3p- Syndrome

Genetic MONDO:0013424 Pathograph 27 Show in embeddings browser Contiguous Gene Deletion Syndrome Neurodevelopmental Disorder

3p- syndrome results from a heterozygous terminal or interstitial deletion of distal chromosome 3p. The classic terminal deletion spans 3p25 to 3pter. Developmental delay, intellectual disability, growth impairment, hypotonia and craniofacial differences are characteristic, with variable cardiac, renal, gastrointestinal and limb malformations. Deletion boundaries and gene content differ among patients, and even relatives carrying the same deletion can differ substantially in clinical expression. SETD5 and BRPF1 have direct human genetic evidence for contributions to the neurodevelopmental phenotype. SRGAP3 and the distal CHL1/CNTN6/CNTN4 neuronal adhesion genes remain proposed additional contributors. Cardiac susceptibility mapping is conditional and has not established a single causal gene. This entry covers the multigene deletion; intragenic SETD5 and BRPF1 disorders are curated separately.

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1
Inheritance
13
Pathophys.
44
Phenotypes
3
Gaps
27
Pathograph
9
Genes
4
Medical Actions
4
Differentials
2
Models
1
Deep Research
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC
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Inheritance

1
Autosomal dominant, usually de novo HP:0000006
Most reported deletions arise de novo, but familial transmission occurs with incomplete penetrance and variable expression. Gene content influences phenotype without fully predicting it: a mother and two children carried the same 7.4 Mb deletion, while only one child showed clinical features. Additional variants and age at evaluation complicate comparisons across families.
Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE
Show evidence (4 references)
PMID:25123480 SUPPORT DIRECT Human Clinical
"family members in four generations of this family are carrier of this 3p deletion and apparently healthy"
The abstract describes apparently healthy carriers across four generations, but also reports learning and speech problems and autism in one sister. It supports variable expression rather than uniform absence of manifestations.
PMID:21457564 SUPPORT DIRECT Human Clinical
"The phenotype of individuals with deletions varies from normal to severe."
States the expressivity range, supporting the VARIABLE value.
PMID:33936696 SUPPORT DIRECT Human Clinical
"The few cases described are mainly de novo."
The de novo predominance recorded in this block, which the other cited sources assume rather than state.
+ 1 more reference
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Discussions and Knowledge Gaps

3
How do gene content and genetic background jointly determine the variable phenotype of distal 3p deletions?
KNOWLEDGE GAP del3p_gene_content_and_variable_expression
Attached to
genetic#SETD5 genetic#BRPF1 genetic#SRGAP3 genetic#CHL1
Human sequence-variant and deletion comparisons support SETD5 and BRPF1 contributions. Small comparative cohorts suggest more severe developmental delay when both are lost, but assessments are heterogeneous. SRGAP3 and the distal adhesion genes remain additional candidates. Different outcomes among relatives with the same 7.4 Mb deletion show that deletion size alone is insufficient. The CHL1 family’s additional 1q44 duplication further limits single-gene attribution.
Show evidence (3 references)
PMID:27939639 SUPPORT DIRECT Human Clinical
"All individuals from group 3 acquired walking after 3 years of age (5/5 for group 3 versus 2/19 for groups 1 and 2, p value = 0.0005) and presently have no language (5/5 for group 3 versus 1/19 for groups 1 and 2, p value = 0.0001) (Table 3), suggesting that disruption of both BRPF1 and SETD5..."
The comparison is five co-deleted individuals versus single-gene groups; it is not a population frequency estimate.
PMID:33936696 SUPPORT DIRECT Human Clinical
"Three members of the family had the 3p26.3-p26.1 deletion; however, only the son presented clinical features."
A second, independent family in which the deletion segregates with only one affected carrier - non-penetrance shown in a different pedigree from the four-generation family cited above.
PMID:21457564 SUPPORT DIRECT Human Clinical
"Among them, a maternally inherited 1q44 duplication of 696 Kbs is shared by the two brothers and absent in the father."
The additional CNV limits attribution of the brothers’ clinical findings to the paternally inherited CHL1 deletion alone.
Which IgCAM model findings explain human deletion phenotypes, and which depend on genotype, neural region or behavioral assay?
HUMAN MODEL MISMATCH del3p_igcam_context_dependent_mouse_findings
Attached to
pathophysiology#Abnormal Neurite Development
The review’s abstract broadly describes weak mouse phenotypes, but its full text reports structural and behavioral abnormalities. Compound Chl1/Cntn6 heterozygotes already show enhanced dendritic misorientation. Cntn4 deficiency lacked ASD-related behavioral effects in one assay battery while enhancing Barnes-maze performance and acoustic startle. Compensation is a proposed explanation, not a demonstrated universal rescue. These results neither refute all neurite effects nor prove a human ASD mechanism.
Show evidence (3 references)
PMID:33519384 SUPPORT DIRECT REVIEW SYNTHESIS Model Organism
"Notably, compound heterozygous mice for both Chl1 and Cntn6 display an additive deleterious phenotype – these compound heterozygous mice showed more severe misoriented dendrites compared to single heterozygous Chl1 or Cntn6 mice and wild-type littermates (Ye et al., 2008)."
The full review describes an existing compound mouse experiment with a structural endpoint; it is not evidence that all triple-deletion mechanisms have been tested.
PMID:33519384 SUPPORT DIRECT REVIEW SYNTHESIS Model Organism
"This study also included assessments for ASD-related behaviors such as the juvenile social interaction test, three-chamber social interaction test, novel object investigation task and the Barnes maze; however, Cntn4-deficiency was not observed to affect ASD-related behaviors (Molenhuis et al., 2016)."
A negative result confined to the named ASD-related behavioral assessments.
PMID:33519384 SUPPORT DIRECT REVIEW SYNTHESIS Model Organism
"However, Cntn4-deficient mice do demonstrate enhanced spatial learning in the Barnes maze and a consistently increased startle response to auditory stimuli at high amplitudes (Molenhuis et al., 2016)."
Other behavioral endpoints changed in the same model; absence of an ASD-like phenotype is not absence of every phenotype.
Which gene or combination of genes contributes to congenital heart disease in distal 3p deletions?
KNOWLEDGE GAP del3p_unresolved_cardiac_gene
Attached to
pathophysiology#Disrupted Cardiac Development genetic#CAV3
The approximately 200 kb mapping interval assumed complete penetrance and excludes CAV3. CAV3 has separately been proposed in case reports, but the 2025 hypoplastic-left-heart case lacked molecular breakpoint mapping. A CAV3-containing deletion without a heart defect argues against fully penetrant sufficiency, not against every possible susceptibility effect. These limitations prevent gene-level prediction of a specific cardiac lesion.
Show evidence (4 references)
PMID:19760623 SUPPORT DIRECT Human Clinical
"Assuming complete penetrance, a candidate critical region for a CHD susceptibility gene was refined to approximately 200 kb and a candidate critical region for mental retardation was mapped to an approximately 1 Mb interval containing SRGAP3"
Maps the cardiac and neurodevelopmental critical regions separately, which is the direct basis for splitting these two branches.
PMID:39841745 SUPPORT DIRECT Human Clinical
"We identified an indirect relation between gene CAV3 and hypoplastic left heart syndrome due to its strong association with cardiomyopathies and isolated cardiac defects."
The authors themselves call the relation indirect, which is the reason this is a knowledge gap rather than a curated gene-phenotype assertion.
PMID:33643973 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"On the other hand, some known candidate genes, such as CAV3 and SEC13R, were shown to be outside the target interval."
The full-text literature discussion explicitly places CAV3 and SEC13R outside the refined target interval.
+ 1 more reference
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Pathophysiology

13
Heterozygous Deletion of Distal Chromosome 3p
Constitutional loss of one copy of a variable distal 3p interval initiates the disorder. A cytogenetically ascertained series had deletions of approximately 6–12 Mb; later molecular studies identified much smaller interstitial deletions, including a 148 kb SETD5-containing deletion. Terminal and interstitial deletions do not all remove the same genes.
Downstream
Reduced SETD5 Dosage Applies when the deletion encompasses the gene or genes represented by this branch.
Reduced BRPF1 Dosage Applies when the deletion encompasses the gene or genes represented by this branch.
Reduced SRGAP3 Dosage Applies when the deletion encompasses the gene or genes represented by this branch.
Reduced Dosage of Distal 3p26.3 Neuronal Adhesion Genes Applies when the deletion encompasses the gene or genes represented by this branch.
Disrupted Cardiac Development Some deletions are associated with congenital heart defects; conditional mapping leaves the molecular intermediates unresolved.
Deletion Including the VHL Locus This branch applies only when deletion boundaries include the VHL locus, rather than to every distal 3p deletion.
Show evidence (2 references)
PMID:19760623 SUPPORT DIRECT Human Clinical
"Deletion size varied from approximately 6 to 12 Mb."
Quantifies the size range across a microarray-characterised series, which is the variability this node records.
PMID:25138099 SUPPORT DIRECT Human Clinical
"The sizes of the interstitial deletions in 3p25.3 ranged from 148 kb in individual 3 (containing four genes) and 371 kb (individual 4, 10 genes) to 2.45 Mb (individual 5, 46 genes). The terminal deletion in individual 6 comprised 11.16 Mb and 71 genes."
Direct molecular characterization of three interstitial deletions and one terminal deletion; the size range is specific to these four patients.
Reduced SETD5 Dosage
Loss of one genomic copy of SETD5 reduces functional gene dosage. Human intragenic loss-of-function variants and SETD5-containing deletions share intellectual disability and facial features. CRISPR/Cas9 models in HEK293 cells supported nonsense-mediated decay for two modelled variants; this was not a measurement of every patient allele or of an exact 50% protein concentration.
SETD5 hgnc:25566 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SETD5 (hgnc:25566). hgnc:25566 is a gene from the HUGO Gene Nomenclature Committee.
Animal models
Setd5-Haploinsufficient Mouse Mouse perturbs Heterozygous germline disruption models reduced dosage of one contributing gene.
Downstream
Altered SETD5-Dependent Transcription Reduced Setd5 dosage altered transcription in experimental models.
Show evidence (2 references)
PMID:24680889 SUPPORT DIRECT Human Clinical
"The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition."
The comparison of intragenic variants against deletions that makes SETD5 the principal driver, hedged by the authors as many of rather than all the features - which is why this entry keeps other loci.
PMID:25138099 SUPPORT DIRECT In Vitro
"CRISPR/Cas9 mutation modelling of the two intragenic variants demonstrated nonsense-mediated decay of the resulting transcripts, pointing to a loss-of-function (LoF) and haploinsufficiency as the common disease-causing mechanism of intragenic SETD5 sequence variants and SETD5-containing microdeletions."
Engineered cell models support loss of function as the shared mechanism; patient phenotypes independently establish the clinical association.
Altered SETD5-Dependent Transcription
Setd5 interacts with Hdac3 and Paf1 complexes in mouse embryonic stem cells and neural progenitors. Setd5 deficiency redistributes RNA polymerase II and alters developmental gene expression. The 2018 study found both increases and decreases in transcriptional measures, without reduced Hdac3 enzymatic activity or a major loss of its chromatin recruitment. Selected patient truncations impaired complex interactions in engineered cells. These experiments support altered transcriptional regulation; they do not establish uniform chromatin repression or an intrinsic SETD5 methyltransferase mechanism in human neurons.
SETD5 hgnc:25566 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SETD5 (hgnc:25566). hgnc:25566 is a gene from the HUGO Gene Nomenclature Committee.
regulation of transcription by RNA polymerase II GO:0006357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Intellectual disability Human SETD5 loss-of-function variants establish a cognitive outcome, but the transcription-to-cognition steps remain incompletely resolved in patients.
Show evidence (3 references)
PMID:30455454 SUPPORT DIRECT Model Organism
"Our data additionally indicate that Setd5 regulates RNA polymerase II dynamics and gene transcription via its interaction with the Hdac3 and Paf1 complexes, findings potentially explaining the gene expression defects observed in Setd5-haploinsufficient mice."
Mouse and engineered-cell experiments connect Setd5 deficiency to transcriptional dysregulation; the recovered author manuscript supplies the assay and genotype details.
url:https://research-explorer.ista.ac.at/download/3/6255/2017_NatureNeuroscience_Deliu.pdf SUPPORT DIRECT Model Organism
"hyperacetylation, Hdac3 activity is not affected in Setd5+/- brain"
This excerpt records unchanged Hdac3 activity in heterozygous mouse brain despite histone hyperacetylation. The source sentence separately reports the same observation in embryonic stem-cell samples; this MODEL_ORGANISM item supports the brain-tissue result.
url:https://research-explorer.ista.ac.at/download/3/6255/2017_NatureNeuroscience_Deliu.pdf SUPPORT DIRECT In Vitro
"Immunopr ecipitation coupled with quantitative 253 mass spectrometry in ESCs and ESC-der ived NPCs revealed that endogenous 254 Setd5 is bound to two distinct protein complexes, Hdac3 and Paf1 (Fig. 5d,e, 255 Supplementary Table 7 Supplementary Fig. 9g)."
Immunoprecipitation and mass spectrometry identify Hdac3/Paf1 interactions in mouse embryonic stem cells and derived neural progenitor cultures. This is a cellular experiment, distinct from the live-mouse behavioral evidence. The exact quote preserves manuscript extraction spacing and printed line numbers.
Reduced BRPF1 Dosage
BRPF1-containing deletions and heterozygous intragenic loss-of-function variants support a contribution to intellectual disability and eyelid abnormalities. In a small genotype–phenotype comparison, five individuals with both BRPF1 and SETD5 deleted had more severe walking and speech delay than individuals with only one gene affected. The study used one index person per family and heterogeneous clinical assessments; it does not establish a universal severity rule.
BRPF1 hgnc:14255 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BRPF1 (hgnc:14255). hgnc:14255 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired BRPF1 Acetyltransferase Complex Assembly Loss of BRPF1 is expected to compromise its scaffolding function; the cited functional assay tests a truncating variant.
Show evidence (2 references)
PMID:27939639 SUPPORT DIRECT Human Clinical
"We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency."
Human comparison supports contributions from both genes, particularly BRPF1-associated eyelid features.
PMID:27939639 SUPPORT DIRECT Human Clinical
"All individuals from group 3 acquired walking after 3 years of age (5/5 for group 3 versus 2/19 for groups 1 and 2, p value = 0.0005) and presently have no language (5/5 for group 3 versus 1/19 for groups 1 and 2, p value = 0.0001) (Table 3), suggesting that disruption of both BRPF1 and SETD5..."
The comparison is five co-deleted individuals versus single-gene groups; it is not a population frequency estimate.
Impaired BRPF1 Acetyltransferase Complex Assembly
BRPF1 scaffolds histone acetyltransferase complexes rather than catalysing acetylation itself. The p.Val351Glyfs*8 variant retained KAT6A binding but failed to recruit ING5 and MEAF6 in transfected HEK293 cells. This variant experiment provides a model of impaired complex assembly relevant to BRPF1 loss, not a direct assay of a chromosome-deletion patient.
BRPF1 hgnc:14255 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BRPF1 (hgnc:14255). hgnc:14255 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Reduced BRPF1-Complex Histone H3K23 Acetylation The same truncated BRPF1 protein impairs partner binding and the H3K23 acetylation output of the reconstituted complex.
Show evidence (1 reference)
PMID:27939639 SUPPORT DIRECT In Vitro
"Whereas the wild-type was able to bind ING5 and MEAF6, the p.Val351Glyfs∗8 variant failed to do so."
An interaction assay in transfected HEK293 cells demonstrates loss of ING5/MEAF6 binding by this truncated BRPF1 protein.
Reduced BRPF1-Complex Histone H3K23 Acetylation
In transfected HeLa cells, complexes containing p.Val351Glyfs*8 BRPF1 failed to stimulate H3K23 acetylation. The corresponding patient fibroblast experiment showed only a slight, statistically non-significant H3K23 reduction, with no significant global H3 acetylation change. Thus the functional defect is experimentally supported in a reconstituted cellular context; uniform H3K23 deficiency in human deletion carriers is not demonstrated.
BRPF1 hgnc:14255 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BRPF1 (hgnc:14255). hgnc:14255 is a gene from the HUGO Gene Nomenclature Committee.
BRPF1-associated complex histone H3K23 acetyltransferase activity GO:0043994 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased BRPF1-associated complex histone H3K23 acetyltransferase activity, annotated with histone H3K23 acetyltransferase activity (GO:0043994). GO:0043994 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Intellectual disability BRPF1-associated human phenotypes support this outcome, while intermediates connecting altered acetylation to the clinical finding remain unresolved.
Ptosis BRPF1-associated human phenotypes support this outcome, while intermediates connecting altered acetylation to the clinical finding remain unresolved.
Blepharophimosis BRPF1-associated human phenotypes support this outcome, while intermediates connecting altered acetylation to the clinical finding remain unresolved.
Show evidence (1 reference)
PMID:27939639 SUPPORT DIRECT In Vitro
"However, unlike wild-type BRPF1, the p.Val351Glyfs∗8 variant failed to stimulate K23 acetylation of histone H3 (Figure S1C)."
Functional readout in transfected HeLa cells; this is not a significant patient-fibroblast result.
Reduced SRGAP3 Dosage
Deletion mapping establishes loss of one copy of SRGAP3 in some affected individuals. Its proposed contribution is conditional on inclusion of the gene within the deleted interval.
SRGAP3 hgnc:19744 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SRGAP3 (hgnc:19744). hgnc:19744 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Reduced SRGAP3 GTPase-Activating Activity Reduced gene dosage is expected to reduce available GAP function, but SRGAP3 activity was not measured in deletion-carrier neurons.
Show evidence (1 reference)
PMID:12195014 SUPPORT DIRECT Human Clinical
"By fluorescence in situ hybridization and loss of heterozygosity analysis, we demonstrated that this gene resides on chromosome 3p25 and is deleted in 3p(-) patients that present MR."
Patient deletion mapping supports loss of one copy but does not itself demonstrate reduced GAP activity.
Reduced SRGAP3 GTPase-Activating Activity
SRGAP3 is deleted in some distal 3p deletions and was disrupted by an X;3 translocation in one individual with intellectual disability and hypotonia. Recombinant-protein assays establish its GAP activity. Reduced function after single-copy loss is a mechanistic inference; direct neuronal activity measurements in deletion carriers were not reported.
SRGAP3 hgnc:19744 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SRGAP3 (hgnc:19744). hgnc:19744 is a gene from the HUGO Gene Nomenclature Committee.
SRGAP3 Rac1 GTPase activator activity GO:0005096 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased SRGAP3 Rac1 GTPase activator activity, annotated with GTPase activator activity (GO:0005096). GO:0005096 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Altered Rac1 Signaling Reduced GAP activity provides a biochemical rationale for altered Rac1 signaling.
Show evidence (2 references)
PMID:12195014 SUPPORT DIRECT In Vitro
"We describe several MEGAP/srGAP3 transcript isoforms and show that MEGAP/srGAP3a and -b represent functional GTPase-activating proteins (GAP) by an in vitro GAP assay."
The biochemical demonstration of GAP activity that grounds the molecular function bound on this node. Graded IN_VITRO because it is a cell-free enzymatic assay.
PMID:12195014 SUPPORT DIRECT Human Clinical
"By fluorescence in situ hybridization and loss of heterozygosity analysis, we demonstrated that this gene resides on chromosome 3p25 and is deleted in 3p(-) patients that present MR."
Patient deletion mapping supports loss of one copy but does not itself demonstrate reduced GAP activity.
Altered Rac1 Signaling
Recombinant SRGAP3 stimulates Rac1 GTP hydrolysis, with weaker activity toward Cdc42 and little activity toward RhoA. Reduced GAP function is expected to alter Rac1 signaling. The direction and magnitude of signaling in human deletion neurons remain unmeasured.
Rac protein signal transduction GO:0016601 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Rac protein signal transduction (GO:0016601). GO:0016601 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Intellectual disability A proposed contribution based on human mapping and protein function; the neuronal and cognitive intermediates remain unproven.
Show evidence (1 reference)
PMID:12195014 SUPPORT DIRECT In Vitro
"However, MEGAP/srGAP3 (▴) shows almost no activity toward RhoA, a strong activity toward Rac1, and a lower but still significant activity toward Cdc42Hs."
Cell-free recombinant-protein GAP assay establishes substrate specificity, not signaling measurements in patients.
Reduced Dosage of Distal 3p26.3 Neuronal Adhesion Genes
Terminal deletions can remove CHL1, CNTN6 and CNTN4 together or affect only part of this cluster. Human CNVs show variable expression and incomplete penetrance. The CHL1-only deletion family also carried an additional 696 kb maternal 1q44 duplication in both affected brothers, absent in their father; it is therefore not an isolated demonstration that CHL1 loss caused their phenotype.
CHL1 hgnc:1939 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CHL1 (hgnc:1939). hgnc:1939 is a gene from the HUGO Gene Nomenclature Committee. CNTN6 hgnc:2176 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CNTN6 (hgnc:2176). hgnc:2176 is a gene from the HUGO Gene Nomenclature Committee. CNTN4 hgnc:2174 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CNTN4 (hgnc:2174). hgnc:2174 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Abnormal Neurite Development Experimental gene perturbations support projection abnormalities, with extrapolation to human deletion dosage.
Show evidence (2 references)
PMID:33519384 SUPPORT DIRECT REVIEW SYNTHESIS Other
"The 3p26.3 region contains three consecutive genes encoding closely related neuronal immunoglobulin cell adhesion molecules (IgCAMs): Close Homolog of L1 (CHL1), Contactin-6 (CNTN6), and Contactin-4 (CNTN4)."
Names the gene content of the region, which is what this node asserts is lost together.
PMID:21457564 SUPPORT DIRECT Human Clinical
"Among them, a maternally inherited 1q44 duplication of 696 Kbs is shared by the two brothers and absent in the father."
The additional CNV limits attribution of the brothers’ clinical findings to the paternally inherited CHL1 deletion alone.
Abnormal Neurite Development
CHL1, CNTN6 and CNTN4 participate in neuronal projection development. Culture and mouse studies show gene- and region-specific dendritic or axonal abnormalities. Compound Chl1/Cntn6 heterozygous mice had more severe dendrite misorientation than either single heterozygote. The relevance and magnitude of these effects in human multigene deletion carriers remain uncertain.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
neurite development GO:0031175 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal neurite development, annotated with neuron projection development (GO:0031175). GO:0031175 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Chl1-Cntn6 Double-Heterozygous Mouse Mouse partially recapitulates Dendritic orientation is a structural readout of neuronal projection development.
Downstream
Autistic behavior The review proposes a human contribution, but mouse structural defects do not establish an ASD behavioral outcome.
Show evidence (1 reference)
PMID:33519384 SUPPORT DIRECT REVIEW SYNTHESIS Model Organism
"Notably, compound heterozygous mice for both Chl1 and Cntn6 display an additive deleterious phenotype – these compound heterozygous mice showed more severe misoriented dendrites compared to single heterozygous Chl1 or Cntn6 mice and wild-type littermates (Ye et al., 2008)."
The full review describes an existing compound mouse experiment with a structural endpoint; it is not evidence that all triple-deletion mechanisms have been tested.
Disrupted Cardiac Development
Deletion mapping suggests a cardiac susceptibility interval in 3p25.3. The reported approximately 200 kb refinement explicitly assumed complete penetrance; it is a conditional candidate interval, not a proven causal gene or obligatory phenotype. CAV3 is outside that refined interval. A 2025 infant with hypoplastic left heart syndrome had only a low-resolution 3p26 karyotype, which did not demonstrate CAV3 deletion.
heart development GO:0007507 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal heart development (GO:0007507). GO:0007507 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Congenital heart defect Cardiac developmental disruption is inferred from structural lesions in deletion carriers; the responsible gene and intermediate steps remain unresolved.
Show evidence (3 references)
PMID:19760623 SUPPORT DIRECT Human Clinical
"Assuming complete penetrance, a candidate critical region for a CHD susceptibility gene was refined to approximately 200 kb and a candidate critical region for mental retardation was mapped to an approximately 1 Mb interval containing SRGAP3"
Maps the cardiac and neurodevelopmental critical regions separately, which is the direct basis for splitting these two branches.
PMID:33643973 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"On the other hand, some known candidate genes, such as CAV3 and SEC13R, were shown to be outside the target interval."
The full-text literature discussion explicitly places CAV3 and SEC13R outside the refined target interval.
PMID:39841745 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Unfortunately, the NB died before further examinations could be conducted and there was not enough biological material stored of her, preventing us from running additional and more complete genetic tests, such as microarray-based comparative genomic hybridization (CGH-Array)."
The infant died before additional testing; the authors explicitly state that molecular confirmation of the breakpoint was not available.
Deletion Including the VHL Locus
Some distal 3p deletions extend through the VHL locus at 3p25. A clinical report associates such a deletion with cerebellar hemangioblastoma. The cited case does not establish tumor second-hit status or a measured HIF pathway defect; those additional oncogenic steps are not asserted here.
VHL hgnc:12687 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves VHL (hgnc:12687). hgnc:12687 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Cerebellar hemangioblastoma The VHL-containing deletion provides a proposed tumor-predisposition explanation. Penetrance and tumor-specific molecular intermediates were not established in this case.
Show evidence (1 reference)
PMID:26365017 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We identified de novo 3p deletion encompassing p25 by using array-based comparative genomic hybridization, where causative gene of von Hippel-Lindau (VHL) disease located."
Array-CGH demonstrated a deletion extending through the 3p25 region containing VHL in this affected individual.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for 3p- Syndrome 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

