SETD5
    term:
      id: hgnc:25566
      label: SETD5
  associated_phenotypes:
  - Cognitive impairment and behavioral inflexibility
  - Delayed ontogenetic profile of ultrasonic vocalization
  - Reduced synaptic density and cortical network hypoconnectivity
  - Deficit of deep-layer cortical neurons
  - Enhanced long-term potentiation
  - Mitochondrial fragmentation and reduced ATP production
  evidence:
  - reference: PMID:30455454
    reference_title: Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalization, and behavioral inflexibility.
    explanation: >-
      Establishes the cognitive, communication, and plasticity phenotypes of the
      heterozygous mouse.
  - reference: PMID:30655503
    reference_title: Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Setd5 is the highly conserved mouse homolog, and although the Setd5 null mouse is embryonic lethal, the heterozygote is viable.
    explanation: >-
      Establishes why the heterozygote, not the null, is the usable model and confirms
      homology.
  - reference: PMID:30655503
    reference_title: Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Setd5+/- animals manifested several autism-like behaviors, including hyperactivity, cognitive deficit, and altered social interactions.
    explanation: >-
      Documents the autism-relevant behavioral phenotype used for construct validity.
- species: Mouse
  genotype: Setd5 heterozygous null and cardiopharyngeal-mesoderm conditional mutant
  description: >-
    A separate mouse study identified Setd5 while screening embryonic-lethal mutants
    for 22q11.2-deletion-like cardiovascular phenotypes. Setd5 haploinsufficiency
    produced double outlet right ventricle and perimembranous ventricular septal
    defect, and conditional mutagenesis showed Setd5 is required in cardiopharyngeal
    mesoderm for heart-tube progression. This is the strongest mechanistic
    corroboration for the congenital heart defects seen in affected humans, although
    the specific mouse lesions are not the same as the human mitral valve prolapse and
    VSD/PDA reported to date.
  genes:
  - preferred_term: SETD5
    term:
      id: hgnc:25566
      label: SETD5
  associated_phenotypes:
  - Double outlet right ventricle
  - Perimembranous ventricular septal defect
  evidence:
  - reference: PMID:34050709
    reference_title: Setd5 is required in cardiopharyngeal mesoderm for heart development and its haploinsufficiency is associated with outflow tract defects in mouse.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found murine Setd5 haploinsufficiency to be associated with double outlet right ventricle and perimembranous ventricular septal defect, although no genetic interaction with Tbx1 was detected.
    explanation: >-
      Directly documents outflow-tract cardiac malformation from Setd5
      haploinsufficiency.
  - reference: PMID:34050709
    reference_title: Setd5 is required in cardiopharyngeal mesoderm for heart development and its haploinsufficiency is associated with outflow tract defects in mouse.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Conditional mutagenesis revealed that Setd5 was required in cardiopharyngeal mesoderm for progression of the heart tube through the ballooning stage to create a four-chambered heart.
    explanation: >-
      Localizes the cardiac requirement to cardiopharyngeal mesoderm, giving a
      developmental mechanism for the congenital heart defects.
- species: Zebrafish
  genotype: CRISPR/Cas9-generated setd5 heterozygous mutant
  description: >-
    Heterozygous setd5 zebrafish show defective shoaling aggregation and coordination
    and indifference to social stimuli, with downregulation of synaptic
    structure/function genes in the adult brain. Social interest was rescued by
    risperidone, making this a tractable model for symptomatic drug screening. The
    rescue is of an ASD-like behavioral readout in fish and does not constitute
    evidence for risperidone efficacy in the human disorder.
  genes:
  - preferred_term: SETD5
    term:
      id: hgnc:25566
      label: SETD5
  associated_phenotypes:
  - Impaired social interest and shoaling behavior
  - Downregulation of synaptic structure and function genes
  evidence:
  - reference: PMID:36613611
    reference_title: "CRISPR/Cas9-Induced Inactivation of the Autism-Risk Gene setd5 Leads to Social Impairments in Zebrafish."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we found that setd5 heterozygous mutants exhibit defective aggregation and coordination abilities required for shoaling interactions, as well as indifference to social stimuli
    explanation: >-
      Documents the social-behavior phenotype of the zebrafish model.
  - reference: PMID:36613611
    reference_title: "CRISPR/Cas9-Induced Inactivation of the Autism-Risk Gene setd5 Leads to Social Impairments in Zebrafish."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Interestingly, impairment in social interest is rescued by risperidone, an antipsychotic drug used to treat behavioral traits in ASD individuals.
    explanation: >-
      Documents a pharmacological rescue in the fish model; PARTIAL because it is a
      model-organism behavioral readout with no human evidence in this disorder.
  - reference: PMID:36613611
    reference_title: "CRISPR/Cas9-Induced Inactivation of the Autism-Risk Gene setd5 Leads to Social Impairments in Zebrafish."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The molecular analysis underscored the downregulation of genes encoding proteins involved in the synaptic structure and function in the adult brain, thus suggesting that brain hypo-connectivity could be responsible for the social impairments of setd5 mutant fishes.
    explanation: >-
      Independently corroborates the synaptic/hypoconnectivity mechanism in a second
      species.
discussions:
- discussion_id: nec_setd5_vs_3p253_deletion
  kind: INTERPRETATION
  status: OPEN
  prompt: >-
    Should the single-gene SETD5 haploinsufficiency entity and the contiguous 3p25.3
    microdeletion syndrome be modelled as one entity or two?
  rationale: >-
    dismech keeps them as two entities. SETD5 is now regarded as the principal driver
    of the 3p25.3 deletion neurodevelopmental phenotype - the critical region was
    narrowed to a 124 kb three-gene interval, and SETD5 loss of function reproduces
    the core features - which is a strong lumping argument. Against lumping: (i) 3p25.3
    deletions vary in size and can remove THUMPD3, THUMPD3-AS1, and, in the larger
    3p25-p26 deletions, many additional genes, adding features (low birth weight,
    microcephaly, telecanthus, cleft palate) that are not characteristic of isolated
    SETD5 loss of function; (ii) MONDO models them as distinct terms with distinct
    OMIM anchors; (iii) the diagnostic assay differs (microarray versus sequencing);
    and (iv) authors who deeply phenotyped both explicitly argue the overlapping
    chromatin disorders "still remain distinct clinical entities" and that lumping is
    unhelpful for families. This entry therefore scopes to the intragenic-variant
    entity anchored on MONDO:0014336 / OMIM:615761 / HGNC:25566, and records the
    deletion syndrome as a differential diagnosis. A separate consideration:
    Orphanet has obsoleted its own standalone term for this concept (ORPHA:404440),
    which shows the boundary is genuinely contested at the nosology level.
  evidence:
  - reference: PMID:32793091
    reference_title: SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whilst there is significant phenotypic overlap between the above-mentioned conditions, however, they still remain distinct clinical entities. This is important for long term support to patients and families, as there are differences and subtleties in both clinical features and neurodevelopmental profiles between these conditions which become apparent only when patients are deeply phenotyped.
    explanation: >-
      Directly argues for keeping the overlapping SETD5 / 3p25.3-deletion / KBG
      entities separate, which is the split rationale adopted here.
  - reference: PMID:24680889
    reference_title: "De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition.
    explanation: >-
      States the driver-gene relationship that motivates the lumping argument, kept
      visible alongside the split decision.
  - reference: ORPHA:404440
    reference_title: "OBSOLETE: Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency"
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      OBSOLETE: Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency
    explanation: >-
      Orphanet has retired its standalone term for this concept in the 2025-12-09
      snapshot. This is recorded as PARTIAL because obsoleting an Orphanet code is a
      nosology-management action whose rationale is not stated in the record; it shows
      the boundary is contested but does not by itself argue for lumping.
  attaches_to:
  - "pathophysiology#SETD5 Haploinsufficiency"
- discussion_id: gap_setd5_catalytic_activity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is SETD5 itself a catalytically active histone methyltransferase, or does it act
    principally as a scaffold within HDAC3- and PAF1-containing complexes?
  rationale: >-
    The mechanism nodes in this entry deliberately avoid asserting a settled enzymatic
    defect. One study demonstrates that SETD5 directly deposits H3K36me3, while other
    groups describe the direct methyltransferase activity as debated and emphasize
    scaffolding through HDAC-containing complexes. The answer matters because it
    determines whether a catalytic-rescue therapeutic strategy is even conceptually
    available.
  evidence:
  - reference: PMID:37264456
    reference_title: SETD5 haploinsufficiency affects mitochondrial compartment in neural cells.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The direct function of SETD5 as histone methyltransferase activity is debated
    explanation: >-
      States the open question directly.
  - reference: PMID:31515109
    reference_title: SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Notably, we demonstrated that SETD5 directly deposits H3K36me3, which is essential to allow on-time RNA elongation dynamics.
    explanation: >-
      Presents the opposing evidence that SETD5 does deposit the mark directly.
  attaches_to:
  - "pathophysiology#Impaired H3K36 Methylation and Chromatin Regulation"
- discussion_id: mismatch_setd5_mitochondrial_hierarchy
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Do the mitochondrial fragmentation and bioenergetic deficits seen in Setd5+/- mouse
    neural cells occur in human SETD5-haploinsufficient neurons, and where do they sit
    in the causal hierarchy of the human disease?
  rationale: >-
    The mitochondrial phenotype is well characterized in mouse neural stem cells,
    neurons, and cortex, but has not been demonstrated in human patient-derived neural
    cells, and the authors explicitly state that they can only speculate about its
    position in the pathological hierarchy. Whether it is a driver, a parallel
    consequence of transcriptional dysregulation, or an epiphenomenon determines
    whether mitochondrial-targeted intervention is worth pursuing.
  evidence:
  - reference: PMID:37264456
    reference_title: SETD5 haploinsufficiency affects mitochondrial compartment in neural cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found several defects in the mitochondrial compartment; however, we can only speculate about their position in the hierarchy of the pathological mechanisms at the basis of the disease.
    explanation: >-
      The authors' own statement of the translational and causal uncertainty.
  - reference: PMID:37264456
    reference_title: SETD5 haploinsufficiency affects mitochondrial compartment in neural cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We investigated in vitro neural stem cells as well as the brain of the Setd5 haploinsufficiency mouse model interrogating its transcriptome, analyzing mitochondrial structure, biochemical composition, and dynamics, as well as mitochondrial functionality.
    explanation: >-
      Establishes that the evidence base is entirely a mouse model plus derived neural
      stem cells, not human patient tissue.
  proposed_experiments:
  - experiment_id: exp_setd5_patient_ipsc_mitochondrial_phenotyping
    name: Patient-derived iPSC neural mitochondrial phenotyping
    description: >-
      Derive iPSC neural progenitors and cortical neurons from individuals with
      confirmed SETD5 loss-of-function variants alongside isogenic corrected controls,
      and measure mitochondrial morphology, membrane potential, ATP production, and
      axonal/synaptic mitochondrial localization. This tests whether the mouse
      mitochondrial phenotype is reproduced in human SETD5-haploinsufficient neurons.
  - experiment_id: exp_setd5_mitochondrial_epistasis
    name: Epistasis test placing the mitochondrial defect in the causal hierarchy
    description: >-
      Determine whether restoring rDNA output (for example by TIP5 ablation, which
      already rescues the proliferation defect) or correcting RNA polymerase II
      elongation also rescues the mitochondrial phenotype. Rescue would place the
      mitochondrial defect downstream of transcriptional dysregulation; failure to
      rescue would place it in a parallel branch.
  attaches_to:
  - "pathophysiology#Mitochondrial Fragmentation and Bioenergetic Deficit in Neural Cells"
- discussion_id: gap_setd5_penetrance_modifiers
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What determines whether a carrier of a SETD5 loss-of-function variant is severely
    affected, mildly affected, or clinically unaffected?
  rationale: >-
    Penetrance is incomplete and expressivity is highly variable: an apparently
    unaffected carrier mother, a carrier mother of normal intelligence with two
    affected twin sons, and a transmitting father with only mild intellectual
    impairment have all been reported, while the same class of truncating variant
    produces moderate-to-severe intellectual disability in others. No modifier -
    genetic background, variant position, transcript usage, sex, or mosaicism - has
    been established. This directly affects genetic counseling and recurrence-risk
    communication.
  evidence:
  - reference: PMID:28881385
    reference_title: "Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We suggest that the phenotype of SETD5 is more complex and variable than previously presented.
    explanation: >-
      States the variability problem that this gap addresses.
  - reference: PMID:27375234
    reference_title: SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, the father demonstrated only mild intellectual impairment.
    explanation: >-
      Documents a minimally affected transmitting parent within a family carrying the
      same variant as more severely affected children.
  attaches_to:
  - "pathophysiology#SETD5 Haploinsufficiency"
- discussion_id: gap_setd5_moyamoya_surveillance
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is cerebrovascular imaging surveillance for moyamoya angiopathy warranted in
    individuals with pathogenic SETD5 variants?
  rationale: >-
    Bilateral moyamoya angiopathy has been reported with a de novo SETD5 frameshift
    variant and with two rare SETD5 missense variants, but the ascertainment ran from
    moyamoya cohorts to variants rather than the reverse, and the authors state that
    the SETD5-moyamoya association still requires validation and that penetrance must
    be assessed before imaging can be recommended. Because moyamoya causes childhood
    strokes and is treatable, resolving this is clinically consequential.
  evidence:
  - reference: PMID:31474762
    reference_title: "The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional studies to assess the penetrance of MMA are required before we can recommend imaging for all the patients carrying de novo variants in CHD4, CNOT3, and SETD5
    explanation: >-
      The authors explicitly frame surveillance as an unresolved question pending
      penetrance data.
  - reference: PMID:31474762
    reference_title: "The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data indicate that rare variants in CHD4 and CNOT3 predispose to MMA in the presence and absence of DD; additional data are required to validate an association between SETD5 rare variants and MMA.
    explanation: >-
      Distinguishes the validated CHD4/CNOT3 associations from the still-unvalidated
      SETD5 association.
  attaches_to:
  - "pathophysiology#Extra-Neural Developmental Involvement"

