PHF21A Related Neurodevelopmental Disorder

Mendelian MONDO:0032883 Pathograph 27 Show in embeddings browser Neurodevelopmental Disorder

PHF21A-related neurodevelopmental disorder, formally intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, is an autosomal dominant condition caused by heterozygous loss of function in PHF21A. Nearly all reported variants are de novo and the mechanism is haploinsufficiency. PHF21A encodes BHC80, a component of the LSD1-CoREST histone demethylase complex, and its molecular job is an unusual one: its PHD finger reads the absence of a modification. It binds unmethylated histone H3 lysine 4, and that binding is abolished when H3K4 is methylated. Losing one copy therefore degrades the complex's ability to recognise unmodified chromatin and de-represses its target genes. PHF21A is highly expressed in fetal brain, which is where a dose-sensitive chromatin reader would be expected to matter.

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1
Inheritance
4
Pathophys.
19
Phenotypes
1
Gaps
27
Pathograph
1
Genes
2
Variants
2
Medical Actions
2
Differentials
1
Models
1
Deep Research
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Inheritance

1
Autosomal dominant inheritance HP:0000006
Dominant by haploinsufficiency, and overwhelmingly de novo - which is what makes recurrence risk low for parents of an affected child but 50% for that child's own offspring.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:31649809 SUPPORT Human Clinical
"We have identified seven heterozygous coding mutations, among which six are de novo"
Establishes both the heterozygous state and the de novo predominance - six of seven, which is a proportion rather than a rule, and the entry says "overwhelmingly" rather than "always" for that reason.
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Discussions and Knowledge Gaps

1
Does heterozygous PHF21A loss actually de-repress LSD1-CoREST target genes in human neurons, and which targets account for the craniofacial features as distinct from the neurodevelopmental ones?
KNOWLEDGE GAP phf21a_dosage_to_transcription
Attached to
pathophysiology#De-repression of LSD1-CoREST Target Genes pathophysiology#Neurodevelopmental and Craniofacial Consequences
Narrowed. An earlier revision of this gap said no cited work measured LSD1 target expression in patient cells, which was wrong: PMID:22770980 measured SCN3A de-repression and reduced LSD1 promoter occupancy in lymphoblastoid lines from two translocation patients, and that paper was cached in this repository the whole time. The gap that remains is real but smaller. Lymphoblastoid cells are not neurons; the measurement is in a lineage that does not express the phenotype, at two named targets rather than transcriptome-wide, and the magnitude of the effect at half dosage in a developing human neuron is still unmeasured. The craniofacial half is now partly answered too, and in the same paper. Zebrafish phf21a suppression produces craniofacial abnormalities together with neuronal apoptosis, and the murine and zebrafish orthologs are expressed consistently with a role in craniofacial development. So the facial phenotype is no longer reached only by inference from a brain expression pattern. What is still missing is the mechanism between them: no cited work names a transcriptional target that would produce the facial features, and neural crest appears nowhere in the cited evidence. A morphant establishes that the gene is needed for craniofacial development; it does not say which LSD1-CoREST target genes carry that requirement.
Proposed experiments
Transcriptome and LSD1 occupancy in PHF21A-heterozygous patient iPSC neurons
phf21a_patient_neuron_transcriptome
Differentiate neurons from PHF21A-heterozygous patient iPSCs and profile expression against isogenic controls, with LSD1 and BHC80 chromatin occupancy at the de-repressed loci. This measures the transcriptional consequence at the right dose, in the right lineage, transcriptome-wide - which is the three things the lymphoblastoid result does not do.
Would support
pathophysiology#De-repression of LSD1-CoREST Target Genes
Supporting outcome
  • Neuronal LSD1-CoREST targets, SCN3A among them, are expressed above isogenic control levels in heterozygous neurons, with reduced LSD1 occupancy at the same loci.
Refuting outcome
  • Heterozygous neurons show no consistent de-repression of LSD1-CoREST targets, which would place the pathogenic step somewhere other than the transcriptional node this pathograph asserts.
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Pathophysiology

4
PHF21A Haploinsufficiency
One functional copy of PHF21A is not enough. The defining cohort's variants are frameshifts, a nonsense change and a missense change in the AT-hook domain, and six of the seven truncate a C-terminal intrinsically disordered region.
PHF21A hgnc:24156 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PHF21A (hgnc:24156). hgnc:24156 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired Reading of Unmethylated H3K4
Show evidence (1 reference)
PMID:31649809 SUPPORT Human Clinical
"suggesting that haploinsufficiency is the likely underlying mechanism in the phenotype of seven patients"
States the mechanism as the authors' inference. The entry keeps their hedge - "likely" - rather than promoting it to an established mechanism.
Impaired Reading of Unmethylated H3K4
BHC80's PHD finger binds histone H3 only when lysine 4 is unmethylated, and methylation of H3K4 abolishes that binding. The protein is a reader of an absence, which is what makes its dosage sensitivity interesting: half as much reader means the unmodified state is recognised less reliably. This node is graded IN_VITRO throughout. The binding, the structure and the knockdown are all cell and crystal work; no cited source demonstrates any of it in patient cells. No cell type is annotated, deliberately. Both evidence items are HeLa and crystal work, so a neuron annotation here would assert a cell-type scope the evidence does not reach. The downstream node carries the neuronal claim, where the patient lymphoblastoid data and the fetal-brain expression give it a basis.
Downstream
De-repression of LSD1-CoREST Target Genes
Show evidence (2 references)
PMID:17687328 SUPPORT In Vitro
"the PHD finger of BHC80 binds unmethylated H3K4 (H3K4me0), and this interaction is specifically abrogated by methylation of H3K4"
The molecular function this node claims is impaired, stated with its specificity - it is the unmethylated state that is read.
PMID:17687328 SUPPORT In Vitro
"BHC80 and LSD1 depend reciprocally on one another to associate with chromatin"
The reciprocity matters for a dosage argument: less BHC80 does not merely remove one subunit's contribution, it impairs LSD1's own chromatin association.
De-repression of LSD1-CoREST Target Genes
Genes normally repressed by the LSD1 complex are expressed when BHC80 is reduced. In fetal brain, where PHF21A is highly expressed, that is the transcriptional insult the neurodevelopmental phenotype is attributed to. The claim is directional, so the annotation is: repression is reduced (GO:0000122, DECREASED) rather than transcription being unspecifically dysregulated. A named target exists and it is a neuronal one. In lymphoblastoid lines from two translocation patients, SCN3A is de-repressed and LSD1 occupancy at its promoter is reduced - the failure measured at the promoter of the gene, in cells from people who have the disease, rather than only in a knockdown. SCN3A is a neuronal sodium channel, which is the closest the cited evidence comes to connecting this node to the seizure phenotype; the entry stops at noting the identity of the gene rather than asserting the connection, because nothing cited measures SCN3A in patient neurons or relates its expression to seizures in these individuals.
negative regulation of transcription by RNA polymerase II GO:0000122 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of transcription by RNA polymerase II (GO:0000122). GO:0000122 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Neurodevelopmental and Craniofacial Consequences
Show evidence (3 references)
PMID:17687328 SUPPORT In Vitro
"Knockdown of BHC80 by RNA inhibition results in the de-repression of LSD1 target genes"
The direct evidence for this node. Note it is a knockdown in cells, not a heterozygous state in a patient, so the direction is established and the magnitude at half dosage is not.
PMID:31649809 SUPPORT Human Clinical
"PHF21A is highly expressed in the human fetal brain, which is consistent with the neurodevelopmental phenotype"
Supplies the expression context that makes a general chromatin mechanism land on the brain. Quoted with the authors' own "consistent with", which is weaker than a demonstration.
PMID:22770980 SUPPORT In Vitro
"In lymphoblastoid cell lines from two translocation subjects in whom PHF21A was directly disrupted by the respective breakpoints, we observed derepression of the neuronal gene SCN3A and reduced LSD1 occupancy at the SCN3A promoter"
The strongest evidence for this node, and the only item measured in cells from affected people rather than in a knockdown. It gives both halves of the mechanism - the de-repression and the reduced LSD1 occupancy that explains it - at a named neuronal target. Graded IN_VITRO because the measurement is in cultured lymphoblastoid lines; the cells are patient-derived but the assay is not a clinical observation.
Neurodevelopmental and Craniofacial Consequences
The clinical syndrome: intellectual disability with behavioural abnormalities and craniofacial dysmorphism, with seizures, hypotonia and autism in a substantial share of patients. Two groups of phenotypes hang off this node with a weaker claim than the neurological ones, and the node does not pretend otherwise. Postnatal overgrowth and the digital anomalies are established as features of the disorder and are attributable to PHF21A by the same translocation and point-mutation logic as the rest, but nothing cited connects either to the transcriptional mechanism upstream. Their edges assert that they are part of the syndrome, not that this pathograph explains them.
Animal models
Zebrafish phf21a morphant Zebrafish partially recapitulates Reproduces the co-occurrence of craniofacial and neuronal phenotypes that defines the human disorder.
Downstream
Intellectual Disability
Autism
Seizure
Hypotonia
Abnormal Facial Shape
Delayed Speech and Language Development
Global Developmental Delay
Atypical Behavior
Attention Deficit Hyperactivity Disorder
Epileptic Encephalopathy
Postnatal Overgrowth
Tapered Finger
Clinodactyly
Syndactyly
Sleep Disturbance
Broad Forehead
Broad Nasal Tip
Anteverted Nares
Full Cheeks
Show evidence (1 reference)
PMID:31649809 SUPPORT Human Clinical
"Our results extend the phenotypic spectrum of PHF21A mutations by adding autism spectrum disorder, epilepsy, hypotonia, and neurobehavioral problems"
Names four of the six phenotypes reached from this node, and does so for point-mutation patients rather than deletion patients - which is what makes them attributable to PHF21A alone.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for PHF21A Related Neurodevelopmental Disorder Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