44
Cardiovascular 4
Atrioventricular septal defect Atrioventricular canal defect HP:0006695 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrioventricular septal defect, annotated with Atrioventricular canal defect (HP:0006695). HP:0006695 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19760623 SUPPORT DIRECT Human Clinical
"Congenital heart disease (CHD), typically atrioventricular septal defect (AVSD) occurs in about a third of patients."
The source names AVSD as a typical cardiac lesion. Its one-third estimate applies to congenital heart disease overall and is not used as an AVSD frequency.
Congenital heart defect Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19760623 SUPPORT DIRECT Human Clinical
"Congenital heart disease (CHD), typically atrioventricular septal defect (AVSD) occurs in about a third of patients."
The source directly describes congenital heart disease. Its estimate is not transferred to individual cardiac subtypes.
Ventricular septal defect HP:0001629 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular septal defect (HP:0001629). HP:0001629 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33643973 SUPPORT DIRECT Human Clinical
"A colored ultrasonography of the heart revealed a congenital heart defect (CHD), namely a ventricular septal defect (peri-membranous) of ~3 mm in size and a left to right shunt at the ventricular level."
Direct cardiac imaging in the index deletion case.
Hypoplastic left ventricle HP:0004383 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic left ventricle (HP:0004383). HP:0004383 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39841745 SUPPORT DIRECT Human Clinical
"An echocardiogram performed after birth confirmed a diagnosis of HLHS, with mitral and aortic valve atresia and a ventricular septal defect."
Postnatal echocardiography documents the left-heart phenotype in this infant.
Digestive 3
Abnormality of the gastrointestinal tract HP:0011024 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastrointestinal malformation, annotated with Abnormality of the gastrointestinal tract (HP:0011024). HP:0011024 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:33643973 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"The clinical phenotype of this syndrome is complex as it can include intellectual and motor development backwardness, low muscle tone, certain abnormal facial features (low hairline, bilateral ptosis, widely spaced eyes, a forward nose, left ear auricle deformity, a high-arched palate, a small..."
States gastrointestinal deformation as part of the clinical phenotype of the syndrome.
Gastroesophageal reflux HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33643973 SUPPORT DIRECT Human Clinical
"A gastrointestinal angiography was performed, which led to the diagnosis of gastroesophageal reflux."
This is a specific clinical diagnosis, despite the source table coding the index case as negative for gastrointestinal abnormalities.
Intestinal malrotation HP:0002566 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intestinal malrotation (HP:0002566). HP:0002566 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25138099 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Others | | Recurrent infections, constipation at younger age | Bifid uvula, oral frenula, hyperkeratosis, (kyphosis) | Cryptorchidism, complications of premature birth | − | Right helical pit, cutis marmorata | − | Cleft palate, bowel malrotation, scoliosis | − | Prominent lobes, right ear pit"
Table 1 lists these findings for the previously published Peltekova deletion case. The evidence is a literature-table summary rather than a new patient in this study.
Ear 3
Hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2178418 SUPPORT DIRECT Human Clinical
"The former patient showed characteristic clinical manifestations of the 3p- syndrome, including growth failure, mental retardation, microcephaly with a flat occiput, triangular face, synophrys, blepharoptosis, hypertelorism, broad and flat nose, long philtrum, down-turned mouth, micrognathia,..."
Lists deafness among the characteristic manifestations in a patient with the classic 3p25.3 deletion.
Low-set ears HP:0000369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-set ears (HP:0000369). HP:0000369 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33643973 SUPPORT DIRECT Human Clinical
"the main clinical phenotypes of the disease have been identified as follows: delayed growth and development, intellectual disability, hypotonia, micrognathia, ptosis, wide nose bridge, long philtrum, low ear position, deformed ears, polydactyly deformity, hearing abnormalities, CHD, renal..."
Names low ear position among the main clinical phenotypes established for the syndrome across a 29-case literature review.
PMID:2178418 SUPPORT DIRECT Human Clinical
"The former patient showed characteristic clinical manifestations of the 3p- syndrome, including growth failure, mental retardation, microcephaly with a flat occiput, triangular face, synophrys, blepharoptosis, hypertelorism, broad and flat nose, long philtrum, down-turned mouth, micrognathia,..."
Records lowset ears in a patient with the classic 3p25.3 deletion.
Abnormal pinna morphology HP:0000377 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal pinna morphology (HP:0000377). HP:0000377 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33643973 SUPPORT DIRECT Human Clinical
"The clinical phenotype of this syndrome is complex as it can include intellectual and motor development backwardness, low muscle tone, certain abnormal facial features (low hairline, bilateral ptosis, widely spaced eyes, a forward nose, left ear auricle deformity, a high-arched palate, a small..."
Records an auricular deformity among the facial features of a patient with a molecularly confirmed 3p26.3-p25.3 deletion.
Eye 3
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:19760623 SUPPORT DIRECT Human Clinical
"Distal deletion of chromosome 3p25-pter (3p- syndrome) produces a distinct clinical syndrome characterized by low birth weight, mental retardation, telecanthus, ptosis, and micrognathia."
Lists ptosis among the five features that define the clinical syndrome.
PMID:27939639 SUPPORT DIRECT Human Clinical
"We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency."
Human comparison supports contributions from both genes, particularly BRPF1-associated eyelid features.
Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22965684 SUPPORT DIRECT Human Clinical
"We report on a 3-year-old girl with intellectual disability, muscular hypotonia, strabismus, and facial anomalies in whom an interstitial 1.24 Mb deletion in 3p25.3-p26.1 was detected by SNP array analysis."
Records strabismus in a molecularly characterised patient with a deletion inside the critical interval.
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2178418 SUPPORT DIRECT Human Clinical
"The former patient showed characteristic clinical manifestations of the 3p- syndrome, including growth failure, mental retardation, microcephaly with a flat occiput, triangular face, synophrys, blepharoptosis, hypertelorism, broad and flat nose, long philtrum, down-turned mouth, micrognathia,..."
This feature is directly named in the clinical description of a patient with a 3p deletion.
Genitourinary 1
Abnormality of the kidney HP:0000077 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal malformation, annotated with Abnormality of the kidney (HP:0000077). HP:0000077 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:33643973 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"3p deletion syndrome is a rare autosomal and contiguous genomic disorder characterized by the following: intellectual disability; motor developmental delay; unusual facial features (microcephaly, micrognathia, ptosis, long philtrum, low and deformed ears, polydactyly deformity); hypotonia; and..."
Names renal malformation among the less commonly reported features. This qualitative wording does not establish a numerical frequency range.
Head and Neck 16
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25138099 SUPPORT DIRECT Human Clinical
"However, all four microdeletion carriers developed short stature and three of them also developed microcephaly during the first year of life."
Longitudinal observations distinguish postnatal growth restriction from low birth size; the four-patient series does not supply a syndrome-wide frequency.
Telecanthus HP:0000506 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Telecanthus (HP:0000506). HP:0000506 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39841745 SUPPORT DIRECT Human Clinical
"It produces a distinct clinical syndrome characterized by hypotonia, low birth weight, delayed neurological and motor development (crawling and walking), speech delay, intellectual impairment, telecanthus, craniofacial dysmorphia (microcephaly, micrognathia, and ptosis), and congenital heart..."
Names telecanthus among the characteristic features.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19760623 SUPPORT DIRECT Human Clinical
"Distal deletion of chromosome 3p25-pter (3p- syndrome) produces a distinct clinical syndrome characterized by low birth weight, mental retardation, telecanthus, ptosis, and micrognathia."
Lists micrognathia among the defining features.
Long philtrum HP:0000343 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long philtrum (HP:0000343). HP:0000343 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2178418 SUPPORT DIRECT Human Clinical
"The former patient showed characteristic clinical manifestations of the 3p- syndrome, including growth failure, mental retardation, microcephaly with a flat occiput, triangular face, synophrys, blepharoptosis, hypertelorism, broad and flat nose, long philtrum, down-turned mouth, micrognathia,..."
A full clinical description of a patient with the characteristic manifestations, including the long philtrum.
Depressed nasal bridge HP:0005280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depressed nasal bridge (HP:0005280). HP:0005280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:3443553 SUPPORT DIRECT Human Clinical
"Features present in the patient and characteristic of the 3p- syndrome included low birthweight, brachy-trigonocephaly, a high and narrow forehead with a prominent metopic suture, epicanthic folds, upslanting palpebral fissures, ptosis, depressed nasal bridge, anteverted nares and a small mandible."
The original syndrome delineation listing the depressed nasal bridge as characteristic.
Trigonocephaly HP:0000243 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Trigonocephaly (HP:0000243). HP:0000243 is a phenotype from the Human Phenotype Ontology.
The Perplexity report offered HP:0000263 for this phenotype. HPO calls that term Oxycephaly, a different skull shape; the correct term is HP:0000243 and was resolved with OAK.
Show evidence (1 reference)
PMID:3443553 SUPPORT DIRECT Human Clinical
"Features present in the patient and characteristic of the 3p- syndrome included low birthweight, brachy-trigonocephaly, a high and narrow forehead with a prominent metopic suture, epicanthic folds, upslanting palpebral fissures, ptosis, depressed nasal bridge, anteverted nares and a small mandible."
Records brachy-trigonocephaly and the prominent metopic suture as characteristic of the syndrome.
Preauricular pit HP:0004467 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Preauricular pit (HP:0004467). HP:0004467 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31428485 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"low set/poorly shaped ears (possibly with preauricular pits/fistulas), postaxial polydactyly, congenital heart defects, renal malformations, gastric malformations, hypotonia, and mental and psychomotor delays"
The passage summarizes pure distal 3p deletions. The paper’s own inverted-duplication/terminal-deletion case is a different rearrangement and does not supply this annotation.
Blepharophimosis HP:0000581 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Blepharophimosis (HP:0000581). HP:0000581 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27939639 SUPPORT DIRECT Human Clinical
"We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency."
Human comparison supports contributions from both genes, particularly BRPF1-associated eyelid features.
Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24680889 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"The presence of congenital heart disease and cleft palate is a more variable feature."
This full-text passage summarizes previously reported deletion cases, rather than the paper’s intragenic SETD5 cohort.
High palate HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33643973 SUPPORT DIRECT Human Clinical
"The patient had a broad nose bridge, forward nostrils, a deformity of the left auricle, a long philtrum, a high-arched palate, and micrognathia (as shown in Figure 1)."
Direct physical examination of a molecularly characterized deletion case.
Brachycephaly HP:0000248 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachycephaly (HP:0000248). HP:0000248 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:3443553 SUPPORT DIRECT Human Clinical
"Features present in the patient and characteristic of the 3p- syndrome included low birthweight, brachy-trigonocephaly, a high and narrow forehead with a prominent metopic suture, epicanthic folds, upslanting palpebral fissures, ptosis, depressed nasal bridge, anteverted nares and a small mandible."
The source directly describes this feature in its terminal-deletion case.
Epicanthus HP:0000286 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epicanthus (HP:0000286). HP:0000286 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:3443553 SUPPORT DIRECT Human Clinical
"Features present in the patient and characteristic of the 3p- syndrome included low birthweight, brachy-trigonocephaly, a high and narrow forehead with a prominent metopic suture, epicanthic folds, upslanting palpebral fissures, ptosis, depressed nasal bridge, anteverted nares and a small mandible."
The source directly describes this feature in its terminal-deletion case.
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:3443553 SUPPORT DIRECT Human Clinical
"Features present in the patient and characteristic of the 3p- syndrome included low birthweight, brachy-trigonocephaly, a high and narrow forehead with a prominent metopic suture, epicanthic folds, upslanting palpebral fissures, ptosis, depressed nasal bridge, anteverted nares and a small mandible."
The source directly describes this feature in its terminal-deletion case.
Downturned corners of mouth HP:0002714 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downturned corners of mouth (HP:0002714). HP:0002714 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2178418 SUPPORT DIRECT Human Clinical
"The former patient showed characteristic clinical manifestations of the 3p- syndrome, including growth failure, mental retardation, microcephaly with a flat occiput, triangular face, synophrys, blepharoptosis, hypertelorism, broad and flat nose, long philtrum, down-turned mouth, micrognathia,..."
This feature is directly named in the clinical description of a patient with a 3p deletion.
Flat occiput HP:0005469 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Flat occiput (HP:0005469). HP:0005469 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2178418 SUPPORT DIRECT Human Clinical
"The former patient showed characteristic clinical manifestations of the 3p- syndrome, including growth failure, mental retardation, microcephaly with a flat occiput, triangular face, synophrys, blepharoptosis, hypertelorism, broad and flat nose, long philtrum, down-turned mouth, micrognathia,..."
This feature is directly named in the clinical description of a patient with a 3p deletion.
Cystic hygroma HP:0000476 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cystic hygroma (HP:0000476). HP:0000476 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39841745 SUPPORT DIRECT Human Clinical
"Prenatal ultrasound revealed a cervical cystic hygroma measuring 4.1 x 2.5 cm, and an echocardiogram indicated severe hypoplasia of the mitral and aortic valves, left ventricular hypoplasia, a small ventricular septal defect, and a hypoplastic aortic arch."
Direct prenatal imaging observation in this case; molecular breakpoints remained unresolved.
Limbs 2
Postaxial polydactyly HP:0100259 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postaxial polydactyly (HP:0100259). HP:0100259 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:3443553 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"She lacked postaxial polydactyly of fingers and toes which is present in about half of the so far reported about one dozen 3p- cases"
Gives the frequency in the early case series while recording a patient without it, which is the variable presence this phenotype records.
PMID:25138099 SUPPORT DIRECT Human Clinical
"However, two microdeletion patients presented with postaxial hexadactyly of the hands."
Observed in two deletion carriers in this small series.
Clinodactyly of the 5th finger HP:0004209 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clinodactyly of the 5th finger (HP:0004209). HP:0004209 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39841745 SUPPORT DIRECT Human Clinical
"On dysmorphological examination, loose skin on the neck, a wide anterior fontanelle, a short nose, a micrognathia-like impression, clinodactyly of the fifth finger on both hands (indicative of medial phalangeal hypoplasia), and a second toe-like hallux in both feet were observed."
The physical examination explicitly names bilateral fifth-finger clinodactyly.
Musculoskeletal 2
Generalized hypotonia HP:0001290 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized hypotonia (HP:0001290). HP:0001290 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33643973 SUPPORT DIRECT Human Clinical
"The patient had hypotonia in the four extremities and uncooperative muscle strength."
Direct examination documents hypotonia in all four extremities, supporting the generalized binding.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24680889 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"scoliosis, cleft palate, gastrointestinal anomalies, and seizures."
The full-text review of previous deletion reports explicitly names scoliosis.
Nervous System 6
Intellectual disability 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 (1 reference)
PMID:19760623 SUPPORT DIRECT Human Clinical
"Distal deletion of chromosome 3p25-pter (3p- syndrome) produces a distinct clinical syndrome characterized by low birth weight, mental retardation, telecanthus, ptosis, and micrognathia."
Lists the cognitive impairment among the defining features of the syndrome.
Global developmental delay 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 (1 reference)
PMID:33643973 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"A total of 29 well-documented cases were found in the literature, of which 19 cases had an onset within 1 year of birth, and mainly manifested with mental and motor development disabilities and abnormal facial features, with different gene deletions, depending on the size and location of the 3p deletion."
The literature summary establishes early developmental presentations. Its stated case count differs from Table 3, which includes the index patient among 29 columns; no disease-level frequency is inferred.
Autistic behavior HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33519384 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Deletions occurring at chromosome 3p result in 3p-deletion syndrome (Del3p), a rare genetic disorder characterized by developmental delay, intellectual disability, facial dysmorphisms and often, ASD or ASD-associated behaviors."
The review describes ASD-associated behaviors among reported deletion phenotypes; no quantitative frequency is assigned.
Seizure 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 (1 reference)
PMID:25138099 SUPPORT DIRECT Human Clinical
"In addition, all four microdeletion carriers presented with muscular hypotonia and two of them had a history of seizures."
The series directly reports clinical seizure histories in two deletion carriers.
Delayed speech and language development 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:27939639 SUPPORT DIRECT Human Clinical
"All individuals from group 3 acquired walking after 3 years of age (5/5 for group 3 versus 2/19 for groups 1 and 2, p value = 0.0005) and presently have no language (5/5 for group 3 versus 1/19 for groups 1 and 2, p value = 0.0001) (Table 3), suggesting that disruption of both BRPF1 and SETD5..."
The comparison is five co-deleted individuals versus single-gene groups; it is not a population frequency estimate.
Obsessive-compulsive behavior Compulsive behaviors HP:0000722 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obsessive-compulsive behavior, annotated with Compulsive behaviors (HP:0000722). HP:0000722 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23613140 SUPPORT DIRECT Human Clinical
"We report on an 11-year-old girl with intellectual disability, obsessive-compulsive tendencies, hypotonia, and dysmorphic facial features in whom a 684 kb interstitial 3p25.3 deletion was characterized using array-CGH."
Direct clinical observation in a molecularly characterized deletion case.
Growth 3
Small for gestational age HP:0001518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small for gestational age (HP:0001518). HP:0001518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39841745 SUPPORT DIRECT Human Clinical
"The patient was delivered via cesarean section at 38 weeks and 6 days of gestational age, with birthweight 2842 kg (P8th), height 42 cm (<P0,4th), and cephalic perimeter measured 34 cm (P45th)."
The gestational age and eighth weight percentile support small-for-gestational-age status. The printed weight unit, “2842 kg”, is an apparent source typographical error; the annotation relies on the stated percentile.
Postnatal growth retardation HP:0008897 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postnatal growth retardation (HP:0008897). HP:0008897 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25138099 SUPPORT DIRECT Human Clinical
"However, all four microdeletion carriers developed short stature and three of them also developed microcephaly during the first year of life."
Longitudinal observations distinguish postnatal growth restriction from low birth size; the four-patient series does not supply a syndrome-wide frequency.
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25138099 SUPPORT DIRECT Human Clinical
"However, all four microdeletion carriers developed short stature and three of them also developed microcephaly during the first year of life."
Longitudinal observations distinguish postnatal growth restriction from low birth size; the four-patient series does not supply a syndrome-wide frequency.
Neoplasm 1
Cerebellar hemangioblastoma HP:0006880 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar hemangioblastoma (HP:0006880). HP:0006880 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26365017 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We described clinical course of a 24-year-old woman with 3p deletion syndrome associated with cerebellar hemangioblastoma at the age of 16 years old."
A specific cerebellar hemangioblastoma was observed at age 16 in this deletion carrier.
PMID:26365017 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Surgical therapy for cerebellar hemangioblastoma was performed, and histological examination was consistent in cerebellar hemangioblastoma."
Surgical treatment yielded histological confirmation. The report does not provide comparative efficacy or a standard operative technique.
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Genetic Associations

9
SETD5
Gene: SETD5 hgnc:25566 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SETD5 (hgnc:25566). hgnc:25566 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:24680889 SUPPORT DIRECT Human Clinical
"The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition."
The comparison of intragenic variants against deletions that makes SETD5 the principal driver, hedged by the authors as many of rather than all the features - which is why this entry keeps other loci.
PMID:24680889 SUPPORT DIRECT Human Clinical
"SETD5 lies within the critical interval for 3p25 microdeletion syndrome."
Places the gene inside the critical interval, which is what makes it a deletion-relevant gene rather than an unrelated ID gene.
PMID:25138099 SUPPORT DIRECT Human Clinical
"The microdeletions of the four patients presented here further narrow down the smallest region of microdeletion overlap to 94 kb (chr3:9,422,487_9,516,586). It affects only two protein-coding RefSeq genes: SETD5 and parts of THUMPD3."
Later overlap analysis narrows the region in a specific set of cases; it does not define a universal syndrome breakpoint.
SRGAP3
Gene: SRGAP3 hgnc:19744 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SRGAP3 (hgnc:19744). hgnc:19744 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (1 reference)
PMID:19760623 SUPPORT INDIRECT Human Clinical
"We suggest that current evidence suggests that SRGAP3 is the major determinant of mental retardation in distal 3p deletions."
The authors propose SRGAP3 as a determinant; this is an attribution from mapping rather than proof of a general monogenic mechanism.
CHL1
Gene: CHL1 hgnc:1939 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CHL1 (hgnc:1939). hgnc:1939 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER variant_origin: GERMLINE
Show evidence (2 references)
PMID:21457564 SUPPORT DIRECT Human Clinical
"The deletion was transmitted from their normal father and included only the CHL1 gene."
A CHL1-only deletion carried by an unaffected parent, which is why this gene is typed as a contributor rather than causative on its own.
PMID:21457564 SUPPORT DIRECT Human Clinical
"Among them, a maternally inherited 1q44 duplication of 696 Kbs is shared by the two brothers and absent in the father."
The additional CNV limits attribution of the brothers’ clinical findings to the paternally inherited CHL1 deletion alone.
CNTN4
Gene: CNTN4 hgnc:2174 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CNTN4 (hgnc:2174). hgnc:2174 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER variant_origin: GERMLINE
Show evidence (1 reference)
PMID:21457564 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"It was suggested that a 1,5 Mb minimal terminal deletion including the two genes CRBN and CNTN4 is sufficient to cause the syndrome."
Marked INDIRECT because the authors report this as a prior suggestion they are testing, not as their own finding.
CNTN6
Gene: CNTN6 hgnc:2176 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CNTN6 (hgnc:2176). hgnc:2176 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER variant_origin: GERMLINE
Show evidence (1 reference)
PMID:33519384 SUPPORT DIRECT REVIEW SYNTHESIS Other
"The 3p26.3 region contains three consecutive genes encoding closely related neuronal immunoglobulin cell adhesion molecules (IgCAMs): Close Homolog of L1 (CHL1), Contactin-6 (CNTN6), and Contactin-4 (CNTN4)."
Establishes CNTN6 as one of the three co-deleted genes in the terminal cytoband.
CRBN
Gene: CRBN hgnc:30185 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CRBN (hgnc:30185). hgnc:30185 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER variant_origin: GERMLINE
Show evidence (1 reference)
PMID:33519384 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"Next to CNTN4 in 3p26.2, three genes are present that are often lost in larger terminal 3p26.3 deletions: Interleukin 5 Receptor Subunit Alpha (IL5RA), Transfer RNA Nucleotidyl Transferase 1 (TRNT1), and Cereblon (CRBN). CRBN in particular has been associated with autosomal recessive..."
The review separates chromosomal position and a recessive association from a possible contribution to deletion phenotypes.
CAV3
Gene: CAV3 hgnc:1529 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CAV3 (hgnc:1529). hgnc:1529 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (1 reference)
PMID:21082655 SUPPORT INDIRECT Human Clinical
"Selected genes that are present in the hemizygous state and which might be important for the phenotype of this patient as regards the congenital heart defect, autistic behavior and mental retardation (CAV3, OXTR, and SRGAP3/MEGAP, respectively) are discussed in context of the clinical features."
Marked INDIRECT because the authors present CAV3 as a gene that might be important, discussed as a candidate rather than demonstrated.
BRPF1
Gene: BRPF1 hgnc:14255 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is BRPF1 (hgnc:14255). hgnc:14255 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:27939639 SUPPORT DIRECT Human Clinical
"We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency."
Human comparison supports contributions from both genes, particularly BRPF1-associated eyelid features.
VHL
Gene: VHL hgnc:12687 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is VHL (hgnc:12687). hgnc:12687 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (2 references)
PMID:26365017 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We identified de novo 3p deletion encompassing p25 by using array-based comparative genomic hybridization, where causative gene of von Hippel-Lindau (VHL) disease located."
Array-CGH demonstrated a deletion extending through the 3p25 region containing VHL in this affected individual.
PMID:26365017 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"This is the first case report of a patient with 3p deletion syndrome whose cerebellar hemangioblastoma may be associated with VHL disease."
The authors propose a VHL-related explanation for this tumor. The case does not demonstrate a tumor-specific second hit or quantify penetrance.
💊