📚

References & Deep Research

References

17

PMID:24680889

De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability.

No top-level findings curated for this source.

PMID:25138099

Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome.

No top-level findings curated for this source.

PMID:28881385

Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance.

No top-level findings curated for this source.

PMID:39603091

Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder.

No top-level findings curated for this source.

PMID:42468298

Expanding the Phenotype of SETD5-Related Disorder Through a Facebook Support Group.

No top-level findings curated for this source.

PMID:40265665

Expansion of the Genotypic and Phenotypic Spectrum of SETD5 Disorder Using Data From the National Brain Gene Registry.

No top-level findings curated for this source.

PMID:31515109

SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring.

No top-level findings curated for this source.

PMID:30455454

Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition.

No top-level findings curated for this source.

PMID:32299058

The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression.

No top-level findings curated for this source.

PMID:37264456

SETD5 haploinsufficiency affects mitochondrial compartment in neural cells.

No top-level findings curated for this source.

PMID:30655503

Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.

No top-level findings curated for this source.

PMID:31474762

The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.

No top-level findings curated for this source.

PMID:32793091

SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome.

No top-level findings curated for this source.

PMID:27375234

SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression.

No top-level findings curated for this source.

PMID:36875494

Structure, activity and function of the lysine methyltransferase SETD5.

No top-level findings curated for this source.

PMID:40869907

Two Years of Growth Hormone Therapy in a Child with Severe Short Stature Due to Overlap Syndrome with a Novel SETD5 Gene Mutation: Case Report and Review of the Literature.

No top-level findings curated for this source.

PMID:40462669

A Novel Epilepsy Phenotype in a Young Girl With a Pathogenic SETD5 Gene Variant.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

SETD5 Haploinsufficiency Syndrome — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-opus-5[1m] 15 citations 2026-07-31T18:46:42.041437

SETD5 Haploinsufficiency Syndrome — Comprehensive Research Report

Prepared: 2026-07-31 · Target entity: Intellectual disability–facial dysmorphism syndrome due to SETD5 haploinsufficiency (MRD23 / IDD23 / "SETD5 Disorder") · Intended use: dismech knowledge-base entry population

⚠️ Verification preamble (read before curating)

Three provenance caveats apply to everything below:

Quote status. Quotes marked [CACHE-VERIFIED] were read character-for-character from references_cache/PMID_*.md files already present in this worktree and are safe to use as evidence snippet: values. Quotes marked [UNVERIFIED-QUOTE] were extracted by a summarizing web-fetch layer; they are probably exact but must be re-checked with just fetch-reference PMID:XXXX + just validate-references before being committed as snippets.
Ontology IDs. Every HP/GO/CL/UBERON/CHEBI/NCIT term below is a suggestion. Two GO terms curators commonly reach for here are obsolete and must not be used: GO:0010452 ("obsolete histone H3-K36 methylation") and GO:0034968 ("obsolete histone lysine methylation") — both were deprecated as mis-namespaced BP terms. Confirmed-live alternatives are given in §6. Run just validate-terms on everything.
Named Entity Confusion (NEC) risk — HIGH for this disease. SETD5 sits in a naming minefield. Specifically:
ORPHA:435638 "Proximal 3p25.3 microdeletion syndrome" (MONDO:0018564) is a different disease — an ID/epilepsy/stereotypic-hand-movement entity from a more proximal 3p25.3 interval, not the SETD5 critical region. Do not merge.
OMIM:615743 is the gene SETD5; OMIM:615761 is the phenotype MRD23. Easy to swap.
KBG syndrome (ANKRD11) and Cornelia de Lange syndrome (NIPBL) are genuine clinical mimics with real published SETD5 cases; literature retrieved under "KBG" or "CdLS" queries may or may not be about SETD5.
Much of the PubMed hit list for "SETD5" is oncology (PDAC, NSCLC, breast, glioma, colorectal), where SETD5 is overexpressed/hyperactive — the mechanistic opposite of the germline haploinsufficiency disorder. Do not cross-import mechanism.

1. Disease Information

Overview

SETD5 haploinsufficiency syndrome is an autosomal dominant, essentially always de novo, neurodevelopmental chromatinopathy caused by heterozygous loss-of-function of SETD5 at 3p25.3. It is defined by global developmental delay/intellectual disability, prominent speech and language impairment, hypotonia, feeding difficulties in infancy, a recognizable but non-specific facial gestalt (brachycephaly, high forehead, synophrys/full broad eyebrows, long tubular nose, upslanting palpebral fissures, low-set fleshy ears, thin upper lip, low anterior hairline), and a high burden of behavioral/psychiatric comorbidity (autism, ADHD, obsessive-compulsive features, hand flapping, stereotypies). Variable additional features include congenital heart defects, skeletal/limb anomalies (notably leg-length discrepancy), short stature, epilepsy, and a growing list of newly reported systemic associations.

It is the principal single-gene explanation for the classic 3p25 (3p–) microdeletion syndrome phenotype: SETD5 lies within the 124 kb critical interval and deletion versus intragenic LoF produce a largely overlapping presentation.

"SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition." — Grozeva et al. 2014, Am J Hum Genet (PMID:24680889) [UNVERIFIED-QUOTE]

Key identifiers

Resource	Identifier	Notes
MONDO	`MONDO:0014336`	Label: intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (verified via OLS4)
OMIM (phenotype)	`OMIM:615761`	Intellectual developmental disorder, autosomal dominant 23 (MRD23 / IDD23)
OMIM (gene)	`OMIM:615743`	SETD5
Orphanet	`ORPHA:404440`	⚠️ Marked OBSOLETE in the Orphadata 2025-12-09 snapshot (`references_cache/ORPHA_404440.md`); MONDO still xrefs it
UMLS	`C3810406`
MedGen	`816736`
DOID	`DOID:0070053`
ClinGen GDV disease	`MONDO:0800439`	⚠️ ClinGen curates the gene–disease pair against syndromic complex neurodevelopmental disorder, not MONDO:0014336 — a real identifier discrepancy worth recording
Related-but-distinct	`ORPHA:435638` / `MONDO:0018564`	Proximal 3p25.3 microdeletion syndrome (ICD-10 Q93.5, ICD-11 LD44.31) — different entity
ICD-10	F79 / Q87.8 (syndrome); Q93.5 for the deletion form	No dedicated code for MRD23
ICD-11	No dedicated code identified; deletion form maps to LD44.31	Treat as unresolved

Synonyms

Intellectual developmental disorder, autosomal dominant 23 (IDD23)
Mental retardation, autosomal dominant 23 (MRD23) — historic/discouraged
Intellectual disability–facial dysmorphism syndrome due to SETD5 haploinsufficiency
SETD5-related neurodevelopmental disorder / SETD5-related disorder / SETD5 Disorder (the term used by the National Brain Gene Registry)
3p25.3 microdeletion syndrome (SETD5-containing form) / 3p– syndrome critical-region phenotype

Data provenance type — mixed

Both individual-patient and aggregated. Notably: - EHR/billing-code-derived: the National Brain Gene Registry cohort explicitly validated 10 clinical features against ICD-10 billing codes vs. manual chart review (PMID:40265665) — a rare instance of EHR-derived phenotyping in this disorder. - Patient-reported/registry: a 2026 Facebook support-group survey (n=51, 12 countries) (PMID:42468298). - Clinician-ascertained case series: the 28-patient European multicenter cohort (PMID:39603091), Powis et al. diagnostic-exome cohort (PMID:28881385). - Aggregated resources: HPO/OMIM annotations (currently derived from only ~7–9 individuals — see §3), ClinGen, ClinVar, DECIPHER, SFARI Gene.

2. Etiology

Disease causal factors

Purely genetic and monogenic: heterozygous loss of function of SETD5, arising as either (a) an intragenic sequence variant (nonsense, frameshift, canonical splice) or (b) a copy-number deletion encompassing the gene (interstitial 3p25.3 microdeletion or larger 3p terminal deletion). Haploinsufficiency is the established mechanism — nonsense-mediated decay of the mutant transcript has been directly demonstrated:

"CRISPR/Cas9 mutation modelling of the two intragenic variants demonstrated nonsense-mediated decay of the resulting transcripts, pointing to a loss-of-function (LoF) and haploinsufficiency as the common disease-causing mechanism of intragenic SETD5 sequence variants and SETD5-containing microdeletions." — Kuechler et al. 2015, Eur J Hum Genet (PMID:25138099) [UNVERIFIED-QUOTE]

ClinGen dosage sensitivity: Haploinsufficiency score 3 — "Sufficient Evidence for Haploinsufficiency" (curated 2014-11-06); Triplosensitivity score 0 — No Evidence (source: ClinGen Dosage Map, HGNC:25566). ClinGen Gene-Disease Validity: DEFINITIVE, autosomal dominant, Intellectual Disability and Autism GCEP, evaluated 2023-07-27.

Genetic risk factors

Causal variant class: LoF only. No convincing missense/GoF disease mechanism has been established.
Constraint: SETD5 is among the most LoF-intolerant genes in the genome. ExAC pLI = 0.9999996 (rank 259 / 18,225 genes); Sanders TADA score 0.0025 (rank 22 / 18,665); EAGLE score 28.05 ("Strong"); SFARI Gene score 1S (High Confidence, Syndromic), 181 rare variants catalogued, 0 common variants (source: SFARI Gene, gene.sfari.org/database/human-gene/SETD5).
Genomics England PanelApp: GREEN (diagnostic-grade) on Intellectual disability, DDG2P, Fetal anomalies, Skeletal dysplasia, and Early onset or syndromic epilepsy; AMBER on Cerebral vascular malformations and Monogenic short stature. All monoallelic.
Genetic background / "second hits": rare variants in the genetic background modulate expressivity in this class of disorder (Pizzo et al. 2019, Genet Med 21:816–825). A functional two-hit study showed SETD5 homologs synergistically interact with MOSMO homologs in Drosophila and X. laevis, producing axon-outgrowth defects absent with single knockdown (PMID:33819264) [UNVERIFIED-QUOTE].

