Diets-Jongmans Syndrome

Mendelian MONDO:0030012 Pathograph 17 Show in embeddings browser Neurodevelopmental disorder Chromatinopathy Epigenetic machinery disorder

Diets-Jongmans syndrome (DIJOS) is an autosomal dominant neurodevelopmental syndrome caused by heterozygous germline variants in KDM3B (5q31.2), which encodes a JmjC-domain histone demethylase that removes mono- and di-methylation from histone H3 lysine 9 (H3K9me1/2) and, in mouse hematopoietic cells, symmetric dimethylation from histone H4 arginine 3. The syndrome was delineated in 2019 from 17 individuals (14 probands and 3 similarly affected parents) and is defined by developmental delay or mild to moderate intellectual disability affecting motor and language function, short stature, neonatal feeding difficulties, and a facial gestalt (long ears, broad nasal tip, low-hanging columella, wide mouth, thin upper lip vermilion, pointed chin) that computational facial analysis separates from other intellectual-disability syndromes. Behavioral features (ADHD, autism spectrum disorder), childhood hypotonia, epilepsy, joint hypermobility, hearing loss and isolated congenital anomalies (hernias, cryptorchidism) are variably present. Most variants arise de novo; transmission from similarly or more mildly affected parents is documented, and later reports describe individuals whose presentation is predominantly growth restriction with normal or mildly impaired cognition, so expressivity is markedly variable. Two of the 17 founding individuals developed a childhood hematologic malignancy (acute myeloid leukemia, Hodgkin lymphoma), but both were ascertained through a childhood cancer predisposition study, and whether germline KDM3B variants raise cancer risk is unresolved.

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1
Mappings
1
Inheritance
6
Pathophys.
30
Phenotypes
3
Gaps
17
Pathograph
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Genes
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Medical Actions
3
Models
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Deep Research
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC
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Mappings

MONDO
MONDO:0858999 KDM3B-related intellectual disability-facial dysmorphism-short stature syndrome
skos:exactMatch Orphanet
MONDO:0858999 is MONDO's class for ORPHA:633004. Orphanet maps ORPHA:633004 to OMIM:618846 (the OMIM entry behind MONDO:0030012) as an exact match and gives "Diets-Jongmans Syndrome" as its synonym, so the two MONDO classes denote the same disease.
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Inheritance

1
Autosomal dominant, mostly de novo HP:0000006
Heterozygous KDM3B variants cause the syndrome in a dominant manner. Most arise de novo, but parent-to-child transmission is documented, including from parents with milder phenotypes (a mother with short stature and no intellectual disability; a family in which only one of four affected relatives met criteria for intellectual developmental disorder), which is the basis for recording variable expressivity. Penetrance has not been formally estimated.
Autosomal dominant inheritance Expressivity: VARIABLE De novo rate: Across the published cases the great majority of variants are de novo, with only a minority inherited from a similarly affected parent.
Show evidence (4 references)
PMID:30929739 SUPPORT Human Clinical
"By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature."
The founding report identifies both de novo variants and variants inherited from affected parents.
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"In terms of variant origin, the vast majority were sporadic de novo variants, with only a minority being familial."
Pooled variant-origin tally across the published cases, supporting the recorded de novo rate.
PMID:41878155 SUPPORT Human Clinical
"Short stature without intellectual disability was noted in the mother, indicating intrafamilial phenotypic variability."
A transmitting parent with a milder phenotype than her child, supporting variable expressivity.
+ 1 more reference
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Discussions and Knowledge Gaps