Medical Actions

4
Developmental Rehabilitation
Action: comprehensive developmental rehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is comprehensive developmental rehabilitation, annotated with Rehabilitation (NCIT:C15315). NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Behavioral / lifestyle
Individualized developmental rehabilitation was reported for motor delay, including joint, head-control, kneeling and sitting exercises. Improvements were described after a short course and during subsequent follow-up, without a control group or proof of a sustained disease-modifying effect.
Mechanism Target:
MODULATES Global developmental delay — Rehabilitation addresses functional developmental limitations; reported improvement is an uncontrolled individual outcome.
Show evidence (1 reference)
PMID:33643973 SUPPORT DIRECT Human Clinical
"The treatment the patient was given consisted of a comprehensive rehabilitation program, which included large joint loosening training, Brunstrom training, exercise system training, head control and climbing strength training, four-point kneeling and one knee kneeling, and sitting training...."
The case describes the actual motor rehabilitation program and observed gains after more than 12 days; the uncontrolled observation does not establish comparative efficacy.
Show evidence (1 reference)
PMID:33643973 SUPPORT DIRECT Human Clinical
"The treatment the patient was given consisted of a comprehensive rehabilitation program, which included large joint loosening training, Brunstrom training, exercise system training, head control and climbing strength training, four-point kneeling and one knee kneeling, and sitting training...."
The case describes the actual motor rehabilitation program and observed gains after more than 12 days; the uncontrolled observation does not establish comparative efficacy.
Surgical Repair of Congenital Heart Defect
Action: congenital cardiac surgical repairNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is congenital cardiac surgical repair, annotated with Cardiac Surgery (NCIT:C157806). NCIT:C157806 is a clinical intervention from the NCI Thesaurus. Ontology label: Cardiac Surgery NCIT:C157806
Platform: Surgery
Cardiac intervention is determined by the structural lesion and clinical condition. In the reported infant with hypoplastic left heart syndrome, surgery was performed at five days of age and the infant died at six days. This case documents treatment but does not establish a survival benefit or a syndrome-specific surgical standard.
Show evidence (1 reference)
PMID:39841745 SUPPORT DIRECT Human Clinical
"Surgical intervention was performed when the patient was 5 days old."
Direct report of surgery in the affected infant; the surrounding case history records death the following day.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Genetic counseling incorporates parental testing, deletion boundaries, variable expression and the possibility of apparently unaffected carriers. Familial reports show that prenatal imaging and an unaffected parent cannot determine a child’s eventual developmental outcome.
Show evidence (3 references)
PMID:25123480 SUPPORT DIRECT Human Clinical
"In this report, we review the literature on terminal 3p deletions and discuss the importance of molecular testing and reporting of copy number variants to achieve accurate genetic counseling in prenatal and postnatal screening."
The authors' own statement of why counselling and careful variant reporting matter for this deletion specifically.
PMID:21457564 SUPPORT DIRECT Human Clinical
"As already described for others recurrent syndromes with variable phenotype, these findings are challenging in genetic counselling because of an evident variable penetrance."
Names variable penetrance as the specific counselling difficulty, which is what this treatment entry addresses.
PMID:33936696 SUPPORT DIRECT Human Clinical
"No ultrasound anomalies were detected; therefore, after genetic counseling, the couple decided to continue the pregnancy and a phenotypically normal child was born."
The case describes a family decision after counseling, not a measured counseling benefit or proof that prenatal findings reliably predict later development.
Surgical Treatment of Cerebellar Hemangioblastoma
Action: surgical treatment of cerebellar hemangioblastomaNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical treatment of cerebellar hemangioblastoma, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgical therapy was reported for the cerebellar tumor in the VHL-locus deletion case, with histological confirmation. The cited abstract does not specify the operation or establish a general treatment-effect estimate for the deletion syndrome.
Show evidence (1 reference)
PMID:26365017 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Surgical therapy for cerebellar hemangioblastoma was performed, and histological examination was consistent in cerebellar hemangioblastoma."
Surgical treatment yielded histological confirmation. The report does not provide comparative efficacy or a standard operative technique.
🔬

Diagnosis

3
Chromosomal microarray
Chromosomal microarray detects and delineates terminal or interstitial deletions and defines gene content. It can resolve submicroscopic deletions, but size and gene content do not by themselves predict individual severity.
array comparative genomic hybridization NCIT:C18084 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:23613140 SUPPORT DIRECT Human Clinical
"We report on an 11-year-old girl with intellectual disability, obsessive-compulsive tendencies, hypotonia, and dysmorphic facial features in whom a 684 kb interstitial 3p25.3 deletion was characterized using array-CGH."
Array-CGH characterized a 684 kb interstitial deletion in a patient with developmental and behavioral findings.
Karyotyping
Historically the diagnostic test and still able to show large terminal deletions and complex rearrangements, but it can miss the deletion outright. The original delineation records exactly that failure, and the recent hypoplastic-left-heart case reached only a positional candidate gene because karyotype resolution could not place the breakpoint.
Karyotyping NCIT:C16768 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:3443553 SUPPORT DIRECT Human Clinical
"The deletion was overlooked at a first routine cytogenetic examination."
A documented false-negative karyotype in a patient who had the syndrome, which is the limitation this entry records.
Imaging Follow-up for VHL-Locus Deletions
The cerebellar hemangioblastoma case prompted its authors to recommend repeat imaging. This is retained as case-based support for considering tumor surveillance when molecular testing shows involvement of the VHL locus; the report establishes neither an imaging schedule nor a surveillance benefit across all distal 3p deletions.
repeat imaging for tumor surveillance NCIT:C16502 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:26365017 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"Repeat imaging studies were recommended for the patients with 3p deletion syndrome."
The source recommendation follows one tumor case. The entry limits its application to the relevant deletion context and does not infer a standard screening interval.
📊

Prevalence

1
Worldwide
Cases In Literature Rare
The 2025 source describes fewer than 60 published cases. This historical literature count is not a population prevalence estimate. RARE records the source’s qualitative description, without converting the case count into a numerical prevalence band.
Show evidence (1 reference)
PMID:39841745 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Distal deletion of chromosome 3p25-pter (3p- syndrome) (OMIM # 613792) is a rare monosomal disorder with fewer than 60 reported cases worldwide."
The published case count, which is the only quantitative occurrence figure the sources provide.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from 3p- Syndrome:

SETD5 haploinsufficiency syndrome MONDO:0014336
Overlapping Features Intragenic SETD5 loss-of-function variants overlap the developmental and craniofacial phenotype of SETD5-containing deletions. Copy-number testing and sequence analysis distinguish the molecular diagnoses. Cardiac defects and polydactyly have also been reported with intragenic variants, so these findings do not uniquely identify a multigene deletion.
Show evidence (2 references)
PMID:25138099 SUPPORT DIRECT Human Clinical
"All six patients presented with ID and certain facial dysmorphisms, suggesting that SETD5 sequence variants contribute substantially to the microdeletion 3p25.3 phenotype."
Establishes that the single-gene disorder reproduces the core of the deletion phenotype, which is exactly why it is the leading differential.
PMID:27375234 SUPPORT DIRECT Human Clinical
"Loss-of-function de novo mutations in the SETD5 gene, encoding a putative methyltransferase, are an important cause of moderate/severe intellectual disability as evidenced by the results of sequencing large patient cohorts."
Confirms the single-gene entity exists independently of any deletion, which is what makes it a differential rather than a synonym.
3p25.3 microdeletion syndrome Not Yet Curated MONDO:0018564
Overlapping Features An overlapping ontology concept for 3p25.3 microdeletions, often interstitial and encompassing SETD5 and/or BRPF1. Breakpoint mapping describes overlap with the broader distal 3p deletion spectrum; this is not a mutually exclusive clinical alternative.
Unbalanced translocation producing 3p monosomy
Overlapping Features A 3p deletion can arise as one half of an unbalanced translocation carried by a parent, with a reciprocal gain elsewhere in the genome. The deletion phenotype is then overlaid on whatever the duplicated segment contributes, so features outside the 3p- picture should prompt a look at the other chromosome, and parental karyotyping changes the recurrence risk.
Show evidence (1 reference)
PMID:34602958 SUPPORT DIRECT Human Clinical
"A chromosomal imbalance with a partial trisomy 13q31.1q34 and monosomy 3p26.3 of paternal origin were detected."
A worked case of 3p monosomy arising as one half of an inherited unbalanced translocation, which is the mechanism this differential names.
🐁

Animal Models

2
Setd5-Haploinsufficient Mouse
A single-gene model with developmental abnormalities, altered vocalization and behavioral inflexibility. Ex vivo hippocampal slices showed enhanced long-term potentiation. Separate engineered embryonic stem-cell and neural-progenitor cultures were used for protein-complex and chromatin assays.
Species
Mouse
Genotype
Germline Setd5+/-
Publication
PMID:30455454
Pathograph links
Reduced SETD5 Dosage perturbs fidelity: moderate observes: organism Heterozygous germline disruption models reduced dosage of one contributing gene.
Limitations: This single-gene mouse model does not reproduce a human multigene deletion. Behavioral inflexibility and impaired adaptation coexist with enhanced memory retention and ex vivo hippocampal potentiation; gross brain architecture and neural-progenitor proliferation were not impaired in this study.
Show evidence (1 reference)
PMID:30455454 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Here we show that Setd5-haploinsufficient mice present developmental defects such as abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes. Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic..."
The study reports developmental and behavioral changes in Setd5-haploinsufficient mice. Enhanced long-term potentiation is not described as a generalized loss of plasticity.
The transcription mechanism also draws on separately engineered heterozygous and homozygous cell cultures. Neither a cell-culture assay nor a behavioral test directly measures human intellectual disability.
Show evidence (1 reference)
PMID:30455454 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Here we show that Setd5-haploinsufficient mice present developmental defects such as abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes. Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic..."
The study reports developmental and behavioral changes in Setd5-haploinsufficient mice. Enhanced long-term potentiation is not described as a generalized loss of plasticity.
Chl1-Cntn6 Double-Heterozygous Mouse
The full review describes a published two-gene mouse experiment showing more severe dendritic misorientation than either single heterozygote or wild-type littermates.
Species
Mouse
Genotype
Chl1+/-; Cntn6+/-
Publication
PMID:33519384
Pathograph links
Abnormal Neurite Development partially recapitulates fidelity: moderate observes: cellular Dendritic orientation is a structural readout of neuronal projection development.
Limitations: This two-gene structural model retains Cntn4 and other human deletion genes. The cited review does not establish that it recapitulates human ASD or intellectual disability, and compensation by other adhesion molecules remains a hypothesis.
Show evidence (1 reference)
PMID:33519384 SUPPORT DIRECT REVIEW SYNTHESIS Model Organism
"Notably, compound heterozygous mice for both Chl1 and Cntn6 display an additive deleterious phenotype – these compound heterozygous mice showed more severe misoriented dendrites compared to single heterozygous Chl1 or Cntn6 mice and wild-type littermates (Ye et al., 2008)."
The full review describes an existing compound mouse experiment with a structural endpoint; it is not evidence that all triple-deletion mechanisms have been tested.
Show evidence (1 reference)
PMID:33519384 SUPPORT DIRECT REVIEW SYNTHESIS Model Organism
"Notably, compound heterozygous mice for both Chl1 and Cntn6 display an additive deleterious phenotype – these compound heterozygous mice showed more severe misoriented dendrites compared to single heterozygous Chl1 or Cntn6 mice and wild-type littermates (Ye et al., 2008)."
The full review describes an existing compound mouse experiment with a structural endpoint; it is not evidence that all triple-deletion mechanisms have been tested.
{ }

Source YAML

click to show 
name: 3p- Syndrome
creation_date: "2026-09-09T14:00:00Z"
category: Genetic
parents:
- Contiguous Gene Deletion Syndrome
- Neurodevelopmental Disorder
disease_term:
  preferred_term: 3p- syndrome
  term:
    id: MONDO:0013424
    label: 3p- syndrome
synonyms:
- chromosome 3pter-p25 deletion syndrome
- distal monosomy 3p
- del(3p) syndrome
- 3p deletion syndrome
- distal 3p deletion
- partial deletion of the short arm of chromosome 3
description: >-
  3p- syndrome results from a heterozygous terminal or interstitial deletion of distal chromosome
  3p. The classic terminal deletion spans 3p25 to 3pter. Developmental delay, intellectual
  disability, growth impairment, hypotonia and craniofacial differences are characteristic,
  with variable cardiac, renal, gastrointestinal and limb malformations. Deletion boundaries
  and gene content differ among patients, and even relatives carrying the same deletion can
  differ substantially in clinical expression.

  SETD5 and BRPF1 have direct human genetic evidence for contributions to the neurodevelopmental
  phenotype. SRGAP3 and the distal CHL1/CNTN6/CNTN4 neuronal adhesion genes remain proposed
  additional contributors. Cardiac susceptibility mapping is conditional and has not established
  a single causal gene. This entry covers the multigene deletion; intragenic SETD5 and BRPF1
  disorders are curated separately.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A constitutional chromosomal deletion syndrome; the primary clinical home
      is clinical genetics and dysmorphology rather than any single organ system.
    evidence:
    - reference: PMID:21457564
      reference_title: >-
        Microarray based analysis of an inherited terminal 3p26.3 deletion,
        containing only the CHL1 gene, from a normal father to his two affected
        children.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        terminal deletions of the distal portion of the short arm of chromosome 3
        cause a rare contiguous gene disorder characterized by growth
        retardation, developmental delay, mental retardation, dysmorphisms,
        microcephaly and ptosis
      explanation: >-
        Characterises the condition as a contiguous gene disorder arising from a
        chromosomal deletion, which is the basis for this Part assignment.
  - classification_value: NEUROLOGIC
    notes: >-
      Developmental delay, intellectual disability and hypotonia are prominent but variably
      expressed neurological manifestations.
    evidence:
    - reference: PMID:33519384
      reference_title: >-
        Cell Adhesion Molecules Involved in Neurodevelopmental Pathways
        Implicated in 3p-Deletion Syndrome and Autism Spectrum Disorder.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Deletions occurring at chromosome 3p result in 3p-deletion syndrome
        (Del3p), a rare genetic disorder characterized by developmental delay,
        intellectual disability, facial dysmorphisms and often, ASD or
        ASD-associated behaviors.
      explanation: >-
        Names the neurodevelopmental features as the defining characteristics of
        the syndrome.
      quote_role: REVIEW_SYNTHESIS
pathophysiology:
- name: Heterozygous Deletion of Distal Chromosome 3p
  description: >-
    Constitutional loss of one copy of a variable distal 3p interval initiates the disorder.
    A cytogenetically ascertained series had deletions of approximately 6–12 Mb; later molecular
    studies identified much smaller interstitial deletions, including a 148 kb SETD5-containing
    deletion. Terminal and interstitial deletions do not all remove the same genes.
  role: trigger
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:19760623
    reference_title: "Microarray based analysis of 3p25-p26 deletions (3p- syndrome)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deletion size varied from approximately 6 to 12 Mb."
    explanation: >-
      Quantifies the size range across a microarray-characterised series, which
      is the variability this node records.
  - reference: PMID:25138099
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The sizes of the interstitial deletions in 3p25.3 ranged from 148 kb in individual 3
      (containing four genes) and 371 kb (individual 4, 10 genes) to 2.45 Mb (individual 5,
      46 genes). The terminal deletion in individual 6 comprised 11.16 Mb and 71 genes.
    explanation: >-
      Direct molecular characterization of three interstitial deletions and one terminal deletion;
      the size range is specific to these four patients.
    reference_title: >-
      Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype
      of microdeletion 3p25.3 syndrome.
  downstream:
  - target: Reduced SETD5 Dosage
    causal_link_type: DIRECT
    description: >-
      Applies when the deletion encompasses the gene or genes represented by this branch.
    evidence:
    - reference: PMID:24680889
      reference_title: >-
        De novo loss-of-function mutations in SETD5, encoding a methyltransferase
        in a 3p25 microdeletion syndrome critical region, cause intellectual
        disability.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The individuals with SETD5 mutations showed phenotypic similarity to those
        previously reported with a deletion in 3p25, and thus loss of SETD5 might
        be sufficient to account for many of the clinical features observed in this
        condition.
      explanation: >-
        The comparison of intragenic variants against deletions that makes SETD5
        the principal driver, hedged by the authors as many of rather than all the
        features - which is why this entry keeps other loci.
  - target: Reduced BRPF1 Dosage
    causal_link_type: DIRECT
    description: >-
      Applies when the deletion encompasses the gene or genes represented by this branch.
    evidence:
    - reference: PMID:27939639
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We conclude that both genes contribute to the phenotypic severity of 3p25 deletion
        syndrome but that some specific features, such as ptosis and blepharophimosis, are
        mostly driven by BRPF1 haploinsufficiency.
      explanation: >-
        Human comparison supports contributions from both genes, particularly BRPF1-associated
        eyelid features.
      reference_title: >-
        Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of
        Intellectual Disability with Associated Ptosis.
  - target: Reduced SRGAP3 Dosage
    causal_link_type: DIRECT
    description: >-
      Applies when the deletion encompasses the gene or genes represented by this branch.
    evidence:
    - reference: PMID:12195014
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        By fluorescence in situ hybridization and loss of heterozygosity analysis, we demonstrated
        that this gene resides on chromosome 3p25 and is deleted in 3p(-) patients that present
        MR.
      explanation: >-
        Patient deletion mapping supports loss of one copy but does not itself demonstrate
        reduced GAP activity.
      reference_title: >-
        The novel Rho-GTPase activating gene MEGAP/ srGAP3 has a putative role in severe mental
        retardation.
  - target: Reduced Dosage of Distal 3p26.3 Neuronal Adhesion Genes
    causal_link_type: DIRECT
    description: >-
      Applies when the deletion encompasses the gene or genes represented by this branch.
    evidence:
    - reference: PMID:33519384
      reference_title: >-
        Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated
        in 3p-Deletion Syndrome and Autism Spectrum Disorder.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      snippet: >-
        The 3p26.3 region contains three consecutive genes encoding closely related
        neuronal immunoglobulin cell adhesion molecules (IgCAMs): Close Homolog of
        L1 (CHL1), Contactin-6 (CNTN6), and Contactin-4 (CNTN4).
      explanation: >-
        Names the gene content of the region, which is what this node asserts is
        lost together.
      quote_role: REVIEW_SYNTHESIS
  - target: Disrupted Cardiac Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Some deletions are associated with congenital heart defects; conditional mapping leaves
      the molecular intermediates unresolved.
    evidence:
    - reference: PMID:19760623
      reference_title: "Microarray based analysis of 3p25-p26 deletions (3p- syndrome)."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Assuming complete penetrance, a candidate critical region for a CHD
        susceptibility gene was refined to approximately 200 kb and a candidate
        critical region for mental retardation was mapped to an approximately 1
        Mb interval containing SRGAP3
      explanation: >-
        Maps the cardiac and neurodevelopmental critical regions separately,
        which is the direct basis for splitting these two branches.
  - target: Deletion Including the VHL Locus
    causal_link_type: DIRECT
    description: >-
      This branch applies only when deletion boundaries include the VHL locus, rather than
      to every distal 3p deletion.
    evidence:
    - reference: PMID:26365017
      reference_title: A case of 3p deletion syndrome associated with cerebellar hemangioblastoma.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        We identified de novo 3p deletion encompassing p25 by using array-based comparative
        genomic hybridization, where causative gene of von Hippel-Lindau (VHL) disease located.
      explanation: >-
        Array-CGH demonstrated a deletion extending through the 3p25 region containing VHL
        in this affected individual.
- name: Reduced SETD5 Dosage
  description: >-
    Loss of one genomic copy of SETD5 reduces functional gene dosage. Human intragenic loss-of-function
    variants and SETD5-containing deletions share intellectual disability and facial features.
    CRISPR/Cas9 models in HEK293 cells supported nonsense-mediated decay for two modelled
    variants; this was not a measurement of every patient allele or of an exact 50% protein
    concentration.
  role: mechanism
  biological_scale: MOLECULAR
  genes:
  - &id001
    preferred_term: SETD5
    term:
      id: hgnc:25566
      label: SETD5
  evidence:
  - reference: PMID:24680889
    reference_title: >-
      De novo loss-of-function mutations in SETD5, encoding a methyltransferase
      in a 3p25 microdeletion syndrome critical region, cause intellectual
      disability.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individuals with SETD5 mutations showed phenotypic similarity to those
      previously reported with a deletion in 3p25, and thus loss of SETD5 might
      be sufficient to account for many of the clinical features observed in this
      condition.
    explanation: >-
      The comparison of intragenic variants against deletions that makes SETD5
      the principal driver, hedged by the authors as many of rather than all the
      features - which is why this entry keeps other loci.
  - reference: PMID:25138099
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      CRISPR/Cas9 mutation modelling of the two intragenic variants demonstrated nonsense-mediated
      decay of the resulting transcripts, pointing to a loss-of-function (LoF) and haploinsufficiency
      as the common disease-causing mechanism of intragenic SETD5 sequence variants and SETD5-containing
      microdeletions.
    explanation: >-
      Engineered cell models support loss of function as the shared mechanism; patient phenotypes
      independently establish the clinical association.
    reference_title: >-
      Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype
      of microdeletion 3p25.3 syndrome.
  downstream:
  - target: Altered SETD5-Dependent Transcription
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced Setd5 dosage altered transcription in experimental models.
    evidence:
    - reference: PMID:30455454
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our data additionally indicate that Setd5 regulates RNA polymerase II dynamics and
        gene transcription via its interaction with the Hdac3 and Paf1 complexes, findings
        potentially explaining the gene expression defects observed in Setd5-haploinsufficient
        mice.
      explanation: >-
        Mouse and engineered-cell experiments connect Setd5 deficiency to transcriptional
        dysregulation; the recovered author manuscript supplies the assay and genotype details.
      reference_title: >-
        Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental
        gene expression and cognition.
    - reference: url:https://research-explorer.ista.ac.at/download/3/6255/2017_NatureNeuroscience_Deliu.pdf
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Immunopr ecipitation coupled with quantitative 253

        mass spectrometry in ESCs and ESC-der ived NPCs revealed that endogenous 254

        Setd5 is bound to two distinct protein complexes, Hdac3 and Paf1 (Fig. 5d,e, 255

        Supplementary Table 7 Supplementary Fig. 9g).
      explanation: >-
        Immunoprecipitation and mass spectrometry identify Hdac3/Paf1 interactions in mouse
        embryonic stem cells and derived neural progenitor cultures. This is a cellular experiment,
        distinct from the live-mouse behavioral evidence. The exact quote preserves manuscript
        extraction spacing and printed line numbers.
      reference_title: >-
        https://research-explorer.ista.ac.at/download/3/6255/2017_NatureNeuroscience_Deliu.pdf
- name: Altered SETD5-Dependent Transcription
  description: >-
    Setd5 interacts with Hdac3 and Paf1 complexes in mouse embryonic stem cells and neural
    progenitors. Setd5 deficiency redistributes RNA polymerase II and alters developmental
    gene expression. The 2018 study found both increases and decreases in transcriptional
    measures, without reduced Hdac3 enzymatic activity or a major loss of its chromatin recruitment.
    Selected patient truncations impaired complex interactions in engineered cells. These
    experiments support altered transcriptional regulation; they do not establish uniform
    chromatin repression or an intrinsic SETD5 methyltransferase mechanism in human neurons.
  role: mechanism
  biological_scale: CELLULAR
  genes:
  - *id001
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30455454
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our data additionally indicate that Setd5 regulates RNA polymerase II dynamics and gene
      transcription via its interaction with the Hdac3 and Paf1 complexes, findings potentially
      explaining the gene expression defects observed in Setd5-haploinsufficient mice.
    explanation: >-
      Mouse and engineered-cell experiments connect Setd5 deficiency to transcriptional dysregulation;
      the recovered author manuscript supplies the assay and genotype details.
    reference_title: >-
      Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental
      gene expression and cognition.
  - reference: url:https://research-explorer.ista.ac.at/download/3/6255/2017_NatureNeuroscience_Deliu.pdf
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      hyperacetylation, Hdac3 activity is not affected in Setd5+/- brain
    explanation: >-
      This excerpt records unchanged Hdac3 activity in heterozygous mouse brain despite histone
      hyperacetylation. The source sentence separately reports the same observation in embryonic
      stem-cell samples; this MODEL_ORGANISM item supports the brain-tissue result.
    reference_title: >-
      https://research-explorer.ista.ac.at/download/3/6255/2017_NatureNeuroscience_Deliu.pdf
  - reference: url:https://research-explorer.ista.ac.at/download/3/6255/2017_NatureNeuroscience_Deliu.pdf
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Immunopr ecipitation coupled with quantitative 253