Environmental risk factors

None established. Paternal age effects for de novo variants are plausible in principle (as for all de novo dominant disorders) but have not been demonstrated specifically for SETD5. No toxin, infectious, dietary, or occupational exposure has been implicated. Not applicable / no data.

Protective factors

No protective genetic or environmental factors identified. No data.

However, the existence of transmitting parents with mild or no phenotype (see §9 Penetrance) implies unmeasured genetic or stochastic buffering. Powis et al. describe "an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons" [CACHE-VERIFIED, PMID:28881385]. Mechanistic basis unknown — this is a genuine knowledge gap.

Gene–environment interactions

No documented GxE for SETD5. One review positions SETD5 among NSPC-proliferation regulators that converge with teratogenic insults (Zika, valproate, metabolic stress) on shared cell-cycle control (PMID:41283518) — a hypothesis-generating convergence claim, not a demonstrated interaction. Curate as such if at all.

3. Phenotypes

3.1 Authoritative HPO annotation set (OMIM:615761, via ontology.jax.org)

⚠️ Critical caveat for KB frequency curation: the current HPO annotation frequencies for this disease derive from a very small seed cohort (denominators of 7, 9, or 2). Do not convert these fractions to HPO FrequencyEnum bands without acknowledging the tiny n. Prefer the larger cohorts in §3.2 for frequency claims.

Inheritance: HP:0000006 (Autosomal dominant inheritance)

HPO ID	Phenotype	HPO frequency (n/N)
HP:0001263	Global developmental delay	7/7
HP:0001249	Intellectual disability	7/7
HP:0000750	Delayed speech and language development	8/9
HP:0000729	Autistic behavior	5/7
HP:0031936	Delayed ability to walk	2/2
HP:0000722	Compulsive behaviors	3/7
HP:0000369	Low-set ears	5/7
HP:0000582	Upslanted palpebral fissure	5/7
HP:0000664	Synophrys	5/7
HP:0000219	Thin upper lip vermilion	5/7
HP:0011968	Feeding difficulties	5/7
HP:0000463	Anteverted nares	4/9
HP:0000678	Dental crowding	3/7
HP:0005280	Depressed nasal bridge	3/7
HP:0000347	Micrognathia	3/7
HP:0000248	Brachycephaly	3/7
HP:0002307	Drooling	3/7
HP:0000343	Long philtrum	2/2
HP:0002714	Downturned corners of mouth	2/2
HP:0000294	Low anterior hairline	2/2
HP:0000414	Bulbous nose	2/2
HP:0000431	Wide nasal bridge	2/2
HP:0100559	Lower limb asymmetry	2/7
HP:0003307	Hyperlordosis	2/7
HP:0000960	Sacral dimple	2/7
HP:0000494	Downslanted palpebral fissures	2/9
HP:0000545	Myopia	1/2
HP:0000483	Astigmatism	1/2
HP:0009836	Broad distal phalanx of finger	1/2
HP:0001852	Sandal gap	1/2
HP:0000486	Strabismus	1/7
HP:0000508	Ptosis	1/7
HP:0100259	Postaxial polydactyly	1/7
HP:0000348	High forehead	1/7
HP:0003593	Infantile onset	2/2
HP:0000319	Smooth philtrum	(annotated, no frequency)
HP:0002650	Scoliosis	(annotated, no frequency)
HP:0002808	Kyphosis	(annotated, no frequency)
HP:0000047	Hypospadias	(annotated, no frequency)

3.2 Frequencies from larger, better-powered cohorts (preferred for curation)

European multicenter neurological/psychiatric cohort, n = 28 (De Falco et al. 2025, PMID:39603091) — 26 SNV, 2 CNV:

"In our cohort neurological symptoms include hypotonia (39.2 %), hyperkinetic movement disorders including stereotypies and chorea (21.4 %) and gait abnormalities ranging from tip-toe or unsteady walking and alterations of fine motor skills (35.7 %). Epilepsy was present in about 14 % of patients, including different types of seizures as epileptic spasms, focal motor, and non-motor seizures. Concerning the cognitive phenotype, intellectual disability or global developmental delay depending on age, ranging from mild to severe, was present in 75 % of cohort, 21.4 % exhibit borderline intellectual functioning while an individual has a normal intelligence quotient. Other psychiatric comorbidities include autism, ADHD, psychotic disorder and other internalizing and externalizing symptoms." [CACHE-VERIFIED]

Feature	Frequency	Suggested HP term
ID or GDD (mild→severe)	75%	HP:0001249 / HP:0001263
Borderline intellectual functioning	21.4%	HP:0006889 (verify)
Hypotonia	39.2%	HP:0001252
Gait abnormality (tip-toe/unsteady, fine-motor)	35.7%	HP:0001288
Hyperkinetic movement disorder (stereotypies, chorea)	21.4%	HP:0002072 (verify); stereotypy HP:0000733; chorea HP:0002072
Epilepsy	~14% (spasms, focal motor, focal non-motor)	HP:0001250; epileptic spasms HP:0011097
Autism, ADHD, psychotic disorder, internalizing/externalizing	present, unquantified	HP:0000729, HP:0007018, HP:0000709

Facebook support-group survey, n = 51 respondents from 12 countries (Talaba et al. 2026, Pediatr Neurol, PMID:42468298) — patient/caregiver-reported; 80% of affected individuals <18 years; mean age at diagnosis 9.2 years:

"Common features included developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%). Potential novel findings included high pain tolerance (43%), persistent leg pain (31%), and joint pain (27%)." [CACHE-VERIFIED]

Feature	Frequency	Suggested HP term
Developmental delay	96%	HP:0001263
Hypotonia	78%	HP:0001252
Intellectual disability	75%	HP:0001249
Gait abnormality	59%	HP:0001288
Vision problems	51%	HP:0000505 (broad)
Constipation	47%	HP:0002019
Anxiety	47%	HP:0000739
High pain tolerance (novel)	43%	HP:0007021 (Pain insensitivity — verify)
Persistent leg pain (novel)	31%	HP:0030838 (Limb pain — verify)
Joint pain (novel)	27%	HP:0002829 (Arthralgia)

Note the striking discordance between HPO's hypotonia annotation (absent) and both cohorts (39–78%) — hypotonia is under-annotated in HPO for this disease and should be curated as FREQUENT.

National Brain Gene Registry, n = 13, ages 2–37 y (Callahan et al. 2025, PMID:40265665):

"Participants in our cohort had features not previously reported, including brain and musculoskeletal abnormalities. One participant had cerebral palsy." [CACHE-VERIFIED]

3.3 Phenotypes by category

Behavioral / psychiatric (search: HPO, DSM-5) - Autistic behavior / ASD (HP:0000729) — the most consistently reported comorbidity; SFARI 1S gene - Obsessive-compulsive behavior with hand flapping and ritualized behavior (HP:0000722, HP:0100023 stereotypical hand wringing — verify) — Grozeva et al. 2014 called these "prominent features" - ADHD (HP:0007018) - Anxiety (HP:0000739) — 47% - Psychotic disorder (HP:0000709) — reported in the De Falco cohort; notable and under-recognized - Internalizing/externalizing symptoms - SETD5 also emerged in a whole-genome de-novo-mutation study of obsessive-compulsive disorder (Lin et al. 2022, Sci Adv 8:eabi6180)

Neurological - Hypotonia; motor delay; delayed ability to walk (HP:0031936) - Gait abnormality including toe-walking (HP:0040083 — verify) - Hyperkinetic movement disorder: stereotypies, chorea - Epilepsy (~14%): epileptic spasms, focal motor and focal non-motor seizures. A dedicated case report documents evolution to focal and generalized seizures in a 6-year-old (PMID:40462669) — "epilepsy may arise after SETD5 variants, with subtle clinical manifestations" [UNVERIFIED-QUOTE] - Severe cerebral cortical dysplasia (HP:0002539) in one nonsense case with congenital diaphragmatic hernia (PMID:28263952) - Cerebral palsy in 1/13 BGR participants - Moyamoya angiopathy (HP:0011834 — verify) — a de novo SETD5 variant identified among 39 MMA trios (PMID:31474762); adult-onset cerebrovascular pleiotropy. Interpretive caution: the paper's replication support was for CHD4/CNOT3, not SETD5 — curate as PARTIAL/emerging, not established. - Drooling (HP:0002307)

Speech / language - Delayed speech and language development (HP:0000750) — 8/9; among the most consistent features - Receptive–expressive language disorder, speech disorder

Craniofacial (the gestalt) — from Grozeva 2014, verbatim description: brachycephaly; prominent high forehead with synophrys or "striking full and broad eyebrows"; long, thin, tubular nose; long, narrow upslanting palpebral fissures; large, fleshy low-set ears. Plus: low anterior hairline, thin upper lip vermilion, long/smooth philtrum, downturned corners of mouth, micrognathia, depressed/wide nasal bridge, bulbous nose, anteverted nares, dental crowding.

Skeletal / musculoskeletal - Leg-length discrepancy / lower limb asymmetry (HP:0100559) — distinctive and repeatedly reported ("significant leg-length discrepancy... a frequent finding") - Scoliosis (HP:0002650), kyphosis (HP:0002808), hyperlordosis (HP:0003307) - Variable hand and skeletal abnormalities (Powis 2018) - Broad distal phalanges, sandal gap, postaxial polydactyly (rare) - Bone fragility — novel association (Anderson et al. 2021, Clin Genet 100:352–354, PMID:34169511); HP:0002659 (Increased susceptibility to fractures — verify) - Vertebral fusion in the Setd5 het mouse (IMPC) — worth a targeted look in humans

Growth - Growth retardation / short stature (HP:0004322); a severe case at −5.22 SDS height with delayed bone age (PMID:40869907) - PanelApp lists SETD5 (Amber) on the Monogenic short stature panel - Feeding difficulties in infancy (HP:0011968) — 5/7

Cardiac - Congenital heart defects: ASD, VSD (including ostium primum ASD detected prenatally, PMID:41368699), conotruncal/outflow-tract defects. Mouse Setd5 haploinsufficiency produces double outlet right ventricle and perimembranous VSD (PMID:34050709), giving strong mechanistic corroboration.

Ophthalmologic - Myopia, astigmatism, strabismus, ptosis; "vision problems" 51% in survey - Ptosis was the presenting feature in a 10.1-Mb 3p25 terminal deletion (PMID:28951171)

Gastrointestinal / genitourinary / other - Constipation (47%) - Inguinal hernia; hypospadias (HP:0000047) - Congenital diaphragmatic hernia (HP:0000776) — rare, one case - CAKUT — machine-learning analysis of 515 clinical-exome cases "implicated ADNP and SETD5 genes as associated with increased CAKUT risk" (PMID:40913078) [UNVERIFIED-QUOTE]; emerging, low confidence - Congenital hypopituitarism — variants in SETD5 found in a CH cohort after mouse pituitary-malformation screening (PMID:38822427); emerging - Aberrant blind-ending bronchus (single case, PMID:28905509) - Neuroblastoma — one report expanding SETD5 haploinsufficiency into neuroblastoma (PMID:32748512). Curate cautiously: no cohort-level cancer-risk estimate exists; there is currently no evidence base for tumor surveillance.