3
Do germline KDM3B variants predispose to childhood hematologic malignancy, and should people with Diets-Jongmans syndrome have any cancer surveillance?
OPEN QUESTION OPEN dijos_cancer_predisposition
Attached to
phenotypes#Acute myeloid leukemia phenotypes#Hodgkin lymphoma pathophysiology#Impaired Hematopoietic Stem and Progenitor Cell Differentiation
Two of the 17 founding individuals had a childhood hematologic malignancy, but both were recruited through a childhood cancer predisposition exome study, which introduces ascertainment bias. None of the later case reports and series cited in this entry (about ten further individuals) describes a malignancy, though follow-up in them is short. Separately, KDM3B lies in the 5q31 region lost in myeloid neoplasms and was proposed as a candidate somatic tumor suppressor there, and homozygous Kdm3b-null mice have hematopoietic abnormalities resembling myelodysplastic syndrome. The somatic evidence is not uniformly tumor-suppressive: in other leukemia cell work KDM3B activates the LMO2 oncogene and represses differentiation. None of this somatic or homozygous-model evidence establishes that a single germline loss-of-function allele raises cancer risk, and no surveillance guideline addresses the syndrome. One later report cites the leukemia association when weighing growth hormone therapy.
Proposed experiments
Malignancy incidence in individuals ascertained for developmental phenotypes
exp_dijos_malignancy_incidence_cohort
Follow individuals with DIJOS ascertained through developmental or growth referral (not through cancer studies) and compare observed with expected childhood hematologic malignancy incidence.
Hematopoiesis in Kdm3b heterozygous mice
exp_kdm3b_heterozygous_hematopoiesis
Test whether heterozygous, rather than homozygous-null, Kdm3b mice develop myelodysplasia-like changes or leukemia with aging or cooperating lesions.
Show evidence (6 references)
PMID:29351919 SUPPORT Human Clinical
"In addition, we identified two genes, KDM3B and TYK2, which are possibly involved in genetic cancer predisposition."
The childhood cancer predisposition exome study through which the two affected individuals were ascertained proposes KDM3B only as a possible predisposition gene.
PMID:11687974 SUPPORT In Vitro
"We propose 5qNCA is a good candidate for the del(5q) tumor suppressor gene based on its predicted function and growth suppressive activities"
Somatic context only. 5qNCA is the former name of KDM3B; proposed as a 5q31 myeloid tumor suppressor candidate from somatic deletion mapping and cell-line growth suppression, not from germline data.
PMID:21536236 SUPPORT Human Clinical
"suggests that the proximal boundary of the common deleted region may lie within the KDM3B gene"
Somatic context only: a myelodysplastic-syndrome case with a cryptic 5q31.2 deletion places the deleted-region boundary within KDM3B.
+ 3 more references
Do the disease-associated KDM3B missense variants reduce demethylase activity (haploinsufficiency-equivalent), or act by another mechanism, and does variant class predict neurodevelopmental severity?
KNOWLEDGE GAP OPEN dijos_missense_mechanism
Attached to
pathophysiology#KDM3B Heterozygous Loss of Function genetic#KDM3B
Haploinsufficiency is inferred from truncating and splice variants. About half of reported variants are missense, and their effect on demethylase activity has not been measured: the one reported assessment of a missense variant is an in silico structural prediction. A later review suggests that truncating variants may be associated with milder neurodevelopmental involvement than missense variants, which would imply that some missense variants act other than by simple loss of function, but that observation rests on small numbers.
Proposed experiments
Demethylase activity of patient missense variants
exp_kdm3b_missense_demethylase_assay
Measure H3K9me1/2 (and H4R3me2s) demethylase activity and protein stability of each reported missense variant against wild type at matched expression levels.
Show evidence (2 references)
PMID:41898828 SUPPORT Computational
"Experimental validation is required to confirm the predicted local conformational changes and their functional implications for KDM3B enzymatic activity."
The only reported assessment of a disease-associated missense variant is an in silico structural prediction, which its authors state needs experimental validation.
PMID:41898828 SUPPORT Human Clinical
"This finding suggests that LOF variants may confer a relatively milder neurodevelopmental phenotype"
Tentative genotype-phenotype suggestion from pooled small numbers.
Is the cerebellar motor-memory consolidation deficit of Kdm3b heterozygous mice a valid model of the developmental delay and intellectual disability of Diets-Jongmans syndrome?
HUMAN MODEL MISMATCH OPEN dijos_mouse_to_human_neurodevelopment
Attached to
pathophysiology#Altered Expression of Plasticity-Related Genes pathophysiology#Impaired Memory Consolidation
The heterozygous mouse is the right genetic model for a haploinsufficiency disorder, and it shows increased H3K9me2 and altered plasticity-gene expression in the cerebellum. But its phenotype is a selective deficit in consolidating one cerebellum-dependent memory, with normal acquisition and basal performance, whereas the human syndrome is global developmental and language delay beginning in infancy. No developmental, cortical or language-relevant phenotype has been reported in the mouse, and no patient-derived neural cells have been studied.
Proposed experiments
Patient-derived neuronal chromatin and transcriptome profiling
exp_kdm3b_patient_ipsc_neurons
Profile H3K9me2 and gene expression in iPSC-derived cortical neurons from individuals with truncating and missense KDM3B variants against isogenic corrected controls.
Show evidence (1 reference)
PMID:34217333 SUPPORT Model Organism
"In the cerebellum-dependent optokinetic response (OKR) learning, Kdm3b+/- mice show deficits in memory consolidation, whereas they are normal in basal oculomotor performance and OKR acquisition."
The mouse phenotype is narrow and adult-behavioral, unlike the human developmental phenotype.
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Pathophysiology