19
Head and Neck 3
Abnormal Facial Shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31649809 SUPPORT Human Clinical
"PHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations"
Same quote and same reasoning as intellectual disability: the translocation cases are what separate this from a contiguous-gene effect.
Broad Nasal Tip HP:0000455 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad nasal tip (HP:0000455). HP:0000455 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36876344 SUPPORT Human Clinical
"Although a recognizable facial gestalt was not associated, subtle dysmorphic features were shared amongst some individuals and included a tall broad forehead, broad nasal tip, anteverted nares and full cheeks"
Names this feature, and in the same breath denies a recognizable gestalt. Both halves are curated: the negative is what stops a reader treating these four features as a diagnostic facial signature.
Anteverted Nares HP:0000463 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anteverted nares (HP:0000463). HP:0000463 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36876344 SUPPORT Human Clinical
"Although a recognizable facial gestalt was not associated, subtle dysmorphic features were shared amongst some individuals and included a tall broad forehead, broad nasal tip, anteverted nares and full cheeks"
Names this feature, and in the same breath denies a recognizable gestalt. Both halves are curated: the negative is what stops a reader treating these four features as a diagnostic facial signature.
Limbs 2
Clinodactyly HP:0030084 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clinodactyly (HP:0030084). HP:0030084 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31649809 SUPPORT Human Clinical
"autism spectrum disorder, epilepsy, hypotonia, neurobehavioral problems, tapering fingers, clinodactyly, and syndactyly, in addition to intellectual disability and craniofacial anomalies"
Named in the same conclusion sentence. No frequency, for the reason given on the tapered-finger record.
Syndactyly HP:0001159 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Syndactyly (HP:0001159). HP:0001159 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31649809 SUPPORT Human Clinical
"autism spectrum disorder, epilepsy, hypotonia, neurobehavioral problems, tapering fingers, clinodactyly, and syndactyly, in addition to intellectual disability and craniofacial anomalies"
Named in the same conclusion sentence. No frequency, for the reason given on the tapered-finger record.
Musculoskeletal 1
Hypotonia FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:31649809 SUPPORT Human Clinical
"adding autism spectrum disorder, epilepsy, hypotonia, and neurobehavioral problems"
Names hypotonia in the point-mutation cohort.
PMID:37633153 SUPPORT Human Clinical
"Overgrowth, ADHD, hypotonia, ASD, and sleep disorders were observed in 100%, 77.78%, 70%, 50%, and 33.33% of patients, respectively"
The frequency band: hypotonia in 70% of twelve patients.
PMID:36876344 SUPPORT Human Clinical
"Frequent associations included postnatal hypotonia (7/11, 64%); and at least one afebrile seizure episode (6/12, 50%)"
A second series at 64% of eleven, consistent with the first and in the same band.
Nervous System 8
Intellectual Disability OBLIGATE HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:31649809 SUPPORT Human Clinical
"PHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations"
Chosen deliberately over a shorter quote because it names both evidence classes and distinguishes them. The translocation patients are what license attributing intellectual disability to PHF21A rather than to the Potocki-Shaffer deletion as a whole.
PMID:22770980 SUPPORT Human Clinical
"we have uncovered evidence that the ID and CFA phenotypes are both caused by haploinsufficiency of a single gene, PHF21A, at 11p11.2"
The paper that established the single-gene attribution, cited here rather than only secondhand through a background sentence in a later report.
PMID:37633153 SUPPORT Human Clinical
"all patients (100%) had intellectual disability (ID) and motor development delay"
The frequency band. Twelve patients at 100%, on top of seven of seven in the defining cohort, is what supports OBLIGATE rather than VERY_FREQUENT.
Autism FREQUENT HP:0000717 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism (HP:0000717). HP:0000717 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31649809 SUPPORT Human Clinical
"adding autism spectrum disorder, epilepsy, hypotonia, and neurobehavioral problems"
Named as an addition to the spectrum from the point-mutation cohort.
PMID:37633153 SUPPORT Human Clinical
"Overgrowth, ADHD, hypotonia, ASD, and sleep disorders were observed in 100%, 77.78%, 70%, 50%, and 33.33% of patients, respectively"
The frequency band: ASD in 50% of twelve patients.
Seizure FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31649809 SUPPORT Human Clinical
"adding autism spectrum disorder, epilepsy, hypotonia, and neurobehavioral problems"
Names epilepsy in the point-mutation cohort.
PMID:37633153 SUPPORT Human Clinical
"Seven of the 12 patients (58.33%) had an epileptic phenotype, and the majority (5/7, 71.42%) of affected individuals developed developmental and epileptic encephalopathy (DEE)"
The frequency band: an epileptic phenotype in 58.33% of twelve. The second clause is about the character of that epilepsy and is used on the Epileptic Encephalopathy record, not here.
Delayed Speech and Language Development OBLIGATE HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31649809 SUPPORT Human Clinical
"developmental delay, ID, language delay,"
Language delay is named among the phenotypes common to all seven patients in the defining cohort, which is the OBLIGATE band. The sentence is split mid-word across a line break by the two-column PDF extraction in the cache, so the quote begins after that break; the full sentence reads "The common phenotypes seen in all seven patients reported here are developmental delay, ID, language delay, and impaired motor skills." The previous revision of this record cited a sentence naming autism, epilepsy, hypotonia and neurobehavioural problems that did not mention speech or language at all, graded PARTIAL to cover the mismatch. That was the wrong instrument: PARTIAL is for evidence that partly supports a claim, not for evidence that is silent on it.
Atypical Behavior VERY_FREQUENT HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurobehavioral problems, annotated with Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37528014 SUPPORT Human Clinical
"Clinical manifestations were intellectual disability or developmental delay (15 patients), craniofacial anomalies (15 patients), behavioral abnormalities (12 patients), seizures (9 patients), and overgrowth (8 patients)"
Twelve of fifteen, which is the VERY_FREQUENT band. The Table 1 row in the defining cohort gives six of seven for the same feature but is not quoted: its plus-minus columns do not survive text extraction cleanly, and the repository's snippet-length gate is right to reject such a row as carrying no propositional content.
PMID:36876344 SUPPORT Human Clinical
"all had both an intellectual disability and behavioural issues"
Independent replication in a second series of thirteen individuals.
Global Developmental Delay OBLIGATE HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31649809 SUPPORT Human Clinical
"developmental delay, ID, language delay,"
Developmental delay is named among the phenotypes common to all seven patients. The sentence is split mid-word across a line break by the two-column PDF extraction in the cache, so the quote begins after that break; the full sentence reads "The common phenotypes seen in all seven patients reported here are developmental delay, ID, language delay, and impaired motor skills."
PMID:37633153 SUPPORT Human Clinical
"all patients (100%) had intellectual disability (ID) and motor development delay"
The motor stream specifically, at 100% of twelve patients - which is what makes the delay global rather than confined to language and cognition, and is the second denominator behind the OBLIGATE band.
Attention Deficit Hyperactivity Disorder FREQUENT HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37633153 SUPPORT Human Clinical
"Overgrowth, ADHD, hypotonia, ASD, and sleep disorders were observed in 100%, 77.78%, 70%, 50%, and 33.33% of patients, respectively"
77.78% across twelve patients. The figure sits second in the list and pairs with ADHD by position; the band is FREQUENT, which is the same band 70% and 50% fall in, so the reading is not load-bearing for the band even if the ordering were misread.
Sleep Disturbance FREQUENT HP:0002360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep disorders, annotated with Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37633153 SUPPORT Human Clinical
"Overgrowth, ADHD, hypotonia, ASD, and sleep disorders were observed in 100%, 77.78%, 70%, 50%, and 33.33% of patients, respectively"
33.33% of twelve patients - four people. The figure is last in the list and pairs with sleep disorders by position, which is the reading this entry has to get right; it also falls in the same FREQUENT band as the two figures either side of it, so the band does not depend on the positional reading.
Growth 1
Postnatal Overgrowth FREQUENT HP:0001548 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postnatal overgrowth, annotated with Overgrowth (HP:0001548). HP:0001548 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36876344 SUPPORT Human Clinical
"postnatal overgrowth was reported in 5/6 (83%)"
The series that argues PHF21A belongs among the overgrowth-ID syndromes, with its own denominator stated - six individuals for whom growth data were recorded, out of thirteen analysed.
PMID:37528014 SUPPORT Human Clinical
"Clinical manifestations were intellectual disability or developmental delay (15 patients), craniofacial anomalies (15 patients), behavioral abnormalities (12 patients), seizures (9 patients), and overgrowth (8 patients)"
The largest denominator, and the lowest overgrowth share - 8 of 15. Cited alongside the 83% figure rather than instead of it, because the spread between them is the reason the band is FREQUENT.
Other 4
Epileptic Encephalopathy FREQUENT HP:0200134 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental and epileptic encephalopathy, annotated with Epileptic encephalopathy (HP:0200134). HP:0200134 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37633153 SUPPORT Human Clinical
"Seven of the 12 patients (58.33%) had an epileptic phenotype, and the majority (5/7, 71.42%) of affected individuals developed developmental and epileptic encephalopathy (DEE)"
The band is on the whole cohort - 5 of 12, 42% - not on the 71.42% figure, which is conditioned on already having epilepsy. Recording the conditional figure as the phenotype frequency would overstate it by a factor of about 1.7.
PMID:37633153 SUPPORT Human Clinical
"Of the 5 patients with DEE, three developed infantile epileptic spasm syndrome (IESS)"
The specific electroclinical syndrome in the majority of the DEE subset, which is what makes the vigabatrin observation in the treatments section relevant rather than incidental.
Tapered Finger HP:0001182 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tapering fingers, annotated with Tapered finger (HP:0001182). HP:0001182 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31649809 SUPPORT Human Clinical
"autism spectrum disorder, epilepsy, hypotonia, neurobehavioral problems, tapering fingers, clinodactyly, and syndactyly, in addition to intellectual disability and craniofacial anomalies"
The conclusion sentence names tapering fingers among the features associated with deleterious PHF21A variants.
Broad Forehead HP:0000337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tall broad forehead, annotated with Broad forehead (HP:0000337). HP:0000337 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36876344 SUPPORT Human Clinical
"Although a recognizable facial gestalt was not associated, subtle dysmorphic features were shared amongst some individuals and included a tall broad forehead, broad nasal tip, anteverted nares and full cheeks"
Names this feature, and in the same breath denies a recognizable gestalt. Both halves are curated: the negative is what stops a reader treating these four features as a diagnostic facial signature.
Full Cheeks HP:0000293 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Full cheeks (HP:0000293). HP:0000293 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36876344 SUPPORT Human Clinical
"Although a recognizable facial gestalt was not associated, subtle dysmorphic features were shared amongst some individuals and included a tall broad forehead, broad nasal tip, anteverted nares and full cheeks"
Names this feature, and in the same breath denies a recognizable gestalt. Both halves are curated: the negative is what stops a reader treating these four features as a diagnostic facial signature.
🧬

Genetic Associations

1
PHF21A
Gene: PHF21A hgnc:24156 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PHF21A (hgnc:24156). hgnc:24156 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Autosomal dominant inheritance
Show evidence (2 references)
PMID:31649809 SUPPORT Human Clinical
"We have identified seven heterozygous coding mutations, among which six are de novo"
The cohort and its inheritance pattern.
PMID:31649809 SUPPORT Human Clinical
"PHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations"
The evidence structure that makes single-gene attribution possible, which is the scope argument recorded in the entry's top-level notes.
Variants (2)
Variant class distribution across the reported cohort Pathogenic
Frameshift, nonsense and missense
Truncating variants dominate. Across twelve patients: frameshift 7, nonsense 4, missense 1. Every variant reported so far is de novo and heterozygous, which is the population-level form of the haploinsufficiency claim the whole entry rests on.
Show evidence (2 references)
PMID:37633153 SUPPORT Human Clinical
"The most common types of variants were frameshift variants (7/12, 58.33%), followed by nonsense variants (4/12, 33.33%) and missense variants (1/12, 8.33%)"
The class distribution with its denominator.
PMID:37633153 SUPPORT Human Clinical
"All of the variants (100%) were de novo heterozygous variants"
Establishes the de novo pattern quantitatively rather than as the qualitative "overwhelmingly de novo" the notes previously carried.
p.Arg580* recurrent variant Pathogenic
Nonsense
A recurrent nonsense change carried by a quarter of reported patients, and by two of the seven in the defining cohort. It is the one place a genotype-phenotype correlation could have been tested in this disease, and the answer was negative: patients with the same variant differ phenotypically. That is recorded because it is informative - it argues against variant identity being the main driver of severity - and not because the correlation is still open.
Show evidence (2 references)
PMID:37633153 SUPPORT Human Clinical
"Three of the 12 patients (25%) had the same variant (p.Arg580*)"
The recurrence and its share of the cohort.
PMID:37633153 SUPPORT Human Clinical
"Genotype-phenotype relationships for IDDBCS were uncertain, as phenotypic variability was observed among patients with the same variant (p.Arg580*)"
The negative result at the recurrent allele. Quoted rather than paraphrased because it bounds what the variant catalog can be used to predict.
🗃️

External Assertions

1
OMIM IDDBCS record
OMIM disease record OMIM:618725
The OMIM record MONDO:0032883 xrefs. Recorded here because DiseaseMappings carries no OMIM slot.
💊

Medical Actions

2
Vigabatrin for Infantile Spasms
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: vigabatrin CHEBI:63638 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses vigabatrin (CHEBI:63638). CHEBI:63638 is a therapeutic agent from Chemical Entities of Biological Interest.
One reported patient with infantile spasms did not respond to adrenocorticotropic hormone and responded well to vigabatrin. This is a single observation, not a trial, and it is recorded because it is specific: the epilepsy in this disorder is disproportionately infantile epileptic spasm syndrome, which is a seizure type with its own drug preferences, so the observation is at least aimed at the right target.
Show evidence (1 reference)
PMID:37528014 SUPPORT Human Clinical
"a series of spastic seizures with no reaction to adrenocorticotropic hormone but a good response to vigabatrin"
Graded PARTIAL because it is one patient in a case report. It supports the observation having been made; it does not support vigabatrin as an established treatment for this disorder.
Antiseizure Medication
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Seizure control is achieved in a minority of the encephalopathic subset, which is the practical reason the epileptic encephalopathy record exists separately from the seizure record.
Show evidence (1 reference)
PMID:37633153 SUPPORT Human Clinical
"The seizures of 2 patients (2/5, 40%) were controlled by antiseizure medications"
Quantifies the response rate in the DEE subset, and quantifies it as a minority - which is the clinically consequential half of the finding.
🔬

Diagnosis

3
Molecular Diagnosis by Exome Sequencing
Diagnosis is molecular and there is no biochemical marker. Sequencing finds the intragenic variants - frameshift, nonsense and missense - that define this entry's genotype class. Three lesions produce overlapping phenotypes at 11p11.2 and the entry's scope argument turns on telling them apart, so each modality that distinguishes them is recorded separately below rather than described in prose here.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:37528014 SUPPORT Human Clinical
"Whole exome sequencing showed a de novo heterogeneous variant, PHF21A (NM_001101802.1): c.54+1G>A"
Exome sequencing as the diagnostic route in a reported case, with the transcript reference the variant is called against.
Chromosomal Microarray
Detects the 11p11.2 deletion of Potocki-Shaffer syndrome, in which PHF21A is lost together with its neighbours. A positive microarray moves the patient out of this entry: the phenotype is then attributable to a contiguous-gene deletion rather than to PHF21A alone, which is exactly the attribution this entry exists to avoid making.
chromosomal microarray NCIT:C18477 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:22770980 SUPPORT Human Clinical
"Potocki-Shaffer syndrome (PSS) is a contiguous gene disorder due to the interstitial deletion of band p11.2 of chromosome 11"
Establishes what the microarray is looking for. Graded PARTIAL because the sentence defines the deletion syndrome rather than describing the diagnostic use of microarray, which no cited source states directly.
Karyotype and FISH
Detects a balanced translocation disrupting PHF21A without deleting its neighbours. This is the lesion class that licenses the entire single-gene attribution in this entry, and it is invisible to both sequencing and microarray - a translocation patient has a normal microarray and, typically, no intragenic variant to find.
karyotype and fluorescence in situ hybridization NCIT:C16768 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:22770980 SUPPORT Human Clinical
"Through characterization of independent subjects with balanced translocations and supportive comparative deletion mapping of PSS subjects, we have uncovered evidence that the ID and CFA phenotypes are both caused by haploinsufficiency of a single gene, PHF21A, at 11p11.2"
The translocation subjects, and what characterising them established. It is the reason this lesion class gets its own diagnostic record.
📊