3.4 Phenotype characteristics

Onset: congenital to infantile (HP:0003593 Infantile onset annotated 2/2). Facial dysmorphism and CHD are congenital; hypotonia/feeding difficulty neonatal–infantile; DD apparent in the first 1–2 years; behavioral/psychiatric features school-age; epilepsy variable.
Severity: highly variable — from normal IQ (1 individual in the 28-patient cohort) and borderline functioning (21.4%) through mild, moderate, to severe ID. Original series emphasized "moderate to severe ID."
Progression: the core cognitive phenotype is static/non-progressive (a developmental, not neurodegenerative, disorder). Musculoskeletal features (scoliosis, leg-length discrepancy) and epilepsy may be progressive/emergent. Late-onset cerebrovascular (moyamoya) pleiotropy has been proposed, prompting the recommendation to "assess clinical complications into adulthood" (PMID:31474762).
Quality-of-life impact: no EQ-5D/SF-36/PROMIS study exists for this disorder — data gap. The Facebook survey is the closest proxy: it documents caregiver-reported burden domains (feeding, gait, vision, constipation, anxiety, pain) and found that group participation "empowered families through shared experiences and information exchange" [CACHE-VERIFIED, PMID:42468298]. The mean 9.2-year diagnostic delay is itself a QoL-relevant finding.

4. Genetic / Molecular Information

Causal gene

Field	Value
Symbol	SETD5
HGNC	`HGNC:25566` (dismech form: `hgnc:25566`)
Approved name	SET domain containing 5
Location	3p25.3
Entrez Gene	55209
Ensembl	ENSG00000168137
UniProt	Q9C0A6
OMIM (gene)	615743
Aliases	FLJ10707, SETD5A, KIAA1757, 2900045N06Rik / mKIAA1757 (mouse)
Structure	1,442 aa; 31 exons; SET domain (degenerate, Set3/Set4 subfamily) + a predicted PHD-like region; NLS motif
Reference transcript	NM_001080517.3 (used in ClinVar/published nomenclature)
Expression	Ubiquitous; high in brain (cerebral cortex across developmental stages), thyroid, skin, ovary, lung, endometrium

Source for structure/expression: Li et al. 2023 review (PMID:36875494), read from cached full text: "The human SETD5 gene (OMIM 615743), also known as MRD23, SETD5A, 2900045N06Rik or mKIAA1757, is located on the chromosome 3p25.3 and encodes the SETD5 protein composed of 1442 amino acids... The SETD5 gene consists of 31 exons and is ubiquitously expressed in human tissues such as the brain, thyroid, skin, ovary, lung and endometrium." [CACHE-VERIFIED]

Pathogenic variants

Variant classes observed (all LoF): nonsense > frameshift > canonical splice-site > whole-gene/partial-gene deletion. No pathogenic missense mechanism established.

Landmark allelic series — Grozeva et al. 2014 (PMID:24680889), 7 de novo LoF variants:

Variant (cDNA)	Protein	Type
c.1195A>T	p.Lys399*	nonsense
c.1333C>T	p.Arg445*	nonsense
c.1866C>G	p.Tyr622*	nonsense
c.3001C>T	p.Arg1001*	nonsense (in ClinVar, RCV000114962)
c.2177_2178del	p.Thr726Asnfs*39	frameshift
c.3771dup	p.Ser1258Glufs*65	frameshift
c.3856del	p.Ser1286Leufs*84	frameshift

Additional published alleles: - c.3848_3849insC (Chr3:9,517,294 A>AC) — mild ID in a 36-year-old male (PMID:28549204) - c.890_891delTT — severe short stature + overlap syndrome, rhGH-treated (PMID:40869907) - NM_001080517.3:c.3601_3605del, p.Trp1201GlufsTer2 — de novo, prenatally ascertained via ostium primum ASD (PMID:41368699) - Frameshift in exon 12 — ID + aberrant blind-ending bronchus (PMID:28905509) - 81 bp deletion spanning a splice-donor site + a nonsense variant, both NMD-confirmed (PMID:25138099) - SETD5^S1257 — a functional truncation used experimentally: it abolishes HDAC3/PAF1 interaction and separates SETD5's proliferation function from its anti-apoptotic function (PMID:36349512*)

Variant classification distribution (National Brain Gene Registry, PMID:40265665): of 11 unique P/LP variants in 13 individuals from 11 families — 6 nonsense, 4 frameshift, 1 splice site [CACHE-VERIFIED].

Allele frequency: pathogenic SETD5 LoF alleles are absent/singleton in population databases; the gene is extremely LoF-depleted (ExAC pLI 0.9999996). No recurrent/founder allele has been described.

Germline vs somatic: disease alleles are germline, overwhelmingly de novo. SETD5 is separately somatically altered/overexpressed in multiple cancers (PDAC, NSCLC, breast, ESCC, bladder amplification ~10%, high-grade glioma, ALL, prostate, colorectal, neuroblastoma) — do not conflate with the germline haploinsufficiency disorder.

Functional consequence: loss of function via NMD → 50% dosage → haploinsufficiency. No dominant-negative or GoF mechanism demonstrated for germline disease.

Modifier genes

No validated Mendelian modifier. Genetic-background rare-variant burden is the leading model (Pizzo 2019).
MOSMO is a demonstrated genetic interactor in invertebrate/amphibian two-hit assays (PMID:33819264) — model-organism evidence only.
ANKRD11 is an upstream regulator of SETD5 (see §6), which reframes the KBG/SETD5 overlap as a pathway relationship rather than coincidental phenocopy.

Epigenetic information

A validated DNA-methylation episignature exists for MRD23/SETD5. SETD5 is in the EpiSign validated-disorder panel (EpiSign V2/V3 classifiers; ~25 reference samples reported for MRD23). Foundational methodology: Aref-Eshghi et al. 2020, Am J Hum Genet (PMID:32109418), "Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders" — "This study more than doubles the number of published syndromes with DNA methylation episignatures." [UNVERIFIED-QUOTE]; chromatinopathy application: Levy et al. 2022, Genet Med (PMID:34906459).
A 2026 study of 400 NDD individuals confirmed episignature concordance for SETD5 among chromatinopathy genes and used EpiSign to reclassify VUS (PMID:41957673): "26 individuals (43%) exhibited disorder-specific episignatures consistent with the associated clinical diagnosis" [UNVERIFIED-QUOTE].
The primary molecular lesion is itself epigenetic — see §6.

Chromosomal abnormalities

3p25.3 interstitial microdeletions encompassing SETD5: e.g., a 684 kb deletion refining a 124 kb critical region containing only THUMPD3, SETD5, and LOC440944 (Kellogg et al. 2013, PMID:23613140); a 116 kb deletion partially involving SETD5 in a KBG-suspected patient (PMID:32793091); four independent de novo non-recurrent microdeletions (PMID:25138099).
3p terminal deletions (3p– syndrome), e.g., a de novo 10.1 Mb 3p25 terminal deletion (PMID:28951171). Larger deletions add features not attributable to SETD5 alone (microcephaly, seizures, more severe cardiac disease) — the 684 kb case notably lacked cardiac defects, seizures, and microcephaly, supporting a contiguous-gene contribution in larger deletions.
Detection: chromosomal microarray (aCGH/SNP array); DECIPHER and dbVar hold the CNV records.

5. Environmental Information

Environmental factors: none identified. Not applicable.
Lifestyle factors: none identified. Not applicable.
Infectious agents: none. Not applicable.

The only environmental-adjacent literature is a general review noting that teratogens (Zika, valproate) can phenocopy NSPC-proliferation defects also produced by SETD5 loss (PMID:41283518) — a mechanistic convergence claim, not an etiologic factor for this disease.

6. Mechanism / Pathophysiology

6.1 The central unresolved question — is SETD5 a methyltransferase?

This is the single most important mechanistic controversy for this entry and should be curated explicitly as competing mechanistic_hypotheses rather than silently resolved.

Hypothesis A — SETD5 is a genuine H3K36 methyltransferase (canonical/"catalytic" model). Sessa et al. 2019, Neuron (PMID:31515109):

"Mutations in one SETD5 allele are genetic causes of intellectual disability and autistic spectrum disorders. However, the mechanisms by which SETD5 regulates brain development and function remain largely elusive. Herein, we found that Setd5 haploinsufficiency impairs the proliferative dynamics of neural progenitors and synaptic wiring of neurons, ultimately resulting in behavioral deficits in mice. Mechanistically, Setd5 inactivation in neural stem cells, zebrafish, and mice equally affects genome-wide levels of H3K36me3 on active gene bodies. Notably, we demonstrated that SETD5 directly deposits H3K36me3, which is essential to allow on-time RNA elongation dynamics. Hence, Setd5 gene loss leads to abnormal transcription, with impaired RNA maturation causing detrimental effects on gene integrity and splicing." [CACHE-VERIFIED]

Hypothesis B — SETD5 is catalytically dead and acts as a co-repressor scaffold ("scaffold" model). Wang et al. 2020, Cancer Cell (PMID:32442403):

"SETD5 lacks histone methyltransferase activity but scaffolds a co-repressor complex, including HDAC3 and G9a." [UNVERIFIED-QUOTE]

The 2023 review (PMID:36875494) states both positions and adds the enzymological detail [CACHE-VERIFIED from full text]:

"SETD5 contains a SET (Su(var)3-9, enhancer-of-zeste, trithorax) domain and is thus annotated as a candidate protein of lysine methyltransferase, which methylates H3K36 up to the tri-methyl form (H3K36me3)... However, there is evidence that SETD5 lacks the methyltransferase activity but scaffolds a co-repressor complex, including HDAC3, NCoR, G9a, and PAF1, which couples selective deacetylation of H3K9ac with methylation of this residue."

And on subfamily context: "The yeast SET3 and SET4, Drosophila UpSET, and human MLL5 are homologous to SETD5 over their SET domains and, except for SETD5, contain a PHD finger." [CACHE-VERIFIED]

Curation guidance: model as two hypothesis_group_ids (e.g. setd5_h3k36me3_catalytic [EMERGING/CONTESTED] and setd5_corepressor_scaffold [EMERGING/CONTESTED]), with the downstream node "impaired RNA Pol II elongation and transcriptional fidelity" as a convergent hub that both hypotheses feed. Add a discussions entry with kind: KNOWLEDGE_GAP attached to the catalysis node.

6.2 Substrate/complex map (from PMID:36875494 Table 1, CACHE-VERIFIED)

Complex	Substrate	Site	Effect
Unknown	Histone H3	K36 (methylation)	Preservation of global transcriptional fidelity during brain development and neuronal wiring
G9a, HDAC3, NCoR1	Histone H3	K9 (methylation)	Promotes H3K9 methylation; enhances PDAC resistance to MEKi
HDAC3, NCoR, PAF1	Histone H3	K27 (deacetylation)	Recruits HDAC3/NCoR co-repressor; suppresses adipogenesis
HDAC3	Histone H4	K16 (deacetylation)	Elevates rDNA expression by removing H4K16ac/TIP5; promotes neural cell proliferation

Additional partners: PAF1 complex (Ctr9), NCoR/HDAC3, G9a/EHMT2, HCF-1, TBL1XR1, BRD2, OGT (in cancer), RNA Pol II.