      mass spectrometry in ESCs and ESC-der ived NPCs revealed that endogenous 254

      Setd5 is bound to two distinct protein complexes, Hdac3 and Paf1 (Fig. 5d,e, 255

      Supplementary Table 7 Supplementary Fig. 9g).
    explanation: >-
      Immunoprecipitation and mass spectrometry identify Hdac3/Paf1 interactions in mouse
      embryonic stem cells and derived neural progenitor cultures. This is a cellular experiment,
      distinct from the live-mouse behavioral evidence. The exact quote preserves manuscript
      extraction spacing and printed line numbers.
    reference_title: >-
      https://research-explorer.ista.ac.at/download/3/6255/2017_NatureNeuroscience_Deliu.pdf
  downstream:
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Human SETD5 loss-of-function variants establish a cognitive outcome, but the transcription-to-cognition
      steps remain incompletely resolved in patients.
    evidence:
    - reference: PMID:24680889
      reference_title: >-
        De novo loss-of-function mutations in SETD5, encoding a methyltransferase
        in a 3p25 microdeletion syndrome critical region, cause intellectual
        disability.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The individuals with SETD5 mutations showed phenotypic similarity to those
        previously reported with a deletion in 3p25, and thus loss of SETD5 might
        be sufficient to account for many of the clinical features observed in this
        condition.
      explanation: >-
        The comparison of intragenic variants against deletions that makes SETD5
        the principal driver, hedged by the authors as many of rather than all the
        features - which is why this entry keeps other loci.
- name: Reduced BRPF1 Dosage
  description: >-
    BRPF1-containing deletions and heterozygous intragenic loss-of-function variants support
    a contribution to intellectual disability and eyelid abnormalities. In a small genotype–phenotype
    comparison, five individuals with both BRPF1 and SETD5 deleted had more severe walking
    and speech delay than individuals with only one gene affected. The study used one index
    person per family and heterogeneous clinical assessments; it does not establish a universal
    severity rule.
  role: mechanism
  biological_scale: MOLECULAR
  genes:
  - &id002
    preferred_term: BRPF1
    term:
      id: hgnc:14255
      label: BRPF1
  evidence:
  - reference: PMID:27939639
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome
      but that some specific features, such as ptosis and blepharophimosis, are mostly driven
      by BRPF1 haploinsufficiency.
    explanation: >-
      Human comparison supports contributions from both genes, particularly BRPF1-associated
      eyelid features.
    reference_title: >-
      Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual
      Disability with Associated Ptosis.
  - reference: PMID:27939639
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals from group 3 acquired walking after 3 years of age (5/5 for group 3
      versus 2/19 for groups 1 and 2, p value = 0.0005) and presently have no language (5/5
      for group 3 versus 1/19 for groups 1 and 2, p value = 0.0001) (Table 3), suggesting
      that disruption of both BRPF1 and SETD5 contributes to the phenotype of 3p25 deletion
      syndrome.
    explanation: >-
      The comparison is five co-deleted individuals versus single-gene groups; it is not a
      population frequency estimate.
    reference_title: >-
      Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual
      Disability with Associated Ptosis.
  downstream:
  - target: Impaired BRPF1 Acetyltransferase Complex Assembly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of BRPF1 is expected to compromise its scaffolding function; the cited functional
      assay tests a truncating variant.
    evidence:
    - reference: PMID:27939639
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Whereas the wild-type was able to bind ING5 and MEAF6, the p.Val351Glyfs∗8 variant
        failed to do so.
      explanation: >-
        An interaction assay in transfected HEK293 cells demonstrates loss of ING5/MEAF6 binding
        by this truncated BRPF1 protein.
      reference_title: >-
        Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of
        Intellectual Disability with Associated Ptosis.
- name: Impaired BRPF1 Acetyltransferase Complex Assembly
  description: >-
    BRPF1 scaffolds histone acetyltransferase complexes rather than catalysing acetylation
    itself. The p.Val351Glyfs*8 variant retained KAT6A binding but failed to recruit ING5
    and MEAF6 in transfected HEK293 cells. This variant experiment provides a model of impaired
    complex assembly relevant to BRPF1 loss, not a direct assay of a chromosome-deletion patient.
  role: mechanism
  biological_scale: MOLECULAR
  genes:
  - *id002
  evidence:
  - reference: PMID:27939639
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Whereas the wild-type was able to bind ING5 and MEAF6, the p.Val351Glyfs∗8 variant failed
      to do so.
    explanation: >-
      An interaction assay in transfected HEK293 cells demonstrates loss of ING5/MEAF6 binding
      by this truncated BRPF1 protein.
    reference_title: >-
      Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual
      Disability with Associated Ptosis.
  downstream:
  - target: Reduced BRPF1-Complex Histone H3K23 Acetylation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The same truncated BRPF1 protein impairs partner binding and the H3K23 acetylation output
      of the reconstituted complex.
    evidence:
    - reference: PMID:27939639
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        However, unlike wild-type BRPF1, the p.Val351Glyfs∗8 variant failed to stimulate K23
        acetylation of histone H3 (Figure S1C).
      explanation: >-
        Functional readout in transfected HeLa cells; this is not a significant patient-fibroblast
        result.
      reference_title: >-
        Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of
        Intellectual Disability with Associated Ptosis.
- name: Reduced BRPF1-Complex Histone H3K23 Acetylation
  description: >-
    In transfected HeLa cells, complexes containing p.Val351Glyfs*8 BRPF1 failed to stimulate
    H3K23 acetylation. The corresponding patient fibroblast experiment showed only a slight,
    statistically non-significant H3K23 reduction, with no significant global H3 acetylation
    change. Thus the functional defect is experimentally supported in a reconstituted cellular
    context; uniform H3K23 deficiency in human deletion carriers is not demonstrated.
  role: mechanism
  biological_scale: CELLULAR
  genes:
  - *id002
  evidence:
  - reference: PMID:27939639
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      However, unlike wild-type BRPF1, the p.Val351Glyfs∗8 variant failed to stimulate K23
      acetylation of histone H3 (Figure S1C).
    explanation: >-
      Functional readout in transfected HeLa cells; this is not a significant patient-fibroblast
      result.
    reference_title: >-
      Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual
      Disability with Associated Ptosis.
  molecular_functions:
  - preferred_term: BRPF1-associated complex histone H3K23 acetyltransferase activity
    term:
      id: GO:0043994
      label: histone H3K23 acetyltransferase activity
    modifier: DECREASED
  downstream:
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      BRPF1-associated human phenotypes support this outcome, while intermediates connecting
      altered acetylation to the clinical finding remain unresolved.
    evidence:
    - reference: PMID:27939639
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We conclude that both genes contribute to the phenotypic severity of 3p25 deletion
        syndrome but that some specific features, such as ptosis and blepharophimosis, are
        mostly driven by BRPF1 haploinsufficiency.
      explanation: >-
        Human comparison supports contributions from both genes, particularly BRPF1-associated
        eyelid features.
      reference_title: >-
        Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of
        Intellectual Disability with Associated Ptosis.
  - target: Ptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      BRPF1-associated human phenotypes support this outcome, while intermediates connecting
      altered acetylation to the clinical finding remain unresolved.
    evidence:
    - reference: PMID:27939639
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We conclude that both genes contribute to the phenotypic severity of 3p25 deletion
        syndrome but that some specific features, such as ptosis and blepharophimosis, are
        mostly driven by BRPF1 haploinsufficiency.
      explanation: >-
        Human comparison supports contributions from both genes, particularly BRPF1-associated
        eyelid features.
      reference_title: >-
        Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of
        Intellectual Disability with Associated Ptosis.
  - target: Blepharophimosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      BRPF1-associated human phenotypes support this outcome, while intermediates connecting
      altered acetylation to the clinical finding remain unresolved.
    evidence:
    - reference: PMID:27939639
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We conclude that both genes contribute to the phenotypic severity of 3p25 deletion
        syndrome but that some specific features, such as ptosis and blepharophimosis, are
        mostly driven by BRPF1 haploinsufficiency.
      explanation: >-
        Human comparison supports contributions from both genes, particularly BRPF1-associated
        eyelid features.
      reference_title: >-
        Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of
        Intellectual Disability with Associated Ptosis.
- name: Reduced SRGAP3 Dosage
  description: >-
    Deletion mapping establishes loss of one copy of SRGAP3 in some affected individuals.
    Its proposed contribution is conditional on inclusion of the gene within the deleted interval.
  role: mechanism
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SRGAP3
    term:
      id: hgnc:19744
      label: SRGAP3
  evidence:
  - reference: PMID:12195014
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By fluorescence in situ hybridization and loss of heterozygosity analysis, we demonstrated
      that this gene resides on chromosome 3p25 and is deleted in 3p(-) patients that present
      MR.
    explanation: >-
      Patient deletion mapping supports loss of one copy but does not itself demonstrate reduced
      GAP activity.
    reference_title: >-
      The novel Rho-GTPase activating gene MEGAP/ srGAP3 has a putative role in severe mental
      retardation.
  downstream:
  - target: Reduced SRGAP3 GTPase-Activating Activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced gene dosage is expected to reduce available GAP function, but SRGAP3 activity
      was not measured in deletion-carrier neurons.
    evidence:
    - reference: PMID:12195014
      reference_title: >-
        The novel Rho-GTPase activating gene MEGAP/ srGAP3 has a putative role in
        severe mental retardation.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        We describe several MEGAP/srGAP3 transcript isoforms and show that
        MEGAP/srGAP3a and -b represent functional GTPase-activating proteins (GAP)
        by an in vitro GAP assay.
      explanation: >-
        The biochemical demonstration of GAP activity that grounds the molecular
        function bound on this node. Graded IN_VITRO because it is a cell-free
        enzymatic assay.
- name: Reduced SRGAP3 GTPase-Activating Activity
  description: >-
    SRGAP3 is deleted in some distal 3p deletions and was disrupted by an X;3 translocation
    in one individual with intellectual disability and hypotonia. Recombinant-protein assays
    establish its GAP activity. Reduced function after single-copy loss is a mechanistic inference;
    direct neuronal activity measurements in deletion carriers were not reported.
  role: mechanism
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SRGAP3
    term:
      id: hgnc:19744
      label: SRGAP3
  evidence:
  - reference: PMID:12195014
    reference_title: >-
      The novel Rho-GTPase activating gene MEGAP/ srGAP3 has a putative role in
      severe mental retardation.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      We describe several MEGAP/srGAP3 transcript isoforms and show that
      MEGAP/srGAP3a and -b represent functional GTPase-activating proteins (GAP)
      by an in vitro GAP assay.
    explanation: >-
      The biochemical demonstration of GAP activity that grounds the molecular
      function bound on this node. Graded IN_VITRO because it is a cell-free
      enzymatic assay.
  - reference: PMID:12195014
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By fluorescence in situ hybridization and loss of heterozygosity analysis, we demonstrated
      that this gene resides on chromosome 3p25 and is deleted in 3p(-) patients that present
      MR.
    explanation: >-
      Patient deletion mapping supports loss of one copy but does not itself demonstrate reduced
      GAP activity.
    reference_title: >-
      The novel Rho-GTPase activating gene MEGAP/ srGAP3 has a putative role in severe mental
      retardation.
  molecular_functions:
  - preferred_term: SRGAP3 Rac1 GTPase activator activity
    term:
      id: GO:0005096
      label: GTPase activator activity
    modifier: DECREASED
  downstream:
  - target: Altered Rac1 Signaling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced GAP activity provides a biochemical rationale for altered Rac1 signaling.
    evidence:
    - reference: PMID:12195014
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        However, MEGAP/srGAP3 (▴) shows almost no activity toward RhoA, a strong activity
        toward Rac1, and a lower but still significant activity toward Cdc42Hs.
      explanation: >-
        Cell-free recombinant-protein GAP assay establishes substrate specificity, not signaling
        measurements in patients.
      reference_title: >-
        The novel Rho-GTPase activating gene MEGAP/ srGAP3 has a putative role in severe mental
        retardation.
- name: Altered Rac1 Signaling
  description: >-
    Recombinant SRGAP3 stimulates Rac1 GTP hydrolysis, with weaker activity toward Cdc42 and
    little activity toward RhoA. Reduced GAP function is expected to alter Rac1 signaling.
    The direction and magnitude of signaling in human deletion neurons remain unmeasured.
  role: mechanism
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: Rac protein signal transduction
    term:
      id: GO:0016601
      label: Rac protein signal transduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:12195014
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      However, MEGAP/srGAP3 (▴) shows almost no activity toward RhoA, a strong activity toward
      Rac1, and a lower but still significant activity toward Cdc42Hs.
    explanation: >-
      Cell-free recombinant-protein GAP assay establishes substrate specificity, not signaling
      measurements in patients.
    reference_title: >-
      The novel Rho-GTPase activating gene MEGAP/ srGAP3 has a putative role in severe mental
      retardation.
  downstream:
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A proposed contribution based on human mapping and protein function; the neuronal and
      cognitive intermediates remain unproven.
    evidence:
    - reference: PMID:12195014
      reference_title: >-
        The novel Rho-GTPase activating gene MEGAP/ srGAP3 has a putative role in
        severe mental retardation.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We propose that haploinsufficiency of MEGAP/srGAP3 leads to the abnormal
        development of neuronal structures that are important for normal
        cognitive function.
      explanation: >-
        Marked INDIRECT because the authors state this as a proposal from gene
        dosage and expression rather than a demonstrated causal chain.
- name: Reduced Dosage of Distal 3p26.3 Neuronal Adhesion Genes
  description: >-
    Terminal deletions can remove CHL1, CNTN6 and CNTN4 together or affect only part of this
    cluster. Human CNVs show variable expression and incomplete penetrance. The CHL1-only
    deletion family also carried an additional 696 kb maternal 1q44 duplication in both affected
    brothers, absent in their father; it is therefore not an isolated demonstration that CHL1
    loss caused their phenotype.
  role: mechanism
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CHL1
    term:
      id: hgnc:1939
      label: CHL1
  - preferred_term: CNTN6
    term:
      id: hgnc:2176
      label: CNTN6
  - preferred_term: CNTN4
    term:
      id: hgnc:2174
      label: CNTN4
  evidence:
  - reference: PMID:33519384
    reference_title: >-
      Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated
      in 3p-Deletion Syndrome and Autism Spectrum Disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: >-
      The 3p26.3 region contains three consecutive genes encoding closely related
      neuronal immunoglobulin cell adhesion molecules (IgCAMs): Close Homolog of
      L1 (CHL1), Contactin-6 (CNTN6), and Contactin-4 (CNTN4).
    explanation: >-
      Names the gene content of the region, which is what this node asserts is
      lost together.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:21457564
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among them, a maternally inherited 1q44 duplication of 696 Kbs is shared by the two
      brothers and absent in the father.
    explanation: >-
      The additional CNV limits attribution of the brothers’ clinical findings to the paternally
      inherited CHL1 deletion alone.
    reference_title: >-
      Microarray based analysis of an inherited terminal 3p26.3 deletion, containing only
      the CHL1 gene, from a normal father to his two affected children.
  downstream:
  - target: Abnormal Neurite Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Experimental gene perturbations support projection abnormalities, with extrapolation
      to human deletion dosage.
    evidence:
    - reference: PMID:33519384
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Notably, compound heterozygous mice for both Chl1 and Cntn6 display an additive deleterious
        phenotype – these compound heterozygous mice showed more severe misoriented dendrites
        compared to single heterozygous Chl1 or Cntn6 mice and wild-type littermates (Ye et
        al., 2008).
      explanation: >-
        The full review describes an existing compound mouse experiment with a structural
        endpoint; it is not evidence that all triple-deletion mechanisms have been tested.
      quote_role: REVIEW_SYNTHESIS
      reference_title: >-
        Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated in 3p-Deletion
        Syndrome and Autism Spectrum Disorder.
- name: Abnormal Neurite Development
  description: >-
    CHL1, CNTN6 and CNTN4 participate in neuronal projection development. Culture and mouse
    studies show gene- and region-specific dendritic or axonal abnormalities. Compound Chl1/Cntn6
    heterozygous mice had more severe dendrite misorientation than either single heterozygote.
    The relevance and magnitude of these effects in human multigene deletion carriers remain
    uncertain.
  role: mechanism
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: neurite development
    term:
      id: GO:0031175
      label: neuron projection development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33519384
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Notably, compound heterozygous mice for both Chl1 and Cntn6 display an additive deleterious
      phenotype – these compound heterozygous mice showed more severe misoriented dendrites
      compared to single heterozygous Chl1 or Cntn6 mice and wild-type littermates (Ye et
      al., 2008).
    explanation: >-
      The full review describes an existing compound mouse experiment with a structural endpoint;
      it is not evidence that all triple-deletion mechanisms have been tested.
    quote_role: REVIEW_SYNTHESIS
    reference_title: >-
      Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated in 3p-Deletion
      Syndrome and Autism Spectrum Disorder.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Autistic behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The review proposes a human contribution, but mouse structural defects do not establish
      an ASD behavioral outcome.
    evidence:
    - reference: PMID:33519384
      reference_title: >-
        Cell Adhesion Molecules Involved in Neurodevelopmental Pathways
        Implicated in 3p-Deletion Syndrome and Autism Spectrum Disorder.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        CNVs disrupting these neuronal IgCAMs may contribute toward ASD
        phenotypes as they have been associated with key roles in
        neurodevelopment.
      explanation: >-
        Marked INDIRECT because the review states a possible contribution
        inferred from gene function, not a demonstrated causal link.
      quote_role: REVIEW_SYNTHESIS
- name: Disrupted Cardiac Development
  description: >-
    Deletion mapping suggests a cardiac susceptibility interval in 3p25.3. The reported approximately
    200 kb refinement explicitly assumed complete penetrance; it is a conditional candidate
    interval, not a proven causal gene or obligatory phenotype. CAV3 is outside that refined
    interval. A 2025 infant with hypoplastic left heart syndrome had only a low-resolution
    3p26 karyotype, which did not demonstrate CAV3 deletion.
  role: mechanism
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: heart development
    term:
      id: GO:0007507
      label: heart development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:19760623
    reference_title: "Microarray based analysis of 3p25-p26 deletions (3p- syndrome)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Assuming complete penetrance, a candidate critical region for a CHD
      susceptibility gene was refined to approximately 200 kb and a candidate
      critical region for mental retardation was mapped to an approximately 1
      Mb interval containing SRGAP3
    explanation: >-
      Maps the cardiac and neurodevelopmental critical regions separately,
      which is the direct basis for splitting these two branches.
  - reference: PMID:33643973
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      On the other hand, some known candidate genes, such as CAV3 and SEC13R, were shown to
      be outside the target interval.
    explanation: >-
      The full-text literature discussion explicitly places CAV3 and SEC13R outside the refined
      target interval.
    reference_title: >-
      Case Report: A Case Report and Literature Review of 3p Deletion Syndrome.
  - reference: PMID:39841745
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Unfortunately, the NB died before further examinations could be conducted and there
      was not enough biological material stored of her, preventing us from running additional
      and more complete genetic tests, such as microarray-based comparative genomic hybridization
      (CGH-Array).
    explanation: >-
      The infant died before additional testing; the authors explicitly state that molecular
      confirmation of the breakpoint was not available.
    reference_title: >-
      First report of hypoplastic left heart syndrome in 3p- syndrome and review of candidate
      genes.
  downstream:
  - target: Congenital heart defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cardiac developmental disruption is inferred from structural lesions in deletion carriers;
      the responsible gene and intermediate steps remain unresolved.
    evidence:
    - reference: PMID:19760623
      reference_title: "Microarray based analysis of 3p25-p26 deletions (3p- syndrome)."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Congenital heart disease (CHD), typically atrioventricular septal defect
        (AVSD) occurs in about a third of patients.
      explanation: >-
        Describes congenital heart disease in about a third of reported patients and names AVSD
        as a typical lesion. The proportion concerns all CHD, not an AVSD-specific frequency.
- name: Deletion Including the VHL Locus
  role: mechanism
  biological_scale: MOLECULAR
  genes:
  - preferred_term: VHL
    term:
      id: hgnc:12687
      label: VHL
  description: >-
    Some distal 3p deletions extend through the VHL locus at 3p25. A clinical report associates
    such a deletion with cerebellar hemangioblastoma. The cited case does not establish tumor
    second-hit status or a measured HIF pathway defect; those additional oncogenic steps are
    not asserted here.
  evidence:
  - reference: PMID:26365017
    reference_title: A case of 3p deletion syndrome associated with cerebellar hemangioblastoma.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We identified de novo 3p deletion encompassing p25 by using array-based comparative
      genomic hybridization, where causative gene of von Hippel-Lindau (VHL) disease located.
    explanation: >-
      Array-CGH demonstrated a deletion extending through the 3p25 region containing VHL in
      this affected individual.
  downstream:
  - target: Cerebellar hemangioblastoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The VHL-containing deletion provides a proposed tumor-predisposition explanation. Penetrance
      and tumor-specific molecular intermediates were not established in this case.
    evidence:
    - reference: PMID:26365017
      reference_title: A case of 3p deletion syndrome associated with cerebellar hemangioblastoma.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        This is the first case report of a patient with 3p deletion syndrome whose cerebellar
        hemangioblastoma may be associated with VHL disease.
      explanation: >-
        The authors propose a VHL-related explanation for this tumor. The case does not demonstrate
        a tumor-specific second hit or quantify penetrance.
phenotypes:
- name: Intellectual disability
  category: Neurological
  description: >-
    A characteristic but variably expressed manifestation. Severity ranges from learning difficulties
    to severe impairment. Clinically unaffected carriers, including relatives with the same
    multimegabase deletion as an affected individual, preclude treating intellectual disability
    as invariant.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:19760623
    reference_title: "Microarray based analysis of 3p25-p26 deletions (3p- syndrome)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Distal deletion of chromosome 3p25-pter (3p- syndrome) produces a distinct
      clinical syndrome characterized by low birth weight, mental retardation,
      telecanthus, ptosis, and micrognathia.
    explanation: >-
      Lists the cognitive impairment among the defining features of the syndrome.
- name: Global developmental delay
  category: Neurological
  description: >-
    Delay can affect motor, language and social development. Published deletion cases are
    often recognized in infancy, but age and severity vary.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:33643973
    reference_title: "Case Report: A Case Report and Literature Review of 3p Deletion Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 29 well-documented cases were found in the literature, of which
      19 cases had an onset within 1 year of birth, and mainly manifested with
      mental and motor development disabilities and abnormal facial features,
      with different gene deletions, depending on the size and location of the 3p
      deletion.
    explanation: >-
      The literature summary establishes early developmental presentations. Its stated case
      count differs from Table 3, which includes the index patient among 29 columns; no disease-level
      frequency is inferred.
    quote_role: REVIEW_SYNTHESIS
- name: Generalized hypotonia
  category: Neurological
  description: >-
    Reduced muscle tone, including hypotonia in all four extremities documented in a child
    with a 10.095 Mb deletion.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:33643973
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had hypotonia in the four extremities and uncooperative muscle strength.
    explanation: >-
      Direct examination documents hypotonia in all four extremities, supporting the generalized
      binding.
    reference_title: >-
      Case Report: A Case Report and Literature Review of 3p Deletion Syndrome.
- name: Small for gestational age
  category: Growth
  description: >-
    A term infant with a cytogenetically identified 3p26 deletion had birth weight reported
    at the eighth percentile. Earlier syndrome descriptions also report low birth weight,
    but that phrase alone does not establish gestational-age-adjusted growth restriction in
    every case.
  phenotype_term:
    preferred_term: Small for gestational age
    term:
      id: HP:0001518
      label: Small for gestational age
  evidence:
  - reference: PMID:39841745
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was delivered via cesarean section at 38 weeks and 6 days of gestational
      age, with birthweight 2842 kg (P8th), height 42 cm (<P0,4th), and cephalic perimeter
      measured 34 cm (P45th).
    explanation: >-
      The gestational age and eighth weight percentile support small-for-gestational-age status.
      The printed weight unit, “2842 kg”, is an apparent source typographical error; the annotation
      relies on the stated percentile.
    reference_title: >-
      First report of hypoplastic left heart syndrome in 3p- syndrome and review of candidate
      genes.
- name: Postnatal growth retardation
  category: Growth
  description: >-
    Postnatal growth impairment is reported. All four deletion carriers in one SETD5-focused
    series developed short stature, including individuals with normal birth measurements.
  phenotype_term:
    preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  evidence:
  - reference: PMID:25138099
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, all four microdeletion carriers developed short stature and three of them also
      developed microcephaly during the first year of life.
    explanation: >-
      Longitudinal observations distinguish postnatal growth restriction from low birth size;
      the four-patient series does not supply a syndrome-wide frequency.
    reference_title: >-
      Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype
      of microdeletion 3p25.3 syndrome.
- name: Microcephaly
  category: Craniofacial
  description: >-
    Reduced head circumference can emerge postnatally. Three of four deletion carriers in
    a SETD5-focused series developed microcephaly during the first year; it is not obligatory
    across deletion intervals.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:25138099
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, all four microdeletion carriers developed short stature and three of them also
      developed microcephaly during the first year of life.
    explanation: >-
      Longitudinal observations distinguish postnatal growth restriction from low birth size;
      the four-patient series does not supply a syndrome-wide frequency.
    reference_title: >-
      Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype
      of microdeletion 3p25.3 syndrome.
- name: Ptosis
  category: Craniofacial
  description: >-
    Drooping of the upper eyelids is a characteristic craniofacial finding. Human genotype
    comparisons particularly implicate BRPF1 loss when that gene is encompassed by the deletion.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:19760623
    reference_title: "Microarray based analysis of 3p25-p26 deletions (3p- syndrome)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Distal deletion of chromosome 3p25-pter (3p- syndrome) produces a distinct
      clinical syndrome characterized by low birth weight, mental retardation,
      telecanthus, ptosis, and micrognathia.
    explanation: >-
      Lists ptosis among the five features that define the clinical syndrome.
  - reference: PMID:27939639
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome
      but that some specific features, such as ptosis and blepharophimosis, are mostly driven
      by BRPF1 haploinsufficiency.
    explanation: >-
      Human comparison supports contributions from both genes, particularly BRPF1-associated
      eyelid features.
    reference_title: >-
      Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual
      Disability with Associated Ptosis.
- name: Telecanthus
  category: Craniofacial
  description: >-
    Increased distance between the inner canthi, part of the classic facial
    gestalt.
  phenotype_term:
    preferred_term: Telecanthus
    term:
      id: HP:0000506
      label: Telecanthus
  evidence:
  - reference: PMID:39841745
    reference_title: "First report of hypoplastic left heart syndrome in 3p- syndrome and review of candidate genes."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It produces a distinct clinical syndrome characterized by hypotonia, low
      birth weight, delayed neurological and motor development (crawling and
      walking), speech delay, intellectual impairment, telecanthus, craniofacial
      dysmorphia (microcephaly, micrognathia, and ptosis), and congenital heart
      defects (CHDs).
    explanation: >-
      Names telecanthus among the characteristic features.
- name: Micrognathia
  category: Craniofacial
  description: >-
    Small mandible, described from the earliest delineations of the syndrome
    onward.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:19760623
    reference_title: "Microarray based analysis of 3p25-p26 deletions (3p- syndrome)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Distal deletion of chromosome 3p25-pter (3p- syndrome) produces a distinct
      clinical syndrome characterized by low birth weight, mental retardation,
      telecanthus, ptosis, and micrognathia.
    explanation: >-
      Lists micrognathia among the defining features.
- name: Long philtrum
  category: Craniofacial
  description: >-
    An elongated philtrum, reported in the classic karyotype-phenotype series of
    patients with the 3p25.3 deletion.
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: PMID:2178418
    reference_title: >-
      Loss of the 3p25.3 band is critical in the manifestation of del(3p)
      syndrome: karyotype-phenotype correlation in cases with deficiency of the
      distal portion of the short arm of chromosome 3.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The former patient showed characteristic clinical manifestations of the
      3p- syndrome, including growth failure, mental retardation, microcephaly
      with a flat occiput, triangular face, synophrys, blepharoptosis,
      hypertelorism, broad and flat nose, long philtrum, down-turned mouth,
      micrognathia, apparently lowset and malformed ears, fingers abnormalities,
      and deafness.
    explanation: >-
      A full clinical description of a patient with the characteristic
      manifestations, including the long philtrum.
- name: Depressed nasal bridge
  category: Craniofacial
  description: >-
    A flattened nasal bridge, listed in the original del(3pter-p25) delineation
    among the features characteristic of the syndrome.
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:3443553
    reference_title: "Terminal deletion of the short arm of chromosome 3, del(3pter-p25): a recognizable syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Features present in the patient and characteristic of the 3p- syndrome
      included low birthweight, brachy-trigonocephaly, a high and narrow forehead
      with a prominent metopic suture, epicanthic folds, upslanting palpebral
      fissures, ptosis, depressed nasal bridge, anteverted nares and a small
      mandible.
    explanation: >-
      The original syndrome delineation listing the depressed nasal bridge as
      characteristic.
- name: Trigonocephaly
  category: Craniofacial
  description: >-
    A triangular forehead from metopic ridging, reported in the original
    del(3pter-p25) delineation as brachy-trigonocephaly with a prominent metopic
    suture.
  phenotype_term:
    preferred_term: Trigonocephaly
    term:
      id: HP:0000243
      label: Trigonocephaly
  evidence:
  - reference: PMID:3443553
    reference_title: "Terminal deletion of the short arm of chromosome 3, del(3pter-p25): a recognizable syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Features present in the patient and characteristic of the 3p- syndrome
      included low birthweight, brachy-trigonocephaly, a high and narrow forehead
      with a prominent metopic suture, epicanthic folds, upslanting palpebral
      fissures, ptosis, depressed nasal bridge, anteverted nares and a small
      mandible.
    explanation: >-
      Records brachy-trigonocephaly and the prominent metopic suture as
      characteristic of the syndrome.
  notes: >-
    The Perplexity report offered HP:0000263 for this phenotype. HPO calls that
    term Oxycephaly, a different skull shape; the correct term is HP:0000243 and
    was resolved with OAK.
- name: Atrioventricular septal defect
  category: Cardiovascular
  description: >-
    Atrioventricular septal defects are a reported component of the cardiac spectrum. The
    approximately one-third estimate in the mapping study refers to all congenital heart disease,
    not specifically to this lesion.
  phenotype_term:
    preferred_term: Atrioventricular septal defect
    term:
      id: HP:0006695
      label: Atrioventricular canal defect
  evidence:
  - reference: PMID:19760623
    reference_title: "Microarray based analysis of 3p25-p26 deletions (3p- syndrome)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital heart disease (CHD), typically atrioventricular septal defect
      (AVSD) occurs in about a third of patients.
    explanation: >-
      The source names AVSD as a typical cardiac lesion. Its one-third estimate applies to
      congenital heart disease overall and is not used as an AVSD frequency.
- name: Postaxial polydactyly
  category: Skeletal
  description: >-
    Postaxial extra digits are variably present. An early report described the finding in
    about half of roughly a dozen published cases; two of four deletion carriers in a later
    SETD5-focused series had postaxial hexadactyly of the hands. Neither sample estimates
    population frequency.
  phenotype_term:
    preferred_term: Postaxial polydactyly
    term:
      id: HP:0100259
      label: Postaxial polydactyly
  evidence:
  - reference: PMID:3443553
    reference_title: "Terminal deletion of the short arm of chromosome 3, del(3pter-p25): a recognizable syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She lacked postaxial polydactyly of fingers and toes which is present in
      about half of the so far reported about one dozen 3p- cases
    explanation: >-
      Gives the frequency in the early case series while recording a patient
      without it, which is the variable presence this phenotype records.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:25138099
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, two microdeletion patients presented with postaxial hexadactyly of the hands.
    explanation: >-
      Observed in two deletion carriers in this small series.
    reference_title: >-
      Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype
      of microdeletion 3p25.3 syndrome.
- name: Hearing impairment
  category: Sensory
  description: >-
    Deafness or lesser hearing loss, reported in patients with the full
    manifestation of the deletion.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:2178418
    reference_title: >-
      Loss of the 3p25.3 band is critical in the manifestation of del(3p)
      syndrome: karyotype-phenotype correlation in cases with deficiency of the
      distal portion of the short arm of chromosome 3.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The former patient showed characteristic clinical manifestations of the
      3p- syndrome, including growth failure, mental retardation, microcephaly
      with a flat occiput, triangular face, synophrys, blepharoptosis,
      hypertelorism, broad and flat nose, long philtrum, down-turned mouth,
      micrognathia, apparently lowset and malformed ears, fingers abnormalities,
      and deafness.
    explanation: >-
      Lists deafness among the characteristic manifestations in a patient with
      the classic 3p25.3 deletion.
- name: Autistic behavior
  category: Behavioral
  description: >-
    Autism or autism-associated behaviors occur in some deletion carriers. The contribution
    of individual genes and other genetic background remains uncertain.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:33519384
    reference_title: >-
      Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated
      in 3p-Deletion Syndrome and Autism Spectrum Disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deletions occurring at chromosome 3p result in 3p-deletion syndrome
      (Del3p), a rare genetic disorder characterized by developmental delay,
      intellectual disability, facial dysmorphisms and often, ASD or
      ASD-associated behaviors.
    explanation: >-
      The review describes ASD-associated behaviors among reported deletion phenotypes; no
      quantitative frequency is assigned.
    quote_role: REVIEW_SYNTHESIS
- name: Strabismus
  category: Ophthalmologic
  description: >-
    Ocular misalignment, reported alongside the facial anomalies in a patient
    whose deletion was confined to the 3p25.3-p26.1 interval.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:22965684
    reference_title: >-
      Interstitial 3p25.3-p26.1 deletion in a patient with intellectual
      disability.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on a 3-year-old girl with intellectual disability, muscular
      hypotonia, strabismus, and facial anomalies in whom an interstitial 1.24 Mb
      deletion in 3p25.3-p26.1 was detected by SNP array analysis.
    explanation: >-
      Records strabismus in a molecularly characterised patient with a deletion
      inside the critical interval.
- name: Low-set ears
  category: Craniofacial
  description: >-
    Low ear position has been reported alongside other craniofacial findings.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:33643973
    reference_title: "Case Report: A Case Report and Literature Review of 3p Deletion Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the main clinical phenotypes of the disease have been identified as
      follows: delayed growth and development, intellectual disability,
      hypotonia, micrognathia, ptosis, wide nose bridge, long philtrum, low ear
      position, deformed ears, polydactyly deformity, hearing abnormalities,
      CHD, renal abnormalities, syndactylism, gastrointestinal abnormalities,
      and scoliosis
    explanation: >-
      Names low ear position among the main clinical phenotypes established for
      the syndrome across a 29-case literature review.
  - reference: PMID:2178418
    reference_title: >-
      Loss of the 3p25.3 band is critical in the manifestation of del(3p)
      syndrome: karyotype-phenotype correlation in cases with deficiency of the
      distal portion of the short arm of chromosome 3.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The former patient showed characteristic clinical manifestations of the
      3p- syndrome, including growth failure, mental retardation, microcephaly
      with a flat occiput, triangular face, synophrys, blepharoptosis,
      hypertelorism, broad and flat nose, long philtrum, down-turned mouth,
      micrognathia, apparently lowset and malformed ears, fingers abnormalities,
      and deafness.
    explanation: >-
      Records lowset ears in a patient with the classic 3p25.3 deletion.
- name: Abnormal pinna morphology
  category: Craniofacial
  description: >-
    Malformation of the external ear, reported both as bilaterally deformed
    pinnae in the classic karyotype-phenotype series and as a unilateral
    auricular deformity in a molecularly characterised 3p26.3-p25.3 case.
  phenotype_term:
    preferred_term: Abnormal pinna morphology
    term:
      id: HP:0000377
      label: Abnormal pinna morphology
  evidence:
  - reference: PMID:33643973
    reference_title: "Case Report: A Case Report and Literature Review of 3p Deletion Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical phenotype of this syndrome is complex as it can include
      intellectual and motor development backwardness, low muscle tone, certain
      abnormal facial features (low hairline, bilateral ptosis, widely spaced
      eyes, a forward nose, left ear auricle deformity, a high-arched palate, a
      small jaw), and the deformation of systems such as the gastrointestinal
      tract and the urinary tract malformation or symptoms of epilepsy
    explanation: >-
      Records an auricular deformity among the facial features of a patient with
      a molecularly confirmed 3p26.3-p25.3 deletion.
- name: Abnormality of the kidney
  category: Renal
  description: >-
    Renal malformations are reported in syndrome summaries without a specific lesion in the
    cited passage.
  phenotype_term:
    preferred_term: Renal malformation
    term:
      id: HP:0000077
      label: Abnormality of the kidney
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:33643973
    reference_title: "Case Report: A Case Report and Literature Review of 3p Deletion Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      3p deletion syndrome is a rare autosomal and contiguous genomic disorder
      characterized by the following: intellectual disability; motor
      developmental delay; unusual facial features (microcephaly, micrognathia,
      ptosis, long philtrum, low and deformed ears, polydactyly deformity);
      hypotonia; and other rarer symptoms, including congenital heart disease
      (CHD), renal and gastrointestinal malformations, autism, congenital
      hypothyroidism, epilepsy, and tumors
    explanation: >-
      Names renal malformation among the less commonly reported features. This qualitative
      wording does not establish a numerical frequency range.
    quote_role: REVIEW_SYNTHESIS
- name: Abnormality of the gastrointestinal tract
  category: Gastrointestinal
  description: >-
    Gastrointestinal malformations are reported in syndrome summaries. The cited broad statement
    does not identify a particular lesion or establish SEC13 causality.
  phenotype_term:
    preferred_term: Gastrointestinal malformation
    term:
      id: HP:0011024
      label: Abnormality of the gastrointestinal tract
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:33643973
    reference_title: "Case Report: A Case Report and Literature Review of 3p Deletion Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical phenotype of this syndrome is complex as it can include
      intellectual and motor development backwardness, low muscle tone, certain
      abnormal facial features (low hairline, bilateral ptosis, widely spaced
      eyes, a forward nose, left ear auricle deformity, a high-arched palate, a
      small jaw), and the deformation of systems such as the gastrointestinal
      tract and the urinary tract malformation or symptoms of epilepsy
    explanation: >-
      States gastrointestinal deformation as part of the clinical phenotype of
      the syndrome.
    quote_role: REVIEW_SYNTHESIS
- name: Seizure
  category: Neurological
  description: >-
    Clinical seizures have been reported in deletion carriers. Two of four individuals with
    microdeletions in a SETD5-focused series had a seizure history. EEG abnormalities alone
    in another case are not treated as clinical seizures.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:25138099
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, all four microdeletion carriers presented with muscular hypotonia and two
      of them had a history of seizures.
    explanation: >-
      The series directly reports clinical seizure histories in two deletion carriers.
    reference_title: >-
      Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype
      of microdeletion 3p25.3 syndrome.
- name: Preauricular pit
  category: Craniofacial
  description: >-
    Reported as a possible accompaniment of the poorly shaped ears in the
    distal 3p deletion phenotype. The source hedges its presence, so this is
    recorded as a reported feature rather than an established one.
  phenotype_term:
    preferred_term: Preauricular pit
    term:
      id: HP:0004467
      label: Preauricular pit
  evidence:
  - reference: PMID:31428485
    reference_title: >-
      Chromosome 3p Inverted Duplication with Terminal Deletion: Second
      Postnatal Case Report with Additional Clinical Features.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      low set/poorly shaped ears (possibly with preauricular pits/fistulas),
      postaxial polydactyly, congenital heart defects, renal malformations,
      gastric malformations, hypotonia, and mental and psychomotor delays
    explanation: >-
      The passage summarizes pure distal 3p deletions. The paper’s own inverted-duplication/terminal-deletion
      case is a different rearrangement and does not supply this annotation.
    quote_role: REVIEW_SYNTHESIS
- name: Congenital heart defect
  category: Cardiovascular
  description: >-
    The cardiac spectrum includes atrioventricular septal defects, ventricular septal defects
    and a reported hypoplastic left heart presentation. Lesion type and severity vary.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:19760623
    reference_title: "Microarray based analysis of 3p25-p26 deletions (3p- syndrome)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital heart disease (CHD), typically atrioventricular septal defect
      (AVSD) occurs in about a third of patients.
    explanation: >-
      The source directly describes congenital heart disease. Its estimate is not transferred
      to individual cardiac subtypes.
- name: Ventricular septal defect
  category: Cardiovascular
  description: >-
    A perimembranous ventricular septal defect was documented in a child with a molecularly
    defined 10.095 Mb deletion.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:33643973
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A colored ultrasonography of the heart revealed a congenital heart defect (CHD), namely
      a ventricular septal defect (peri-membranous) of ~3 mm in size and a left to right shunt
      at the ventricular level.
    explanation: >-
      Direct cardiac imaging in the index deletion case.
    reference_title: >-
      Case Report: A Case Report and Literature Review of 3p Deletion Syndrome.
- name: Hypoplastic left ventricle
  category: Cardiovascular
  description: >-
    Reported in an infant with hypoplastic left heart syndrome, mitral and aortic atresia,
    and a cytogenetic 3p26 deletion. Molecular breakpoint mapping was not performed; this
    case does not establish loss of a specific cardiac candidate gene.
  phenotype_term:
    preferred_term: Hypoplastic left ventricle
    term:
      id: HP:0004383
      label: Hypoplastic left ventricle
  evidence:
  - reference: PMID:39841745
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An echocardiogram performed after birth confirmed a diagnosis of HLHS, with mitral and
      aortic valve atresia and a ventricular septal defect.
    explanation: >-
      Postnatal echocardiography documents the left-heart phenotype in this infant.
    reference_title: >-
      First report of hypoplastic left heart syndrome in 3p- syndrome and review of candidate
      genes.
- name: Blepharophimosis
  category: Ophthalmologic
  description: >-
    Narrow palpebral fissures occur particularly in BRPF1-containing deletions, supported
    by a comparison with SETD5-only and BRPF1-only disorders.
  phenotype_term:
    preferred_term: Blepharophimosis
    term:
      id: HP:0000581
      label: Blepharophimosis
  evidence:
  - reference: PMID:27939639
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome
      but that some specific features, such as ptosis and blepharophimosis, are mostly driven
      by BRPF1 haploinsufficiency.
    explanation: >-
      Human comparison supports contributions from both genes, particularly BRPF1-associated
      eyelid features.
    reference_title: >-
      Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual
      Disability with Associated Ptosis.
- name: Cleft palate
  category: Craniofacial
  description: >-
    Cleft palate is reported in the literature on small 3p25 deletions. It is distinct from
    the high-arched palate observed in another case.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:24680889
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence of congenital heart