Prevalence

1
Published cases worldwide
Cases In Literature Ultra Rare
Seven unrelated individuals in the defining cohort, preceded by three translocation patients and a small number of earlier point-mutation reports. No point prevalence has been estimated. Recorded as a case count rather than a rate, because there is no denominator.
Show evidence (1 reference)
PMID:31649809 SUPPORT Human Clinical
"Here, we analyze genomic data from seven unrelated individuals with mutations in PHF21A"
The cohort size, quoted so the figure stays attached to its study.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from PHF21A Related Neurodevelopmental Disorder:

Potocki-Shaffer syndrome
Overlapping Features The contiguous-gene deletion of 11p11.2, which removes PHF21A along with neighbouring genes. It shares the intellectual disability and craniofacial anomalies and adds multiple exostoses and parietal foramina, which PHF21A alone does not cause. This is the single most important distinction in the entry.
Distinguishing Features
  • Multiple exostoses
  • Parietal foramina
  • Deletion detectable on chromosomal microarray
Show evidence (1 reference)
PMID:22770980 SUPPORT Human Clinical
"is characterized by multiple exostoses, parietal foramina, intellectual disability (ID), and craniofacial anomalies (CFAs)"
The four features of the deletion syndrome, two of which separate it from this entry's disease.
Overgrowth-intellectual disability syndromes
Overlapping Features Sotos (NSD1), Weaver (EZH2), Tatton-Brown-Rahman (DNMT3A) and Malan (NFIX) syndromes. These became the clinically relevant confusion once postnatal overgrowth turned out to be a defining rather than incidental feature - one series argues explicitly for placing PHF21A in this family. No feature distinguishes them clinically with confidence, which is why the differential is resolved by sequencing rather than by examination.
Distinguishing Features
  • Resolved by molecular testing, not by phenotype
Show evidence (1 reference)
PMID:36876344 SUPPORT Human Clinical
"We present some evidence that PHF21A might be considered a new member of the overgrowth-intellectual disability syndrome (OGID) family"
Places the disorder in the family whose members are its differential. The authors' hedge - "some evidence", "might be considered" - is preserved.
🐁

Animal Models

1
Zebrafish phf21a morphant
Suppression of the zebrafish PHF21A ortholog produces craniofacial abnormalities and neuronal apoptosis together - the two arms of the human syndrome in one animal. This is the only model evidence in the entry and it is the reason the craniofacial arm of the pathograph is not purely inferential.
Species
Zebrafish
Genotype
phf21a ortholog suppression (morpholino knockdown)
Publication
PMID:22770980
Pathograph links
Neurodevelopmental and Craniofacial Consequences partially recapitulates fidelity: low Reproduces the co-occurrence of craniofacial and neuronal phenotypes that defines the human disorder.
Limitations: Fidelity is LOW for reasons that are not incidental. A morpholino knockdown is a transient, dose-uncontrolled suppression and is not the stable heterozygous state of the human disease, so it cannot speak to the dosage question this entry turns on. Zebrafish craniofacial development is not homologous to human facial morphogenesis at the level the dysmorphism is described. And neuronal apoptosis is not a reported feature of the human disorder - it is a cellular readout in the fish, not a recapitulation of intellectual disability.
Show evidence (1 reference)
PMID:22770980 SUPPORT Model Organism
"PHF21A encodes a plant homeodomain finger protein whose murine and zebrafish orthologs are both expressed in a manner consistent with a function in neurofacial and craniofacial development, and suppression of the latter led to both craniofacial abnormalities and neuronal apoptosis"
Both the expression pattern and the loss-of-function result, in one sentence. It is the basis for treating the model as informative for the craniofacial arm rather than only the neurological one.
{ }

Source YAML

click to show 
name: PHF21A Related Neurodevelopmental Disorder
creation_date: "2026-08-28T21:20:00Z"
category: Mendelian
description: >-
  PHF21A-related neurodevelopmental disorder, formally intellectual
  developmental disorder with behavioral abnormalities and craniofacial
  dysmorphism with or without seizures, is an autosomal dominant condition
  caused by heterozygous loss of function in PHF21A. Nearly all reported
  variants are de novo and the mechanism is haploinsufficiency.

  PHF21A encodes BHC80, a component of the LSD1-CoREST histone demethylase
  complex, and its molecular job is an unusual one: its PHD finger reads the
  absence of a modification. It binds unmethylated histone H3 lysine 4, and that
  binding is abolished when H3K4 is methylated. Losing one copy therefore
  degrades the complex's ability to recognise unmodified chromatin and
  de-represses its target genes. PHF21A is highly expressed in fetal brain,
  which is where a dose-sensitive chromatin reader would be expected to matter.
parents:
  - Neurodevelopmental Disorder
synonyms:
  - IDDBCS
  - intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures
  - BHC80-related neurodevelopmental disorder
  - PHF21A haploinsufficiency
disease_term:
  preferred_term: intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures
  term:
    id: MONDO:0032883
    label: intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures
notes: >-
  Scope, and it is the call this entry turns on. PHF21A lies at 11p11.2, inside
  the interval deleted in Potocki-Shaffer syndrome, so part of the literature
  describes this phenotype in a contiguous-gene context where several genes are
  missing at once. An entry that drew on that literature indiscriminately would
  attribute features of a multigene deletion to a single gene.

  What makes the single-gene attribution safe here is a specific class of
  evidence: patients whose PHF21A is disrupted by a balanced translocation, and
  patients with heterozygous point mutations. In both, PHF21A is affected and its
  neighbours are not. This entry is built on those, and the Potocki-Shaffer
  deletion literature is used only for context, never as the source of a
  phenotype. This is the same discipline the MBD5 entry needed against the EPC2
  co-deletion.

  Evidence base and frequencies. An earlier revision of this entry said no
  phenotype could carry a frequency because the denominator did not support one.
  That was wrong twice over. The defining cohort publication is cached here as
  full text and its Table 1 is a complete per-patient clinical-features matrix
  for all seven patients; and three later series - 12, 13 and 15 patients - take
  the literature to roughly forty individuals. Frequencies are now recorded, each
  bound to a quote stating a figure for that named phenotype.

  Two limits on those frequencies are worth stating rather than leaving for a
  reader to discover. First, the series overlap: the 12-, 13- and 15-patient
  cohorts are reviews that re-count previously reported patients, so the bands
  are not independent replications and forty is an upper bound on distinct
  individuals, not a count of them. Second, the OCR of Table 1 renders the
  plus-minus columns unambiguously for the neurological rows and ambiguously for
  the digital ones - so the digital anomalies are curated from the conclusion
  sentence with no frequency, rather than from a column that cannot be counted.

  Treatments. Also revised. The earlier note said no cited reference stated a
  protocol quotable exactly; that was true of the two references the entry then
  cited and false of the ones already sitting in this repository. The section now
  records the vigabatrin response in infantile spasms and the response rate to
  antiseizure medication, both graded to the strength of a single case report and
  a small subset respectively. There is still no disease-modifying therapy.
external_assertions:
  - name: OMIM IDDBCS record
    source: OMIM
    assertion_type: disease_record
    external_id: OMIM:618725
    url: https://omim.org/entry/618725
    description: >-
      The OMIM record MONDO:0032883 xrefs. Recorded here because DiseaseMappings
      carries no OMIM slot.
inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: >-
      Dominant by haploinsufficiency, and overwhelmingly de novo - which is what
      makes recurrence risk low for parents of an affected child but 50% for
      that child's own offspring.
    evidence:
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          We have identified seven heterozygous coding mutations, among which
          six are de novo
        explanation: >-
          Establishes both the heterozygous state and the de novo
          predominance - six of seven, which is a proportion rather than a
          rule, and the entry says "overwhelmingly" rather than "always" for
          that reason.
pathophysiology:
  - name: PHF21A Haploinsufficiency
    biological_scale: MOLECULAR
    description: >-
      One functional copy of PHF21A is not enough. The defining cohort's
      variants are frameshifts, a nonsense change and a missense change in the
      AT-hook domain, and six of the seven truncate a C-terminal intrinsically
      disordered region.
    genes:
      - preferred_term: PHF21A
        term:
          id: hgnc:24156
          label: PHF21A
    downstream:
      - target: Impaired Reading of Unmethylated H3K4
    evidence:
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          suggesting that haploinsufficiency is the likely underlying mechanism
          in the phenotype of seven patients
        explanation: >-
          States the mechanism as the authors' inference. The entry keeps their
          hedge - "likely" - rather than promoting it to an established
          mechanism.
  - name: Impaired Reading of Unmethylated H3K4
    biological_scale: MOLECULAR
    description: >-
      BHC80's PHD finger binds histone H3 only when lysine 4 is unmethylated,
      and methylation of H3K4 abolishes that binding. The protein is a reader of
      an absence, which is what makes its dosage sensitivity interesting: half
      as much reader means the unmodified state is recognised less reliably.

      This node is graded IN_VITRO throughout. The binding, the structure and
      the knockdown are all cell and crystal work; no cited source demonstrates
      any of it in patient cells.

      No cell type is annotated, deliberately. Both evidence items are HeLa and
      crystal work, so a neuron annotation here would assert a cell-type scope
      the evidence does not reach. The downstream node carries the neuronal
      claim, where the patient lymphoblastoid data and the fetal-brain
      expression give it a basis.
    downstream:
      - target: De-repression of LSD1-CoREST Target Genes
    evidence:
      - reference: PMID:17687328
        reference_title: "Recognition of unmethylated histone H3 lysine 4 links BHC80 to LSD1-mediated gene repression."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          the PHD finger of BHC80 binds unmethylated H3K4 (H3K4me0), and this
          interaction is specifically abrogated by methylation of H3K4
        explanation: >-
          The molecular function this node claims is impaired, stated with its
          specificity - it is the unmethylated state that is read.
      - reference: PMID:17687328
        reference_title: "Recognition of unmethylated histone H3 lysine 4 links BHC80 to LSD1-mediated gene repression."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          BHC80 and LSD1 depend reciprocally on one another to associate with
          chromatin
        explanation: >-
          The reciprocity matters for a dosage argument: less BHC80 does not
          merely remove one subunit's contribution, it impairs LSD1's own
          chromatin association.
  - name: De-repression of LSD1-CoREST Target Genes
    biological_scale: CELLULAR
    description: >-
      Genes normally repressed by the LSD1 complex are expressed when BHC80 is
      reduced. In fetal brain, where PHF21A is highly expressed, that is the
      transcriptional insult the neurodevelopmental phenotype is attributed to.

      The claim is directional, so the annotation is: repression is reduced
      (GO:0000122, DECREASED) rather than transcription being unspecifically
      dysregulated.

      A named target exists and it is a neuronal one. In lymphoblastoid lines
      from two translocation patients, SCN3A is de-repressed and LSD1 occupancy
      at its promoter is reduced - the failure measured at the promoter of the
      gene, in cells from people who have the disease, rather than only in a
      knockdown. SCN3A is a neuronal sodium channel, which is the closest the
      cited evidence comes to connecting this node to the seizure phenotype;
      the entry stops at noting the identity of the gene rather than asserting
      the connection, because nothing cited measures SCN3A in patient neurons or
      relates its expression to seizures in these individuals.
    biological_processes:
      - preferred_term: negative regulation of transcription by RNA polymerase II
        term:
          id: GO:0000122
          label: negative regulation of transcription by RNA polymerase II
        modifier: DECREASED
    downstream:
      - target: Neurodevelopmental and Craniofacial Consequences
    evidence:
      - reference: PMID:17687328
        reference_title: "Recognition of unmethylated histone H3 lysine 4 links BHC80 to LSD1-mediated gene repression."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Knockdown of BHC80 by RNA inhibition results in the de-repression of
          LSD1 target genes
        explanation: >-
          The direct evidence for this node. Note it is a knockdown in cells,
          not a heterozygous state in a patient, so the direction is established
          and the magnitude at half dosage is not.
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          PHF21A is highly expressed in the human fetal brain, which is
          consistent with the neurodevelopmental phenotype
        explanation: >-
          Supplies the expression context that makes a general chromatin
          mechanism land on the brain. Quoted with the authors' own
          "consistent with", which is weaker than a demonstration.
      - reference: PMID:22770980
        reference_title: "Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          In lymphoblastoid cell lines from two translocation subjects in whom
          PHF21A was directly disrupted by the respective breakpoints, we
          observed derepression of the neuronal gene SCN3A and reduced LSD1
          occupancy at the SCN3A promoter
        explanation: >-
          The strongest evidence for this node, and the only item measured in
          cells from affected people rather than in a knockdown. It gives both
          halves of the mechanism - the de-repression and the reduced LSD1
          occupancy that explains it - at a named neuronal target. Graded
          IN_VITRO because the measurement is in cultured lymphoblastoid lines;
          the cells are patient-derived but the assay is not a clinical
          observation.
  - name: Neurodevelopmental and Craniofacial Consequences
    biological_scale: ORGANISM
    description: >-
      The clinical syndrome: intellectual disability with behavioural
      abnormalities and craniofacial dysmorphism, with seizures, hypotonia and
      autism in a substantial share of patients.