6.3 Causal chain — germline haploinsufficiency (proposed pathograph)

Trigger (MOLECULAR): Heterozygous SETD5 LoF variant / 3p25.3 deletion → NMD → ~50% SETD5 protein ↓ MOLECULAR: Loss of SETD5-dependent chromatin state — reduced genome-wide H3K36me3 on active gene bodies (Hypothesis A) and/or failure of SETD5–NCoR/HDAC3/G9a/PAF1 co-repressor scaffolding with enhancer/promoter hyperacetylation (Hypothesis B). Osipovich et al. showed Setd5-deficient cells have increased histone acetylation at transcription start sites and downstream regions (PMID:27864380). ↓ MOLECULAR: Dysregulated RNA Pol II dynamics — altered promoter-proximal pausing/release (with HCF-1 and PAF1; demonstrated on E2F target genes in HSCs, PMID:34853439), impaired elongation kinetics, and defective RNA maturation, splicing, and gene integrity (Sessa 2019). ↓ (parallel branch) MOLECULAR: Reduced rDNA transcription — SETD5 normally recruits HDAC3 to the rDNA promoter, removing H4K16ac and its reader TIP5 (a repressor of rDNA); SETD5 loss ⇒ rDNA repression ⇒ ↓ global translation ⇒ specifically ↓ cyclin D1 translation (PMID:32299058). ↓ CELLULAR: Neural stem/progenitor cell proliferation defect and altered cell-cycle dynamics; premature/altered differentiation; deficit of deep-layer cortical neurons (PMID:30655503). ↓ (parallel branch) CELLULAR: Mitochondrial compartment failure — "Low levels of SETD5 resulted in fragmented mitochondria, reduced mitochondrial membrane potential" and reduced ATP production, with mitochondria depleted from neurites and synapses; "Mitochondrial impairment is facilitated by transcriptional aberrations originated by SETD5" (PMID:37264456) [UNVERIFIED-QUOTE]. ↓ (parallel branch, non-cell-autonomous) CELLULAR: Astrocyte dysfunction — SETD5-deficient hiPSC-derived astrocytes show increased extracellular ROS, glutamate, IL-6 and IL-8; "Elevated astrocytic IL-6 exerts a non-cell autonomous harmful effect on healthy neurons", driven by JAK/STAT (PMID:41993368, bioRxiv preprint 2026 — preprint, not peer-reviewed; curate as EMERGING) [UNVERIFIED-QUOTE]. ↓ CELLULAR/TISSUE: Reduced synaptic density and neuritic outgrowth; decreased network activity and synchrony on MEA; abnormal postsynaptic density protein expression; enhanced long-term potentiation (a paradoxical/dissociated LTP finding worth flagging) (PMID:30655503, PMID:30455454). ↓ (developmental branch) TISSUE: Neural crest–derived and cardiopharyngeal-mesoderm developmental defects → craniofacial dysmorphism and outflow-tract cardiac malformation. "Setd5 was required in cardiopharyngeal mesoderm for progression of the heart tube" through the ballooning stage (PMID:34050709) [UNVERIFIED-QUOTE]; Deliu et al. report "neural crest defect-associated phenotypes" [CACHE-VERIFIED]. ↓ ORGANISM: Global developmental delay, intellectual disability, autism/ADHD/OCD, hypotonia, dysmorphism, CHD, skeletal anomalies.

6.4 Molecular pathways (KEGG/Reactome/GO framing)

Chromatin/transcription: H3K36 methylation; H3K9 methylation (via G9a); H3K27/H3K9/H4K16 deacetylation (via NCoR-HDAC3); RNA Pol II pausing and elongation (PAF1, HCF-1); enhancer priming→activation transition
Ribosome biogenesis / translation: rDNA transcription (RNA Pol I), TIP5/NoRC, cyclin D1 translational control
Cell cycle: E2F target genes, cyclin D1, G1/S
PI3K–AKT(–mTOR): implicated chiefly in the cancer literature (PMID:37963940, PMID:35063407); its relevance to the germline NDD is unproven — flag as a knowledge gap
JAK/STAT–IL-6: astrocytic, preprint-stage
Semaphorin/axon guidance: SetD5–BRD2 co-occupancy at the Sema3a promoter/TSS regulates Sema3A in retinal ganglion cells, independent of the SET domain (PMID:29180574) — a clean, published SET-domain-independent function
Protein turnover: APC/C-mediated ubiquitin–proteasome degradation of SETD5 acts as a molecular switch for enhancer activation (PMID:34857762)

6.5 Suggested GO / CL / UBERON / CHEBI terms

Molecular function (OLS-verified live): - GO:0046975 — histone H3K36 methyltransferase activity ✅ verified - GO:0140955 — histone H3K36 trimethyltransferase activity ✅ verified - GO:0140003 — histone H3K36me3 reader activity ✅ verified

❌ DO NOT USE (confirmed obsolete): GO:0010452, GO:0034968.

Biological process (suggested — all require OAK verification): - GO:0006357 regulation of transcription by RNA polymerase II - GO:0032968 positive regulation of transcription elongation by RNA polymerase II - GO:0006338 chromatin remodeling - GO:0006360 transcription by RNA polymerase I (rDNA branch) - GO:0042254 ribosome biogenesis - GO:0006412 translation - GO:0000381 regulation of alternative mRNA splicing, via spliceosome - GO:0008283 cell population proliferation - GO:0021895 cerebral cortex neuron differentiation - GO:0007416 synapse assembly - GO:0000266 mitochondrial fission - GO:0014032 neural crest cell development - GO:0016575 histone deacetylation (verify — this namespace was affected by the same GO cleanup)

Cell types (CL — verify each): - CL:0000047 neuronal stem cell / CL:0011020 neural progenitor cell — primary proliferative target - CL:0000679 glutamatergic neuron; deep-layer cortical projection neurons - CL:0000127 astrocyte — non-cell-autonomous IL-6 arm - CL:0000333 migratory cranial neural crest cell — craniofacial/cardiac - CL:0000604 retinal rod cell; CL:0000636 Mueller cell — retinal survival/proliferation (PMID:36349512) - CL:0000037 hematopoietic stem cell — quiescence (PMID:34853439) - CL:0000115 endothelial cell — miR-126-5p/SetD5/Sema3A axis - CL:0000136 adipocyte — adipogenic enhancer switch

Anatomy (UBERON — verify each): see §7.

Chemicals (CHEBI — verify each): - CHEBI:15414 S-adenosyl-L-methionine (methyl donor cofactor) - CHEBI:8871 risperidone (zebrafish rescue) - CHEBI:15361 pyruvate / glycolytic intermediates (cancer arm only)

6.6 Molecular profiling

Transcriptomics: RNA-seq of fetal Setd5^+/− cortical neurons showed a specific subpopulation with altered neurodevelopmental gene expression (PMID:30655503); Setd5-null mESCs show "substantially altered gene expression" (PMID:27864380); adult zebrafish setd5 brain shows "downregulation of genes encoding proteins involved in the synaptic structure and function" (PMID:36613611). Datasets in GEO under these accessions (specific GSE IDs not retrieved — look up before citing).
Epigenomics: genome-wide H3K36me3 ChIP-seq (Sessa 2019); H3/H4 acetylation ChIP (Osipovich 2016); Pol II ChIP/pausing-index (Deliu 2018, Li 2022); blood DNA-methylation EPIC arrays for episignature.
Proteomics: SETD5 interactome (PAF1/Ctr9, NCoR/HDAC3, TBL1XR1, G9a, HCF-1, BRD2) — mass-spec IP studies in Osipovich 2016, Deliu 2018, Wang 2020, Li 2022.
Metabolomics / lipidomics: none for the germline disorder. Bioenergetic (ATP, ΔΨm) readouts only (PMID:37264456). Data gap.
Single-cell / spatial: no published scRNA-seq or spatial transcriptomics of patient tissue. Data gap.
Functional genomics screens: a scalable high-throughput neural-development platform assayed shared ASD-gene impact on cell fate/differentiation including SETD5 (cached as PMID_35197626). DepMap holds SETD5 dependency data for cancer lines.

7. Anatomical Structures Affected

Organ level — primary - Brain / central nervous system — UBERON:0000955 brain; UBERON:0000956 cerebral cortex (deep layers particularly); UBERON:0002336 corpus callosum (MRI abnormalities reported); UBERON:0002037 cerebellum (ataxia/gait). Adult Setd5^+/− mice show MRI-detectable anatomical differences and abnormal brain-to-body weight ratio. - Craniofacial skeleton — UBERON:0001474 bone element / UBERON:0007811 craniocervical region; neural-crest-derived facial structures.

Organ level — secondary / systemic - Heart — UBERON:0000948; specifically outflow tract UBERON:0004145, interventricular septum UBERON:0002094, interatrial septum UBERON:0002085 - Skeleton / limbs — UBERON:0002101 limb; vertebral column UBERON:0000955→ use UBERON:0002240 spinal column (verify); asymmetric long-bone growth - Eye / retina — UBERON:0000966 retina - Pituitary gland — UBERON:0000007 (congenital hypopituitarism, emerging) - Kidney / urinary tract — UBERON:0002113 kidney (CAKUT, emerging) - GI tract — UBERON:0001155 colon (constipation) - Cerebral vasculature — UBERON:0001621/UBERON:0001627 cerebral artery (moyamoya, emerging) - Diaphragm — UBERON:0001103 (CDH, rare) - Lung/airway — UBERON:0002185 bronchus (single aberrant-bronchus case)

Body systems: nervous (dominant), cardiovascular, musculoskeletal, visual, endocrine, digestive, genitourinary.

Tissue and cell level: neuroepithelium/ventricular zone (proliferating NSPCs), cortical plate neurons, astroglia, cranial neural crest, cardiopharyngeal mesoderm, retinal photoreceptors and Müller glia, bone (fragility), hematopoietic compartment (mouse only).

Subcellular level (GO CC — verify): - GO:0005634 nucleus — principal localization; NLS-dependent - GO:0000785 chromatin - GO:0005730 nucleolus / rDNA promoter (SETD5 acts on rDNA but is not itself nucleolar-resident in all reports) - GO:0005739 mitochondrion — secondary, disease-relevant compartment (fragmentation, ΔΨm loss) - GO:0045202 synapse — reduced mitochondrial occupancy in mutant neurites/synapses - GO:0000502 proteasome complex — APC/C-mediated SETD5 turnover

Localization/lateralization: bilateral and symmetric. Lower-limb asymmetry (leg-length discrepancy) is the notable exception and is an asymmetric skeletal feature.

8. Temporal Development

Onset - Congenital: facial dysmorphism, CHD (detectable on fetal cardiac ultrasound — PMID:41368699), CDH, structural brain anomalies - Neonatal–infantile: hypotonia, feeding difficulties, drooling - Infancy/toddlerhood: global developmental delay, delayed walking, delayed speech (HP:0003593 Infantile onset) - Childhood: ID becomes quantifiable; autism/ADHD/OCD/stereotypies; epilepsy when present - Adolescence/adulthood: scoliosis, short stature, psychiatric decompensation; rare late cerebrovascular events (moyamoya) - Onset pattern: chronic, insidious, developmental

Progression - Core cognitive phenotype: static/non-progressive. There is no evidence of neurodegeneration. - Progressive elements: scoliosis/kyphosis, leg-length discrepancy, possibly bone fragility. - Episodic elements: epilepsy (~14%); psychiatric exacerbations. - Duration: chronic, lifelong. Oldest reported individuals: 37 years (BGR cohort), 36 years (case report), plus mildly affected transmitting parents into middle age. - Progression rate: not formally quantified — no natural-history study exists. This is the single largest clinical-data gap.

Patterns - Remission: none. - Critical periods: (a) embryonic — neural tube closure, somitogenesis, cardiac ballooning, neural crest migration (mouse null lethal at E10.5–11.5); (b) fetal/early postnatal cortical neurogenesis (deep-layer neuron generation); (c) early childhood — the window for developmental/behavioral intervention; (d) growth — the case report of rhGH initiated at age 12 with +3.16 SDS gain in year 1 argues the pubertal window is actionable for the growth phenotype. - Diagnostic delay: mean age at diagnosis 9.2 years (survey, PMID:42468298) — an actionable health-services finding.

9. Inheritance and Population

Epidemiology

No population prevalence or incidence estimate exists. Orphanet's entry (ORPHA:404440) is obsolete and carries no prevalence class. For a dismech Prevalence record, the defensible values are measure_type: CASES_IN_LITERATURE and prevalence_class: ULTRA_RARE / NOT_YET_DOCUMENTED, with a notes field explaining why.
Cumulative reported cases: "The disorder was first described in 2014 with fewer than 75 reported cases in the literature to date" (Talaba et al. 2026, PMID:42468298) [CACHE-VERIFIED]. That count predates the 28-patient De Falco cohort and the 13-person BGR cohort being fully absorbed into the literature tally, so ~120–150 published individuals is a reasonable 2026 estimate.
Diagnostic yield within ID cohorts — the best available "frequency" anchor: ~0.7%. Two independent cohorts converge:
Grozeva 2014: 7 LoF variants in 996 individuals screened → "rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID" (PMID:24680889) [UNVERIFIED-QUOTE]
Kuechler 2015: "The present report of two SETD5 LoF variants in 301 patients demonstrates a prevalence of 0.7% and thus SETD5 variants as a relatively frequent cause of ID" (PMID:25138099) [UNVERIFIED-QUOTE]

⚠️ Curate this carefully: 0.7% is a diagnostic yield within an ascertained moderate-to-severe ID cohort, not a population prevalence. Do not enter it as rate_per_100000.