6
KDM3B Heterozygous Loss of Function
Mechanism confidence: Provisional
A heterozygous germline KDM3B variant reduces functional KDM3B, a JmjC-domain demethylase of H3K9me1/2. Haploinsufficiency is the proposed mechanism on the strength of the nonsense, frameshift and splice variants (one splice variant shown to produce truncated transcripts) and the gene's constraint against loss of function. It is not established for the missense variants, whose effect on demethylase activity has not been measured experimentally. The confidence is therefore PROVISIONAL rather than ESTABLISHED.
KDM3B hgnc:1337 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KDM3B (hgnc:1337). hgnc:1337 is a gene from the HUGO Gene Nomenclature Committee.
histone H3K9me1/me2 demethylase activity GO:0140683 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased histone H3K9me1/me2 demethylase activity, annotated with histone H3K9me/H3K9me2 demethylase activity (GO:0140683). GO:0140683 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Increased H3K9 Methylation at KDM3B Target Loci Reduced KDM3B dosage lowers removal of H3K9me1/2 at the loci it acts on.
Show evidence (4 references)
PMID:30929739 SUPPORT Human Clinical
"We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome."
The founding cohort proposes haploinsufficiency from the variant spectrum.
PMID:36757469 SUPPORT In Vitro
"Transcriptional experiments of the splicing variant c.5070 + 1G > A revealed aberrant transcripts leading to truncated protein products."
Minigene evidence that a canonical splice variant yields truncated products, consistent with loss of function.
PMID:23593242 SUPPORT In Vitro
"We show that full-length KDM3A and KDM3B are H3K9me1/2 histone demethylases whereas we fail to observe histone demethylase activity for JMJD1C using immunocytochemical and biochemical approaches."
Establishes KDM3B's substrate specificity (H3K9me1/2), the activity the GO binding records.
+ 1 more reference
Increased H3K9 Methylation at KDM3B Target Loci
Mechanism confidence: Provisional
With less KDM3B, repressive H3K9me1/2 accumulates at its target loci. This has been shown in Kdm3b heterozygous mouse cerebellum (H3K9me2) and in Kdm3b knockout mouse ovary and uterus (H3K9me1/2/3). In homozygous Jmjd1b-null mouse hematopoietic cells, symmetric dimethylation of histone H4 arginine 3 (H4R3me2s) also fails to be removed at a distinct set of genes. The state has not been measured in cells or tissue from people with the syndrome.
cerebellar granule cell CL:0001031 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebellar granule cell (CL:0001031). CL:0001031 is a cell type from the Cell Ontology.
epigenetic regulation of gene expression GO:0040029 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal epigenetic regulation of gene expression (GO:0040029). GO:0040029 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Kdm3b heterozygous knockout mouse Mouse recapitulates Heterozygous loss raises H3K9me2 in cerebellar granule cells, matching the dosage of the human disorder.
Downstream
Altered Expression of Plasticity-Related Genes H3K9me2 is a repressive mark; its accumulation is expected to lower activation of KDM3B target genes. Shown for plasticity-related genes in heterozygous mouse cerebellum.
Reduced Circulating IGF-1 In Kdm3b knockout mice, loss of Kdm3b lowers renal IGFBP-3 expression and circulating IGF-1. The chromatin intermediates between Kdm3b loss and reduced IGFBP-3 expression were not characterized.
Impaired Hematopoietic Stem and Progenitor Cell Differentiation In homozygous Jmjd1b-null mice, failure to demethylate H4R3me2s and/or H3K9me2 blocks activation of genes needed for hematopoietic stem and progenitor cell differentiation.
Show evidence (2 references)
PMID:25892958 SUPPORT Model Organism
"these female reproductive phenotypes were associated with significantly increased levels of H3K9me1/2/3 in the ovary and uterus."
Kdm3b loss raises H3K9 methylation in vivo in the tissues examined.
PMID:29641999 SUPPORT Model Organism
"knockout of JMJD1B blocks demethylation of H4R3me2s and/or H3K9me2 at distinct clusters of genes and impairs the activation of genes important for HSPC differentiation and development."
In homozygous knockout hematopoietic cells, loss of JMJD1B (KDM3B) leaves H3K9me2 and H4R3me2s in place at specific gene clusters.
Impaired Memory Consolidation
Mechanism confidence: Hypothetical
Kdm3b heterozygous mice have normal basal oculomotor performance and normal acquisition of cerebellum-dependent optokinetic learning but fail to consolidate the memory. This is the only neural-plasticity phenotype reported for a Kdm3b haploinsufficiency model. Its relevance to the human intellectual disability and developmental delay is an inference, and the edges from this node to those phenotypes carry no direct evidence.
motor learning GO:0061743 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased motor learning (GO:0061743). GO:0061743 is a biological process from the Gene Ontology. ↓ DECREASED memory GO:0007613 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased memory (GO:0007613). GO:0007613 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Kdm3b heterozygous knockout mouse Mouse partially recapitulates Deficit in consolidation of cerebellum-dependent optokinetic memory.
Downstream
Intellectual disability Inferred by analogy with the module chain; no study links the mouse memory-consolidation deficit to the human cognitive phenotype.
Global developmental delay Inferred by analogy with the module chain; not directly tested.
Delayed speech and language development Inferred by analogy with the module chain; not directly tested.
Motor delay Inferred; the mouse deficit is in cerebellar motor-memory consolidation, whereas the human phenotype is delayed motor milestones.
Show evidence (1 reference)
PMID:34217333 SUPPORT Model Organism
"In the cerebellum-dependent optokinetic response (OKR) learning, Kdm3b+/- mice show deficits in memory consolidation, whereas they are normal in basal oculomotor performance and OKR acquisition."
Direct behavioral evidence of the plasticity deficit in the haploinsufficiency model.
Reduced Circulating IGF-1
Mechanism confidence: Hypothetical
In Kdm3b knockout mice, loss of Kdm3b reduces renal IGFBP-3 expression and circulating IGFBP-3, which accelerates IGF-1 degradation and lowers circulating IGF-1, with restricted postnatal growth. A later review proposes this as the explanation for the short stature of people with KDM3B variants; it has not been demonstrated in patients. This mouse mechanism is IGF-1 loss through IGFBP-3, not growth hormone deficiency; growth hormone deficiency, documented in one individual, is recorded separately as a phenotype.
insulin-like growth factor receptor signaling pathway GO:0048009 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased insulin-like growth factor receptor signaling pathway (GO:0048009). GO:0048009 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Kdm3b knockout mouse (growth) Mouse recapitulates Kdm3b ablation reduces IGFBP-3 and circulating IGF-1 with restricted postnatal growth.
Downstream
Short stature Lower circulating IGF-1 restricts postnatal somatic growth in the mouse; proposed, not demonstrated, as the cause of human short stature.
Show evidence (2 references)
PMID:25892958 SUPPORT Model Organism
"We found that Kdm3b ablation decreased IGFBP-3 expressed in the kidney by 53% and significantly reduced IGFBP-3 in the blood, which caused an accelerated degradation of IGF-1 and a 36% decrease in circulating IGF-1 concentration."
Mouse knockout evidence for the IGFBP-3/IGF-1 mechanism.
PMID:41898828 SUPPORT INDIRECT REVIEW SYNTHESIS Model Organism
"Notably, postnatal somatic growth restriction in Kdm3b-null mice is closely associated with reduced levels of insulin-like growth factor binding protein-3 (IGFBP-3) in the kidney and blood, as well as reduced serum insulin-like growth factor-1 (IGF-1)."
The review restates the mouse IGFBP-3/IGF-1 result as the proposed explanation for short stature in this syndrome; the quoted sentence describes knockout mice, not patients, so the human claim follows only by extrapolation.
Impaired Hematopoietic Stem and Progenitor Cell Differentiation
Mechanism confidence: Hypothetical
Homozygous Jmjd1b (Kdm3b) knockout mice fail to activate genes needed for hematopoietic stem and progenitor cell differentiation and show leukocytosis, mild anemia and granulocytosis, which the authors correlate with myelodysplastic syndrome. This is a homozygous-null phenotype. It has not been shown in heterozygous animals or in people with the syndrome, and it is deliberately not connected to the leukemia, lymphoma or neutropenia phenotypes, whose relationship to germline KDM3B variants is unestablished (see the cancer-predisposition discussion).
hematopoietic stem cell CL:0000037 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hematopoietic stem cell (CL:0000037). CL:0000037 is a cell type from the Cell Ontology.
hematopoietic progenitor cell differentiation GO:0002244 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased hematopoietic progenitor cell differentiation (GO:0002244). GO:0002244 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Jmjd1b knockout mouse (hematopoiesis) Mouse recapitulates Homozygous null mice show hematopoietic defects resembling myelodysplastic syndrome.
Show evidence (2 references)
PMID:29641999 SUPPORT Model Organism
"Consequently, JMJD1B-/- mice show defects in hematopoiesis."
Homozygous knockout evidence for the hematopoietic defect.
PMID:29641999 SUPPORT Model Organism
"Consequently, JMJD1B−/− mice displayed abnormal phenotypes in the hematopoietic system, which are correlated with myelodysplastic syndrome (MDS), including leukocytosis, mild anemia, and granulocytosis."
Describes the blood-count phenotype of the null mice and its resemblance to myelodysplastic syndrome.
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Pathograph