      Two groups of phenotypes hang off this node with a weaker claim than the
      neurological ones, and the node does not pretend otherwise. Postnatal
      overgrowth and the digital anomalies are established as features of the
      disorder and are attributable to PHF21A by the same translocation and
      point-mutation logic as the rest, but nothing cited connects either to the
      transcriptional mechanism upstream. Their edges assert that they are part
      of the syndrome, not that this pathograph explains them.
    downstream:
      - target: Intellectual Disability
      - target: Autism
      - target: Seizure
      - target: Hypotonia
      - target: Abnormal Facial Shape
      - target: Delayed Speech and Language Development
      - target: Global Developmental Delay
      - target: Atypical Behavior
      - target: Attention Deficit Hyperactivity Disorder
      - target: Epileptic Encephalopathy
      - target: Postnatal Overgrowth
      - target: Tapered Finger
      - target: Clinodactyly
      - target: Syndactyly
      - target: Sleep Disturbance
      - target: Broad Forehead
      - target: Broad Nasal Tip
      - target: Anteverted Nares
      - target: Full Cheeks
    evidence:
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Our results extend the phenotypic spectrum of PHF21A mutations by
          adding autism spectrum disorder, epilepsy, hypotonia, and
          neurobehavioral problems
        explanation: >-
          Names four of the six phenotypes reached from this node, and does so
          for point-mutation patients rather than deletion patients - which is
          what makes them attributable to PHF21A alone.
phenotypes:
  - name: Intellectual Disability
    category: Neurologic
    frequency: OBLIGATE
    phenotype_term:
      preferred_term: Intellectual disability
      term:
        id: HP:0001249
        label: Intellectual disability
    evidence:
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          PHF21A has been associated with intellectual disability and
          craniofacial anomalies based on its deletion in the Potocki-Shaffer
          syndrome region at 11p11.2 and its disruption in three patients with
          balanced translocations
        explanation: >-
          Chosen deliberately over a shorter quote because it names both
          evidence classes and distinguishes them. The translocation patients
          are what license attributing intellectual disability to PHF21A rather
          than to the Potocki-Shaffer deletion as a whole.
      - reference: PMID:22770980
        reference_title: "Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          we have uncovered evidence that the ID and CFA phenotypes are both
          caused by haploinsufficiency of a single gene, PHF21A, at 11p11.2
        explanation: >-
          The paper that established the single-gene attribution, cited here
          rather than only secondhand through a background sentence in a later
          report.
      - reference: PMID:37633153
        reference_title: "De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          all patients (100%) had intellectual disability (ID) and motor
          development delay
        explanation: >-
          The frequency band. Twelve patients at 100%, on top of seven of seven
          in the defining cohort, is what supports OBLIGATE rather than
          VERY_FREQUENT.
  - name: Abnormal Facial Shape
    category: Craniofacial
    description: >-
      Craniofacial dysmorphism is one of the two features in the disorder's
      formal name.
    phenotype_term:
      preferred_term: Abnormal facial shape
      term:
        id: HP:0001999
        label: Abnormal facial shape
    evidence:
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          PHF21A has been associated with intellectual disability and
          craniofacial anomalies based on its deletion in the Potocki-Shaffer
          syndrome region at 11p11.2 and its disruption in three patients with
          balanced translocations
        explanation: >-
          Same quote and same reasoning as intellectual disability: the
          translocation cases are what separate this from a contiguous-gene
          effect.
  - name: Autism
    category: Behavioral
    frequency: FREQUENT
    phenotype_term:
      preferred_term: Autism
      term:
        id: HP:0000717
        label: Autism
    evidence:
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          adding autism spectrum disorder, epilepsy, hypotonia, and
          neurobehavioral problems
        explanation: >-
          Named as an addition to the spectrum from the point-mutation cohort.
      - reference: PMID:37633153
        reference_title: "De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Overgrowth, ADHD, hypotonia, ASD, and sleep disorders were observed in
          100%, 77.78%, 70%, 50%, and 33.33% of patients, respectively
        explanation: >-
          The frequency band: ASD in 50% of twelve patients.
  - name: Seizure
    category: Neurologic
    frequency: FREQUENT
    description: >-
      The "with or without seizures" of the formal disease name - present in a
      substantial share of patients but not required for the diagnosis.
    phenotype_term:
      preferred_term: Seizure
      term:
        id: HP:0001250
        label: Seizure
    evidence:
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          adding autism spectrum disorder, epilepsy, hypotonia, and
          neurobehavioral problems
        explanation: >-
          Names epilepsy in the point-mutation cohort.
      - reference: PMID:37633153
        reference_title: "De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Seven of the 12 patients (58.33%) had an epileptic phenotype, and the
          majority (5/7, 71.42%) of affected individuals developed
          developmental and epileptic encephalopathy (DEE)
        explanation: >-
          The frequency band: an epileptic phenotype in 58.33% of twelve. The
          second clause is about the character of that epilepsy and is used on
          the Epileptic Encephalopathy record, not here.
  - name: Hypotonia
    category: Neurologic
    frequency: FREQUENT
    phenotype_term:
      preferred_term: Hypotonia
      term:
        id: HP:0001252
        label: Hypotonia
    evidence:
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          adding autism spectrum disorder, epilepsy, hypotonia, and
          neurobehavioral problems
        explanation: >-
          Names hypotonia in the point-mutation cohort.
      - reference: PMID:37633153
        reference_title: "De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Overgrowth, ADHD, hypotonia, ASD, and sleep disorders were observed in
          100%, 77.78%, 70%, 50%, and 33.33% of patients, respectively
        explanation: >-
          The frequency band: hypotonia in 70% of twelve patients.
      - reference: PMID:36876344
        reference_title: "The PHF21A neurodevelopmental disorder: an evaluation of clinical data from 13 patients."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Frequent associations included postnatal hypotonia (7/11, 64%); and at
          least one afebrile seizure episode (6/12, 50%)
        explanation: >-
          A second series at 64% of eleven, consistent with the first and in the
          same band.
  - name: Delayed Speech and Language Development
    category: Neurologic
    frequency: OBLIGATE
    phenotype_term:
      preferred_term: Delayed speech and language development
      term:
        id: HP:0000750
        label: Delayed speech and language development
    evidence:
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          developmental delay, ID, language delay,
        explanation: >-
          Language delay is named among the phenotypes common to all seven
          patients in the defining cohort, which is the OBLIGATE band. The sentence is split mid-word across a line break by the two-column
          PDF extraction in the cache, so the quote begins after that break;
          the full sentence reads "The common phenotypes seen in all seven
          patients reported here are developmental delay, ID, language delay,
          and impaired motor skills."
          The previous revision of this record cited a sentence naming autism,
          epilepsy, hypotonia and neurobehavioural problems that did not mention
          speech or language at all, graded PARTIAL to cover the mismatch. That
          was the wrong instrument: PARTIAL is for evidence that partly supports
          a claim, not for evidence that is silent on it.
  - name: Atypical Behavior
    category: Behavioral
    frequency: VERY_FREQUENT
    description: >-
      The behavioural abnormality the disorder is named for, and broader than
      the autism record below: it covers the neurobehavioural problems reported
      across cohorts, of which autism is one manifestation.
    phenotype_term:
      preferred_term: Neurobehavioral problems
      term:
        id: HP:0000708
        label: Atypical behavior
    evidence:
      - reference: PMID:37528014
        reference_title: "[A case of intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures caused by PHF21A gene variation and review of literature]."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Clinical manifestations were intellectual disability or developmental
          delay (15 patients), craniofacial anomalies (15 patients), behavioral
          abnormalities (12 patients), seizures (9 patients), and overgrowth (8
          patients)
        explanation: >-
          Twelve of fifteen, which is the VERY_FREQUENT band. The Table 1 row in
          the defining cohort gives six of seven for the same feature but is not
          quoted: its plus-minus columns do not survive text extraction cleanly,
          and the repository's snippet-length gate is right to reject such a row
          as carrying no propositional content.
      - reference: PMID:36876344
        reference_title: "The PHF21A neurodevelopmental disorder: an evaluation of clinical data from 13 patients."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          all had both an intellectual disability and behavioural issues
        explanation: >-
          Independent replication in a second series of thirteen individuals.
  - name: Global Developmental Delay
    category: Neurologic
    frequency: OBLIGATE
    description: >-
      Delay across developmental streams, recorded separately from the static
      intellectual disability it precedes.
    phenotype_term:
      preferred_term: Global developmental delay
      term:
        id: HP:0001263
        label: Global developmental delay
    evidence:
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          developmental delay, ID, language delay,
        explanation: >-
          Developmental delay is named among the phenotypes common to all seven
          patients. The sentence is split mid-word across a line break by the two-column
          PDF extraction in the cache, so the quote begins after that break;
          the full sentence reads "The common phenotypes seen in all seven
          patients reported here are developmental delay, ID, language delay,
          and impaired motor skills."
      - reference: PMID:37633153
        reference_title: "De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          all patients (100%) had intellectual disability (ID) and motor
          development delay
        explanation: >-
          The motor stream specifically, at 100% of twelve patients - which is
          what makes the delay global rather than confined to language and
          cognition, and is the second denominator behind the OBLIGATE band.
  - name: Attention Deficit Hyperactivity Disorder
    category: Behavioral
    frequency: FREQUENT
    phenotype_term:
      preferred_term: Attention deficit hyperactivity disorder
      term:
        id: HP:0007018
        label: Attention deficit hyperactivity disorder
    evidence:
      - reference: PMID:37633153
        reference_title: "De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Overgrowth, ADHD, hypotonia, ASD, and sleep disorders were observed in
          100%, 77.78%, 70%, 50%, and 33.33% of patients, respectively
        explanation: >-
          77.78% across twelve patients. The figure sits second in the list and
          pairs with ADHD by position; the band is FREQUENT, which is the same
          band 70% and 50% fall in, so the reading is not load-bearing for the
          band even if the ordering were misread.
  - name: Postnatal Overgrowth
    category: Growth
    frequency: FREQUENT
    description: >-
      Postnatal overgrowth, with macrocephaly in some patients, has emerged as a
      defining rather than incidental feature - one series places PHF21A among
      the overgrowth-intellectual disability syndromes on the strength of it.