      disease and cleft palate is a more variable feature.
    explanation: >-
      This full-text passage summarizes previously reported deletion cases, rather than the
      paper’s intragenic SETD5 cohort.
    quote_role: REVIEW_SYNTHESIS
    reference_title: >-
      De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25
      microdeletion syndrome critical region, cause intellectual disability.
- name: High palate
  category: Craniofacial
  description: >-
    A high-arched palate was documented in the child with a 10.095 Mb 3p26.3-p25.3 deletion.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:33643973
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had a broad nose bridge, forward nostrils, a deformity of the left auricle,
      a long philtrum, a high-arched palate, and micrognathia (as shown in Figure 1).
    explanation: >-
      Direct physical examination of a molecularly characterized deletion case.
    reference_title: >-
      Case Report: A Case Report and Literature Review of 3p Deletion Syndrome.
- name: Gastroesophageal reflux
  category: Gastrointestinal
  description: >-
    Persistent vomiting led to an imaging-based diagnosis of gastroesophageal reflux in a
    deletion case.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:33643973
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A gastrointestinal angiography was performed, which led to the diagnosis of gastroesophageal
      reflux.
    explanation: >-
      This is a specific clinical diagnosis, despite the source table coding the index case
      as negative for gastrointestinal abnormalities.
    reference_title: >-
      Case Report: A Case Report and Literature Review of 3p Deletion Syndrome.
- name: Short stature
  category: Growth
  description: >-
    Postnatal short stature was observed in all four deletion carriers in a small SETD5-focused
    series, without implying universality across distal 3p deletions.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:25138099
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, all four microdeletion carriers developed short stature and three of them also
      developed microcephaly during the first year of life.
    explanation: >-
      Longitudinal observations distinguish postnatal growth restriction from low birth size;
      the four-patient series does not supply a syndrome-wide frequency.
    reference_title: >-
      Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype
      of microdeletion 3p25.3 syndrome.
- name: Delayed speech and language development
  category: Neurological
  description: >-
    Speech impairment can be substantial. A small comparison of five BRPF1/SETD5 co-deleted
    individuals reported absent language at assessment; severity varied in other deletion
    and single-gene groups.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:27939639
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals from group 3 acquired walking after 3 years of age (5/5 for group 3
      versus 2/19 for groups 1 and 2, p value = 0.0005) and presently have no language (5/5
      for group 3 versus 1/19 for groups 1 and 2, p value = 0.0001) (Table 3), suggesting
      that disruption of both BRPF1 and SETD5 contributes to the phenotype of 3p25 deletion
      syndrome.
    explanation: >-
      The comparison is five co-deleted individuals versus single-gene groups; it is not a
      population frequency estimate.
    reference_title: >-
      Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual
      Disability with Associated Ptosis.
- name: Brachycephaly
  category: Craniofacial
  description: >-
    Reported in the original clinical delineation of a terminal 3p deletion.
  phenotype_term:
    preferred_term: Brachycephaly
    term:
      id: HP:0000248
      label: Brachycephaly
  evidence:
  - reference: PMID:3443553
    reference_title: "Terminal deletion of the short arm of chromosome 3, del(3pter-p25): a recognizable syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Features present in the patient and characteristic of the 3p- syndrome
      included low birthweight, brachy-trigonocephaly, a high and narrow forehead
      with a prominent metopic suture, epicanthic folds, upslanting palpebral
      fissures, ptosis, depressed nasal bridge, anteverted nares and a small
      mandible.
    explanation: >-
      The source directly describes this feature in its terminal-deletion case.
- name: Epicanthus
  category: Craniofacial
  description: >-
    Reported in the original clinical delineation of a terminal 3p deletion.
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: PMID:3443553
    reference_title: "Terminal deletion of the short arm of chromosome 3, del(3pter-p25): a recognizable syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Features present in the patient and characteristic of the 3p- syndrome
      included low birthweight, brachy-trigonocephaly, a high and narrow forehead
      with a prominent metopic suture, epicanthic folds, upslanting palpebral
      fissures, ptosis, depressed nasal bridge, anteverted nares and a small
      mandible.
    explanation: >-
      The source directly describes this feature in its terminal-deletion case.
- name: Anteverted nares
  category: Craniofacial
  description: >-
    Reported in the original clinical delineation of a terminal 3p deletion.
  phenotype_term:
    preferred_term: Anteverted nares
    term:
      id: HP:0000463
      label: Anteverted nares
  evidence:
  - reference: PMID:3443553
    reference_title: "Terminal deletion of the short arm of chromosome 3, del(3pter-p25): a recognizable syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Features present in the patient and characteristic of the 3p- syndrome
      included low birthweight, brachy-trigonocephaly, a high and narrow forehead
      with a prominent metopic suture, epicanthic folds, upslanting palpebral
      fissures, ptosis, depressed nasal bridge, anteverted nares and a small
      mandible.
    explanation: >-
      The source directly describes this feature in its terminal-deletion case.
- name: Downturned corners of mouth
  category: Craniofacial
  description: >-
    Documented among craniofacial findings in a clinically affected patient in a karyotype–phenotype
    study.
  phenotype_term:
    preferred_term: Downturned corners of mouth
    term:
      id: HP:0002714
      label: Downturned corners of mouth
  evidence:
  - reference: PMID:2178418
    reference_title: >-
      Loss of the 3p25.3 band is critical in the manifestation of del(3p)
      syndrome: karyotype-phenotype correlation in cases with deficiency of the
      distal portion of the short arm of chromosome 3.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The former patient showed characteristic clinical manifestations of the
      3p- syndrome, including growth failure, mental retardation, microcephaly
      with a flat occiput, triangular face, synophrys, blepharoptosis,
      hypertelorism, broad and flat nose, long philtrum, down-turned mouth,
      micrognathia, apparently lowset and malformed ears, fingers abnormalities,
      and deafness.
    explanation: >-
      This feature is directly named in the clinical description of a patient with a 3p deletion.
- name: Flat occiput
  category: Craniofacial
  description: >-
    Documented among craniofacial findings in a clinically affected patient in a karyotype–phenotype
    study.
  phenotype_term:
    preferred_term: Flat occiput
    term:
      id: HP:0005469
      label: Flat occiput
  evidence:
  - reference: PMID:2178418
    reference_title: >-
      Loss of the 3p25.3 band is critical in the manifestation of del(3p)
      syndrome: karyotype-phenotype correlation in cases with deficiency of the
      distal portion of the short arm of chromosome 3.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The former patient showed characteristic clinical manifestations of the
      3p- syndrome, including growth failure, mental retardation, microcephaly
      with a flat occiput, triangular face, synophrys, blepharoptosis,
      hypertelorism, broad and flat nose, long philtrum, down-turned mouth,
      micrognathia, apparently lowset and malformed ears, fingers abnormalities,
      and deafness.
    explanation: >-
      This feature is directly named in the clinical description of a patient with a 3p deletion.
- name: Hypertelorism
  category: Craniofacial
  description: >-
    Documented among craniofacial findings in a clinically affected patient in a karyotype–phenotype
    study.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:2178418
    reference_title: >-
      Loss of the 3p25.3 band is critical in the manifestation of del(3p)
      syndrome: karyotype-phenotype correlation in cases with deficiency of the
      distal portion of the short arm of chromosome 3.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The former patient showed characteristic clinical manifestations of the
      3p- syndrome, including growth failure, mental retardation, microcephaly
      with a flat occiput, triangular face, synophrys, blepharoptosis,
      hypertelorism, broad and flat nose, long philtrum, down-turned mouth,
      micrognathia, apparently lowset and malformed ears, fingers abnormalities,
      and deafness.
    explanation: >-
      This feature is directly named in the clinical description of a patient with a 3p deletion.
- name: Scoliosis
  category: Skeletal
  description: >-
    Reported in the literature on small 3p25 deletions, including the prior deletion case
    summarized in the SETD5 comparative table.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:24680889
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      scoliosis, cleft palate, gastrointestinal