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

30
Blood 3
Transient neutropenia Transiently decreased total neutrophil count HP:0410255 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Transient neutropenia, annotated with Transiently decreased total neutrophil count (HP:0410255). HP:0410255 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36757469 SUPPORT Human Clinical
"Both patients had additional clinical presentations, and patient 1 had transient neutropenia."
Single-case report of transient neutropenia.
Acute myeloid leukemia HP:0004808 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acute myeloid leukemia (HP:0004808), qualified as childhood onset. HP:0004808 is a phenotype from the Human Phenotype Ontology.
Onset: CHILDHOOD
Show evidence (1 reference)
PMID:30929739 SUPPORT Human Clinical
"Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood."
One of the two childhood cancers in the founding cohort was acute myeloid leukemia.
Hodgkin lymphoma HP:0012189 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hodgkin lymphoma (HP:0012189), qualified as childhood onset. HP:0012189 is a phenotype from the Human Phenotype Ontology.
Onset: CHILDHOOD
Show evidence (1 reference)
PMID:30929739 SUPPORT Human Clinical
"Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood."
The other childhood cancer in the founding cohort was Hodgkin lymphoma.
Cardiovascular 1
Cardiomyopathy HP:0001638 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomyopathy (HP:0001638). HP:0001638 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36757469 SUPPORT Human Clinical
"Neutropenia and cardiomyopathy are newly found presentations of Diets-Jongmans syndrome."
Single-case report of cardiomyopathy.
Digestive 3
Feeding difficulties in infancy FREQUENT HP:0008872 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neonatal feeding difficulties, annotated with Feeding difficulties in infancy (HP:0008872), qualified as neonatal onset. HP:0008872 is a phenotype from the Human Phenotype Ontology.
Onset: NEONATAL
Show evidence (2 references)
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"Neonatal feeding difficulties | 4/4 | 9/17 | 0/1 | 1/1 | 0/2 | 0/1 | 0/1 | 14/27 (51.9%)"
Pooled frequency (Table 3 of the review): 9 of 17 founding individuals and 14 of 27 published individuals, the FREQUENT band.
PMID:41898828 SUPPORT Human Clinical
"feeding difficulties were present in all of them, followed by the growth retardation."
Feeding difficulties in all four individuals of a later series, before the growth restriction.
Umbilical hernia OCCASIONAL HP:0001537 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Umbilical hernia (HP:0001537). HP:0001537 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"Umbilical hernia | 0/4 | 2/17 | 0/1 | 0/1 | 1/2 | 0/1 | 0/1 | 3/27 (11.1%)"
Pooled frequency (Table 3 of the review): 2 of 17 founding individuals and 3 of 27 published individuals, the OCCASIONAL band.
Inguinal hernia OCCASIONAL HP:0000023 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inguinal hernia (HP:0000023). HP:0000023 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"Inguinal hernia | 0/4 | 2/17 | 0/1 | 0/1 | 0/2 | 0/1 | 0/1 | 2/27 (7.4%)"
Pooled frequency (Table 3 of the review): 2 of 17 founding individuals and 2 of 27 published individuals, the OCCASIONAL band.
Ear 2
Hearing impairment OCCASIONAL HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing loss, annotated with Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"Hearing loss | 0/4 | 4/17 | 0/1 | 0/1 | 0/2 | 0/1 | 0/1 | 4/27 (14.8%)"
Pooled frequency (Table 3 of the review): 4 of 17 founding individuals and 4 of 27 published individuals, the OCCASIONAL band.
PMID:41408900 SUPPORT Human Clinical
"Clinically, Patient 1 had severe developmental retardation, deafness and autistic tilt, whereas Patient 2 had milder retardation and autistic behaviours with normal hearing."
A later case with deafness.
Long ear HP:0400004 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long ears, annotated with Long ear (HP:0400004). HP:0400004 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30929739 SUPPORT Human Clinical
"The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella."
Long ears are among the characteristic facial features of the founding cohort.
Endocrine 1
Growth hormone deficiency Decreased response to growth hormone stimulation test HP:0000824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth hormone deficiency, annotated with Decreased response to growth hormone stimulation test (HP:0000824). HP:0000824 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41878155 SUPPORT Human Clinical
"Biochemical evaluation revealed growth hormone deficiency, which was confirmed by two stimulation tests."
Documents growth hormone deficiency confirmed by two stimulation tests in an individual with molecularly confirmed Diets-Jongmans syndrome.
Genitourinary 1
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"Cryptorchidism | 0/4 | 1/17 | 0/1 | 0/1 | 0/2 | 0/1 | 0/1 | 1/27 (3.7%)"
Pooled frequency (Table 3 of the review): 1 of 17 founding individuals and 1 of 27 published individuals.
PMID:41914422 SUPPORT Human Clinical
"A 5-year-3-month-old boy presented with intellectual disability, autism spectrum disorder, short stature, long ears, large auricles, a broad nasal tip, a pointed chin, and cryptorchidism."
Cryptorchidism in a later case.
Head and Neck 6
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:41239187 SUPPORT Human Clinical
"a seven-month-old male patient evaluated for small stature, microcephaly, facial asymmetry, and mild gross motor delays"
Microcephaly in an infant with the syndrome.
Broad nasal tip HP:0000455 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad nasal tip (HP:0000455). HP:0000455 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"The core phenotypes include mild-to-moderate intellectual disability or developmental delay, predominantly affecting motor and language function, facial dysmorphism (long ears, broad nasal tip, low columella, thin lips and wide mouth), growth retardation, and neonatal feeding difficulties."
A broad nasal tip is one of the recurrent facial features of the syndrome.
PMID:30929739 SUPPORT Human Clinical
"By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID."
The facial features form a recognizable gestalt.
Wide mouth HP:0000154 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide mouth (HP:0000154). HP:0000154 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30929739 SUPPORT Human Clinical
"The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella."
A wide mouth is among the characteristic facial features of the founding cohort.
Thin upper lip vermilion HP:0000219 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin upper lip vermilion (HP:0000219). HP:0000219 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"The disorder is characterized by developmental delay, mild-to-moderate intellectual disability and facial dysmorphism, which includes macrostomia, pointed chin, long ears, broad nasal bridge and thin upper vermilion."
A thin upper vermilion is one of the recurrent facial features of the syndrome.
Pointed chin HP:0000307 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pointed chin (HP:0000307). HP:0000307 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30929739 SUPPORT Human Clinical
"The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella."
A pointed chin is among the characteristic facial features of the founding cohort.