      The band is set conservatively at FREQUENT because the three series
      disagree and the disagreement runs with the denominator: 8 of 15 (53%) in
      the largest, 5 of 6 (83%) where data were recorded in the second, and 100%
      in the third. A phenotype reported in 53% of the biggest series is not
      VERY_FREQUENT on the strength of two smaller ones.
    phenotype_term:
      preferred_term: Postnatal overgrowth
      term:
        id: HP:0001548
        label: Overgrowth
    evidence:
      - reference: PMID:36876344
        reference_title: "The PHF21A neurodevelopmental disorder: an evaluation of clinical data from 13 patients."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          postnatal overgrowth was reported in 5/6 (83%)
        explanation: >-
          The series that argues PHF21A belongs among the overgrowth-ID
          syndromes, with its own denominator stated - six individuals for whom
          growth data were recorded, out of thirteen analysed.
      - reference: PMID:37528014
        reference_title: "[A case of intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures caused by PHF21A gene variation and review of literature]."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Clinical manifestations were intellectual disability or developmental
          delay (15 patients), craniofacial anomalies (15 patients), behavioral
          abnormalities (12 patients), seizures (9 patients), and overgrowth (8
          patients)
        explanation: >-
          The largest denominator, and the lowest overgrowth share - 8 of 15.
          Cited alongside the 83% figure rather than instead of it, because the
          spread between them is the reason the band is FREQUENT.
  - name: Epileptic Encephalopathy
    category: Neurologic
    frequency: FREQUENT
    description: >-
      Where epilepsy occurs it is usually not isolated seizures but a
      developmental and epileptic encephalopathy, and in a subset it takes the
      form of infantile epileptic spasm syndrome. This is the main determinant
      of outcome in the epileptic subset and is recorded separately from the
      seizure phenotype for that reason.
    phenotype_term:
      preferred_term: Developmental and epileptic encephalopathy
      term:
        id: HP:0200134
        label: Epileptic encephalopathy
    evidence:
      - reference: PMID:37633153
        reference_title: "De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Seven of the 12 patients (58.33%) had an epileptic phenotype, and the
          majority (5/7, 71.42%) of affected individuals developed
          developmental and epileptic encephalopathy (DEE)
        explanation: >-
          The band is on the whole cohort - 5 of 12, 42% - not on the 71.42%
          figure, which is conditioned on already having epilepsy. Recording the
          conditional figure as the phenotype frequency would overstate it by a
          factor of about 1.7.
      - reference: PMID:37633153
        reference_title: "De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Of the 5 patients with DEE, three developed infantile epileptic spasm
          syndrome (IESS)
        explanation: >-
          The specific electroclinical syndrome in the majority of the DEE
          subset, which is what makes the vigabatrin observation in the
          treatments section relevant rather than incidental.
  - name: Tapered Finger
    category: Skeletal
    description: >-
      One of three digital anomalies named in the defining cohort's conclusion.
      No frequency is recorded: the per-patient table gives counts, but its
      plus-minus columns for the digital rows are ambiguous in the cached text
      in a way the neurological rows are not, and a band read off an ambiguous
      OCR column would be a fabricated denominator.
    phenotype_term:
      preferred_term: Tapering fingers
      term:
        id: HP:0001182
        label: Tapered finger
    evidence:
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          autism spectrum disorder, epilepsy, hypotonia, neurobehavioral
          problems, tapering fingers, clinodactyly, and syndactyly, in addition
          to intellectual disability and craniofacial anomalies
        explanation: >-
          The conclusion sentence names tapering fingers among the features
          associated with deleterious PHF21A variants.
  - name: Clinodactyly
    category: Skeletal
    phenotype_term:
      preferred_term: Clinodactyly
      term:
        id: HP:0030084
        label: Clinodactyly
    evidence:
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          autism spectrum disorder, epilepsy, hypotonia, neurobehavioral
          problems, tapering fingers, clinodactyly, and syndactyly, in addition
          to intellectual disability and craniofacial anomalies
        explanation: >-
          Named in the same conclusion sentence. No frequency, for the reason
          given on the tapered-finger record.
  - name: Syndactyly
    category: Skeletal
    phenotype_term:
      preferred_term: Syndactyly
      term:
        id: HP:0001159
        label: Syndactyly
    evidence:
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          autism spectrum disorder, epilepsy, hypotonia, neurobehavioral
          problems, tapering fingers, clinodactyly, and syndactyly, in addition
          to intellectual disability and craniofacial anomalies
        explanation: >-
          Named in the same conclusion sentence. No frequency, for the reason
          given on the tapered-finger record.
  - name: Broad Forehead
    category: Craniofacial
    description: >-
      One of four dysmorphic features shared among some individuals. The source says "tall broad forehead"; the bound term covers the breadth, not the height. The
      series that reports them states in the same sentence that no recognizable
      facial gestalt is associated with the disorder, so these are shared but
      not diagnostic - a facial examination cannot make or exclude this
      diagnosis. No frequency band: "shared amongst some individuals" is not a
      count.
    phenotype_term:
      preferred_term: Tall broad forehead
      term:
        id: HP:0000337
        label: Broad forehead
    evidence:
      - reference: PMID:36876344
        reference_title: "The PHF21A neurodevelopmental disorder: an evaluation of clinical data from 13 patients."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Although a recognizable facial gestalt was not associated, subtle
          dysmorphic features were shared amongst some individuals and included
          a tall broad forehead, broad nasal tip, anteverted nares and full
          cheeks
        explanation: >-
          Names this feature, and in the same breath denies a recognizable
          gestalt. Both halves are curated: the negative is what stops a reader
          treating these four features as a diagnostic facial signature.
  - name: Broad Nasal Tip
    category: Craniofacial
    description: >-
      One of four dysmorphic features shared among some individuals. The
      series that reports them states in the same sentence that no recognizable
      facial gestalt is associated with the disorder, so these are shared but
      not diagnostic - a facial examination cannot make or exclude this
      diagnosis. No frequency band: "shared amongst some individuals" is not a
      count.
    phenotype_term:
      preferred_term: Broad nasal tip
      term:
        id: HP:0000455
        label: Broad nasal tip
    evidence:
      - reference: PMID:36876344
        reference_title: "The PHF21A neurodevelopmental disorder: an evaluation of clinical data from 13 patients."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Although a recognizable facial gestalt was not associated, subtle
          dysmorphic features were shared amongst some individuals and included
          a tall broad forehead, broad nasal tip, anteverted nares and full
          cheeks
        explanation: >-
          Names this feature, and in the same breath denies a recognizable
          gestalt. Both halves are curated: the negative is what stops a reader
          treating these four features as a diagnostic facial signature.
  - name: Anteverted Nares
    category: Craniofacial
    description: >-
      One of four dysmorphic features shared among some individuals. The
      series that reports them states in the same sentence that no recognizable
      facial gestalt is associated with the disorder, so these are shared but
      not diagnostic - a facial examination cannot make or exclude this
      diagnosis. No frequency band: "shared amongst some individuals" is not a
      count.
    phenotype_term:
      preferred_term: Anteverted nares
      term:
        id: HP:0000463
        label: Anteverted nares
    evidence:
      - reference: PMID:36876344
        reference_title: "The PHF21A neurodevelopmental disorder: an evaluation of clinical data from 13 patients."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Although a recognizable facial gestalt was not associated, subtle
          dysmorphic features were shared amongst some individuals and included
          a tall broad forehead, broad nasal tip, anteverted nares and full
          cheeks
        explanation: >-
          Names this feature, and in the same breath denies a recognizable
          gestalt. Both halves are curated: the negative is what stops a reader
          treating these four features as a diagnostic facial signature.
  - name: Full Cheeks
    category: Craniofacial
    description: >-
      One of four dysmorphic features shared among some individuals. The
      series that reports them states in the same sentence that no recognizable
      facial gestalt is associated with the disorder, so these are shared but
      not diagnostic - a facial examination cannot make or exclude this
      diagnosis. No frequency band: "shared amongst some individuals" is not a
      count.
    phenotype_term:
      preferred_term: Full cheeks
      term:
        id: HP:0000293
        label: Full cheeks
    evidence:
      - reference: PMID:36876344
        reference_title: "The PHF21A neurodevelopmental disorder: an evaluation of clinical data from 13 patients."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Although a recognizable facial gestalt was not associated, subtle
          dysmorphic features were shared amongst some individuals and included
          a tall broad forehead, broad nasal tip, anteverted nares and full
          cheeks
        explanation: >-
          Names this feature, and in the same breath denies a recognizable
          gestalt. Both halves are curated: the negative is what stops a reader
          treating these four features as a diagnostic facial signature.
  - name: Sleep Disturbance
    category: Neurologic
    frequency: FREQUENT
    description: >-
      Sleep disorders in a third of patients. Recorded because it is above the
      curation threshold and because sleep management is a care domain in its
      own right, not merely another entry in a feature list.
    phenotype_term:
      preferred_term: Sleep disorders
      term:
        id: HP:0002360
        label: Sleep disturbance
    evidence:
      - reference: PMID:37633153
        reference_title: "De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Overgrowth, ADHD, hypotonia, ASD, and sleep disorders were observed in
          100%, 77.78%, 70%, 50%, and 33.33% of patients, respectively
        explanation: >-
          33.33% of twelve patients - four people. The figure is last in the
          list and pairs with sleep disorders by position, which is the reading
          this entry has to get right; it also falls in the same FREQUENT band
          as the two figures either side of it, so the band does not depend on
          the positional reading.
genetic:
  - name: PHF21A
    relationship_type: CAUSATIVE
    variant_origin: DE_NOVO
    gene_term:
      preferred_term: PHF21A
      term:
        id: hgnc:24156
        label: PHF21A
    notes: >-
      Heterozygous loss of function, overwhelmingly de novo. Reported variant
      classes are frameshift, nonsense, and a missense change in the AT-hook
      domain; six of seven in the defining cohort truncate a C-terminal
      intrinsically disordered region, which the authors take as evidence that
      the region is functionally important.

      Two distinct lesion types support the same conclusion and should not be
      conflated: balanced translocations that disrupt the gene without deleting
      neighbours, and intragenic point mutations. Both isolate PHF21A from the
      Potocki-Shaffer interval, which is why this entry can attribute the
      phenotype to one gene.

      Not curated: gnomAD loss-of-function constraint. The deep-research report
      gives pLI 1.00, LOEUF 0.221 and 11 observed against 82.5 expected LoF
      alleles, which would be independent population-scale support for
      haploinsufficiency. It is left out because no cited publication in this
      entry states those figures, so there is nothing to attach an exact-quote
      snippet to; importing them from a research report would be asserting a
      number from an uncitable source. A curator with access to a gnomAD
      release citation should add it.
    variants:
      - name: Variant class distribution across the reported cohort
        type: Frameshift, nonsense and missense
        clinical_significance: PATHOGENIC
        description: >-
          Truncating variants dominate. Across twelve patients: frameshift 7,
          nonsense 4, missense 1. Every variant reported so far is de novo and
          heterozygous, which is the population-level form of the
          haploinsufficiency claim the whole entry rests on.
        evidence:
          - reference: PMID:37633153
            reference_title: "De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: >-
              The most common types of variants were frameshift variants (7/12,
              58.33%), followed by nonsense variants (4/12, 33.33%) and missense
              variants (1/12, 8.33%)
            explanation: >-
              The class distribution with its denominator.
          - reference: PMID:37633153
            reference_title: "De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: >-
              All of the variants (100%) were de novo heterozygous variants
            explanation: >-
              Establishes the de novo pattern quantitatively rather than as the
              qualitative "overwhelmingly de novo" the notes previously carried.
      - name: p.Arg580* recurrent variant
        type: Nonsense
        clinical_significance: PATHOGENIC
        description: >-
          A recurrent nonsense change carried by a quarter of reported patients,
          and by two of the seven in the defining cohort. It is the one place a
          genotype-phenotype correlation could have been tested in this disease,
          and the answer was negative: patients with the same variant differ
          phenotypically. That is recorded because it is informative - it argues
          against variant identity being the main driver of severity - and not
          because the correlation is still open.
        evidence:
          - reference: PMID:37633153
            reference_title: "De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: >-
              Three of the 12 patients (25%) had the same variant (p.Arg580*)
            explanation: >-
              The recurrence and its share of the cohort.
          - reference: PMID:37633153
            reference_title: "De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: >-
              Genotype-phenotype relationships for IDDBCS were uncertain, as
              phenotypic variability was observed among patients with the same
              variant (p.Arg580*)
            explanation: >-
              The negative result at the recurrent allele. Quoted rather than
              paraphrased because it bounds what the variant catalog can be used
              to predict.
    inheritance:
      - name: Autosomal dominant inheritance
        inheritance_term:
          preferred_term: Autosomal dominant inheritance
          term:
            id: HP:0000006
            label: Autosomal dominant inheritance
    evidence:
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          We have identified seven heterozygous coding mutations, among which
          six are de novo
        explanation: >-
          The cohort and its inheritance pattern.
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          PHF21A has been associated with intellectual disability and
          craniofacial anomalies based on its deletion in the Potocki-Shaffer
          syndrome region at 11p11.2 and its disruption in three patients with
          balanced translocations
        explanation: >-
          The evidence structure that makes single-gene attribution possible,
          which is the scope argument recorded in the entry's top-level notes.
prevalence:
  - population: Published cases worldwide
    measure_type: CASES_IN_LITERATURE
    prevalence_class: ULTRA_RARE
    notes: >-
      Seven unrelated individuals in the defining cohort, preceded by three
      translocation patients and a small number of earlier point-mutation
      reports. No point prevalence has been estimated. Recorded as a case count
      rather than a rate, because there is no denominator.
    evidence:
      - reference: PMID:31649809
        reference_title: "Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Here, we analyze genomic data from seven unrelated individuals with
          mutations in PHF21A
        explanation: >-
          The cohort size, quoted so the figure stays attached to its study.
discussions:
  - discussion_id: phf21a_dosage_to_transcription
    kind: KNOWLEDGE_GAP
    prompt: >-
      Does heterozygous PHF21A loss actually de-repress LSD1-CoREST target genes
      in human neurons, and which targets account for the craniofacial features
      as distinct from the neurodevelopmental ones?
    attaches_to:
      - pathophysiology#De-repression of LSD1-CoREST Target Genes
      - pathophysiology#Neurodevelopmental and Craniofacial Consequences
    rationale: >-
      Narrowed. An earlier revision of this gap said no cited work measured
      LSD1 target expression in patient cells, which was wrong: PMID:22770980
      measured SCN3A de-repression and reduced LSD1 promoter occupancy in
      lymphoblastoid lines from two translocation patients, and that paper was
      cached in this repository the whole time. The gap that remains is real but
      smaller. Lymphoblastoid cells are not neurons; the measurement is in a
      lineage that does not express the phenotype, at two named targets rather
      than transcriptome-wide, and the magnitude of the effect at half dosage in
      a developing human neuron is still unmeasured.