Genetic epidemiology

Inheritance pattern: autosomal dominant (HP:0000006). Overwhelmingly de novo.
Penetrance: incomplete/reduced. This is well documented and clinically important for counseling:
Powis et al. 2018: "We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons." [CACHE-VERIFIED, PMID:28881385]
De Falco et al. 2025 explicitly describe the disorder as having "incomplete penetrance" [CACHE-VERIFIED, PMID:39603091]
Szczałuba et al. 2016 reported the first familial case: two siblings and their father, with "the father demonstrated only mild intellectual impairment" (PMID:27375234) [UNVERIFIED-QUOTE]
⚠️ Note tension: Genomics England PanelApp records "complete penetrance" on the Intellectual disability panel. The published literature contradicts this. Curate incomplete penetrance and flag the discrepancy.
Expressivity: highly variable, both between and within families — normal IQ through severe ID in the same series.
Genetic anticipation: none (not a repeat-expansion disorder). Not applicable.
Germline mosaicism: not specifically reported for SETD5, but recurrence in siblings of unaffected parents is theoretically possible; standard counseling caveat applies. No data.
Founder effects: none identified. No data.
Consanguinity: not relevant (dominant LoF). Not applicable.
Carrier frequency: not applicable in the recessive sense; population LoF frequency is essentially zero (pLI ≈ 1).

Population demographics

Affected populations: no ancestry-specific enrichment reported. Cases published from Europe, North America, South America (Brazil), Asia (Japan, China, India), the Middle East, and 12 countries in the support-group survey. The India NDD cohort study (PMID:38114583) confirms presence in LMIC populations.
Geographic distribution: worldwide; no endemic pattern; no variant-specific geography.
Sex ratio: approximately 1:1; no sex bias reported. Autosomal.
Age distribution of ascertained individuals: heavily pediatric — 80% under 18 years in the survey cohort; BGR range 2–37 years. This reflects ascertainment bias (exome sequencing of children with DD), not true age distribution. Adults are systematically under-ascertained — a recognized gap.

10. Diagnostics

Primary diagnostic modality: genomic sequencing

There is no biochemical or imaging biomarker; diagnosis is molecular.

Recommended approach (in practical order): 1. Trio exome sequencing (WES) or genome sequencing (WGS) — the highest-yield first-line test for unexplained GDD/ID with dysmorphism. Essentially every published SETD5 case was ascertained this way. Trio design is essential given the de novo mechanism. 2. Chromosomal microarray (CMA) — mandatory in parallel or first, since a meaningful minority of cases are 3p25.3 microdeletions or 3p terminal deletions that WES may miss (2/28 in the De Falco cohort were CNVs). Resolution matters: the smallest reported deletion is 116 kb. 3. Targeted NGS ID/NDD panels — SETD5 is on all major panels; Genomics England PanelApp lists it GREEN on Intellectual disability, DDG2P, Fetal anomalies, Skeletal dysplasia, and Early onset or syndromic epilepsy. 4. Single-gene SETD5 sequencing — GTR test 582578 (sequence analysis, all coding exons, postnatal) exists but is rarely the right first test. 5. DNA methylation episignature (EpiSign) — a genuinely useful adjunct for this gene. SETD5/MRD23 has a validated episignature in the EpiSign classifier. Use cases: (a) reclassifying a SETD5 VUS; (b) resolving the KBG/CdLS/SETD5 differential; (c) NGS-negative cases with a compelling phenotype. Supporting evidence: PMID:32109418, PMID:34906459, PMID:41957673. 6. Prenatal: fetal cardiac ultrasound detecting ASD/VSD prompted prenatal WES yielding a de novo SETD5 frameshift (PMID:41368699) — "Fetal cardiac ultrasound represents a valuable tool for early screening" [UNVERIFIED-QUOTE].

Not indicated / not applicable: karyotyping (resolution far too low), FISH (unless confirming a known deletion), mtDNA testing, repeat-expansion testing.

Supportive clinical evaluations (not diagnostic, but standard-of-care workup)

Modality	Purpose	LOINC/term note
Brain MRI	Structural anomalies; cortical dysplasia; corpus callosum	The De Falco cohort explicitly collected MRI data and found no distinctive signature
EEG	Epilepsy/EEG abnormalities (~14% clinical epilepsy)	No pathognomonic pattern identified
Echocardiogram	ASD/VSD/outflow-tract defects	Baseline at diagnosis
Formal cognitive/adaptive testing	Quantify ID severity	e.g., Vineland, Bayley, WISC
ADOS-2 / ADI-R	Autism diagnosis
Ophthalmology	Myopia, astigmatism, strabismus, ptosis
Audiology / ABR	Mouse model shows abnormal auditory brainstem response — human data limited
Skeletal survey / scoliosis series / leg-length radiographs	LLD, scoliosis, bone fragility
Growth curve, bone age, GH axis	Short stature; possible hypopituitarism
Renal ultrasound	CAKUT (emerging)

Biomarkers: none validated. Data gap. No FDA/BEST-listed biomarker.

Biopsy/histopathology: not indicated. The only pathology literature is the single case of severe cerebral cortical dysplasia (PMID:28263952).

Clinical criteria and differential diagnosis

No consensus clinical diagnostic criteria exist (unlike CdLS or KBG). Diagnosis = pathogenic/likely pathogenic SETD5 LoF variant or deletion + compatible phenotype.

Differential diagnosis (all are documented real-world misdiagnoses of SETD5 cases):

Condition	Gene	Distinguishing features / evidence
KBG syndrome	ANKRD11	Macrodontia of upper central incisors is the KBG discriminator. Three patients clinically suspected of KBG had SETD5 lesions (PMID:32793091); another SETD5 child had "KBG syndrome-like appearance" (PMID:35132768). Mechanistically linked: ANKRD11 upregulates SETD5 (see below).
Cornelia de Lange syndrome	NIPBL, SMC1A, SMC3, RAD21, HDAC8	SETD5 identified among chromatin regulators in CdLS-overlap patients (PMID:28120103, PMID:31337854); SETD5 also appeared as a single-proband finding in a 105-family WGS study of mutation-negative CdLS (PMID:40677927)
3p terminal deletion (3p–) syndrome	contiguous genes	Larger deletions add microcephaly, more severe seizures/cardiac disease
Proximal 3p25.3 microdeletion syndrome	ORPHA:435638	⚠️ Different locus/entity — do not conflate
Other chromatinopathies	KMT2A (Wiedemann-Steiner), EP300/CREBBP (Rubinstein-Taybi), EHMT1 (Kleefstra), CHD8, KDM5C	Overlapping ID + dysmorphism + growth issues; episignature testing discriminates
Non-specific syndromic ID	many

Mechanistic basis of the KBG overlap (important, recently resolved): ANKRD11 (KBG) sits upstream of SETD5.

"ANKRD11-deficient neural cells exhibit reduced ribosomal RNA (rRNA) and translation"; "it indirectly promotes rRNA expression by upregulating SETD5"; "ANKRD11 interacts with the Setd5 promoter and recruits WDR5"; "Overexpression of ANKRD11 or SETD5 restores rRNA levels and translational activity." — Ito et al. 2025, iScience (PMID:40520101) [UNVERIFIED-QUOTE]

This converts KBG↔SETD5 phenocopy from a clinical curiosity into a shared ANKRD11→SETD5→rRNA/translation axis and is high-value content for a dismech mechanism module.

Screening

Newborn screening: not applicable — no biochemical marker, no NBS program.
Carrier screening: not applicable (de novo dominant).
Cascade screening: appropriate. Because of documented reduced penetrance and mildly affected transmitting parents, parental testing is mandatory when a SETD5 variant is found — do not assume de novo.
Prenatal/PGT: available for families with a known variant; PGT-M feasible.

11. Outcome / Prognosis

⚠️ Prognosis for this disorder is essentially uncharacterized. No natural-history study, no survival analysis, no registry-based outcome data. Everything below is inference from case series.

Survival and mortality - Life expectancy: no data. No published deaths attributable to the syndrome; individuals reported into the fourth decade (36 y, 37 y) and mildly affected transmitting parents into middle age. - Mortality risk, where present, would be driven by comorbidities: congenital heart disease, epilepsy (SUDEP risk applies generically), aspiration in severe hypotonia/feeding difficulty, and — in the rare moyamoya association — stroke. - Homozygous/biallelic loss is presumably not viable in humans: the mouse null is embryonic lethal at E10.5–11.5 (PMID:27864380) and homozygous IMPC animals show "preweaning lethality, complete penetrance." - Disease-specific mortality: no data.

Morbidity and function - Lifelong ID in ~75% (mild→severe) plus 21% borderline; a minority with normal IQ. - Communication impairment is near-universal and functionally dominant. - Motor: 78% hypotonia, 59% gait abnormality; most walk, often late. - Independence: not systematically studied. Most published adults required support. Data gap. - Quality-of-life instruments: none applied. No EQ-5D, SF-36, PROMIS, or disease-specific PROM exists. Priority gap.

Complications Epilepsy; scoliosis/kyphosis requiring orthopedic management; leg-length discrepancy; bone fragility/fractures; constipation; feeding difficulty and growth failure; refractive error and strabismus; psychiatric decompensation (including psychotic disorder); rare cerebrovascular events; single reports of neuroblastoma and hypopituitarism.

Recovery potential: none — the developmental lesion is fixed. Interventions are supportive and habilitative; developmental gains occur with therapy but the underlying dosage defect is not correctable with any current treatment.

Prognostic factors - No validated prognostic model. Candidate factors, all unvalidated: - Variant class/position — De Falco et al. 2025 "conduct a comprehensive review of the available literature, suggesting a possible genotype-phenotype correlation" [CACHE-VERIFIED]. One case-report author speculated a 3'-terminal frameshift might retain partial activity, explaining a mild phenotype (PMID:28549204) — plausible but unproven. - Deletion size — larger 3p terminal deletions → more severe, additional features (microcephaly, seizures, cardiac). - Genetic background / second hits (Pizzo 2019). - Presence of epilepsy, CHD, or severe hypotonia at baseline. - Prognostic biomarkers: none. Data gap.

12. Treatment

There is no disease-modifying or targeted therapy. Management is entirely symptomatic, multidisciplinary, and habilitative.

Standard of care (all suggested NCIT terms require OAK verification)

Intervention	Rationale	Suggested `treatment_term` (NCIT)	`therapeutic_modality`
Early intervention / developmental therapy	GDD in 96%	`NCIT:C15315` Rehabilitation	BEHAVIORAL
Speech and language therapy	Speech delay 8/9; near-universal	`NCIT:C159273` Speech Therapy	BEHAVIORAL
Physical therapy	Hypotonia 78%, gait 59%	`NCIT:C15302` Physical Therapy	BEHAVIORAL
Occupational therapy	Fine motor, ADLs	`NCIT:C121351` Occupational Therapy	BEHAVIORAL
Applied behavior analysis / ASD behavioral intervention	Autism	`NCIT:C181743` Behavioral Counseling (verify)	BEHAVIORAL
Special education / IEP	ID	`NCIT:C15747` Supportive Care	BEHAVIORAL
Genetic counseling	De novo mechanism, reduced penetrance, 50% transmission risk	`NCIT:C15240` Genetic Counseling	BEHAVIORAL
Antiseizure medication	Epilepsy ~14%	`NCIT:C15986` Pharmacotherapy	SMALL_MOLECULE
Psychotropics (SSRIs for anxiety/OCD; stimulants for ADHD; atypical antipsychotics e.g. risperidone/aripiprazole for irritability)	Anxiety 47%, ADHD, OCD, psychosis	`NCIT:C15986` Pharmacotherapy + `therapeutic_agent` per drug	SMALL_MOLECULE
Cardiac surgical repair	ASD/VSD/outflow tract	`NCIT:C15329` Surgical Procedure	SURGERY
Orthopedic management (scoliosis bracing/fusion; LLD epiphysiodesis/lengthening)	Scoliosis, leg-length discrepancy	`NCIT:C16186` Orthopedic Surgical Procedure	SURGERY
Feeding support / gastrostomy; constipation management	Feeding difficulty; constipation 47%	`NCIT:C15433` Nutritional Support (do not auto-tag BEHAVIORAL — see CLAUDE.md)	varies
Ophthalmologic correction	Refractive error 51%	`NCIT:C15747` Supportive Care / DEVICE	DEVICE

Disease-specific pharmacological reports

Recombinant human growth hormone (rhGH) — the only pharmacologic intervention with a published SETD5-specific outcome:

"This is the first case of a patient with overlap syndrome due to SETD5 mutation treated with rhGH"; "After both one year (+3.16 SDS) and two years (+2.9 SDS), the growth rate significantly increased" (PMID:40869907, Genes 2025) [UNVERIFIED-QUOTE]

n = 1. Presented at −5.22 SDS height, bone age 3 years delayed, variant c.890_891delTT. Suggested annotation: treatment_term NCIT:C15986 Pharmacotherapy, therapeutic_agent somatropin (NCIT:C821 — verify), therapeutic_modality: PROTEIN_REPLACEMENT or PEPTIDE, evidence HUMAN_CLINICAL, and mark clearly as a single case report.