Low hanging columella HP:0009765 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-hanging columella, annotated with Low hanging columella (HP:0009765). HP:0009765 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30929739 SUPPORT Human Clinical
"The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella."
A low columella is among the characteristic facial features of the founding cohort.
Musculoskeletal 3
Hypotonia OCCASIONAL HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Childhood hypotonia, annotated with Hypotonia (HP:0001252), qualified as childhood onset. HP:0001252 is a phenotype from the Human Phenotype Ontology.
Onset: CHILDHOOD
Show evidence (1 reference)
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"Childhood hypotonia | 0/4 | 5/17 | 0/1 | 0/1 | 0/2 | 0/1 | 1/1 | 6/27 (22.2%)"
Pooled frequency (Table 3 of the review): 5 of 17 founding individuals and 6 of 27 published individuals, the OCCASIONAL band.
Joint hypermobility HP:0001382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint hypermobility (HP:0001382). HP:0001382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30929739 SUPPORT Human Clinical
"The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella."
Joint hypermobility is one of the shared features of the founding cohort.
Congenital diaphragmatic hernia HP:0000776 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diaphragmatic hernia, annotated with Congenital diaphragmatic hernia (HP:0000776), qualified as congenital onset. HP:0000776 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (1 reference)
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"Additional variable features encompass autism-spectrum disorder, attention-deficit hyperactivity disorder (ADHD), and congenital diaphragmatic, umbilical or inguinal hernias"
The review lists congenital diaphragmatic hernia among the variable features of the syndrome.
Nervous System 8
Global developmental delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263), qualified as infantile onset. HP:0001263 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (2 references)
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"Intellectual disability or developmental delay | 1/4 | 16/17 | 0/1 | 1/1 | 2/2 | 1/1 | 1/1 | 22/27 (81.5%)"
Pooled frequency (Table 3 of the review): 16 of 17 founding individuals and 22 of 27 published individuals.
PMID:41898828 SUPPORT Human Clinical
"Unlike other patients with DIJOS who presented with growth retardation, mild to moderate intellectual developmental disorder and facial dysmorphism, our patients mainly presented with growth retardation, while their neurodevelopment was either normal or mildly impaired."
Shows that developmental delay is not universal.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability, mild to moderate, annotated with Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"The core phenotypes include mild-to-moderate intellectual disability or developmental delay, predominantly affecting motor and language function, facial dysmorphism (long ears, broad nasal tip, low columella, thin lips and wide mouth), growth retardation, and neonatal feeding difficulties."
Intellectual disability in this syndrome is characteristically mild to moderate.
PMID:42186234 SUPPORT Human Clinical
"Scores on intelligence measures for Cases 1-3 (aged 19, 21, and 46) ranged from Below Average to Average, though were predominantly within normative limits."
Some affected relatives do not have intellectual disability.
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), qualified as infantile onset. HP:0000750 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (1 reference)
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"The core phenotypes include mild-to-moderate intellectual disability or developmental delay, predominantly affecting motor and language function, facial dysmorphism (long ears, broad nasal tip, low columella, thin lips and wide mouth), growth retardation, and neonatal feeding difficulties."
The developmental delay predominantly affects motor and language function.
Motor delay FREQUENT HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270), qualified as infantile onset. HP:0001270 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (1 reference)
PMID:41898828 SUPPORT Human Clinical
"Motor delay | 0/4 | 17/17 | 1/1 | 1/1 | 0/2 | 0/1 | 0/1 | 19/27 (70.4%)"
Pooled frequency (Table 3 of the review), FREQUENT band.
Specific learning disability HP:0001328 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Learning difficulties, annotated with Specific learning disability (HP:0001328). HP:0001328 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42186234 SUPPORT Human Clinical
"All cases presented with learning difficulties, mental health symptoms, and features of autism spectrum disorder and attention-deficit hyperactivity disorder."
Learning difficulties in every affected family member.
Attention deficit hyperactivity disorder OCCASIONAL HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"ADHD | 1/4 | 4/17 | 0/1 | 0/1 | 0/2 | 0/1 | 0/1 | 5/27 (18.5%)"
Pooled frequency (Table 3 of the review): 4 of 17 founding individuals and 5 of 27 published individuals, the OCCASIONAL band.
PMID:42186234 SUPPORT Human Clinical
"All cases presented with learning difficulties, mental health symptoms, and features of autism spectrum disorder and attention-deficit hyperactivity disorder."
ADHD features in all four members of one affected family.
Autistic behavior OCCASIONAL HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism spectrum disorder, annotated with Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"Autism spectrum disorder | 0/4 | 3/17 | 0/1 | 1/1 | 0/2 | 0/1 | 0/1 | 4/27 (14.8%)"
Pooled frequency (Table 3 of the review): 3 of 17 founding individuals and 4 of 27 published individuals, the OCCASIONAL band.
PMID:41408900 SUPPORT Human Clinical
"Here we report on two unrelated patients with global developmental delay and autistic features"
Autistic features in two further unrelated individuals.
PMID:41914422 SUPPORT Human Clinical
"A 5-year-3-month-old boy presented with intellectual disability, autism spectrum disorder, short stature, long ears, large auricles, a broad nasal tip, a pointed chin, and cryptorchidism."
A further case report with autism spectrum disorder.
Seizure OCCASIONAL HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epilepsy, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"Epilepsy | 0/4 | 3/17 | 0/1 | 0/1 | 0/2 | 0/1 | 0/1 | 3/27 (11.1%)"
Pooled frequency (Table 3 of the review): 3 of 17 founding individuals and 3 of 27 published individuals, the OCCASIONAL band.
Growth 2
Short stature FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41898828 SUPPORT REVIEW SYNTHESIS Human Clinical
"Height (−2 sd) | 4/4 | 8/17 | 1/1 | 1/1 | 0/2 | 0/1 | 1/1 | 15/27 (55.6%)"
Pooled frequency (Table 3 of the review): height below -2 SD in 8 of 17 founding individuals and 15 of 27 published individuals, the FREQUENT band.
PMID:41898828 SUPPORT Human Clinical
"our patients mainly presented with growth retardation, while their neurodevelopment was either normal or mildly impaired"
Growth restriction can be the leading feature.
Decreased body weight FREQUENT HP:0004325 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low weight for age, annotated with Decreased body weight (HP:0004325). HP:0004325 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41898828 SUPPORT Human Clinical
"Weight (−2 sd) | 4/4 | 11/17 | 1/1 | 0/1 | 0/2 | 0/1 | 0/1 | 16/27 (59.3%)"
Pooled frequency (Table 3 of the review), FREQUENT band.
🧬