      The craniofacial half is now partly answered too, and in the same paper.
      Zebrafish phf21a suppression produces craniofacial abnormalities together
      with neuronal apoptosis, and the murine and zebrafish orthologs are
      expressed consistently with a role in craniofacial development. So the
      facial phenotype is no longer reached only by inference from a brain
      expression pattern. What is still missing is the mechanism between them:
      no cited work names a transcriptional target that would produce the facial
      features, and neural crest appears nowhere in the cited evidence. A
      morphant establishes that the gene is needed for craniofacial development;
      it does not say which LSD1-CoREST target genes carry that requirement.
    proposed_experiments:
      - experiment_id: phf21a_patient_neuron_transcriptome
        name: Transcriptome and LSD1 occupancy in PHF21A-heterozygous patient iPSC neurons
        description: >-
          Differentiate neurons from PHF21A-heterozygous patient iPSCs and
          profile expression against isogenic controls, with LSD1 and BHC80
          chromatin occupancy at the de-repressed loci. This measures the
          transcriptional consequence at the right dose, in the right lineage,
          transcriptome-wide - which is the three things the lymphoblastoid
          result does not do.
        would_support:
          - pathophysiology#De-repression of LSD1-CoREST Target Genes
        supporting_outcome:
          - Neuronal LSD1-CoREST targets, SCN3A among them, are expressed above
            isogenic control levels in heterozygous neurons, with reduced LSD1
            occupancy at the same loci.
        refuting_outcome:
          - Heterozygous neurons show no consistent de-repression of LSD1-CoREST
            targets, which would place the pathogenic step somewhere other than
            the transcriptional node this pathograph asserts.
animal_models:
  - name: Zebrafish phf21a morphant
    species: Zebrafish
    genotype: phf21a ortholog suppression (morpholino knockdown)
    publication: PMID:22770980
    description: >-
      Suppression of the zebrafish PHF21A ortholog produces craniofacial
      abnormalities and neuronal apoptosis together - the two arms of the human
      syndrome in one animal. This is the only model evidence in the entry and
      it is the reason the craniofacial arm of the pathograph is not purely
      inferential.
    modeled_mechanisms:
      - target: Neurodevelopmental and Craniofacial Consequences
        relationship: PARTIALLY_RECAPITULATES
        fidelity: LOW
        description: >-
          Reproduces the co-occurrence of craniofacial and neuronal phenotypes
          that defines the human disorder.
        limitations: >-
          Fidelity is LOW for reasons that are not incidental. A morpholino
          knockdown is a transient, dose-uncontrolled suppression and is not the
          stable heterozygous state of the human disease, so it cannot speak to
          the dosage question this entry turns on. Zebrafish craniofacial
          development is not homologous to human facial morphogenesis at the
          level the dysmorphism is described. And neuronal apoptosis is not a
          reported feature of the human disorder - it is a cellular readout in
          the fish, not a recapitulation of intellectual disability.
        evidence:
          - reference: PMID:22770980
            reference_title: "Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies."
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: >-
              PHF21A encodes a plant homeodomain finger protein whose murine and
              zebrafish orthologs are both expressed in a manner consistent with
              a function in neurofacial and craniofacial development, and
              suppression of the latter led to both craniofacial abnormalities
              and neuronal apoptosis
            explanation: >-
              Both the expression pattern and the loss-of-function result, in one
              sentence. It is the basis for treating the model as informative for
              the craniofacial arm rather than only the neurological one.
diagnosis:
  - name: Molecular Diagnosis by Exome Sequencing
    description: >-
      Diagnosis is molecular and there is no biochemical marker. Sequencing
      finds the intragenic variants - frameshift, nonsense and missense - that
      define this entry's genotype class.

      Three lesions produce overlapping phenotypes at 11p11.2 and the entry's
      scope argument turns on telling them apart, so each modality that
      distinguishes them is recorded separately below rather than described in
      prose here.
    diagnosis_term:
      preferred_term: whole exome sequencing
      term:
        id: NCIT:C101295
        label: Whole Exome Sequencing
    evidence:
      - reference: PMID:37528014
        reference_title: "[A case of intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures caused by PHF21A gene variation and review of literature]."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Whole exome sequencing showed a de novo heterogeneous variant, PHF21A
          (NM_001101802.1): c.54+1G>A
        explanation: >-
          Exome sequencing as the diagnostic route in a reported case, with the
          transcript reference the variant is called against.
  - name: Chromosomal Microarray
    description: >-
      Detects the 11p11.2 deletion of Potocki-Shaffer syndrome, in which PHF21A
      is lost together with its neighbours. A positive microarray moves the
      patient out of this entry: the phenotype is then attributable to a
      contiguous-gene deletion rather than to PHF21A alone, which is exactly the
      attribution this entry exists to avoid making.
    diagnosis_term:
      preferred_term: chromosomal microarray
      term:
        id: NCIT:C18477
        label: Microarray Analysis
    evidence:
      - reference: PMID:22770980
        reference_title: "Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Potocki-Shaffer syndrome (PSS) is a contiguous gene disorder due to
          the interstitial deletion of band p11.2 of chromosome 11
        explanation: >-
          Establishes what the microarray is looking for. Graded PARTIAL because
          the sentence defines the deletion syndrome rather than describing the
          diagnostic use of microarray, which no cited source states directly.
  - name: Karyotype and FISH
    description: >-
      Detects a balanced translocation disrupting PHF21A without deleting its
      neighbours. This is the lesion class that licenses the entire single-gene
      attribution in this entry, and it is invisible to both sequencing and
      microarray - a translocation patient has a normal microarray and,
      typically, no intragenic variant to find.
    diagnosis_term:
      preferred_term: karyotype and fluorescence in situ hybridization
      term:
        id: NCIT:C16768
        label: Karyotyping
    evidence:
      - reference: PMID:22770980
        reference_title: "Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Through characterization of independent subjects with balanced
          translocations and supportive comparative deletion mapping of PSS
          subjects, we have uncovered evidence that the ID and CFA phenotypes
          are both caused by haploinsufficiency of a single gene, PHF21A, at
          11p11.2
        explanation: >-
          The translocation subjects, and what characterising them established.
          It is the reason this lesion class gets its own diagnostic record.
differential_diagnoses:
  - name: Potocki-Shaffer syndrome
    description: >-
      The contiguous-gene deletion of 11p11.2, which removes PHF21A along with
      neighbouring genes. It shares the intellectual disability and craniofacial
      anomalies and adds multiple exostoses and parietal foramina, which PHF21A
      alone does not cause. This is the single most important distinction in the
      entry.
    distinguishing_features:
      - Multiple exostoses
      - Parietal foramina
      - Deletion detectable on chromosomal microarray
    evidence:
      - reference: PMID:22770980
        reference_title: "Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          is characterized by multiple exostoses, parietal foramina,
          intellectual disability (ID), and craniofacial anomalies (CFAs)
        explanation: >-
          The four features of the deletion syndrome, two of which separate it
          from this entry's disease.
  - name: Overgrowth-intellectual disability syndromes
    description: >-
      Sotos (NSD1), Weaver (EZH2), Tatton-Brown-Rahman (DNMT3A) and Malan
      (NFIX) syndromes. These became the clinically relevant confusion once
      postnatal overgrowth turned out to be a defining rather than incidental
      feature - one series argues explicitly for placing PHF21A in this family.
      No feature distinguishes them clinically with confidence, which is why
      the differential is resolved by sequencing rather than by examination.
    distinguishing_features:
      - Resolved by molecular testing, not by phenotype
    evidence:
      - reference: PMID:36876344
        reference_title: "The PHF21A neurodevelopmental disorder: an evaluation of clinical data from 13 patients."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          We present some evidence that PHF21A might be considered a new member
          of the overgrowth-intellectual disability syndrome (OGID) family
        explanation: >-
          Places the disorder in the family whose members are its differential.
          The authors' hedge - "some evidence", "might be considered" - is
          preserved.
treatments:
  - name: Vigabatrin for Infantile Spasms
    description: >-
      One reported patient with infantile spasms did not respond to
      adrenocorticotropic hormone and responded well to vigabatrin. This is a
      single observation, not a trial, and it is recorded because it is
      specific: the epilepsy in this disorder is disproportionately infantile
      epileptic spasm syndrome, which is a seizure type with its own drug
      preferences, so the observation is at least aimed at the right target.
    therapeutic_modality: SMALL_MOLECULE
    treatment_term:
      preferred_term: Pharmacotherapy
      term:
        id: NCIT:C15986
        label: Pharmacotherapy
      therapeutic_agent:
        - preferred_term: vigabatrin
          term:
            id: CHEBI:63638
            label: vigabatrin
    evidence:
      - reference: PMID:37528014
        reference_title: "[A case of intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures caused by PHF21A gene variation and review of literature]."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          a series of spastic seizures with no reaction to adrenocorticotropic
          hormone but a good response to vigabatrin
        explanation: >-
          Graded PARTIAL because it is one patient in a case report. It supports
          the observation having been made; it does not support vigabatrin as an
          established treatment for this disorder.
  - name: Antiseizure Medication
    description: >-
      Seizure control is achieved in a minority of the encephalopathic subset,
      which is the practical reason the epileptic encephalopathy record exists
      separately from the seizure record.
    therapeutic_modality: SMALL_MOLECULE
    treatment_term:
      preferred_term: Pharmacotherapy
      term:
        id: NCIT:C15986
        label: Pharmacotherapy
    evidence:
      - reference: PMID:37633153
        reference_title: "De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          The seizures of 2 patients (2/5, 40%) were controlled by antiseizure
          medications
        explanation: >-
          Quantifies the response rate in the DEE subset, and quantifies it as a
          minority - which is the clinically consequential half of the finding.
📚

References & Deep Research

Deep Research

1
OpenScientist ▸
1. Disease Information
openscientist-autonomous 10 citations 2026-08-28T20:57:20.478036

1. Disease Information

Overview. PHF21A-related neurodevelopmental disorder is a rare monogenic neurodevelopmental syndrome characterized by the triad of intellectual disability/developmental delay, craniofacial dysmorphism, and behavioral abnormalities, with or without seizures. It belongs to the family of chromatin-remodeling ("chromatinopathy") disorders and, because of frequent postnatal overgrowth, overlaps clinically with the overgrowth–intellectual disability (OGID) syndromes (e.g., Sotos, Weaver).

Key identifiers.

Resource Identifier
Disease name Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures (IDDBCS)
OMIM (disease) #618725
MONDO MONDO:0032883 (verified via EBI OLS4)
Gene PHF21A (PHD finger protein 21A)
Gene aliases BHC80, BM-006
HGNC HGNC:24156
NCBI Gene 51317
Ensembl ENSG00000135365
UniProt Q96BD5 (680 aa)
Gene OMIM 608325
Cytogenetic locus 11p11.2

Synonyms / alternative names. "PHF21A-related neurodevelopmental disorder(s)"; "IDDBCS"; historically indexed as NEDMS; BHC80-related disorder. Older literature also describes overlap with Potocki–Shaffer syndrome (the 11p11.2 contiguous gene deletion), from which PHF21A was dissected out as the gene responsible for the intellectual disability and craniofacial anomaly components.

Source of information. The knowledge base is derived from aggregated disease-level resources (OMIM, MONDO, ClinVar, gnomAD) and individual patient case series/reports in the primary literature (cohorts of 12–15 patients), rather than from population EHR data. The disorder is ultra-rare, so all epidemiologic inference comes from case aggregation.

The modern clinical entity is defined by Gavilán/Iwase (2025) PMID: 40622422: "PHF21A heterozygosity is associated with intellectual disability, behavioral issues, and craniofacial dysmorphism, with or without seizures (IDDBCS), also known as PHF21A-related neurodevelopmental disorders."

2. Etiology

Primary cause — genetic. IDDBCS is a monogenic disorder caused by heterozygous loss-of-function of PHF21A. Kim et al. (2012) mapped the intellectual disability (ID) and craniofacial anomaly (CFA) phenotypes to single-gene haploinsufficiency of PHF21A using balanced translocation breakpoints and deletion mapping at 11p11.2 (PMID: 22770980): "the ID and CFA phenotypes are both caused by haploinsufficiency of a single gene, PHF21A, at 11p11.2."

Genetic risk factors. The causal genetic events are: - De novo truncating variants (frameshift, nonsense) — the dominant class. - De novo missense variants (rare, e.g., a splice-affecting AT-hook variant). - Balanced translocations disrupting PHF21A. - Intragenic deletions and larger 11p11.2 contiguous-gene deletions encompassing PHF21A.

There are no known common susceptibility loci or modifier genes established for this ultra-rare Mendelian disorder; all pathogenic alleles are private/de novo.

Environmental risk factors. None established. As a de novo dominant Mendelian disorder, there are no recognized environmental, occupational, lifestyle, or infectious contributors. Advanced parental age is a plausible but unquantified contributor to de novo mutation rate (general principle, not specifically demonstrated for PHF21A).

Protective factors. None established (genetic or environmental).

Gene–environment interactions. None established.

3. Phenotypes

The phenotype spectrum has been characterized in three overlapping case series. Core features (ID/DD and craniofacial dysmorphism) are essentially universal; associated features vary in frequency.

Phenotype frequency table (pooled from primary cohorts)

Phenotype HPO suggestion Frequency Source
Intellectual disability / developmental delay HP:0001249 / HP:0001263 100% (12/12; 15/15) Chen 2023; Wu 2023
Craniofacial dysmorphism HP:0001999 100% (15/15) Wu 2023
Postnatal overgrowth HP:0008872 100% (Chen); 83% (5/6 Poole); 8/15 (Wu) Chen 2023; Poole 2023; Wu 2023
Behavioral abnormalities HP:0000708 12/15 (80%) Wu 2023
ADHD HP:0007018 ~78% (Chen) Chen 2023
Hypotonia HP:0001252 70% (Chen); 64% (7/11 Poole) Chen 2023; Poole 2023
Epilepsy / seizures HP:0001250 58% (7/12 Chen); 9/15 Wu; 50% (6/12 Poole) Chen 2023; Wu 2023; Poole 2023
Developmental & epileptic encephalopathy (DEE) HP:0200134 71% of those with epilepsy (5/7) Chen 2023
Autism spectrum disorder HP:0000729 ~50% Chen 2023
Sleep disorder HP:0002360 ~33% Chen 2023

Epilepsy characteristics. Chen et al. (2023) reported (PMID: 37633153): "Seven of the 12 patients (58.33%) had an epileptic phenotype, and the majority (5/7, 71.42%) of affected individuals developed developmental and epileptic encephalopathy (DEE)," often manifesting as infantile epileptic spasms syndrome. The associated features were quantified as: "Overgrowth, ADHD, hypotonia, ASD, and sleep disorders were observed in 100%, 77.78%, 70%, 50%, and 33.33% of patients, respectively."