Preclinical / experimental leads (none in human trials)

Risperidone (CHEBI:8871) — rescued the social-interest deficit in setd5 heterozygous zebrafish: "Impairment in social interest is rescued by risperidone, an antipsychotic drug used to treat behavioral traits in ASD" (PMID:36613611) [UNVERIFIED-QUOTE]. evidence_source: MODEL_ORGANISM. Note this is a repurposed symptomatic agent, not disease-modifying.
JAK/STAT inhibition — in SETD5-deficient hiPSC astrocytes, "Pharmacological JAK-STAT inhibition restored extracellular IL-6 to basal levels and partially rescued astrocyte morphology and neuronal deficits" (PMID:41993368) [UNVERIFIED-QUOTE]. ⚠️ bioRxiv preprint (2026), not peer-reviewed. evidence_source: IN_VITRO, status EMERGING.
Mitochondrial targeting — the authors of PMID:37264456 propose "mitochondrial activity and dynamics may represent new therapeutic targets," explicitly contingent on confirmation in patient-derived systems [UNVERIFIED-QUOTE]. evidence_source: IN_VITRO/MODEL_ORGANISM; hypothesis-stage.
HDAC3 / epigenetic modulation — mechanistically motivated by the SETD5–HDAC3–NCoR axis, but no in vivo NDD rescue has been shown. Directionality is non-obvious (SETD5 loss already de-represses acetylation). Curate only as a hypothesis with the direction problem flagged.
ANKRD11/SETD5–rRNA axis — overexpression of either restored rRNA/translation in KBG models (PMID:40520101); a conceptual, not clinical, lead.

Clinical trials

No interventional clinical trial specific to SETD5 haploinsufficiency was identified on ClinicalTrials.gov. The relevant registries are observational: - National Brain Gene Registry (BGR) — includes SETD5 Disorder participants; multi-site US (PMID:38632549, PMID:40265665). Look up its NCT/registry identifier before citing as a clinical_trials entry. - Patient community: a SETD5-related disorder Facebook support group serving as an informal registry (PMID:42468298).

Pharmacogenomics

No SETD5-specific pharmacogenomic guidance. Standard CPIC guidance applies to any psychotropic/antiseizure drugs used (e.g., CYP2D6 for risperidone/aripiprazole; HLA-B15:02 for carbamazepine). Not disease-specific.*

Gene/RNA/cell therapy

None in development. Conceptually, a haploinsufficiency disorder with a 1,442-aa nuclear scaffold protein and a largely prenatal developmental critical window presents severe barriers to gene replacement or ASO-mediated upregulation. No data.

13. Prevention

Primary prevention: not possible. The disorder arises from de novo mutation; no modifiable exposure is known.

Secondary prevention (early detection): - Early genomic diagnosis is the actionable target. Mean age at diagnosis is 9.2 years — a substantial, reducible delay. First-tier trio WES/WGS + CMA in unexplained GDD/ID would compress this. - Prenatal detection via fetal cardiac ultrasound → prenatal WES has been demonstrated (PMID:41368699). - No population screening program is applicable.

Tertiary prevention (complication prevention in diagnosed individuals): — this is where prevention effort actually lives. Note that no formal surveillance guideline exists for SETD5; the list below is a reasoned synthesis of reported complications, not a published protocol, and should be curated as such. - Baseline echocardiogram at diagnosis - EEG if paroxysmal events; low threshold given ~14% epilepsy with subtle presentations - Serial scoliosis and leg-length assessment through growth - Bone health assessment given the reported fragility association - Growth monitoring; GH-axis evaluation for significant short stature - Ophthalmology and audiology baseline plus periodic re-evaluation - Nutrition/GI review (feeding, constipation) - Proactive psychiatric screening (anxiety 47%; psychotic disorder reported) - Renal ultrasound is reasonable but unproven given the emerging CAKUT signal - No cancer surveillance is recommended — the neuroblastoma link rests on a single report with no risk estimate

Immunization: routine schedule; no contraindication or special schedule. Not applicable as disease-specific prevention.

Genetic screening / counseling: - Parental testing is required in every case — reduced penetrance means an apparently unaffected parent may carry the variant (PMID:28881385). - Recurrence risk: ~1% (gonadal mosaicism) if both parents test negative; 50% if a parent is a carrier, with the crucial caveat that severity is unpredictable. - Prenatal diagnosis and PGT-M available for known familial variants. - Suggested term: NCIT:C15240 Genetic Counseling.

Public health / environmental interventions: not applicable.

14. Other Species / Natural Disease

Naturally occurring disease in other species: none reported. No OMIA entry for a natural SETD5-related disorder in any domestic or wild species. All animal disease is experimentally induced. Not applicable.
Zoonotic potential / cross-species transmission: not applicable (non-infectious genetic disorder).
Veterinary relevance: none.

Orthologs and evolutionary conservation

Species	NCBI Taxon	Gene	Notes
Homo sapiens	NCBITaxon:9606	SETD5 (Entrez 55209)
Mus musculus	NCBITaxon:10090	Setd5 (MGI:1920145)	Highly conserved; null lethal E10.5–11.5
Danio rerio	NCBITaxon:7955	setd5	ASD-like social phenotypes in het CRISPR mutants (PMID:36613611)
Drosophila melanogaster	NCBITaxon:7227	UpSET	Functional homolog; recruits HDAC complexes, restricts chromatin accessibility/acetylation at promoters (Rincon-Arano et al. 2012, Cell 151:1214–1228)
Saccharomyces cerevisiae	NCBITaxon:4932	SET3, SET4	Set3/Set4 SET-domain subfamily; Set4 promotes survival in oxidative stress (PMID:30523388)
Xenopus laevis	NCBITaxon:8355	setd5	Two-hit interaction study (PMID:33819264)
Kryptolebias marmoratus	NCBITaxon:37003	Setd5	Kmt family survey; gastrula-stage expression peak (PMID:30458291)
Human paralog	—	MLL5 / KMT2E	Same SET-domain subfamily; MLL5 retains a PHD finger that SETD5 lacks

Comparative pathology: the Setd5^+/− mouse recapitulates the human disorder's neural-crest/craniofacial, cardiac, cognitive, and behavioral axes remarkably well (see §15). Conservation extends to the biochemical mechanism: "SETD5 functions in a manner similar to yeast Set3p and Drosophila UpSET" (PMID:27864380) [UNVERIFIED-QUOTE] — i.e., the HDAC-recruiting, acetylation-restricting function is conserved from yeast to human, which is strong support for Hypothesis B (§6.1).

15. Model Organisms

15.1 Mouse — the primary model

Alleles/resources: - Setd5<tm1a(EUCOMM)Wtsi> — knockout-first conditional-ready; IMPC/KOMP/EUCOMM. MGI:1920145. Available via IMSR/EMMA/MMRRC. - Conditional (floxed) alleles used for cardiopharyngeal mesoderm–specific deletion (PMID:34050709) - Independent lab-generated Setd5^+/− lines: Osipovich/Magnuson (Vanderbilt), Deliu/Novarino (IST Austria), Moore/Muotri-adjacent (PMID:30655503), Sessa/Broccoli (San Raffaele), Nakagawa (Tohoku)

Homozygous null: embryonic lethal E10.5–11.5, with "severe defects in neural tube formation, somitogenesis and cardiac development" and aberrant vasculogenesis in embryo, yolk sac, and placenta (PMID:27864380). IMPC: "Preweaning lethality, complete penetrance."

Heterozygous — IMPC systematic phenotyping (Setd5<tm1a(EUCOMM)Wtsi>, het):

MP phenotype	p-value
Abnormal snout morphology	8.23E-11
Abnormal cranium morphology	6.16E-10
Abnormal coat/hair pigmentation	3.22E-09
Abnormal maxilla morphology	6.47E-07
Abnormal tooth morphology	3.90E-06
Abnormal incisor morphology	6.43E-06
Absent pinna reflex	9.77E-06
Abnormal auditory brainstem response	2.89E-05 – 3.64E-05
Vertebral fusion	3.92E-05
Decreased grip strength	7.49E-05
Decreased circulating glucose level	6.99E-05
Increased regulatory T cell number	~0
Increased monocyte cell number	~0

Note the strong craniofacial/dental signal — an excellent cross-species match to the human facial gestalt and dental crowding, and a hint that hearing (ABR) and dentition deserve more systematic human assessment.

Heterozygous — hypothesis-driven studies:

Deliu et al. 2018, Nat Neurosci (PMID:30455454) [CACHE-VERIFIED]:

"Setd5-haploinsufficient mice present developmental defects such as abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes. Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalization, and behavioral inflexibility. Behavioral issues are accompanied by abnormal expression of postsynaptic density proteins previously associated with cognition. Our data additionally indicate that Setd5 regulates RNA polymerase II dynamics and gene transcription via its interaction with the Hdac3 and Paf1 complexes."

Moore et al. 2019, Transl Psychiatry (PMID:30655503): reduced synaptic density and neuritic outgrowth in cultured cortical neurons; reduced MEA network activity and synchrony; altered gene expression in a fetal cortical neuron subpopulation; hyperactivity, cognitive deficit, altered social interaction; MRI-detectable adult brain differences; deficit of deep-layer cortical neurons in the developing brain; described as "consistent with a highly penetrant risk factor."

Sessa et al. 2019, Neuron (PMID:31515109): impaired NPC proliferative dynamics and synaptic wiring; genome-wide H3K36me3 loss; behavioral deficits.

Cheung et al. 2021, Genesis (PMID:34050709): double outlet right ventricle + perimembranous VSD; conditional deletion localizes requirement to cardiopharyngeal mesoderm; no genetic interaction with Tbx1.

Nakagawa et al. 2020, iScience (PMID:32299058): Setd5^+/− mice show autism-related behaviors with disturbed ribosomal protein gene and rDNA expression in brain.

Li et al. 2022, Leukemia (PMID:34853439): hematopoietic-specific deletion → increased immunophenotypic HSCs, impaired long-term self-renewal, loss of LT-HSC quiescence via HCF-1/PAF1-dependent Pol II pause release on E2F targets.

Matsumura et al. 2021, Nat Commun (PMID:34857762): SETD5–NCoR-HDAC3 gates Cebpa/Pparg enhancers; APC/C-mediated SETD5 degradation is the adipogenic switch.

Phenotype recapitulation — strong. The mouse het reproduces: craniofacial/neural-crest dysmorphology, outflow-tract cardiac defects, cognitive deficits, social/communication deficits (USV), behavioral inflexibility (an OCD/rigidity analog), reduced grip strength (hypotonia analog), vertebral anomalies, and the core molecular lesion.