Genetic Associations

1
KDM3B
Gene: KDM3B hgnc:1337 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KDM3B (hgnc:1337). hgnc:1337 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (5 references)
CGGV:assertion_4be69167-24df-4a3b-81c7-429399d0c727-2024-02-21T050000.000Z SUPPORT Other
"KDM3B | HGNC:1337 | syndromic intellectual disability | MONDO:0000508 | AD | Definitive"
ClinGen Intellectual Disability and Autism GCEP classifies the KDM3B relationship with autosomal dominant syndromic intellectual disability as Definitive.
PMID:30929739 SUPPORT Human Clinical
"By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature."
Founding report establishing KDM3B as the causal gene.
PMID:41898828 SUPPORT Computational
"The c.4580T>C p.(Leu1527Pro) missense variant is located within the JmjC domain and is predicted to impair demethylase activity."
A reported missense variant lies in the catalytic JmjC domain; the functional consequence is an in silico prediction, not a measurement.
+ 2 more references
💊

Medical Actions

2
Recombinant human growth hormone
Action: recombinant human growth hormone therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is recombinant human growth hormone therapy, annotated with Hormone Replacement Therapy (NCIT:C15599). NCIT:C15599 is a clinical intervention from the NCI Thesaurus. Ontology label: Hormone Replacement Therapy NCIT:C15599
Agent: somatropin NCIT:C837 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses somatropin (NCIT:C837). NCIT:C837 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
Recombinant human growth hormone has been given to one individual with the syndrome, whose height moved from below -3 SD to between -1 and -2 SD over about six years, with IGF-1, thyroid function and glucose remaining within normal ranges on monitoring. The treating authors describe the effect as partially promoting growth and do not report growth hormone deficiency in this individual, so the indication was short stature rather than a documented hormone deficit; growth hormone deficiency in this syndrome, documented in two other individuals, is recorded separately as a phenotype. The treating authors caution that, because KDM3B has been linked to myelodysplastic syndrome and acute myeloid leukemia, the potential oncogenic risk of growth hormone must be weighed; no guideline addresses this. Evidence is a single treated case.
Mechanism Target:
Short stature — Growth-promoting therapy aimed at the short stature; one treated case.
Show evidence (1 reference)
PMID:41898828 SUPPORT Human Clinical
"One patient treated with recombinant human growth hormone (rhGH) showed improvement in growth."
Single-case evidence of growth response.
Show evidence (3 references)
PMID:41898828 SUPPORT Human Clinical
"One patient treated with recombinant human growth hormone (rhGH) showed improvement in growth."
Growth response in one treated individual.
PMID:41898828 SUPPORT Human Clinical
"For the first time, we demonstrate that rhGH therapy can partially promote growth, providing novel evidence for genetic counseling."
The treating authors characterize the effect as partial growth promotion, not as replacement of a documented growth hormone deficit.
PMID:41898828 SUPPORT Human Clinical
"the potential oncogenic risk of rhGH must be carefully weighed"
The treating authors' caution about growth hormone given KDM3B's links to myeloid neoplasia.
Early developmental rehabilitation
Action: developmental rehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is 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
Management is supportive and multidisciplinary; early referral to rehabilitation services with individualized programs for cognitive and motor deficits is recommended. No disease-specific therapy exists.
Mechanism Target:
Global developmental delay — Supportive therapy for developmental delay.
Show evidence (1 reference)
PMID:41898828 SUPPORT Human Clinical
"Children with developmental delay should be referred early to rehabilitation services."
Management recommendation from the most recent case series and review.
📊