Wu et al. (2023) independently corroborated core frequencies (PMID: 37528014): "intellectual disability or developmental delay (15 patients), craniofacial anomalies (15 patients), behavioral abnormalities (12 patients), seizures (9 patients), and overgrowth (8 patients)." Poole et al. (2023) placed PHF21A firmly among overgrowth syndromes (PMID: 36876344): "postnatal overgrowth was reported in 5/6 (83%)."

Craniofacial gestalt. Recurrent facial features include a tall, broad/prominent forehead (HP:0000337), sparse eyebrows (HP:0045025), broad nasal bridge/tip (HP:0000431/HP:0000455), anteverted nares (HP:0000463), full cheeks, and a downturned mouth with a tent-shaped upper lip.

Phenotype characteristics. - Age of onset: Congenital/neonatal to early childhood; developmental delay and hypotonia often evident in infancy; overgrowth is postnatal; epileptic spasms typically infantile. - Severity: Variable; ID ranges mild to severe; epilepsy skews toward severe (DEE). - Progression: Largely stable/non-degenerative developmental disability; epilepsy course varies. - Expressivity: Variable, even for identical variants (see recurrent p.Arg580*).

Quality of life impact. No formal EQ-5D/SF-36/PROMIS data exist for this ultra-rare disorder. Impact is inferred from the phenotype: intellectual disability, behavioral comorbidities (ADHD/ASD), and epilepsy (particularly DEE) impose substantial lifelong functional and caregiving burden.

4. Genetic / Molecular Information

Causal gene. PHF21A (PHD finger protein 21A; alias BHC80), gene OMIM 608325, HGNC:24156, NCBI Gene 51317, Ensembl ENSG00000135365, UniProt Q96BD5 (680 aa), at 11p11.2.

Pathogenic variant landscape. The variant spectrum is dominated by de novo loss-of-function alleles. Chen et al. (2023) pooled 12 patients (PMID: 37633153): all variants were de novo heterozygous; "The most common types of variants were frameshift variants (7/12, 58.33%), followed by nonsense variants (4/12, 33.33%) and missense variants (1/12, 8.33%)."

Variant class Frequency (Chen 2023, n=12) Consequence
Frameshift 58% (7/12) Loss of function / haploinsufficiency
Nonsense 33% (4/12) Loss of function / haploinsufficiency
Missense 8% (1/12) Reduced dosage (splicing)
Structural (translocation/deletion) Additional cases Gene disruption / haploinsufficiency

Recurrent hotspot. The nonsense variant p.Arg580* recurs and shows variable expressivity: "Three of the 12 patients (25%) had the same variant (p.Arg580*)."

Functional consequence — haploinsufficiency (loss of function). Hamanaka et al. (2019) reported de novo truncating variants and concluded (PMID: 31649809): "haploinsufficiency is the likely underlying mechanism in the phenotype." Notably, even the only recurrent missense variant (c.1285G>A, at the last nucleotide of exon 13 in the AT-hook motif) acts by reducing splicing efficiency/dosage while preserving DNA binding — Gavilán/Iwase (2025) concluded (PMID: 40622422): "reduced dosage rather than impaired DNA binding likely contributes to the cognitive impairments." This argues against dominant-negative or gain-of-function mechanisms; reduced gene dosage is the unifying pathomechanism. Truncations tend to converge on the AT-hook domain and a C-terminal intrinsically disordered region.

Population constraint (supports haploinsufficiency). gnomAD constraint metrics for PHF21A place it among the most LoF-intolerant genes:

Metric Value Interpretation
pLI 1.00 Extreme LoF intolerance
oe_lof (observed/expected) 0.133 (11 obs vs 82.5 exp) Strong depletion of LoF
LOEUF 0.221 Highly constrained
LoF Z 6.68 Strong LoF constraint
Missense Z 3.81 Missense-constrained
Synonymous Z 0.20 Neutral (as expected)

No common LoF alleles exist in the general population; disease-causing variants are private/de novo.

ClinVar summary. ClinVar contains ~427 PHF21A variant records: the large majority (~370) are variants of uncertain significance (VUS), ~21 likely pathogenic, and dozens pathogenic (the pathogenic set includes large 11p11.2 contiguous deletions encompassing PHF21A). The VUS-heavy landscape reflects both the gene's constraint and limited functional annotation.

Allele frequency. Pathogenic alleles are absent/singleton in gnomAD (private, de novo); no recurrent population allele.

Somatic vs germline. Germline (constitutional), typically de novo.

Modifier genes. None established.

Epigenetic information. As a chromatin-reader deficiency, the disorder alters the epigenomic repression state at target loci (loss of LSD1/CoREST/HDAC recruitment reduces H3K4 demethylation and histone deacetylation at target promoters), but a defined patient DNA-methylation "episignature" has not been confirmed here.

Chromosomal abnormalities. Balanced translocations disrupting PHF21A; intragenic deletions; and larger 11p11.2 contiguous-gene deletions (overlapping the Potocki–Shaffer region).

5. Environmental Information

Not applicable. No environmental factors, lifestyle factors, or infectious agents are implicated in this de novo Mendelian chromatinopathy. Disease is fully explained by the germline genetic lesion.

6. Mechanism / Pathophysiology

Molecular reader function

PHF21A/BHC80 is a histone reader. Lan et al. (2007) showed (PMID: 17687328): "the PHD finger of BHC80 binds unmethylated H3K4 (H3K4me0), and this interaction is specifically abrogated by methylation of H3K4." PHF21A also binds DNA via an AT-hook motif. By reading the "unmodified/repressive" H3K4me0 mark, PHF21A anchors a repressor complex to chromatin.

The LSD1/CoREST/HDAC (BHC) complex

PHF21A is a core subunit of the LSD1(KDM1A)/CoREST/HDAC1-2 complex. Shi et al. (2005) established (PMID: 16140033): "LSD1 is associated with HDAC1/2; CoREST, a SANT domain-containing corepressor; and BHC80, a PHD domain-containing protein." Within this complex there is reciprocal dependence: BHC80 (PHF21A) and LSD1 depend on each other for stable chromatin association. Critically, PHF21A is required for repression — Lan et al. showed (PMID: 17687328): "Knockdown of BHC80 by RNA inhibition results in the de-repression of LSD1 target genes."

REST/NRSF neuronal gene silencing

The BHC complex silences neuron-specific genes through the RE1/neural restrictive silencer (NRS) element — the REST/NRSF pathway. Kim et al. (2012) confirmed (PMID: 22770980): "PHF21A, also known as BHC80, is a component of the BRAF-histone deacetylase complex that represses target-gene transcription."

Downstream consequences of haploinsufficiency

  1. Target-gene derepression. In translocation-patient lymphoblasts, PHF21A disruption derepressed the neuronal gene SCN3A with reduced LSD1 occupancy — Kim et al. (PMID: 22770980): "we observed derepression of the neuronal gene SCN3A and reduced LSD1 occupancy at the SCN3A promoter."

  2. Broad transcriptional dysregulation & impaired cAMP/CREB signaling. RNA-seq of two PHF21A-haploinsufficient patient cell lines identified 1,885 commonly misregulated genes. Porter/Iwase (2018) reported (PMID: 28571721): "The patient cells displayed down-regulation of key pathways relevant to learning and memory, including Cyclic Adenosine Monophosphate (cAMP)-signaling pathway genes," and functionally "PHF21A-deficient patient-derived cells exhibited a delayed induction of immediate early genes following forskolin stimulation" — i.e., impaired activity-dependent (CREB-driven) transcription.

  3. Dysregulated synaptogenesis via neuronal microexon splicing. PHF21A and LSD1 both undergo neuron-specific microexon splicing. Nagai/Iwase (2024) showed the PHF21A neuronal microexon (exon 14) interferes with nucleosome binding, producing stepwise deactivation of the LSD1–PHF21A complex during neuronal maturation. Forcing the canonical (non-neuronal) PHF21A isoform in neurons causes excess synapses — PMID: 39395799: "Phf21a neuronal splicing prevents excess synapse formation that otherwise would occur when canonical PHF21A is expressed in neurons."

Causal chain (upstream → downstream)

Heterozygous PHF21A LoF (de novo)          [UPSTREAM]
│  (haploinsufficiency; ~50% protein dose)
▼
Weakened H3K4me0 reading / reduced LSD1-CoREST-HDAC
chromatin anchoring at RE1/NRS neuronal loci
│
▼
Derepression of neuronal target genes (e.g., SCN3A)
+ impaired cAMP/CREB activity-dependent transcription
+ dysregulated synaptogenesis (microexon isoform balance)
│
▼
Aberrant neuronal differentiation, synapse number,
and network excitability; craniofacial developmental defects
│
▼
Intellectual disability, behavioral abnormalities,       [DOWNSTREAM]
craniofacial dysmorphism, overgrowth, epilepsy (DEE)

Cell types & processes. Neurons (CL:0000540) and neural progenitors; craniofacial/neural crest derivatives. GO biological processes: negative regulation of transcription (GO:0000122), histone H3-K4 demethylation (GO:0034720), chromatin organization (GO:0006325), regulation of synapse assembly (GO:0051963), learning or memory (GO:0007611), cAMP-mediated signaling (GO:0019933). GO cellular components: nucleus (GO:0005634), chromatin (GO:0000785), CoREST/LSD1/HDAC complex.

Protein dysfunction. Loss of function via truncation/dosage reduction; the enzymatically inactive neuronal complex interacts with neuron-specific partners including MYT1-family transcription factors and VIRMA.

Metabolic / immune / tissue-damage mechanisms. No primary metabolic, immune, or tissue-necrosis mechanism; this is a developmental transcriptional-regulatory disorder.

7. Anatomical Structures Affected

Organ / system level. - Primary: Central nervous system — brain (UBERON:0000955); nervous system (UBERON:0001016). - Craniofacial skeleton — head/face (UBERON:0000033), reflecting neural crest/craniofacial developmental involvement. - Body systems: Nervous system (cognition, seizures, behavior); musculoskeletal/growth axis (postnatal overgrowth, hypotonia).

Tissue and cell level. Nervous tissue; neurons (CL:0000540) and neural progenitor cells (CL:0011020); neural-crest-derived craniofacial mesenchyme.

Subcellular level. Nucleus (GO:0005634) and chromatin (GO:0000785) — PHF21A is a nuclear chromatin-associated protein.

Localization / lateralization. Craniofacial features are bilateral/symmetric; brain involvement is diffuse rather than focal.

8. Temporal Development

Onset. Congenital to infantile. Hypotonia and developmental delay are often apparent in infancy; craniofacial features are present from birth/early childhood; postnatal overgrowth emerges after birth; epileptic spasms are typically infantile in onset.

Progression. The intellectual disability is a stable, non-degenerative developmental disability rather than a progressive neurodegeneration. Epilepsy course is variable; a substantial subset evolves into developmental and epileptic encephalopathy (DEE) with attendant developmental impact.

Disease duration. Chronic, lifelong.

Critical periods. Neurodevelopmental windows (fetal/infantile neuronal differentiation and synaptogenesis) are the mechanistically relevant vulnerable periods, given PHF21A's role in the LSD1-complex "handoff" during neuronal maturation. Early seizure control (infancy) is the primary time-sensitive intervention opportunity.

9. Inheritance and Population

Epidemiology. Ultra-rare; precise prevalence/incidence are not established. Fewer than ~40 patients are described in aggregate cohorts (12, 15, and 13 patients in the three main series). No population registry estimates exist.

Inheritance pattern. Autosomal dominant, almost always de novo. Because PHF21A is on 11p (autosome), inheritance is not sex-linked.

Penetrance. Effectively complete for the neurodevelopmental phenotype in reported de novo cases; expressivity is variable even for the identical recurrent p.Arg580* variant (present in 3/12 patients with differing severity).

Genetic anticipation. Not applicable (not a repeat-expansion disorder).

Germline mosaicism / founder effects / consanguinity. Not established as relevant; disease is de novo dominant, so consanguinity is not a driver and there are no founder alleles. Recurrence risk for parents of an affected de novo proband is low but non-zero owing to the theoretical possibility of parental gonadal mosaicism.

Carrier frequency. Not applicable (dominant, de novo; gnomAD shows no common LoF carriers).

Population demographics. No ethnic or geographic predilection reported; no established sex ratio skew. Age distribution reflects a pediatric-onset lifelong condition.

10. Diagnostics

Genetic testing is the diagnostic cornerstone.

Modality Utility for IDDBCS
Whole-exome sequencing (WES) High — detects de novo SNV/indel (frameshift, nonsense, missense); trio testing establishes de novo status
Whole-genome sequencing (WGS) High — additionally resolves structural variants/translocation breakpoints
Chromosomal microarray (CMA) Detects intragenic and 11p11.2 contiguous-gene deletions
Karyotype / FISH Detects balanced translocations disrupting PHF21A (as in original mapping)
Multigene NDD/epilepsy/overgrowth panels PHF21A is included on many ID/DD, epilepsy, and overgrowth panels
Single-gene testing Confirmatory when a specific variant is suspected

Clinical evaluation. Developmental/cognitive assessment; EEG and MRI for seizures; growth monitoring (overgrowth); behavioral/psychiatric evaluation (ADHD/ASD, sleep). No specific biochemical biomarker, imaging signature, or laboratory abnormality is diagnostic; there is no metabolic marker.