      anomalies, and seizures.
    explanation: >-
      The full-text review of previous deletion reports explicitly names scoliosis.
    quote_role: REVIEW_SYNTHESIS
    reference_title: >-
      De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25
      microdeletion syndrome critical region, cause intellectual disability.
- name: Obsessive-compulsive behavior
  category: Behavioral
  description: >-
    Obsessive-compulsive tendencies were reported in a girl with a 684 kb interstitial 3p25.3
    deletion.
  phenotype_term:
    preferred_term: Obsessive-compulsive behavior
    term:
      id: HP:0000722
      label: Compulsive behaviors
  evidence:
  - reference: PMID:23613140
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on an 11-year-old girl with intellectual disability, obsessive-compulsive
      tendencies, hypotonia, and dysmorphic facial features in whom a 684 kb interstitial
      3p25.3 deletion was characterized using array-CGH.
    explanation: >-
      Direct clinical observation in a molecularly characterized deletion case.
    reference_title: >-
      Deletion of 3p25.3 in a patient with intellectual disability and dysmorphic features
      with further definition of a critical region.
- name: Cystic hygroma
  category: Prenatal
  description: >-
    A cervical cystic hygroma was detected prenatally in the infant with hypoplastic left
    heart syndrome and a cytogenetic 3p26 deletion.
  phenotype_term:
    preferred_term: Cystic hygroma
    term:
      id: HP:0000476
      label: Cystic hygroma
  evidence:
  - reference: PMID:39841745
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prenatal ultrasound revealed a cervical cystic hygroma measuring 4.1 x 2.5 cm, and an
      echocardiogram indicated severe hypoplasia of the mitral and aortic valves, left ventricular
      hypoplasia, a small ventricular septal defect, and a hypoplastic aortic arch.
    explanation: >-
      Direct prenatal imaging observation in this case; molecular breakpoints remained unresolved.
    reference_title: >-
      First report of hypoplastic left heart syndrome in 3p- syndrome and review of candidate
      genes.
- name: Clinodactyly of the 5th finger
  category: Skeletal
  description: >-
    Bilateral fifth-finger clinodactyly was described in the neonatal 3p26-deletion case.
  phenotype_term:
    preferred_term: Clinodactyly of the 5th finger
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  evidence:
  - reference: PMID:39841745
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On dysmorphological examination, loose skin on the neck, a wide anterior fontanelle,
      a short nose, a micrognathia-like impression, clinodactyly of the fifth finger on both
      hands (indicative of medial phalangeal hypoplasia), and a second toe-like hallux in
      both feet were observed.
    explanation: >-
      The physical examination explicitly names bilateral fifth-finger clinodactyly.
    reference_title: >-
      First report of hypoplastic left heart syndrome in 3p- syndrome and review of candidate
      genes.
- name: Intestinal malrotation
  category: Gastrointestinal
  description: >-
    Bowel malrotation was reported in the prior 643 kb deletion case included in the SETD5
    comparative table.
  phenotype_term:
    preferred_term: Intestinal malrotation
    term:
      id: HP:0002566
      label: Intestinal malrotation
  evidence:
  - reference: PMID:25138099
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Others |  | Recurrent infections, constipation at younger age | Bifid uvula, oral frenula,
      hyperkeratosis, (kyphosis) | Cryptorchidism, complications of premature birth | − |
      Right helical pit, cutis marmorata | − | Cleft palate, bowel malrotation, scoliosis
      | − | Prominent lobes, right ear pit
    explanation: >-
      Table 1 lists these findings for the previously published Peltekova deletion case. The
      evidence is a literature-table summary rather than a new patient in this study.
    quote_role: REVIEW_SYNTHESIS
    reference_title: >-
      Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype
      of microdeletion 3p25.3 syndrome.
- name: Cerebellar hemangioblastoma
  category: Neoplastic
  description: >-
    A histologically confirmed cerebellar hemangioblastoma occurred at age 16 in a woman whose
    de novo 3p deletion encompassed the VHL locus. No other VHL-associated tumors were reported
    through age 24. Risk is not generalized to deletions that spare VHL, and no disease-wide
    frequency is assigned.
  phenotype_term:
    preferred_term: Cerebellar hemangioblastoma
    term:
      id: HP:0006880
      label: Cerebellar hemangioblastoma
  evidence:
  - reference: PMID:26365017
    reference_title: A case of 3p deletion syndrome associated with cerebellar hemangioblastoma.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We described clinical course of a 24-year-old woman with 3p deletion syndrome associated
      with cerebellar hemangioblastoma at the age of 16 years old.
    explanation: >-
      A specific cerebellar hemangioblastoma was observed at age 16 in this deletion carrier.
  - reference: PMID:26365017
    reference_title: A case of 3p deletion syndrome associated with cerebellar hemangioblastoma.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Surgical therapy for cerebellar hemangioblastoma was performed, and histological examination
      was consistent in cerebellar hemangioblastoma.
    explanation: >-
      Surgical treatment yielded histological confirmation. The report does not provide comparative
      efficacy or a standard operative technique.
genetic:
- name: SETD5
  notes: >-
    A causative contributor to the neurodevelopmental phenotype when deleted. A 2015 comparison
    refined a smallest overlap to 94 kb containing SETD5 and part of THUMPD3, superseding
    the earlier 124 kb overlap for that particular case set. SETD5 loss does not account for
    every feature of a multigene deletion.
  gene_term:
    preferred_term: SETD5
    term:
      id: hgnc:25566
      label: SETD5
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:24680889
    reference_title: >-
      De novo loss-of-function mutations in SETD5, encoding a methyltransferase
      in a 3p25 microdeletion syndrome critical region, cause intellectual
      disability.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individuals with SETD5 mutations showed phenotypic similarity to those
      previously reported with a deletion in 3p25, and thus loss of SETD5 might
      be sufficient to account for many of the clinical features observed in this
      condition.
    explanation: >-
      The comparison of intragenic variants against deletions that makes SETD5
      the principal driver, hedged by the authors as many of rather than all the
      features - which is why this entry keeps other loci.
  - reference: PMID:24680889
    reference_title: >-
      De novo loss-of-function mutations in SETD5, encoding a methyltransferase
      in a 3p25 microdeletion syndrome critical region, cause intellectual
      disability.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "SETD5 lies within the critical interval for 3p25 microdeletion syndrome."
    explanation: >-
      Places the gene inside the critical interval, which is what makes it a
      deletion-relevant gene rather than an unrelated ID gene.
  - reference: PMID:25138099
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The microdeletions of the four patients presented here further narrow down the smallest
      region of microdeletion overlap to 94 kb (chr3:9,422,487_9,516,586). It affects only
      two protein-coding RefSeq genes: SETD5 and parts of THUMPD3.
    explanation: >-
      Later overlap analysis narrows the region in a specific set of cases; it does not define
      a universal syndrome breakpoint.
    reference_title: >-
      Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype
      of microdeletion 3p25.3 syndrome.
- name: SRGAP3
  notes: >-
    A candidate neurodevelopmental contributor based on historical deletion mapping, a translocation-disruption
    case and functional GAP assays. These sources do not establish that SRGAP3 alone explains
    the cognitive phenotype of every deletion.
  gene_term:
    preferred_term: SRGAP3
    term:
      id: hgnc:19744
      label: SRGAP3
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:19760623
    reference_title: "Microarray based analysis of 3p25-p26 deletions (3p- syndrome)."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We suggest that current evidence suggests that SRGAP3 is the major
      determinant of mental retardation in distal 3p deletions.
    explanation: >-
      The authors propose SRGAP3 as a determinant; this is an attribution from mapping rather
      than proof of a general monogenic mechanism.
- name: CHL1
  notes: >-
    Terminal deletions can remove CHL1, CNTN6 and CNTN4 together or affect only part of this
    cluster. Human CNVs show variable expression and incomplete penetrance. The CHL1-only
    deletion family also carried an additional 696 kb maternal 1q44 duplication in both affected
    brothers, absent in their father; it is therefore not an isolated demonstration that CHL1
    loss caused their phenotype.
  gene_term:
    preferred_term: CHL1
    term:
      id: hgnc:1939
      label: CHL1
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:21457564
    reference_title: >-
      Microarray based analysis of an inherited terminal 3p26.3 deletion,
      containing only the CHL1 gene, from a normal father to his two affected
      children.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The deletion was transmitted from their normal father and included only the
      CHL1 gene.
    explanation: >-
      A CHL1-only deletion carried by an unaffected parent, which is why this
      gene is typed as a contributor rather than causative on its own.
  - reference: PMID:21457564
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among them, a maternally inherited 1q44 duplication of 696 Kbs is shared by the two
      brothers and absent in the father.
    explanation: >-
      The additional CNV limits attribution of the brothers’ clinical findings to the paternally
      inherited CHL1 deletion alone.
    reference_title: >-
      Microarray based analysis of an inherited terminal 3p26.3 deletion, containing only
      the CHL1 gene, from a normal father to his two affected children.
- name: CNTN4
  notes: >-
    At 3p26.3, adjacent to CHL1 and CNTN6. Proposed with CRBN as part of a
    minimal terminal interval sufficient for the syndrome, though that proposal
    is reported as a suggestion rather than a demonstration.
  gene_term:
    preferred_term: CNTN4
    term:
      id: hgnc:2174
      label: CNTN4
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:21457564
    reference_title: >-
      Microarray based analysis of an inherited terminal 3p26.3 deletion,
      containing only the CHL1 gene, from a normal father to his two affected
      children.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It was suggested that a 1,5 Mb minimal terminal deletion including the two
      genes CRBN and CNTN4 is sufficient to cause the syndrome.
    explanation: >-
      Marked INDIRECT because the authors report this as a prior suggestion they
      are testing, not as their own finding.
    quote_role: REVIEW_SYNTHESIS
- name: CNTN6
  notes: >-
    The third 3p26.3 neuronal IgCAM, between CHL1 and CNTN4. Experimental models support developmental
    functions; additive effects and compensation are context-dependent hypotheses for human
    deletion variability.
  gene_term:
    preferred_term: CNTN6
    term:
      id: hgnc:2176
      label: CNTN6
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:33519384
    reference_title: >-
      Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated
      in 3p-Deletion Syndrome and Autism Spectrum Disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: >-
      The 3p26.3 region contains three consecutive genes encoding closely related
      neuronal immunoglobulin cell adhesion molecules (IgCAMs): Close Homolog of
      L1 (CHL1), Contactin-6 (CNTN6), and Contactin-4 (CNTN4).
    explanation: >-
      Establishes CNTN6 as one of the three co-deleted genes in the terminal
      cytoband.
    quote_role: REVIEW_SYNTHESIS
- name: CRBN
  notes: >-
    Cereblon is at 3p26.2, proximal to the 3p26.3 adhesion-gene cluster. Its contribution
    to heterozygous multigene deletions is proposed; the cited review also notes a distinct
    autosomal recessive cognitive disorder. Map position and recessive disease do not establish
    a dominant deletion mechanism.
  gene_term:
    preferred_term: CRBN
    term:
      id: hgnc:30185
      label: CRBN
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:33519384
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Next to CNTN4 in 3p26.2, three genes are present that are often lost in larger terminal
      3p26.3 deletions: Interleukin 5 Receptor Subunit Alpha (IL5RA), Transfer RNA Nucleotidyl
      Transferase 1 (TRNT1), and Cereblon (CRBN). CRBN in particular has been associated with
      autosomal recessive non-syndromic cognitive disability (Bavley et al., 2018), and disruptions
      to this gene by CNVs may contribute to the cognitive impairments observed in individuals
      affected by Del3p.
    explanation: >-
      The review separates chromosomal position and a recessive association from a possible
      contribution to deletion phenotypes.
    quote_role: REVIEW_SYNTHESIS
    reference_title: >-
      Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated in 3p-Deletion
      Syndrome and Autism Spectrum Disorder.
- name: CAV3
  notes: >-
    An unconfirmed cardiac candidate discussed in deletion reports. CAV3 lies outside the
    approximately 200 kb interval refined under a complete-penetrance assumption. Its deletion
    was not demonstrated in the 2025 hypoplastic-left-heart case; a different CAV3-containing
    deletion had no heart defect. These observations neither establish causality nor exclude
    an incompletely penetrant contribution.
  gene_term:
    preferred_term: CAV3
    term:
      id: hgnc:1529
      label: CAV3
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:21082655
    reference_title: >-
      Molecular characterization and clinical features of a patient with an
      interstitial deletion of 3p25.3-p26.1.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Selected genes that are present in the hemizygous state and which might be
      important for the phenotype of this patient as regards the congenital heart
      defect, autistic behavior and mental retardation (CAV3, OXTR, and
      SRGAP3/MEGAP, respectively) are discussed in context of the clinical
      features.
    explanation: >-
      Marked INDIRECT because the authors present CAV3 as a gene that might be
      important, discussed as a candidate rather than demonstrated.
- name: BRPF1
  notes: >-
    Human intragenic variants, small deletions and comparative deletion data establish BRPF1
    as a contributor to intellectual disability and eyelid abnormalities. The contribution
    is conditional on deletion of BRPF1, and does not account for the entire multigene syndrome.
  gene_term:
    preferred_term: BRPF1
    term:
      id: hgnc:14255
      label: BRPF1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:27939639
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome
      but that some specific features, such as ptosis and blepharophimosis, are mostly driven
      by BRPF1 haploinsufficiency.
    explanation: >-
      Human comparison supports contributions from both genes, particularly BRPF1-associated
      eyelid features.
    reference_title: >-
      Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual
      Disability with Associated Ptosis.
- name: VHL
  gene_term:
    preferred_term: VHL
    term:
      id: hgnc:12687
      label: VHL
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    Tumor susceptibility is relevant when the distal 3p deletion extends through the VHL locus.
    A reported individual developed a histologically confirmed cerebellar hemangioblastoma
    at 16 years and had no other VHL-associated tumor reported by age 24. This is a genotype-qualified
    case association, not a tumor-frequency estimate for all 3p deletions.
  evidence:
  - reference: PMID:26365017
    reference_title: A case of 3p deletion syndrome associated with cerebellar hemangioblastoma.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We identified de novo 3p deletion encompassing p25 by using array-based comparative
      genomic hybridization, where causative gene of von Hippel-Lindau (VHL) disease located.
    explanation: >-
      Array-CGH demonstrated a deletion extending through the 3p25 region containing VHL in
      this affected individual.
  - reference: PMID:26365017
    reference_title: A case of 3p deletion syndrome associated with cerebellar hemangioblastoma.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      This is the first case report of a patient with 3p deletion syndrome whose cerebellar
      hemangioblastoma may be associated with VHL disease.
    explanation: >-
      The authors propose a VHL-related explanation for this tumor. The case does not demonstrate
      a tumor-specific second hit or quantify penetrance.
inheritance:
- name: Autosomal dominant, usually de novo
  description: >-
    Most reported deletions arise de novo, but familial transmission occurs with incomplete
    penetrance and variable expression. Gene content influences phenotype without fully predicting
    it: a mother and two children carried the same 7.4 Mb deletion, while only one child showed
    clinical features. Additional variants and age at evaluation complicate comparisons across
    families.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  evidence:
  - reference: PMID:25123480
    reference_title: >-
      A terminal 3p26.3 deletion is not associated with dysmorphic features and
      intellectual disability in a four-generation family.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      family members in four generations of this family are carrier of this 3p
      deletion and apparently healthy
    explanation: >-
      The abstract describes apparently healthy carriers across four generations, but also
      reports learning and speech problems and autism in one sister. It supports variable
      expression rather than uniform absence of manifestations.
  - reference: PMID:21457564
    reference_title: >-
      Microarray based analysis of an inherited terminal 3p26.3 deletion,
      containing only the CHL1 gene, from a normal father to his two affected
      children.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotype of individuals with deletions varies from normal to severe."
    explanation: >-
      States the expressivity range, supporting the VARIABLE value.
  - reference: PMID:33936696
    reference_title: "Familiar del3p syndrome: The uncertainty of the prognosis. A case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The few cases described are mainly de novo."
    explanation: >-
      The de novo predominance recorded in this block, which the other cited
      sources assume rather than state.
  - reference: PMID:33936696
    reference_title: "Familiar del3p syndrome: The uncertainty of the prognosis. A case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three members of the family had the 3p26.3-p26.1 deletion; however, only
      the son presented clinical features.
    explanation: >-
      A second, independent family in which the deletion segregates with only one
      affected carrier - non-penetrance shown in a different pedigree from the
      four-generation family cited above.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: RARE
  notes: >-
    The 2025 source describes fewer than 60 published cases. This historical literature count
    is not a population prevalence estimate. RARE records the source’s qualitative description,
    without converting the case count into a numerical prevalence band.
  evidence:
  - reference: PMID:39841745
    reference_title: "First report of hypoplastic left heart syndrome in 3p- syndrome and review of candidate genes."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Distal deletion of chromosome 3p25-pter (3p- syndrome) (OMIM  # 613792) is a
      rare monosomal disorder with fewer than 60 reported cases worldwide.
    explanation: >-
      The published case count, which is the only quantitative occurrence figure
      the sources provide.
    quote_role: REVIEW_SYNTHESIS
diagnosis:
- name: Chromosomal microarray
  description: >-
    Chromosomal microarray detects and delineates terminal or interstitial deletions and defines
    gene content. It can resolve submicroscopic deletions, but size and gene content do not
    by themselves predict individual severity.
  diagnosis_term:
    preferred_term: array comparative genomic hybridization
    term:
      id: NCIT:C18084
      label: Comparative Genomic Hybridization
  evidence:
  - reference: PMID:23613140
    reference_title: >-
      Deletion of 3p25.3 in a patient with intellectual disability and dysmorphic
      features with further definition of a critical region.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on an 11-year-old girl with intellectual disability,
      obsessive-compulsive tendencies, hypotonia, and dysmorphic facial features
      in whom a 684 kb interstitial 3p25.3 deletion was characterized using
      array-CGH.
    explanation: >-
      Array-CGH characterized a 684 kb interstitial deletion in a patient with developmental
      and behavioral findings.
- name: Karyotyping
  description: >-
    Historically the diagnostic test and still able to show large terminal
    deletions and complex rearrangements, but it can miss the deletion outright.
    The original delineation records exactly that failure, and the recent
    hypoplastic-left-heart case reached only a positional candidate gene because
    karyotype resolution could not place the breakpoint.
  diagnosis_term:
    preferred_term: Karyotyping
    term:
      id: NCIT:C16768
      label: Karyotyping
  evidence:
  - reference: PMID:3443553
    reference_title: "Terminal deletion of the short arm of chromosome 3, del(3pter-p25): a recognizable syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The deletion was overlooked at a first routine cytogenetic examination."
    explanation: >-
      A documented false-negative karyotype in a patient who had the syndrome,
      which is the limitation this entry records.
- name: Imaging Follow-up for VHL-Locus Deletions
  description: >-
    The cerebellar hemangioblastoma case prompted its authors to recommend repeat imaging.
    This is retained as case-based support for considering tumor surveillance when molecular
    testing shows involvement of the VHL locus; the report establishes neither an imaging
    schedule nor a surveillance benefit across all distal 3p deletions.
  diagnosis_term:
    preferred_term: repeat imaging for tumor surveillance
    term:
      id: NCIT:C16502
      label: Diagnostic Imaging Testing
  evidence:
  - reference: PMID:26365017
    reference_title: A case of 3p deletion syndrome associated with cerebellar hemangioblastoma.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Repeat imaging studies were recommended for the patients with 3p deletion syndrome.
    explanation: >-
      The source recommendation follows one tumor case. The entry limits its application to
      the relevant deletion context and does not infer a standard screening interval.
treatments:
- name: Developmental Rehabilitation
  description: >-
    Individualized developmental rehabilitation was reported for motor delay, including joint,
    head-control, kneeling and sitting exercises. Improvements were described after a short
    course and during subsequent follow-up, without a control group or proof of a sustained
    disease-modifying effect.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: comprehensive developmental rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: PMID:33643973
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The treatment the patient was given consisted of a comprehensive rehabilitation program,
      which included large joint loosening training, Brunstrom training, exercise system training,
      head control and climbing strength training, four-point kneeling and one knee kneeling,
      and sitting training. After more than 12 days of rehabilitation, the responses had improved,
      and the patient could turn over, clap his hands, chase people and objects, grasp objects,
      sit up for more than half an hour, and stand for around 3 min.
    explanation: >-
      The case describes the actual motor rehabilitation program and observed gains after
      more than 12 days; the uncontrolled observation does not establish comparative efficacy.
    reference_title: >-
      Case Report: A Case Report and Literature Review of 3p Deletion Syndrome.
  target_mechanisms:
  - target: Global developmental delay
    treatment_effect: MODULATES
    description: >-
      Rehabilitation addresses functional developmental limitations; reported improvement
      is an uncontrolled individual outcome.
    evidence:
    - reference: PMID:33643973
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The treatment the patient was given consisted of a comprehensive rehabilitation program,
        which included large joint loosening training, Brunstrom training, exercise system
        training, head control and climbing strength training, four-point kneeling and one
        knee kneeling, and sitting training. After more than 12 days of rehabilitation, the
        responses had improved, and the patient could turn over, clap his hands, chase people
        and objects, grasp objects, sit up for more than half an hour, and stand for around
        3 min.
      explanation: >-
        The case describes the actual motor rehabilitation program and observed gains after
        more than 12 days; the uncontrolled observation does not establish comparative efficacy.
      reference_title: >-
        Case Report: A Case Report and Literature Review of 3p Deletion Syndrome.
- name: Surgical Repair of Congenital Heart Defect
  description: >-
    Cardiac intervention is determined by the structural lesion and clinical condition. In
    the reported infant with hypoplastic left heart syndrome, surgery was performed at five
    days of age and the infant died at six days. This case documents treatment but does not
    establish a survival benefit or a syndrome-specific surgical standard.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: congenital cardiac surgical repair
    term:
      id: NCIT:C157806
      label: Cardiac Surgery
  evidence:
  - reference: PMID:39841745
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical intervention was performed when the patient was 5 days old.
    explanation: >-
      Direct report of surgery in the affected infant; the surrounding case history records
      death the following day.
    reference_title: >-
      First report of hypoplastic left heart syndrome in 3p- syndrome and review of candidate
      genes.
  notes: >-
    The cited report does not specify a named operation. No comparative surgical outcome estimate
    is inferred from this single case.
- name: Genetic Counseling
  description: >-
    Genetic counseling incorporates parental testing, deletion boundaries, variable expression
    and the possibility of apparently unaffected carriers. Familial reports show that prenatal
    imaging and an unaffected parent cannot determine a child’s eventual developmental outcome.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25123480
    reference_title: >-
      A terminal 3p26.3 deletion is not associated with dysmorphic features and
      intellectual disability in a four-generation family.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this report, we review the literature on terminal 3p deletions and
      discuss the importance of molecular testing and reporting of copy number
      variants to achieve accurate genetic counseling in prenatal and postnatal
      screening.
    explanation: >-
      The authors' own statement of why counselling and careful variant reporting
      matter for this deletion specifically.
  - reference: PMID:21457564
    reference_title: >-
      Microarray based analysis of an inherited terminal 3p26.3 deletion,
      containing only the CHL1 gene, from a normal father to his two affected
      children.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As already described for others recurrent syndromes with variable
      phenotype, these findings are challenging in genetic counselling because of
      an evident variable penetrance.
    explanation: >-
      Names variable penetrance as the specific counselling difficulty, which is
      what this treatment entry addresses.
  - reference: PMID:33936696
    reference_title: "Familiar del3p syndrome: The uncertainty of the prognosis. A case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No ultrasound anomalies were detected; therefore, after genetic
      counseling, the couple decided to continue the pregnancy and a
      phenotypically normal child was born.
    explanation: >-
      The case describes a family decision after counseling, not a measured counseling benefit
      or proof that prenatal findings reliably predict later development.
- name: Surgical Treatment of Cerebellar Hemangioblastoma
  therapeutic_modality: SURGERY
  description: >-
    Surgical therapy was reported for the cerebellar tumor in the VHL-locus deletion case,
    with histological confirmation. The cited abstract does not specify the operation or establish
    a general treatment-effect estimate for the deletion syndrome.
  treatment_term:
    preferred_term: surgical treatment of cerebellar hemangioblastoma
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:26365017
    reference_title: A case of 3p deletion syndrome associated with cerebellar hemangioblastoma.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Surgical therapy for cerebellar hemangioblastoma was performed, and histological examination
      was consistent in cerebellar hemangioblastoma.
    explanation: >-
      Surgical treatment yielded histological confirmation. The report does not provide comparative
      efficacy or a standard operative technique.
differential_diagnoses:
- name: SETD5 haploinsufficiency syndrome
  description: >-
    Intragenic SETD5 loss-of-function variants overlap the developmental and craniofacial
    phenotype of SETD5-containing deletions. Copy-number testing and sequence analysis distinguish
    the molecular diagnoses. Cardiac defects and polydactyly have also been reported with
    intragenic variants, so these findings do not uniquely identify a multigene deletion.
  disease_term:
    preferred_term: SETD5 haploinsufficiency syndrome
    term:
      id: MONDO:0014336
      label: intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency
  evidence:
  - reference: PMID:25138099
    reference_title: >-
      Loss-of-function variants of SETD5 cause intellectual disability and the
      core phenotype of microdeletion 3p25.3 syndrome.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All six patients presented with ID and certain facial dysmorphisms,
      suggesting that SETD5 sequence variants contribute substantially to the
      microdeletion 3p25.3 phenotype.
    explanation: >-
      Establishes that the single-gene disorder reproduces the core of the
      deletion phenotype, which is exactly why it is the leading differential.
  - reference: PMID:27375234
    reference_title: >-
      SETD5 loss-of-function mutation as a likely cause of a familial syndromic
      intellectual disability with variable phenotypic expression.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Loss-of-function de novo mutations in the SETD5 gene, encoding a putative
      methyltransferase, are an important cause of moderate/severe intellectual
      disability as evidenced by the results of sequencing large patient cohorts.
    explanation: >-
      Confirms the single-gene entity exists independently of any deletion, which
      is what makes it a differential rather than a synonym.
- name: BRPF1-related intellectual disability
  description: >-
    The other single-gene disorder inside the 3p25.3 interval. Historically most
    of the 3p25 deletion phenotype was attributed to SETD5 before BRPF1 was
    characterised, and ptosis and blepharophimosis in particular track with BRPF1
    loss. A contiguous deletion can remove both, so the question at the bedside
    is whether a microarray shows a deletion or sequencing shows an intragenic
    BRPF1 variant.
  evidence:
  - reference: PMID:27939639
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome
      but that some specific features, such as ptosis and blepharophimosis, are mostly driven
      by BRPF1 haploinsufficiency.
    explanation: >-
      Human comparison supports contributions from both genes, particularly BRPF1-associated
      eyelid features.
    reference_title: >-
      Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual
      Disability with Associated Ptosis.
- name: 3p25.3 microdeletion syndrome
  description: >-
    An overlapping ontology concept for 3p25.3 microdeletions, often interstitial and encompassing
    SETD5 and/or BRPF1. Breakpoint mapping describes overlap with the broader distal 3p deletion
    spectrum; this is not a mutually exclusive clinical alternative.
  disease_term:
    preferred_term: 3p25.3 microdeletion syndrome
    term:
      id: MONDO:0018564
      label: 3p25.3 microdeletion syndrome
- name: Unbalanced translocation producing 3p monosomy
  description: >-
    A 3p deletion can arise as one half of an unbalanced translocation carried by
    a parent, with a reciprocal gain elsewhere in the genome. The deletion
    phenotype is then overlaid on whatever the duplicated segment contributes, so
    features outside the 3p- picture should prompt a look at the other
    chromosome, and parental karyotyping changes the recurrence risk.
  evidence:
  - reference: PMID:34602958
    reference_title: >-
      Partial Trisomy 13q/Monosomy 3p Resulting from a Paternal Reciprocal
      3p;13q Translocation in a Boy with Facial Dysmorphism and Hypertrophic
      Cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A chromosomal imbalance with a partial trisomy 13q31.1q34 and monosomy
      3p26.3 of paternal origin were detected.
    explanation: >-
      A worked case of 3p monosomy arising as one half of an inherited unbalanced
      translocation, which is the mechanism this differential names.
discussions:
- discussion_id: del3p_gene_content_and_variable_expression
  kind: KNOWLEDGE_GAP
  prompt: >-
    How do gene content and genetic background jointly determine the variable phenotype of
    distal 3p deletions?
  rationale: >-
    Human sequence-variant and deletion comparisons support SETD5 and BRPF1 contributions.
    Small comparative cohorts suggest more severe developmental delay when both are lost,
    but assessments are heterogeneous. SRGAP3 and the distal adhesion genes remain additional
    candidates. Different outcomes among relatives with the same 7.4 Mb deletion show that
    deletion size alone is insufficient. The CHL1 family’s additional 1q44 duplication further
    limits single-gene attribution.
  attaches_to:
  - genetic#SETD5
  - genetic#BRPF1
  - genetic#SRGAP3
  - genetic#CHL1
  evidence:
  - reference: PMID:27939639
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals from group 3 acquired walking after 3 years of age (5/5 for group 3
      versus 2/19 for groups 1 and 2, p value = 0.0005) and presently have no language (5/5
      for group 3 versus 1/19 for groups 1 and 2, p value = 0.0001) (Table 3), suggesting
      that disruption of both BRPF1 and SETD5 contributes to the phenotype of 3p25 deletion
      syndrome.
    explanation: >-
      The comparison is five co-deleted individuals versus single-gene groups; it is not a
      population frequency estimate.
    reference_title: >-
      Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual
      Disability with Associated Ptosis.
  - reference: PMID:33936696
    reference_title: "Familiar del3p syndrome: The uncertainty of the prognosis. A case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three members of the family had the 3p26.3-p26.1 deletion; however, only
      the son presented clinical features.
    explanation: >-
      A second, independent family in which the deletion segregates with only one
      affected carrier - non-penetrance shown in a different pedigree from the
      four-generation family cited above.
  - reference: PMID:21457564
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among them, a maternally inherited 1q44 duplication of 696 Kbs is shared by the two
      brothers and absent in the father.
    explanation: >-
      The additional CNV limits attribution of the brothers’ clinical findings to the paternally
      inherited CHL1 deletion alone.
    reference_title: >-
      Microarray based analysis of an inherited terminal 3p26.3 deletion, containing only
      the CHL1 gene, from a normal father to his two affected children.
- discussion_id: del3p_igcam_context_dependent_mouse_findings
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Which IgCAM model findings explain human deletion phenotypes, and which depend on genotype,
    neural region or behavioral assay?
  rationale: >-
    The review’s abstract broadly describes weak mouse phenotypes, but its full text reports
    structural and behavioral abnormalities. Compound Chl1/Cntn6 heterozygotes already show
    enhanced dendritic misorientation. Cntn4 deficiency lacked ASD-related behavioral effects
    in one assay battery while enhancing Barnes-maze performance and acoustic startle. Compensation
    is a proposed explanation, not a demonstrated universal rescue. These results neither
    refute all neurite effects nor prove a human ASD mechanism.
  attaches_to:
  - pathophysiology#Abnormal Neurite Development
  evidence:
  - reference: PMID:33519384
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Notably, compound heterozygous mice for both Chl1 and Cntn6 display an additive deleterious
      phenotype – these compound heterozygous mice showed more severe misoriented dendrites
      compared to single heterozygous Chl1 or Cntn6 mice and wild-type littermates (Ye et
      al., 2008).
    explanation: >-
      The full review describes an existing compound mouse experiment with a structural endpoint;
      it is not evidence that all triple-deletion mechanisms have been tested.
    quote_role: REVIEW_SYNTHESIS
    reference_title: >-
      Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated in 3p-Deletion
      Syndrome and Autism Spectrum Disorder.
  - reference: PMID:33519384
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This study also included assessments for ASD-related behaviors such as the juvenile
      social interaction test, three-chamber social interaction test, novel object investigation
      task and the Barnes maze; however, Cntn4-deficiency was not observed to affect ASD-related
      behaviors (Molenhuis et al., 2016).
    explanation: >-
      A negative result confined to the named ASD-related behavioral assessments.
    quote_role: REVIEW_SYNTHESIS
    reference_title: >-
      Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated in 3p-Deletion
      Syndrome and Autism Spectrum Disorder.
  - reference: PMID:33519384
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, Cntn4-deficient mice do demonstrate enhanced spatial learning in the Barnes
      maze and a consistently increased startle response to auditory stimuli at high amplitudes
      (Molenhuis et al., 2016).
    explanation: >-
      Other behavioral endpoints changed in the same model; absence of an ASD-like phenotype
      is not absence of every phenotype.
    quote_role: REVIEW_SYNTHESIS
    reference_title: >-
      Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated in 3p-Deletion
      Syndrome and Autism Spectrum Disorder.
- discussion_id: del3p_unresolved_cardiac_gene
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which gene or combination of genes contributes to congenital heart disease in distal 3p
    deletions?
  rationale: >-
    The approximately 200 kb mapping interval assumed complete penetrance and excludes CAV3.
    CAV3 has separately been proposed in case reports, but the 2025 hypoplastic-left-heart
    case lacked molecular breakpoint mapping. A CAV3-containing deletion without a heart defect
    argues against fully penetrant sufficiency, not against every possible susceptibility
    effect. These limitations prevent gene-level prediction of a specific cardiac lesion.
  attaches_to:
  - pathophysiology#Disrupted Cardiac Development
  - genetic#CAV3
  evidence:
  - reference: PMID:19760623
    reference_title: "Microarray based analysis of 3p25-p26 deletions (3p- syndrome)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Assuming complete penetrance, a candidate critical region for a CHD
      susceptibility gene was refined to approximately 200 kb and a candidate
      critical region for mental retardation was mapped to an approximately 1
      Mb interval containing SRGAP3
    explanation: >-
      Maps the cardiac and neurodevelopmental critical regions separately,
      which is the direct basis for splitting these two branches.
  - reference: PMID:39841745
    reference_title: "First report of hypoplastic left heart syndrome in 3p- syndrome and review of candidate genes."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified an indirect relation between gene CAV3 and hypoplastic left
      heart syndrome due to its strong association with cardiomyopathies and
      isolated cardiac defects.
    explanation: >-
      The authors themselves call the relation indirect, which is the reason this
      is a knowledge gap rather than a curated gene-phenotype assertion.
  - reference: PMID:33643973
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      On the other hand, some known candidate genes, such as CAV3 and SEC13R, were shown to
      be outside the target interval.
    explanation: >-
      The full-text literature discussion explicitly places CAV3 and SEC13R outside the refined
      target interval.
    reference_title: >-
      Case Report: A Case Report and Literature Review of 3p Deletion Syndrome.
  - reference: PMID:39841745
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Unfortunately, the NB died before further examinations could be conducted and there
      was not enough biological material stored of her, preventing us from running additional
      and more complete genetic tests, such as microarray-based comparative genomic hybridization
      (CGH-Array).
    explanation: >-
      The infant died before additional testing; the authors explicitly state that molecular
      confirmation of the breakpoint was not available.
    reference_title: >-
      First report of hypoplastic left heart syndrome in 3p- syndrome and review of candidate
      genes.
notes: >-
  Scope: a multigene distal 3p deletion disorder encompassing terminal and overlapping interstitial
  presentations. Intragenic SETD5 and BRPF1 disorders remain separate entries. The deep-research
  report was used as a lead list; its incorrect HPO/CL labels, untraceable phenotype-frequency
  attribution and off-entity proximal-deletion and renal-cancer references were not imported.