Prevalence

1
Worldwide, published molecularly confirmed individuals
Cases In Literature Ultra Rare
A 2026 literature review counted 27 published individuals (23 from six earlier reports plus its own four). Several further case reports have appeared since, so this is a lower bound on published cases, not a population frequency.
Show evidence (1 reference)
PMID:41898828 SUPPORT Human Clinical
"Combined with our study, a total of 27 patients with DIJOS have been described to date."
Pooled count of published individuals at the time of that review.
🐁

Animal Models

3
Kdm3b heterozygous knockout mouse
Species
Mouse
Genotype
Kdm3b+/-
Publication
PMID:34217333
Pathograph links
Increased H3K9 Methylation at KDM3B Target Loci recapitulates fidelity: moderate observes: molecular Heterozygous loss raises H3K9me2 in cerebellar granule cells, matching the dosage of the human disorder.
Limitations: Measured in adult cerebellum only; the developing brain and other regions were not examined.
Show evidence (1 reference)
PMID:34217333 SUPPORT Model Organism
"H3K9 di-methylation is significantly increased selectively in the granule cell layer of the cerebellum of Kdm3b+/- mice."
Supports the model as informative for the chromatin-state node.
Impaired Memory Consolidation partially recapitulates fidelity: low observes: organism Deficit in consolidation of cerebellum-dependent optokinetic memory.
Limitations: A selective adult memory-consolidation deficit, not the global developmental and language delay of the human syndrome.
Show evidence (1 reference)
PMID:34217333 SUPPORT Model Organism
"In the cerebellum-dependent optokinetic response (OKR) learning, Kdm3b+/- mice show deficits in memory consolidation, whereas they are normal in basal oculomotor performance and OKR acquisition."
The behavioral phenotype of the model.
Kdm3b knockout mouse (growth)
Species
Mouse
Genotype
Kdm3b knockout (Kdm3bKO)
Publication
PMID:25892958
Pathograph links
Reduced Circulating IGF-1 recapitulates fidelity: unknown observes: organism Kdm3b ablation reduces IGFBP-3 and circulating IGF-1 with restricted postnatal growth.
Limitations: A knockout rather than a heterozygous model, and IGF-1 has not been measured systematically in patients, so whether the same mechanism underlies human short stature is untested.
Show evidence (1 reference)
PMID:25892958 SUPPORT Model Organism
"we generated Kdm3b knockout (Kdm3bKO) mice and observed restricted postnatal growth and female infertility in these mice."
The knockout shows the growth phenotype.
Jmjd1b knockout mouse (hematopoiesis)
Species
Mouse
Genotype
Jmjd1b-/-
Publication
PMID:29641999
Pathograph links
Impaired Hematopoietic Stem and Progenitor Cell Differentiation recapitulates fidelity: unknown observes: organism Homozygous null mice show hematopoietic defects resembling myelodysplastic syndrome.
Limitations: Homozygous-null genotype; people with the syndrome are heterozygous, and no hematopoietic phenotype has been described in heterozygous mice.
Show evidence (1 reference)
PMID:29641999 SUPPORT Model Organism
"Consequently, JMJD1B-/- mice show defects in hematopoiesis."
The knockout shows the hematopoietic defect.
{ }

Source YAML

click to show 
name: Diets-Jongmans Syndrome
creation_date: "2026-09-23T00:00:00Z"
category: Mendelian
synonyms:
- DIJOS
- Intellectual developmental disorder with distinctive facial dysmorphism
- KDM3B-related intellectual disability-facial dysmorphism-short stature syndrome
- KDM3B-related neurodevelopmental disorder
description: >-
  Diets-Jongmans syndrome (DIJOS) is an autosomal dominant neurodevelopmental
  syndrome caused by heterozygous germline variants in KDM3B (5q31.2), which
  encodes a JmjC-domain histone demethylase that removes mono- and
  di-methylation from histone H3 lysine 9 (H3K9me1/2) and, in mouse
  hematopoietic cells, symmetric dimethylation from histone H4 arginine 3.
  The syndrome was delineated in 2019 from 17 individuals (14 probands and 3
  similarly affected parents) and is defined by developmental delay or mild to
  moderate intellectual disability affecting motor and language function,
  short stature, neonatal feeding difficulties, and a facial gestalt (long
  ears, broad nasal tip, low-hanging columella, wide mouth, thin upper lip
  vermilion, pointed chin) that computational facial analysis separates from
  other intellectual-disability syndromes. Behavioral features (ADHD, autism
  spectrum disorder), childhood hypotonia, epilepsy, joint hypermobility,
  hearing loss and isolated congenital anomalies (hernias, cryptorchidism) are
  variably present. Most variants arise de novo; transmission
  from similarly or more mildly affected parents is documented, and later
  reports describe individuals whose presentation is predominantly growth
  restriction with normal or mildly impaired cognition, so expressivity is
  markedly variable. Two of the 17 founding individuals developed a childhood
  hematologic malignancy (acute myeloid leukemia, Hodgkin lymphoma), but both
  were ascertained through a childhood cancer predisposition study, and whether
  germline KDM3B variants raise cancer risk is unresolved.
disease_term:
  preferred_term: Diets-Jongmans syndrome
  description: >-
    Autosomal dominant KDM3B-related syndrome of developmental delay or
    intellectual disability, short stature and facial dysmorphism (OMIM:618846).
  term:
    id: MONDO:0030012
    label: Diets-Jongmans syndrome
parents:
- Neurodevelopmental disorder
- Chromatinopathy
- Epigenetic machinery disorder
notes: >-
  Lump/split. The entry is a single Disease: DIJOS has one causal gene, no MONDO
  subtypes, and one conserved mechanism (reduced KDM3B dosage), and no
  allelic subtype has been proposed. The growth-predominant presentations with
  normal or mildly impaired neurodevelopment (PMID:41898828, PMID:41239187, and
  the short-statured transmitting mother without intellectual disability in
  PMID:41878155) are modeled as variable expressivity within the one entity
  rather than as a separate subtype, because they occur in the same families
  and with the same variant classes as the classic presentation. A tentative
  genotype-phenotype suggestion (truncating variants associated with milder
  neurodevelopmental involvement than missense variants; PMID:41898828) is
  recorded as an open question rather than used to split the entry.