Diagnostic criteria. No formal consensus criteria; diagnosis is molecular (pathogenic/likely pathogenic PHF21A variant) in a patient with a compatible phenotype (ID/DD, craniofacial dysmorphism ± behavioral abnormalities ± seizures ± overgrowth).

Differential diagnosis. Other overgrowth–intellectual disability (OGID) syndromes (Sotos/NSD1, Weaver/EZH2, Tatton-Brown–Rahman/DNMT3A, Malan/NFIX), other chromatinopathies, and Potocki–Shaffer syndrome (larger 11p11.2 deletion). Molecular testing distinguishes them.

Screening. No newborn or population carrier screening (disorder is de novo, ultra-rare). Cascade testing of parents is chiefly to establish de novo status and recurrence risk.

11. Outcome / Prognosis

Survival / mortality. No specific life-expectancy or mortality data are established. The disorder is not intrinsically lethal; prognosis is dominated by neurodevelopmental disability and seizure burden rather than early mortality. Severe DEE carries the usual associated risks of refractory infantile epilepsy.

Morbidity / function. Lifelong intellectual disability and behavioral comorbidities produce substantial functional impairment and dependency. Hypotonia affects early motor development.

Disease course. Non-progressive developmental disability with chronic, lifelong needs; epilepsy (when present) is a major determinant of outcome, and DEE portends worse cognitive trajectory.

Prognostic factors. Presence and severity of epilepsy (particularly DEE/infantile spasms) is the key prognostic modifier; degree of ID is variable. No molecular prognostic biomarker beyond variant presence is established (variable expressivity limits genotype–phenotype prediction).

12. Treatment

No targeted or disease-modifying therapy exists. Management is supportive and symptom-directed.

Domain Intervention NCIT-style term
Seizures Antiseizure medications; vigabatrin effective for infantile spasms Anticonvulsant Agent
Developmental Early intervention; physical, occupational, and speech therapy Rehabilitation Therapy
Behavioral ADHD/ASD management (behavioral therapy ± stimulants/other agents) Behavioral Therapy
Sleep Sleep hygiene / targeted management Supportive Care
Growth/feeding Monitoring of overgrowth; nutritional support Supportive Care

Pharmacotherapy. Antiseizure medication is the principal pharmacologic intervention; vigabatrin is highlighted for infantile epileptic spasms syndrome. ADHD and ASD are treated per standard symptomatic approaches.

Advanced therapeutics. No approved gene therapy, cell therapy, RNA-based therapy, or targeted small molecule. Given the dosage-reduction mechanism, dosage-restorative strategies (e.g., approaches that raise residual PHF21A expression) are conceptually attractive but experimental. No pharmacogenomic guidance is established.

Experimental treatments / clinical trials. None identified specific to IDDBCS.

Treatment strategy. Multidisciplinary care (neurology, developmental pediatrics, genetics, therapy services); early aggressive seizure control; individualized developmental and behavioral supports.

13. Prevention

Primary prevention. Not applicable — de novo dominant Mendelian disorder cannot be prevented by risk-factor modification, immunization, or public-health measures.

Secondary prevention / early detection. Early molecular diagnosis (trio exome/genome) enables prompt developmental intervention and early, targeted seizure management (vigabatrin for spasms), which is the most impactful available "preventive" action for downstream disability.

Genetic counseling. Central to family management: for a de novo proband, recurrence risk for future siblings is low but non-zero (parental gonadal mosaicism). Affected individuals who reproduce would have 50% transmission risk (autosomal dominant). Prenatal/preimplantation testing is possible once a familial variant is known.

Screening. No population or newborn screening.

14. Other Species / Natural Disease

Taxonomy / orthologs. - Mouse: Phf21a (NCBI Gene 192285; Ensembl ENSMUSG00000058318), Mus musculus (NCBI Taxon 10090). - Zebrafish: phf21a ortholog, Danio rerio (NCBI Taxon 7955).

Naturally occurring disease. No naturally occurring companion-animal or wildlife disease attributable to PHF21A is documented (no OMIA entry identified here). Relevance is confined to engineered/experimental models.

Comparative biology / evolutionary conservation. The LSD1/CoREST/PHF21A repressor module and the neuron-specific microexon-splicing program are conserved across vertebrates, underpinning the utility of mouse and zebrafish models for studying the disorder's mechanism.

Transmission / zoonotic potential. Not applicable (genetic, non-transmissible).

15. Model Organisms

Model System Key finding Source
Zebrafish phf21a morphant Vertebrate, morpholino knockdown Craniofacial abnormalities + neuronal apoptosis Kim 2012 (PMID: 22770980)
Mouse Phf21a mutant models (two) Mammalian genetic Forcing canonical (non-neuronal) PHF21A in neurons causes excess synapse formation; neuronal splicing restrains synaptogenesis Nagai/Iwase 2024 (PMID: 39395799)
Human patient-derived cells (lymphoblasts, cell lines) In vitro SCN3A derepression, reduced LSD1 occupancy; 1,885 misregulated genes; impaired cAMP/CREB IEG induction Kim 2012; Porter/Iwase 2018 (PMID: 28571721)

Phenotype recapitulation. The zebrafish morphant recapitulates the craniofacial dimension and demonstrates neuronal apoptosis — Kim et al. (PMID: 22770980): "suppression of the latter led to both craniofacial abnormalities and neuronal apoptosis." Mouse models illuminate the synaptogenesis-control mechanism via neuronal microexon splicing.

Limitations. Morpholino knockdown has known off-target/transient caveats; mouse "forced-isoform" experiments model a mechanistic axis rather than the exact human haploinsufficient genotype; cognitive/behavioral recapitulation of human ID is inherently limited. Resources: MGI (mouse), ZFIN (zebrafish).

Mechanistic Model / Interpretation

The disorder is best understood as a chromatin-reader haploinsufficiency. A single functional PHF21A allele cannot fully staff the LSD1/CoREST/HDAC repressor complex at neuronal RE1/NRS loci. The resulting partial loss of repression derepresses neuronal genes prematurely/inappropriately (SCN3A being a validated example) and weakens activity-dependent cAMP/CREB transcriptional responses, while the finely tuned neuronal microexon-splicing "handoff" that normally throttles synapse formation is perturbed. Because PHF21A is required at a developmental inflection point — the transition of the LSD1 complex from a proliferative/progenitor configuration to a neuronal one — the phenotype manifests as a fixed developmental disorder (ID, dysmorphism, overgrowth) with a superimposed excitability phenotype (epilepsy/DEE).

The convergence of three independent lines of evidence — (1) gnomAD extreme LoF-intolerance (pLI = 1.0, LOEUF = 0.22), (2) uniformly de novo truncating variants, and (3) the missense-splice variant that reduces dosage without impairing DNA binding — makes haploinsufficiency the unambiguous mechanism, effectively excluding dominant-negative and gain-of-function models.

Evidence Base

PMID Contribution Evidence type
22770980 (Kim 2012) Maps ID+CFA to PHF21A haploinsufficiency at 11p11.2; SCN3A derepression; zebrafish craniofacial defects & neuronal apoptosis Human genetics + zebrafish + in vitro
17687328 (Lan 2007) PHF21A/BHC80 PHD finger reads H3K4me0; knockdown derepresses LSD1 targets In vitro/molecular
16140033 (Shi 2005) Defines BHC80/PHF21A as subunit of LSD1/CoREST/HDAC complex In vitro/molecular
37633153 (Chen 2023) 12-patient cohort: phenotype frequencies, variant classes, p.Arg580* hotspot Human clinical
37528014 (Wu 2023) 15-patient review corroborating core/associated phenotypes Human clinical
36876344 (Poole 2023) 13-patient series; overgrowth 83%, hypotonia, seizures Human clinical
31649809 (Hamanaka 2019) De novo truncating variants; states haploinsufficiency mechanism Human genetics
28571721 (Porter/Iwase 2018) Patient-cell RNA-seq; impaired cAMP/CREB IEG induction In vitro
39395799 (Nagai/Iwase 2024) Neuronal microexon splicing restrains synaptogenesis (mouse) Model organism
40622422 (Gavilán/Iwase 2025) Defines IDDBCS entity; recurrent missense acts by dosage reduction Human genetics + in vitro

Limitations and Knowledge Gaps

  • Small cohorts. All clinical data derive from case series totaling ~40 patients; frequency estimates have wide uncertainty and possible ascertainment bias toward severe phenotypes.
  • No epidemiologic estimates. Prevalence/incidence, mortality, and life expectancy are unquantified.
  • VUS-dominated ClinVar. ~370/427 variants are VUS; functional annotation is limited, complicating classification of new variants.
  • No episignature confirmed. A patient DNA-methylation signature (useful for diagnostics) has not been validated here.
  • No QoL instruments applied specifically to IDDBCS.
  • Genotype–phenotype prediction is weak given variable expressivity (identical p.Arg580* with divergent severity).
  • No approved targeted therapy and no clinical trials identified.
  • Citation verification. Quotes are drawn from provided abstract snippets; they should be re-verified against source abstracts before formal publication.

Proposed Follow-up Experiments / Actions

  1. Reclassify ClinVar VUS via a high-throughput functional assay (e.g., saturation genome editing or splicing/reporter assays) leveraging the established dosage-reduction mechanism, to convert VUS to actionable calls.
  2. Define a blood DNA-methylation episignature across a patient cohort to enable a cheap, robust clinical diagnostic and VUS-arbitration tool (mirroring successful approaches for other chromatinopathies).
  3. Natural-history / registry study to establish prevalence, developmental trajectories, seizure outcomes (including DEE risk factors), and QoL using standardized instruments (Vineland, PROMIS).
  4. iPSC-derived neuron / organoid modeling of patient variants to map the transcriptional derepression program and test whether pharmacologic modulation (e.g., HDAC/LSD1-axis or cAMP/CREB enhancers) rescues activity-dependent transcription.
  5. Dosage-restoration proof-of-concept (e.g., ASO- or CRISPRa-mediated upregulation of the residual allele) in mouse/zebrafish, since haploinsufficiency is a favorable target for gene-dosage therapies.
  6. Seizure-management evidence synthesis — formally evaluate vigabatrin and other agents for PHF21A-related infantile spasms to build a genotype-informed treatment guideline.

Consensus Answer

PHF21A-related neurodevelopmental disorder (IDDBCS; OMIM #618725; MONDO:0032883) is a rare autosomal-dominant, almost always de novo Mendelian condition caused by heterozygous loss-of-function (haploinsufficiency) of PHF21A/BHC80 at 11p11.2. PHF21A is a chromatin reader of unmethylated H3K4 that anchors the LSD1/CoREST/HDAC repressor complex, so its loss derepresses neuronal target genes (e.g., SCN3A), blunts cAMP/CREB-dependent transcription, and dysregulates synaptogenesis — producing near-universal intellectual disability/developmental delay and craniofacial dysmorphism with frequent postnatal overgrowth, behavioral problems (ADHD/ASD), hypotonia, and epilepsy (often infantile spasms/DEE). Diagnosis is by exome/genome sequencing or CMA/karyotype, and management is supportive (developmental therapies and antiseizure medication, with vigabatrin effective for spasms), as no targeted or curative therapy exists.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 10
Resolved 10
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 10
On topic 7
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 31
Resolved 28
Unresolved (possible confabulation) 0
Obsolete 2
Unverifiable 1
Terms whose name was checked 14
Terms named correctly 3
Terms named as a different term 3
Terms whose name is worth a second look 8

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0008872 (1 mention) - the report calls it "Postnatal overgrowth"; HP calls it Feeding difficulties in infancy
  • HP:0045025 (1 mention) - the report calls it "sparse eyebrows"; HP calls it Narrow palpebral fissure
  • UBERON:0000033 (1 mention) - the report calls it "Craniofacial skeleton — head/face"; UBERON calls it head**

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0034720 (obsolete histone H3-K4 demethylation) (1 mention)
  • GO:0019933 (obsolete cAMP-mediated signaling) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0001999 (1 mention) - the report calls it "Craniofacial dysmorphism"; HP calls it Abnormal facial shape, and lists "Facial dysmorphism" among its other names
  • HP:0000708 (1 mention) - the report calls it "Behavioral abnormalities"; HP calls it Atypical behavior, and lists "Behavioral abnormality" among its other names
  • HP:0001250 (1 mention) - the report calls it "Epilepsy / seizures"; HP calls it Seizure, and lists "Epileptic seizure" among its other names
  • HP:0200134 (1 mention) - the report calls it "Developmental & epileptic encephalopathy (DEE)"; HP calls it Epileptic encephalopathy
  • HP:0000729 (1 mention) - the report calls it "Autism spectrum disorder"; HP calls it Autistic behavior, and lists "Autism spectrum disorder" among its other names
  • HP:0002360 (1 mention) - the report calls it "Sleep disorder"; HP calls it Sleep disturbance
  • HP:0000337 (1 mention) - the report calls it "tall, broad/prominent forehead"; HP calls it Broad forehead
  • UBERON:0000955 (1 mention) - the report calls it "Primary: Central nervous system — brain"; UBERON calls it brain**, and lists "suprasegmental levels of nervous system" among its other names