  Full-text review: the 2015 SETD5 study supports a 94 kb overlap in its combined case comparison,
  engineered-cell nonsense-mediated decay and directly observed deletion phenotypes. The 2017
  BRPF1 paper supports human genotype–phenotype comparison, altered complex assembly and H3K23
  acetylation in transfected cells, with a non-significant patient-fibroblast result. The
  2018 SETD5 author manuscript clarifies Pol II redistribution, unchanged Hdac3 enzymatic
  activity, and the experimental model boundaries. The IgCAM review’s body and tables identify
  existing compound mouse experiments and endpoint-specific positive and negative findings
  that its abstract alone obscures.

  Frequency audit: PMID:33643973 Table 3 has 29 columns including the index case, despite
  prose describing 29 literature cases. It gives CHD in 10/29 columns (five undescribed) and
  hearing abnormalities in 4/29 (nine undescribed), which do not reproduce the narrative 43%
  and 29%. Its motor-development row is not linear growth retardation. The hearing-negative
  index case had failed screens and incompletely resolved follow-up; its gastrointestinal-negative
  table entry coexists with diagnosed reflux. The selected literature sample mixes deletion
  intervals and ascertainment methods. Neither its narrative percentages nor recalculated
  table fractions are used as population frequencies. Qualitative descriptions such as “rare”
  and single-case observations are not converted into HPO frequency bands.

  Phenotype coverage: cleft palate is explicitly mentioned in the full SETD5 paper’s summary
  of earlier deletion reports and in the later comparative table. High palate, reflux, ventricular
  septal defect, hypoplastic left ventricle and other directly described features are curated
  separately. The inverted-duplication/terminal-deletion paper contributes only its literature
  summary of pure deletion phenotypes; its own complex-rearrangement case is not pooled with
  them. No disease-specific GeneReviews or StatPearls chapter was identified in the required
  source checks.

  Deletion-dependent tumor risk: PMID:26365017 adds a cerebellar hemangioblastoma case associated
  with a deletion spanning the VHL locus, and its authors’ repeat-imaging recommendation.
  The phenotype, genetic susceptibility and care implications are restricted to that genomic
  context. A later surveillance-report lead, PMID:35441425, had no PubMed abstract and its
  inaccessible findings were not inferred.
review_notes: >-
  Review focused on distinctions between human observations, experimental models and candidate-gene
  inference. All syndrome-wide frequency bands were removed because the cited evidence did
  not justify their numerical ranges. BRPF1 was upgraded to a supported causal contributor;
  SRGAP3 remains a susceptibility candidate. CAV3 location, conditional cardiac mapping, same-deletion
  familial variability and the additional 1q44 CNV are explicit. Mechanism nodes separate
  gene dosage, complex assembly, acetylation, transcription, Rac signaling and neurite development,
  with unknown intermediates retained where human causal steps are untested.
  Downslanting palpebral fissures, sacral dimple, syndactyly and feeding difficulties in the
  Perplexity artifact trace to aggregators or an unverified frequency table, so they are not
  promoted to additional source-verified phenotypes here. The institutional PDF is the Deliu
  et al. manuscript of "Haploinsufficiency of the intellectual disability gene SETD5 disturbs
  developmental gene expression and cognition"; its generated cache title is the repository URL.
animal_models:
- name: Setd5-Haploinsufficient Mouse
  species: Mouse
  genotype: Germline Setd5+/-
  publication: PMID:30455454
  description: >-
    A single-gene model with developmental abnormalities, altered vocalization and behavioral
    inflexibility. Ex vivo hippocampal slices showed enhanced long-term potentiation. Separate
    engineered embryonic stem-cell and neural-progenitor cultures were used for protein-complex
    and chromatin assays.
  evidence:
  - reference: PMID:30455454
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Here we show that Setd5-haploinsufficient mice present developmental defects such as
      abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes.
      Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term
      potentiation, delayed ontogenetic profile of ultrasonic vocalization, and behavioral
      inflexibility.
    explanation: >-
      The study reports developmental and behavioral changes in Setd5-haploinsufficient mice.
      Enhanced long-term potentiation is not described as a generalized loss of plasticity.
    reference_title: >-
      Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental
      gene expression and cognition.
  modeled_mechanisms:
  - target: Reduced SETD5 Dosage
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Heterozygous germline disruption models reduced dosage of one contributing gene.
    limitations: >-
      This single-gene mouse model does not reproduce a human multigene deletion. Behavioral
      inflexibility and impaired adaptation coexist with enhanced memory retention and ex
      vivo hippocampal potentiation; gross brain architecture and neural-progenitor proliferation
      were not impaired in this study.
    evidence:
    - reference: PMID:30455454
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Here we show that Setd5-haploinsufficient mice present developmental defects such
        as abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes.
        Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term
        potentiation, delayed ontogenetic profile of ultrasonic vocalization, and behavioral
        inflexibility.
      explanation: >-
        The study reports developmental and behavioral changes in Setd5-haploinsufficient
        mice. Enhanced long-term potentiation is not described as a generalized loss of plasticity.
      reference_title: >-
        Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental
        gene expression and cognition.
  notes: >-
    The transcription mechanism also draws on separately engineered heterozygous and homozygous
    cell cultures. Neither a cell-culture assay nor a behavioral test directly measures human
    intellectual disability.
- name: Chl1-Cntn6 Double-Heterozygous Mouse
  species: Mouse
  genotype: Chl1+/-; Cntn6+/-
  publication: PMID:33519384
  description: >-
    The full review describes a published two-gene mouse experiment showing more severe dendritic
    misorientation than either single heterozygote or wild-type littermates.
  evidence:
  - reference: PMID:33519384
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Notably, compound heterozygous mice for both Chl1 and Cntn6 display an additive deleterious
      phenotype – these compound heterozygous mice showed more severe misoriented dendrites
      compared to single heterozygous Chl1 or Cntn6 mice and wild-type littermates (Ye et
      al., 2008).
    explanation: >-
      The full review describes an existing compound mouse experiment with a structural endpoint;
      it is not evidence that all triple-deletion mechanisms have been tested.
    quote_role: REVIEW_SYNTHESIS
    reference_title: >-
      Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated in 3p-Deletion
      Syndrome and Autism Spectrum Disorder.
  modeled_mechanisms:
  - target: Abnormal Neurite Development
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Dendritic orientation is a structural readout of neuronal projection development.
    limitations: >-
      This two-gene structural model retains Cntn4 and other human deletion genes. The cited
      review does not establish that it recapitulates human ASD or intellectual disability,
      and compensation by other adhesion molecules remains a hypothesis.
    evidence:
    - reference: PMID:33519384
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Notably, compound heterozygous mice for both Chl1 and Cntn6 display an additive deleterious
        phenotype – these compound heterozygous mice showed more severe misoriented dendrites
        compared to single heterozygous Chl1 or Cntn6 mice and wild-type littermates (Ye et
        al., 2008).
      explanation: >-
        The full review describes an existing compound mouse experiment with a structural
        endpoint;
        it is not evidence that all triple-deletion mechanisms have been tested.
      quote_role: REVIEW_SYNTHESIS
      reference_title: >-
        Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated in 3p-Deletion
        Syndrome and Autism Spectrum Disorder.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Scope: a multigene distal 3p deletion disorder encompassing terminal and overlapping interstitial presentations. Intragenic SETD5 and BRPF1 disorders remain separate entries. The deep-research report was used as a lead list; its incorrect HPO/CL labels, untraceable phenotype-frequency attribution and off-entity proximal-deletion and renal-cancer references were not imported. Full-text review: the 2015 SETD5 study supports a 94 kb overlap in its combined case comparison, engineered-cell nonsense-mediated decay and directly observed deletion phenotypes. The 2017 BRPF1 paper supports human genotype–phenotype comparison, altered complex assembly and H3K23 acetylation in transfected cells, with a non-significant patient-fibroblast result. The 2018 SETD5 author manuscript clarifies Pol II redistribution, unchanged Hdac3 enzymatic activity, and the experimental model boundaries. The IgCAM review’s body and tables identify existing compound mouse experiments and endpoint-specific positive and negative findings that its abstract alone obscures. Frequency audit: PMID:33643973 Table 3 has 29 columns including the index case, despite prose describing 29 literature cases. It gives CHD in 10/29 columns (five undescribed) and hearing abnormalities in 4/29 (nine undescribed), which do not reproduce the narrative 43% and 29%. Its motor-development row is not linear growth retardation. The hearing-negative index case had failed screens and incompletely resolved follow-up; its gastrointestinal-negative table entry coexists with diagnosed reflux. The selected literature sample mixes deletion intervals and ascertainment methods. Neither its narrative percentages nor recalculated table fractions are used as population frequencies. Qualitative descriptions such as “rare” and single-case observations are not converted into HPO frequency bands. Phenotype coverage: cleft palate is explicitly mentioned in the full SETD5 paper’s summary of earlier deletion reports and in the later comparative table. High palate, reflux, ventricular septal defect, hypoplastic left ventricle and other directly described features are curated separately. The inverted-duplication/terminal-deletion paper contributes only its literature summary of pure deletion phenotypes; its own complex-rearrangement case is not pooled with them. No disease-specific GeneReviews or StatPearls chapter was identified in the required source checks. Deletion-dependent tumor risk: PMID:26365017 adds a cerebellar hemangioblastoma case associated with a deletion spanning the VHL locus, and its authors’ repeat-imaging recommendation. The phenotype, genetic susceptibility and care implications are restricted to that genomic context. A later surveillance-report lead, PMID:35441425, had no PubMed abstract and its inaccessible findings were not inferred.

Create: 3p- Syndrome · 2026-09-09T23:25:52Z · View source

Created kb/disorders/3p-_Syndrome.yaml (MONDO:0013424) and deleted stubs/3p-_Syndrome.yaml. Lump/split: curated as a single DISEASE entry, not a grouping. Co-deleted genes jointly producing one recognisable phenotype is the single-entry case per issue #8727; a grouping is for genuinely distinct diseases converging downstream. Shape follows the existing contiguous-deletion entries (Cri-du-Chat_Syndrome, Chromosome_1p36_Deletion_Syndrome, 22q11.2_Deletion_Syndrome). Boundary against SETD5_Haploinsufficiency_Syndrome (MONDO:0014336) mirrored from that entry's own scope statement rather than duplicating its mechanism content; BRPF1-Related_Intellectual_Disability recorded as the adjacent-gene differential. MONDO:0018564 (3p25.3 microdeletion syndrome) is a different concept and is a differential, not a synonym. Deep research: one Perplexity run, research/3p-_Syndrome-deep-research-perplexity.md. The provider default model sonar-deep-research failed three times with 'Server disconnected without sending a response' at a reproducible 5m05s, which is an infrastructure cut on the long-running request rather than an API fault; --fallback does not cover a runtime failure. Re-ran with --model sonar-pro, which completed in 115s. Still a Perplexity report, so no fallback was recorded. Report validation. Reference validation clean: 19/19 identifiers resolved, confabulation_rate 0.0, 15/19 judged on topic, no unresolved references. Term validation NOT clean: needs_review true, 8 of 55 checked labels named a different term than the report claimed and 14 more were flagged as worth a second look. No CURIE was copied from the report; every binding in the entry was re-derived with OAK (ols:hp, ols:go, ols:cl, ols:mondo, ols:ncit, sqlite:obo:hgnc) at the time it was written. Two of the report's errors would otherwise have been silent: HP:0000263 offered for trigonocephaly is Oxycephaly (correct term HP:0000243), and CL:0000182 offered for cardiac muscle cell is hepatocyte. Citation sweep: every PMID resolvable from the report's citation sidecar is either cited as evidence in the entry or named in notes with a stated reason for exclusion. Three declined for being about a different entity (proximal 3p deletions PMID:17125947 and PMID:29928177; renal-cancer mouse model PMID:37217526), one for having no abstract in PubMed at all (PMID:18553547, content_type unavailable, so nothing quotable), one for being an inverted-duplication rearrangement (PMID:31428485), two as case reports adding nothing (PMID:20101686, PMID:623063). Structured sources attempted and not used: Orphanet ORPHA:1620 and ClinGen dosage sensitivity both failed on upstream release drift against their pinned manifest checksums. Repinning either would rewrite a corpus-wide cache inside a single-disease curation PR, so both were left alone and the reason recorded in notes. Modelling decisions worth review: the entry deliberately names no single driver gene, keeping three separable branches (3p25.3 SETD5/SRGAP3 core, distal 3p26.3 IgCAM cluster, separately mapped 3p25.3 cardiac interval), with the unresolved attribution recorded as three discussions including one HUMAN_MODEL_MISMATCH. CAV3 is typed SUSCEPTIBILITY rather than CAUSATIVE and is not bound on the cardiac pathophysiology node, because the sources reach it by positional candidacy and one cited deletion contains it without a heart defect. Two evidence items are graded REFUTE against the claims they sit under, deliberately. Validation run to completion: just validate (schema + terms + references, 82/82 snippets verified), just validate-terms (passed), just count-verified-snippets, check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-stubs, check-folded-hyphens, check-snippet-length, check-title-snippets, check-reference-titles, check-snippet-grading, check-environmental-evidence, and the batched just validate-disorders.

Perplexity ▸
1. Disease Information
sonar-pro 41 citations 2026-09-09T20:01:17.550056

1. Disease Information

Definition and overview

“Distal monosomy 3p” or 3p deletion syndrome / 3p‑ syndrome is a chromosomal anomaly caused by deletion of a variable segment at the terminal portion of 3p, typically spanning 3p25–pter.[1][2][5][32][34][38][41]

  • Orphanet defines distal monosomy 3p as “a rare chromosomal anomaly syndrome, resulting from a partial deletion of the short arm of chromosome 3, with a highly variable phenotype typically characterized by pre‑ and post‑natal growth retardation, intellectual disability, developmental delay and craniofacial dysmorphism (microcephaly, trigonocephaly, downslanting palpebral fissures, telecanthus, ptosis, micrognathia).”[2]
  • MedlinePlus describes it as a condition “that results from a chromosomal change in which a small piece of chromosome 3 is deleted in each cell… at the end of the short (p) arm,” leading to intellectual disability, developmental delay, and abnormal physical features.[6][18][21]

The disorder is rare, with fewer than ~60 well‑documented distal 3p deletions reported worldwide in recent reviews and case compilations.[4][11][17][31][37][42]

Key identifiers and classification

  • OMIM: #613792 – “CHROMOSOME 3pter‑p25 DELETION” (distal 3p‑ syndrome).[1][23][44]
  • Orphanet: Distal deletion 3p syndrome (ORPHA:1620, also catalogued as partial deletion of short arm of chromosome 3, ORPHA:261875).[2][10]
  • MONDO: MONDO:0013424 – 3p‑ syndrome (ClinVar entry cross‑references MONDO:0013424).[3]
  • MedGen: C4706503 – 3p‑ syndrome.[3][7]
  • MeSH / ICD‑10/ICD‑11: No specific MeSH term; usually coded under “Other specified chromosome abnormalities” (e.g., ICD‑10 Q92.8, Q93.* for deletions of autosomes). This is typically inferred from chromosomal deletion coding practices, not from a dedicated 3p‑ code.
  • Category: Genetic / chromosomal, autosomal dominant (contiguous gene syndrome).[1][23][44]

Synonyms and alternative names

Common synonyms:[1][2][5][8][10][14][34][38][41][44]

  • 3p‑ syndrome (three‑p minus syndrome)
  • 3p deletion syndrome
  • Distal monosomy 3p
  • Chromosome 3pter‑p25 deletion syndrome
  • Partial deletion of the short arm of chromosome 3 syndrome
  • Deletion 3p syndrome
  • Sometimes specified by band: 3p25 deletion, 3p26.3 deletion, etc.

Data type

Most information derives from aggregated disease‑level resources (OMIM, Orphanet, MedGen, MedlinePlus, RareChromosome support documents) summarizing multiple case reports and small series, supported by individual patient reports and microarray‑based cytogenetic studies.[1][2][5][7][16][18][23][31][32][34][37][38][41][42][43][44]

2. Etiology

Primary causal factor

3p‑ syndrome is caused by heterozygous deletion (partial monosomy) of distal chromosome 3p (typically 3p25–pter; deletion sizes ~200 kb to >10 Mb).[5][32][34][37][38][41][43]

  • Phipps et al. (Am J Hum Genet 2004, often cited in OMIM/Orphanet) and subsequent microarray studies show deletions from 3p25.3–p26.3 to 3pter, with variable breakpoints and sizes, defining a contiguous gene syndrome.[27][32][34][43][45]
  • A genotype–phenotype review notes that “3p‑ syndrome is a rare contiguous gene syndrome which is caused by 200 kb to 12.5 Mb deletions in 3pter‑p25 region with a wide clinical spectrum.”[41]

Most deletions are de novo, but familial cases with inherited terminal deletions or interstitial deletions have been reported, sometimes with variable expressivity or non‑penetrance.[5][37][38][40][41][43]

Genetic risk factors

Causal loci and candidate genes

Multiple genes in distal 3p likely contribute to the phenotype; high‑impact candidates include:[5][9][20][31][32][34][37][43][45]

  • SRGAP3 (SLIT‑ROBO Rho GTPase‑activating protein 3):
    “We suggest that current evidence suggests that SRGAP3 is the major determinant of mental retardation in distal 3p deletions.”[32] (microarray‑based analysis of 3p25‑p26 deletions)
  • CHL1 (close homolog of L1): implicated in neurodevelopment; terminal 3p26.3 deletions containing only CHL1 were associated with developmental delay and mental retardation in some familial cases.[5][34]
  • CNTN4, CNTN6 (contactins): involved in neuronal connectivity; recurrently deleted in distal 3p deletions and associated with neurodevelopmental phenotypes.[9][31]
  • CRBN (cereblon): suggested to contribute to cognitive impairment and developmental delay.[5][9]
  • OXTR (oxytocin receptor), CAV3, SRGAP3: discussed as genes affecting autistic behavior, congenital heart defect, and mental retardation in a patient with interstitial 3p25.3–p26.1 deletion.[20]

Karyotype–phenotype studies identified band 3p25.3 as critical for the classic 3p‑ phenotype:[43]

“Karyotype‑phenotype comparisons… suggest that deficiency of the 3p25.3 band is critical to produce the main clinical manifestations of the del(3p) syndrome.”[43]

Variant classification and type

  • The pathogenic lesion is usually a constitutional (germline) structural variant: terminal (or occasionally interstitial) deletion of 3p.[34][37][38][40][41][45]
  • Classified as pathogenic structural variants in ClinVar and OMIM, based on segregation, de novo occurrence, and concordant phenotype.[3][28][31][34]
  • Variants are copy‑number losses (CNVs), not point mutations; types include terminal deletions, interstitial deletions, sometimes combined with inverted duplications of proximal 3p.[29][34][41]

Allele frequencies in population databases (gnomAD, ExAC) are extremely low or absent, consistent with a rare, often severe developmental disorder; this is inferred from general CNV intolerance and not directly quantified for this specific syndrome.

Environmental risk factors

No specific environmental, lifestyle, or toxic exposures have been shown to cause 3p‑ syndrome; the deletion is typically a sporadic chromosomal event during gametogenesis or early embryogenesis.[5][34][37][38][40][41]
Standard obstetric risk factors (advanced maternal age) may modestly increase risk of chromosomal anomalies in general, but specific data for distal 3p deletions are lacking.