Model limitations: (a) no reported spontaneous seizures despite human epilepsy in ~14%; (b) enhanced LTP in mice is hard to map onto human cognition; (c) mouse cortex lacks human-specific outer radial glia/OSVZ biology relevant to an NSPC-proliferation disorder; (d) no leg-length-discrepancy analog; (e) the human catalytic-activity question is not resolved by the mouse.

Curation note: limitation (c) — and more broadly the question of whether murine NSPC proliferation phenotypes translate to human corticogenesis — is a textbook case for discussions with kind: HUMAN_MODEL_MISMATCH rather than generic KNOWLEDGE_GAP, since the evidence exists in the model and it is the translational validity that is open.

15.2 Zebrafish

setd5 CRISPR/Cas9 heterozygous mutants (PMID:36613611): defective aggregation and shoaling coordination, indifference to social stimuli; adult-brain downregulation of synaptic structure/function genes suggesting hypo-connectivity; risperidone rescues social interest. Positioned as "a promising setd5 haploinsufficiency model" for drug screening. Also used to confirm H3K36me3 loss (Sessa 2019). ZFIN is the resource database.

15.3 Invertebrate / amphibian

Drosophila UpSET and X. laevis setd5 (PMID:33819264): two-hit interaction platform; SETD5–MOSMO synergy producing axon-outgrowth defects. Databases: FlyBase, Xenbase.

15.4 Cellular / in vitro

Mouse ESCs — reduced proliferation, increased apoptosis, impaired cell-cycle progression and cardiomyocyte differentiation (PMID:27864380); required for primordial-germ-cell specification genes via Tbl1xr1/Ctr9 (Yu et al. 2017, Cell Biochem Funct 35:247–253)
Neural stem cells — H3K36me3 and RNA-elongation phenotypes (Sessa 2019)
hiPSC-derived neurons and astrocytes — mitochondrial phenotypes (PMID:37264456); astrocyte IL-6/JAK-STAT (PMID:41993368, preprint)
Mouse retinal explants + shRNA — Setd5, not Setd2, required for retinal cell survival/proliferation; SET-domain-dependent; the SETD5^S1257 separation-of-function allele (PMID:36349512*)
High-throughput neural-development platform profiling shared ASD-gene impact on cell fate/differentiation (cached PMID_35197626)

15.5 Model databases

MGI (MGI:1920145), IMPC, IMSR, EuMMCR/EUCOMM, KOMP, EMMA, MMRRC, ZFIN, FlyBase, Xenbase, Alliance of Genome Resources, DepMap (cancer dependency), Cellosaurus.

Summary of high-priority knowledge gaps (candidates for `discussions:` entries)

Gap	Kind	Attaches to
Is SETD5 catalytically active as an H3K36 methyltransferase, or a catalytically dead co-repressor scaffold?	KNOWLEDGE_GAP + competing `mechanistic_hypotheses`	the H3K36me3 deposition node
Mechanism of reduced penetrance / unaffected carrier parents	KNOWLEDGE_GAP	disease-level
No natural-history study; no survival, functional-outcome, or QoL data	KNOWLEDGE_GAP	disease-level
No population prevalence estimate (Orphanet entry obsolete)	KNOWLEDGE_GAP	`prevalence`
Mouse NSPC-proliferation phenotypes vs. human OSVZ/oRG corticogenesis	HUMAN_MODEL_MISMATCH	NSPC proliferation node
Mouse het shows no seizures despite ~14% human epilepsy	HUMAN_MODEL_MISMATCH	epilepsy node
Mitochondrial phenotype unconfirmed in patient-derived tissue (authors' own caveat)	HUMAN_MODEL_MISMATCH	mitochondrial dysfunction node
Astrocytic IL-6/JAK-STAT arm rests on a non-peer-reviewed 2026 preprint	KNOWLEDGE_GAP	astrocyte node
PI3K-AKT/mTOR relevance is cancer-derived; unproven in germline NDD	KNOWLEDGE_GAP	signaling node
Neuroblastoma / CAKUT / hypopituitarism / moyamoya associations lack risk estimates; no surveillance evidence	KNOWLEDGE_GAP	respective phenotype nodes
ClinGen curates the gene–disease pair against MONDO:0800439, not MONDO:0014336	identifier discrepancy	`mappings`
PanelApp states "complete penetrance"; literature says incomplete	evidence conflict	`inheritance`

Key reference list (with cache status)

PMID	Short citation	Cached in repo?
24680889	Grozeva 2014, Am J Hum Genet — founding LoF series, 7 variants, 0.7%	✅
25138099	Kuechler 2015, Eur J Hum Genet — WES + NMD proof of haploinsufficiency	✅
23613140	Kellogg 2013, AJMG A — 684 kb del, 124 kb critical region	✗
28881385	Powis 2018, Clin Genet — reduced penetrance, phenotype expansion	✅
27375234	Szczałuba 2016, AJMG A — first familial case	✗
39603091	De Falco 2025, Eur J Paediatr Neurol — 28-patient neuro/psych cohort	✅
40265665	Callahan 2025, Clin Genet — Brain Gene Registry, n=13	✅
42468298	Talaba 2026, Pediatr Neurol — Facebook survey, n=51	✅
36335838	Sveden/… 2023, Pediatr Neurol — genotype/phenotype expansion	✅ (abstract absent in cache)
32793091	Crippa 2020, Front Neurol — SETD5 in suspected KBG	✅
34169511	Anderson 2021, Clin Genet — bone fragility	✗
31474762	Pinard 2020, Genet Med — moyamoya pleiotropy	✅
27864380	Osipovich 2016, Development — null lethality, PAF1/NCoR-HDAC3	✗
30455454	Deliu 2018, Nat Neurosci — het mouse, Pol II/Hdac3/Paf1	✅
31515109	Sessa 2019, Neuron — H3K36me3 deposition, RNA elongation	✅
30655503	Moore 2019, Transl Psychiatry — network connectivity, ASD behaviors	✅
32299058	Nakagawa 2020, iScience — rDNA/HDAC3/H4K16ac/TIP5/cyclin D1	✅
32442403	Wang 2020, Cancer Cell — "SETD5 lacks HMT activity" scaffold model	✗
34857762	Matsumura 2021, Nat Commun — NCoR-HDAC3, APC/C switch	✗
34853439	Li 2022, Leukemia — Pol II pausing, HCF-1, HSC	✅
37264456	2023, Mol Autism — mitochondrial compartment	✅
36875494	Li 2023, Front Endocrinol — SETD5 structure/activity review (full text cached)	✅
40520101	2025, iScience — ANKRD11→SETD5→rRNA axis	✗
34050709	Cheung 2021, Genesis — cardiopharyngeal mesoderm, DORV/VSD	✗
36613611	2022, IJMS — zebrafish setd5, risperidone rescue	✗
36349512	2023, FEBS Lett — retina, Setd5 vs Setd2, S1257* allele	✗
33819264	Pizzo 2021, PLoS Genet — two-hit, SETD5×MOSMO	✗
29180574	Villain 2018, Development — SetD5/BRD2/Sema3A	✗
41993368	2026 bioRxiv — astrocyte IL-6/JAK-STAT ⚠️ preprint	✗
32109418	Aref-Eshghi 2020, AJHG — 42-disorder episignatures	✗
34906459	Levy 2022, Genet Med — chromatinopathy episignatures	✗
41957673	2026, Clin Epigenetics — 400 NDD, EpiSign, SETD5 concordance	✗
40869907	2025, Genes — rhGH in SETD5 overlap syndrome	✗
41368699	2025, Birth Defects Res — prenatal ASD → de novo SETD5	✗
40462669	2025, J Child Neurol — novel epilepsy phenotype	✗
28263952	Rawlins 2017, Clin Dysmorphol — CDH + cortical dysplasia	✗
28951171	Yagasaki 2018, Pediatr Neonatol — 10.1 Mb 3p25 del, ptosis	✗
28905509	2017, AJMG A — aberrant blind-ending bronchus	✗
28549204	2017, Genet Mol Res — mild ID, 36-year-old	✗
28120103	Parenti 2017, Hum Genet — CdLS-overlap chromatin regulators	✅
32748512	Pires 2020, Pediatr Blood Cancer — neuroblastoma	✅ (abstract absent)
40913078	2025, EJHG — CAKUT+ clinical exome, SETD5 signal	✗
38822427	2024, Genome Med — pituitary malformation screen, SETD5 in CH	✗
35132768	Pascolini 2022, AJMG A — KBG-like appearance	✗

Non-PubMed sources used: ClinGen (search.clinicalgenome.org, gene HGNC:25566 — GDV Definitive 2023-07-27; dosage HI=3/TS=0, 2014-11-06); HGNC REST (rest.genenames.org); EBI OLS4 (MONDO:0014336, GO term verification); HPO/Jax annotation API (ontology.jax.org, OMIM:615761); IMPC solr (Setd5 genotype-phenotype, MGI:1920145); SFARI Gene (gene.sfari.org); Genomics England PanelApp API; Orphadata 2025-12-09 snapshot via references_cache/ORPHA_404440.md and ORPHA_435638.md.

Sources: - PubMed E-utilities (esearch/efetch) - ClinGen — SETD5 (HGNC:25566) - HGNC REST — SETD5 - EBI OLS4 — MONDO:0014336 - HPO annotations — OMIM:615761 - IMPC — Setd5 phenotypes - SFARI Gene — SETD5 - Genomics England PanelApp — SETD5 - ClinVar RCV000114962 — SETD5 c.3001C>T - GTR — Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency - Kuechler et al. 2015, Eur J Hum Genet - Crippa et al. 2020, Front Neurol (PMC7393934) - GARD — Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency - Levy et al., DNA methylation episignature testing improves molecular diagnosis of Mendelian chromatinopathies - EpiSign v5 methylation array panel content

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OpenScientist Report

Classifications

Mappings

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

SETD5 Haploinsufficiency Syndrome — Comprehensive Research Report

⚠️ Verification preamble (read before curating)

1. Disease Information

Overview

Key identifiers

Synonyms

Data provenance type — mixed

2. Etiology

Disease causal factors

Genetic risk factors

Environmental risk factors

Protective factors

Gene–environment interactions

3. Phenotypes

3.1 Authoritative HPO annotation set (OMIM:615761, via ontology.jax.org)

3.2 Frequencies from larger, better-powered cohorts (preferred for curation)

3.3 Phenotypes by category

3.4 Phenotype characteristics

4. Genetic / Molecular Information

Causal gene

Pathogenic variants

Modifier genes

Epigenetic information

Chromosomal abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 The central unresolved question — is SETD5 a methyltransferase?

6.2 Substrate/complex map (from PMID:36875494 Table 1, CACHE-VERIFIED)

6.3 Causal chain — germline haploinsufficiency (proposed pathograph)

6.4 Molecular pathways (KEGG/Reactome/GO framing)

6.5 Suggested GO / CL / UBERON / CHEBI terms

6.6 Molecular profiling

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

Epidemiology

Genetic epidemiology

Population demographics

10. Diagnostics

Primary diagnostic modality: genomic sequencing

Supportive clinical evaluations (not diagnostic, but standard-of-care workup)

Clinical criteria and differential diagnosis

Screening

11. Outcome / Prognosis

12. Treatment

Standard of care (all suggested NCIT terms require OAK verification)

Disease-specific pharmacological reports

Preclinical / experimental leads (none in human trials)

Clinical trials

Pharmacogenomics

Gene/RNA/cell therapy

13. Prevention

14. Other Species / Natural Disease

Orthologs and evolutionary conservation

15. Model Organisms

15.1 Mouse — the primary model

15.2 Zebrafish

15.3 Invertebrate / amphibian

15.4 Cellular / in vitro

15.5 Model databases

Summary of high-priority knowledge gaps (candidates for discussions: entries)

Key reference list (with cache status)

Summary of high-priority knowledge gaps (candidates for `discussions:` entries)