Protective factors and gene–environment interactions

  • Familial reports with terminal 3p26.3 deletions and normal phenotype indicate that small deletions restricted to CHL1 (or to very distal 3p) may lack penetrance or cause only subtle deficits.[5][34][37][40]

    “A terminal 3p26.3 deletion is not associated with dysmorphic features and intellectual disability in a four‑generation family.”[40]

  • Other studies describe chromosomal non‑penetrance or modifier genes in terminal 3p deletions.[37]

No robust gene–environment interaction data (e.g., exposure modifying severity) have been reported. Protective “modifier” alleles are speculative.

3. Phenotypes

Core clinical phenotype

OMIM and MedGen summarize the characteristic features of distal 3p‑ syndrome:[7][23][44]

“Characteristic features of the distal 3p‑ syndrome include low birth weight, microcephaly, trigonocephaly, hypotonia, psychomotor and growth retardation, ptosis, telecanthus, downslanting palpebral fissures, and micrognathia. Postaxial polydactyly, renal anomalies, cleft palate, congenital heart defects (especially atrioventricular septal defects), preauricular pits, sacral dimple, and gastrointestinal anomalies are variable features.”[23][44]

MedlinePlus similarly lists:[18][21]

“slow growth, an abnormally small head (microcephaly), a small jaw (micrognathia), droopy eyelids (ptosis), malformed ears or nose, and widely spaced eyes (hypertelorism)… extra fingers or toes (polydactyly)… cleft palate… seizures, weak muscle tone (hypotonia), intestinal abnormalities, or congenital heart defects.”

The 2021 case report and literature review provides an updated aggregated phenotype list:[16][31]

“After more than 40 years of studies, the main clinical phenotypes… have been identified as follows: delayed growth and development, intellectual disability, hypotonia, micrognathia, ptosis, wide nose bridge, long philtrum, low ear position, deformed ears, polydactyly deformity, hearing abnormalities, CHD, renal abnormalities, syndactylism, gastrointestinal abnormalities, and scoliosis.”[31]

Quantitative frequencies (Phipps et al., 2004 cohort)

A key quantitative summary (Am J Hum Genet, ~2004), often reproduced in reviews, reports phenotype frequencies across compiled cases:[27]

Developmental delay 86%; postnatal growth retardation 86%; ptosis 77%; low birth weight 73%; malformed ears 68%; long philtrum 68%; broad nasal bridge 64%; hypotonia 50%; microcephaly 50%; micrognathia 50%; epicanthal folds 41%; postaxial polydactyly 40%; hypertelorism 36%; feeding problems 29%; clinodactyly 27%; trigonocephaly 23%; downturned corners of mouth 24%; synophrys 18%; low frontal hairline 14.[27]

These are aggregated disease‑level frequencies derived from case series.

Age of onset, severity, progression

  • Onset: Congenital – most features (growth restriction, craniofacial dysmorphism, cardiac defects) are present prenatally or at birth.[2][16][18][23][34][35][38][41][42]
    Prenatal intrauterine growth restriction and cardiac defects have been described.[29]
  • Severity: Intellectual disability typically severe to profound; language remains severely limited.[18][21]

    “Individuals with 3p deletion syndrome typically have severe to profound intellectual disability… language ability usually remains limited.”[21]

  • Progression: Developmental delay is persistent; growth retardation continues postnatally.[2][16][18][21][23][31][34][41]
    Neurological manifestations (hypotonia, seizures) may stabilize but cognitive deficits usually remain lifelong. Severity is highly variable, ranging from normal phenotype to severe multi‑system involvement.[5][34][37][38][40]

Representative phenotype categories and suggested HPO terms

Below is a structured mapping (non‑exhaustive):

  1. Growth and development
  2. Pre‑ and post‑natal growth retardation (HPO: HP:0001511 – growth delay; HP:0008897 – intrauterine growth restriction).[2][23][27][31][34][41]
  3. Psychomotor retardation / developmental delay (HP:0001263 – developmental delay; HP:0001305 – psychomotor delay).[2][7][16][18][23][27][31][34]

  4. Severe intellectual disability (HP:0002342).[16][18][21][23][31][34]

  5. Craniofacial dysmorphism

  6. Microcephaly (HP:0000252).[2][18][21][23][27][31][34][35][39][41][42]
  7. Trigonocephaly / brachy‑trigonocephaly (HP:0000263).[23][27][30][36][39]
  8. Telecanthus (HP:0000506).[2][23][36][41][42][44]
  9. Hypertelorism (HP:0000316).[18][21][23][27][35]
  10. Ptosis (HP:0000508).[2][7][18][21][23][27][31][34][35][39]
  11. Downslanting palpebral fissures (HP:0000494).[23][41][44]
  12. Epicanthal folds (HP:0000286).[18][21][27][39]
  13. Long philtrum (HP:0000343).[27][31][35][36][41][43]
  14. Broad nasal bridge (HP:0000431).[27][31][35][39]
  15. Micrognathia (HP:0000347).[2][18][21][23][27][31][35][39][41][42][44]

  16. Low set/malformed ears (HP:0000369, HP:0000377).[16][18][21][23][27][31][35][41][43]

  17. Limb and skeletal anomalies

  18. Postaxial polydactyly (HP:0001162).[23][27][31][39][44]
  19. Clinodactyly (HP:0030084).[27]
  20. Syndactyly (HP:0001159).[31]
  21. Scoliosis (HP:0002650).[31]

  22. Feeding difficulties (HP:0011968).[27][31]

  23. Neurological and behavioral

  24. Hypotonia (HP:0001290).[2][16][18][21][23][27][31][35][36][41][42][44]
  25. Seizures (HP:0001250).[18][21][31]
  26. Autism spectrum disorder features (HP:0000729 – autistic behavior).[18][20][21][26]
  27. Obsessive–compulsive disorder behaviors (HP:0000722 – obsessive‑compulsive behavior).[18][21]

  28. Hearing abnormalities / deafness (HP:0000365).[31][43]

  29. Cardiac, renal, GI and other system involvement

  30. Congenital heart defects, especially atrioventricular septal defects (HP:0001671 – atrioventricular septal defect).[23][31][41][42][45]
    > “Congenital heart defects (especially atrioventricular septal defects)” are noted as variable features.[23][44]
    First report of hypoplastic left heart syndrome in 3p‑ syndrome has been described.[4][11][42]
  31. Renal anomalies / polycystic renal dysplasia (HP:0000107).[9][23][31][42][44]
  32. Gastrointestinal abnormalities (e.g., hiatal hernia, intestinal malformations, umbilical hernia)[9][23][29][31][44]
  33. Cleft palate (HP:0000175).[18][21][23][44]
  34. Preauricular pits (HP:0004467).[23][44]
  35. Sacral dimple (HP:0000960).[23][44]

Quality‑of‑life impact

Severe intellectual disability, persistent developmental delay, hypotonia, and multi‑system malformations substantially impair daily functioning, autonomy, and communication.[16][18][21][31]

MedlinePlus states that language ability “usually remains limited,” and affected individuals often have significant motor delays, seizures, and behavioral issues, affecting quality of life and caregiver burden.[18][21] No formal EQ‑5D or SF‑36 studies specific to 3p‑ syndrome were identified; extrapolation from severe developmental disorders suggests marked impairment across mobility, self‑care, usual activities, and cognition.

4. Genetic/Molecular Information

Causal genes and candidate “critical regions”

Multiple studies attempt to define “critical regions” and genes within 3p25–pter responsible for specific aspects of the phenotype:[5][9][20][31][32][34][37][38][43][45]

  • SRGAP3 (3p25.3):
    Microarray‑based analysis of multiple 3p25‑p26 deletions concluded:

    “We suggest that current evidence suggests that SRGAP3 is the major determinant of mental retardation in distal 3p deletions.”[32]

  • CHL1 (3p26.3):
    Terminal 3p26.3 deletions containing only CHL1 caused developmental delay and mental retardation in some families, implicating CHL1 in cognitive development, though non‑penetrant cases exist.[5][34][40]
  • CNTN4 / CNTN6:
    These contactin genes are repeatedly deleted in patients with 3p deletion syndrome and are catalogued as associated with developmental delay, intellectual disability, microcephaly, and dysmorphisms.[9][31]
  • CRBN:
    Mentioned as potentially sufficient to cause some typical features when deleted.[5][9]
  • CAV3, OXTR, SRGAP3:
    A 3p25.3–p26.1 interstitial deletion case discussed these genes as candidates for congenital heart defect (CAV3), autistic behavior (OXTR), and mental retardation (SRGAP3).[20]

Variant types and ACMG classification

  • Type: Germline structural deletions (CNVs), either terminal (3pter) or interstitial (3p25–p26, 3p13–p14).[24][26][34][37][38][40][45]
  • Classification: Most are pathogenic or likely pathogenic based on ACMG CNV criteria (large deletion encompassing dosage‑sensitive genes, de novo occurrence, consistent phenotype).[3][28][31][34]
  • Somatic vs. germline: All reported classic 3p‑ syndrome cases involve constitutional germline deletions; somatic 3p loss is a separate oncologic context (renal cell carcinoma, etc.). A recent GEMM modeling extensive 3p deletion in kidney cancer patients underscores the role of 3p loss in tumorigenesis but is not a model of 3p‑ developmental syndrome.[33]

Modifier genes and epigenetics

  • Phenotypic variability and non‑penetrance suggest potential modifier genes and/or epigenetic influences, but specific modifiers have not been conclusively identified.[34][37][38][40][41]
  • A study entitled “Terminal 3p deletions: phenotypic variability, chromosomal non‑penetrance, or gene modification?” explicitly raises this question but does not identify specific modifiers.[37]
  • No disease‑specific DNA methylation or chromatin changes have been described; epigenetic information for 3p‑ syndrome remains largely unexplored.

Chromosomal abnormalities

  • Classic lesions: terminal deletions of 3p25–pter (del(3)(p25‑pter), del(3)(p26.3‑pter)).[30][34][37][38][41][43]
  • Interstitial deletions (e.g., 3p25.3–p26.2; 3p25.3–p26.1; 3p13–p14) produce overlapping but sometimes milder phenotypes.[20][24][26][45]
  • Complex rearrangements: inverted duplication of 3p with adjacent terminal 3p deletion.[29]

5. Environmental Information

No specific non‑genetic factors are established as causal. Published reports emphasize chromosomal deletion as the primary etiology.[5][34][37][38][40][41][43][45]

  • Environmental or lifestyle factors may influence severity of certain complications (e.g., cardiac outcomes) but do not determine syndrome occurrence.
  • Infectious agents have not been implicated.

Accordingly, the disease is best classified as a primary genetic/chromosomal syndrome with minimal documented environmental contribution.

6. Mechanism / Pathophysiology

Ordered causal chain (inferred from human CNV studies)

  1. Heterozygous terminal/interstitial deletion of distal 3p (3p25–pter) leads to hemizygous loss of multiple neurodevelopmental and organ‑development genes (e.g., SRGAP3, CHL1, CNTN4, CNTN6, CRBN), causing disturbed neuronal connectivity and organ morphogenesis.[5][9][20][31][32][34][37][38][43][45]
  2. Gene dosage reduction in SRGAP3 and CHL1 results in impaired axon guidance, synaptic development, and neurodevelopment, leading to intellectual disability, developmental delay, hypotonia, and behavioral abnormalities (autism/OCD); this is inferred from gene function and genotype–phenotype correlation.[5][20][32][34][40][43]
  3. Deletion of cardiac developmental genes (e.g., CAV3, possibly others in 3p25.3–p26) leads to congenital heart defects, particularly atrioventricular septal defects and, rarely, hypoplastic left heart syndrome; this is suggested by individual cases and positional candidate gene analyses.[4][11][20][23][41][42][45]
  4. Loss of genes involved in craniofacial and skeletal development results in craniofacial dysmorphism (microcephaly, trigonocephaly, telecanthus, ptosis, micrognathia) and limb anomalies (polydactyly, clinodactyly, syndactyly, scoliosis).[2][23][27][30][31][35][36][39][41][44]
  5. Deletion of genes involved in renal and gastrointestinal development contributes to structural renal anomalies, intestinal malformations, and hiatal hernia, which in turn lead to feeding difficulties, failure to thrive, and morbidity.[2][9][23][29][31][44]
  6. Global developmental impairment and congenital malformations result in chronic functional disability, reduced quality of life, and increased mortality from cardiac, respiratory, and infectious complications; this is inferred from general patterns in severe multisystem CNV syndromes.[16][18][21][23][31][42]

Molecular pathways and cellular processes (inferred)

Direct pathway studies specific to 3p‑ syndrome are limited; we extrapolate from known functions of candidate genes:

  • SRGAP3: Involved in SLIT‑ROBO signaling, Rho GTPase regulation, and neuronal migration; its haploinsufficiency disrupts axon guidance and synaptic development (GO:0007411 – axon guidance; GO:0048856 – anatomical structure development).[32]
  • CHL1: Member of the L1 cell adhesion molecule family, implicated in neurite outgrowth and synaptic plasticity.[5][34]
  • CNTN4/CNTN6: GPI‑anchored neuronal adhesion molecules influencing axon extension, synapse formation and organization of neural circuits (GO:0007155 – cell adhesion).[9][31]
  • OXTR: Oxytocin receptor; deletion may contribute to social behavior deficits and autistic features via disrupted neuropeptide signaling.[20][26]

Suggested GO biological process terms (upstream):

  • GO:0007399 – nervous system development
  • GO:0007411 – axon guidance
  • GO:0007268 – synaptic transmission
  • GO:0007507 – heart development
  • GO:0001655 – urogenital system development

Suggested CL (Cell Ontology) terms:

  • CL:0000127 – neuron
  • CL:0000182 – cardiac muscle cell
  • CL:0000731 – renal epithelial cell

No specific metabolomic or proteomic signatures have been published for 3p‑ syndrome; multi‑omics work has focused more on somatic 3p loss in cancer (e.g., clear cell renal cell carcinoma GEMM).[33]

7. Anatomical Structures Affected

Organ‑level

Primary involvement:[2][7][9][16][18][21][23][27][31][35][41][42][44]

  • Central nervous system – intellectual disability, hypotonia, seizures, autism/OCD (UBERON:0000955 – brain).
  • Craniofacial structures – skull (microcephaly, trigonocephaly), face, jaw, eyes, ears (UBERON:0008897 – skull; UBERON:0001456 – face; UBERON:0001684 – mandible; UBERON:0000970 – eye; UBERON:0001690 – ear).
  • Cardiovascular system – congenital heart defects, especially atrioventricular septal defects and rare hypoplastic left heart (UBERON:0000948 – heart).[23][41][42][45]
  • Renal/urinary system – renal anomalies, polycystic renal dysplasia (UBERON:0002113 – kidney).[9][23][31][44]
  • Gastrointestinal tract – intestinal malformations, hiatal hernia, umbilical hernia, feeding difficulties (UBERON:0001007 – intestine).[9][23][27][29][31][44]
  • Musculoskeletal system – limb anomalies (polydactyly, clinodactyly, syndactyly, scoliosis) (UBERON:0001444 – hand; UBERON:0002429 – vertebral column).[27][31][39]

Secondary involvement includes respiratory complications (from cardiac defects or hypotonia) and endocrine abnormalities like congenital hypothyroidism in some cases.[31]

Tissue, cell and subcellular levels

  • Predominant impact on neural tissue (cortical and subcortical neurons, glia), cardiac muscle, renal epithelium, and craniofacial mesenchyme.
  • Suggested cell types (CL):
  • CL:0000700 – cortical neuron
  • CL:0000182 – cardiac muscle cell
  • CL:0000731 – renal epithelial cell
  • Subcellular: Genes implicated function in cytoplasm and plasma membrane, modulating cytoskeleton and signaling (GO:0005886 – plasma membrane; GO:0005856 – cytoskeleton).

Localization patterns are systemic rather than localized; lateralization is not a major feature except in specific organ anomalies (e.g., unilateral renal defects).

8. Temporal Development

Onset

  • Congenital/pediatric: Most features are apparent in the neonatal period – low birth weight, craniofacial features, hypotonia, cardiac defects.[2][16][18][21][23][27][31][35][41][42][44]
  • Prenatal detection via ultrasound (growth restriction, cardiac defects) and chromosomal testing is increasingly reported.[29][31]

Progression and disease course

  • Developmental course: Chronic, lifelong developmental disability; language and motor skills remain substantially delayed.[16][18][21][31]
  • Growth: Slow, with persistent short stature and microcephaly in many patients.[2][23][27][31][34][35][41]
  • Course pattern: Generally non‑relapsing but progressive in functional impact (as developmental expectations increase) rather than in structural anomalies.
  • No formal staging or remission patterns are described; natural history is derived from case reports and small series.

9. Inheritance and Population

Inheritance pattern

  • OMIM lists autosomal dominant inheritance for 3p‑ syndrome, reflecting that a single copy‑number loss (heterozygous deletion) is sufficient to cause disease.[1][23]
  • Most cases are de novo; some are familial with dominant transmission and variable expressivity or non‑penetrance.[5][37][38][40][41][43]

Penetrance and expressivity

  • Penetrance: Incomplete – families with terminal 3p26.3 deletions containing only CHL1 have normal or minimally affected individuals.[5][34][37][40]

    “Terminal deletions of the distal part of the short arm of chromosome 3 cause a wide range of phenotypes from normal to dysmorphic including microcephaly, developmental delay and intellectual disability.”[40]

  • Expressivity: Highly variable; phenotype ranges from normal to severe multi‑system involvement.[34][37][38][40][41]

No evidence for genetic anticipation, germline mosaicism, or founder effects specific to 3p‑ syndrome has been clearly documented.

Epidemiology

  • Distal 3p‑ syndrome is classified by Orphanet as a rare disease; worldwide prevalence is extremely low (exact prevalence estimates are not provided but <1/1,000,000 is plausible given <60 reported cases).[2][4][11][37][42]
  • Sex ratio appears roughly equal based on case series; no strong sex predilection is reported.[27][31][35][37][38]
  • Cases have been reported across diverse ethnicities and geographies (Europe, Asia including Korea, Brazil, etc.), with no obvious geographic clustering.[16][17][22][35][42]

10. Diagnostics

Clinical and laboratory evaluation

Diagnosis integrates clinical dysmorphology with cytogenetic and molecular testing.

Clinical features used for suspicion

  • Neonatal low birth weight, hypotonia, craniofacial dysmorphia (microcephaly, trigonocephaly, telecanthus, ptosis, micrognathia), polydactyly, and congenital heart defects raise suspicion of distal 3p deletion.[2][23][27][30][31][35][36][39][41][42][44]
  • MedlinePlus emphasizes severe intellectual disability and characteristic craniofacial features.[18][21]

Routine laboratory tests (e.g., electrolyte panels, thyroid function) are supportive, not diagnostic; congenital hypothyroidism has been reported in individual cases.[31]

Genetic testing

Standard diagnostic approach:[5][16][31][34][37][38][40][41][43][45]

  1. Chromosomal microarray (CMA)
  2. Detects terminal or interstitial deletions of distal 3p.

  3. Microarray studies have been critical in defining deletion size, gene content, and genotype–phenotype correlations.[5][31][32][34][37][38]

  4. Karyotyping

  5. Can identify visible deletions or complex rearrangements (e.g., inverted duplication with adjacent deletion).[29][30][37][38][45]

  6. Early cases (1970s–1990s) relied on conventional karyotyping.[19][30][39][43][45]

  7. Targeted FISH / MLPA

  8. Used historically to confirm 3p deletions and refine breakpoints, especially before high‑resolution arrays.[43][45]

  9. Whole exome/genome sequencing

  10. WES/WGS can detect CNVs but CMA remains first‑line for suspected chromosomal deletion syndromes.
  11. In atypical cases with normal CMA and strong suspicion, WGS may reveal cryptic structural variants.

ClinVar entries note that “clinical presentation may be dependent on the size and location of the deletion,” underscoring the need for precise structural characterization.[28]

Clinical criteria and differential diagnosis

No formal consensus diagnostic criteria beyond “heterozygous terminal 3p25–pter or overlapping CNV plus consistent phenotype.” Differential diagnoses include other syndromic growth‑retardation and craniofacial dysmorphism disorders:

  • Distal duplication 3p syndrome (3p trisomy), which presents with overlapping but distinct craniofacial and developmental features.[12]
  • Other microdeletion syndromes (e.g., 1p36 deletion, 22q11.2 deletion, 4p Wolf–Hirschhorn), distinguished by specific facial gestalt, cardiac defect patterns, and different chromosomal loci.

Screening

Because of rarity and variable expressivity, there are no population screening programs. Prenatal CMA or WGS may detect 3p deletions incidentally or in fetuses with anomalies.

11. Outcome / Prognosis

Survival and mortality

Published reports suggest that many patients survive into childhood and adolescence, but overall prognosis depends on severity of cardiac, renal, and neurologic involvement.[16][17][22][29][31][35][41][42]

  • Hypoplastic left heart and severe atrioventricular septal defects may carry high neonatal mortality.[4][11][42]
  • No systematic 5‑year or 10‑year survival statistics specific to 3p‑ syndrome were found; prognostic data are extrapolated from case series.

Morbidity, disability, and quality of life

  • Severe intellectual disability, language impairment, hypotonia, and congenital anomalies result in high morbidity and long‑term disability.[16][18][21][31]
  • Many patients require ongoing multidisciplinary care (cardiology, neurology, nephrology, developmental pediatrics, physical/speech therapy).
  • Behavioral problems (autism, OCD) and seizures further impact daily functioning.[18][20][21][26][31]

Prognostic factors (inferred):

  • Deletion size and gene content (e.g., inclusion of SRGAP3, CHL1, CAV3, OXTR).[20][32][43][45]
  • Presence and severity of cardiac defects.[4][11][23][41][42]
  • Renal and GI anomalies and feeding issues.
  • Family history and non‑penetrant carriers may indicate milder spectrum.

12. Treatment

Overall strategy

There is no cure or disease‑specific pharmacologic therapy; management is supportive and symptom‑based.[10][16][18][21][31]

“There is no cure for 3p deletion syndrome, and management is supportive and symptom-based.”[10]

Pharmacotherapy and medical management

  • Cardiac management: Standard pediatric cardiology protocols for atrioventricular septal defects and hypoplastic left heart syndrome (NCIT: C34736 – cardiac surgery; C25746 – congenital heart disease).
  • Seizure control: Conventional antiepileptic drugs as indicated (NCIT: C15388 – antiepileptic agent).[18][21][31]
  • Endocrine management: Treatment of congenital hypothyroidism when present (e.g., levothyroxine).
  • Symptom‑directed therapies: Gastroesophageal reflux management, constipation, infections.

No pharmacogenomic data specific to drug

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 19
Resolved 19
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 19
On topic 15
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 59
Resolved 57
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 55
Terms named correctly 33
Terms named as a different term 8
Terms whose name is worth a second look 14

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:0001305 (1 mention) - the report calls it "psychomotor delay"; HP calls it Dandy-Walker malformation
  • HP:0000263 (1 mention) - the report calls it "Trigonocephaly / brachy‑trigonocephaly"; HP calls it Oxycephaly
  • HP:0000107 (1 mention) - the report calls it "Renal anomalies / polycystic renal dysplasia"; HP calls it Renal cyst
  • CL:0000127 (1 mention) - the report calls it "neuron"; CL calls it astrocyte
  • CL:0000182 (2 mentions) - the report calls it "cardiac muscle cell"; CL calls it hepatocyte
  • UBERON:0008897 (1 mention) - the report calls it "skull"; UBERON calls it fin
  • UBERON:0001444 (1 mention) - the report calls it "hand"; UBERON calls it subdivision of head
  • UBERON:0002429 (1 mention) - the report calls it "vertebral column"; UBERON calls it cervical lymph node

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:0001511 (1 mention) - the report calls it "growth delay"; HP calls it Intrauterine growth retardation, and lists "Prenatal growth deficiency" among its other names
  • HP:0008897 (1 mention) - the report calls it "intrauterine growth restriction"; HP calls it Postnatal growth retardation
  • HP:0001263 (1 mention) - the report calls it "developmental delay"; HP calls it Global developmental delay, and lists "Developmental delay" among its other names
  • HP:0002342 (1 mention) - the report calls it "Severe intellectual disability"; HP calls it Moderate intellectual disability
  • HP:0000286 (1 mention) - the report calls it "Epicanthal folds"; HP calls it Epicanthus, and lists "Epicanthal fold" among its other names
  • HP:0001162 (1 mention) - the report calls it "Postaxial polydactyly"; HP calls it Postaxial hand polydactyly
  • HP:0001290 (1 mention) - the report calls it "Hypotonia"; HP calls it Generalized hypotonia
  • HP:0000365 (1 mention) - the report calls it "Hearing abnormalities / deafness"; HP calls it Hearing impairment, and lists "Hearing defect" among its other names
  • HP:0001671 (1 mention) - the report calls it "atrioventricular septal defect"; HP calls it Abnormal cardiac septum morphology, and lists "Heart septal defect" among its other names
  • HP:0004467 (1 mention) - the report calls it "Preauricular pits"; HP calls it Preauricular pit, and lists "Preauricular pits" among its other names
  • GO:0007268 (1 mention) - the report calls it "synaptic transmission"; GO calls it chemical synaptic transmission, and lists "synaptic transmission" among its other names
  • CL:0000731 (2 mentions) - the report calls it "renal epithelial cell"; CL calls it urothelial cell
  • UBERON:0001007 (1 mention) - the report calls it "intestine"; UBERON calls it digestive system, and lists "gastrointestinal system" among its other names
  • CL:0000700 (1 mention) - the report calls it "cortical neuron"; CL calls it dopaminergic neuron

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.