  Ontology duplication. MONDO currently carries two classes for this disease:
  MONDO:0030012 "Diets-Jongmans syndrome" (xref OMIM:618846, a child of
  "hereditary disease") and MONDO:0858999 "KDM3B-related intellectual
  disability-facial dysmorphism-short stature syndrome" (xref ORPHA:633004, a
  child of "multiple congenital anomalies/dysmorphic syndrome-intellectual
  disability"). Orphanet itself maps ORPHA:633004 to OMIM:618846 as an exact
  match and lists "Diets-Jongmans Syndrome" as its synonym, so the two MONDO
  classes denote one disease; MONDO:0858999 is recorded as an exact mapping
  below. Orphanet's own ORPHA:633004 row names MONDO:0858999, not
  MONDO:0030012.

  Germline disorder versus somatic tumor biology. KDM3B lies in the 5q31
  region deleted in myeloid neoplasms and was proposed as a candidate 5q31
  myeloid tumor suppressor from somatic studies (PMID:11687974, PMID:21536236,
  PMID:28540746); homozygous Jmjd1b/Kdm3b-null mice show hematopoietic
  abnormalities the authors correlate with myelodysplastic syndrome
  (PMID:29641999). That somatic and model-organism literature is kept in the
  cancer-predisposition discussion below and is not curated as mechanism of
  this germline syndrome. The acute myeloid leukemia and Hodgkin lymphoma
  phenotypes are recorded because individuals with the syndrome were reported
  with them; they are not connected to any pathophysiology node, because
  causality is unestablished and both cases were ascertained through a
  cancer-predisposition study.

  Evidence available for the founding cohort. The founding report
  (PMID:30929739) is not open access: its publisher blocks PMC XML download,
  Europe PMC serves no full text for it, and the only open location Unpaywall
  lists is a publisher PDF that refuses automated retrieval. Only its PubMed
  abstract can be quoted and checked by this repository's reference validator.
  Founding-cohort phenotype counts are therefore cited from the pooled Table 3
  of the 2026 case series and literature review (PMID:41898828), which
  tabulates each feature for the Diets cohort and for all 27 published
  individuals, and features named only in the founding paper's abstract are
  cited there directly. Statements that exist only in the founding paper's full
  text are not curated: the ocular findings (nystagmus, strabismus, refraction
  anomalies), aggressive behavior without a psychiatric diagnosis, hypospadias,
  the per-feature Table 2 denominators, the transient character of the
  epilepsy, the exclusion of loss of heterozygosity and a second KDM3B hit in
  the leukemia, the inconclusive HEK293 H3K9-methylation assay of the missense
  variants, the statement that no genotype-phenotype correlation was observed,
  and the authors' advice against malignancy screening.

  Gaps. No GeneReviews chapter exists (checked against the Bookshelf index and
  PubMed). ClinGen has a Definitive gene-disease validity assertion for KDM3B,
  but it is made against the broader "syndromic intellectual disability"
  (MONDO:0000508), not against MONDO:0030012; ClinGen has no dosage-sensitivity
  curation for KDM3B. No whole-gene or intragenic KDM3B deletion has been
  reported as a cause of the syndrome: the PubMed query "5q31.2 AND deletion AND
  (intellectual OR developmental) AND KDM3B" returned no records, and every
  reported case carries a single-nucleotide, small-indel or splice variant. No
  patient-derived chromatin, transcriptome or DNA-methylation (episignature)
  data exist; the PubMed query "KDM3B AND (episignature OR DNA methylation
  signature)" returned two records, neither about a KDM3B-associated
  syndrome (PMID:31271662 on JMJD1C inhibitors in leukemia cells, PMID:28706564
  on vitamin C and H3K9me2 in mouse embryonic stem cells). No source was found
  that states a numerical recurrence risk, so none is given. A child with
  pulmonary arterial hypertension and interstitial lung disease carrying both a
  KDM3B and a SIN3A variant (PMID:38314229) is not curated as a phenotype,
  because the second diagnosis confounds attribution.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian autosomal dominant syndrome, mostly de novo, caused by
      variants in a chromatin-modifying enzyme.
  - classification_value: NEUROLOGIC
    notes: >-
      The principal clinical burden is developmental and behavioral, managed in
      developmental pediatrics and clinical genetics.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0858999
      label: KDM3B-related intellectual disability-facial dysmorphism-short stature
        syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet
    mapping_justification: >-
      MONDO:0858999 is MONDO's class for ORPHA:633004. Orphanet maps
      ORPHA:633004 to OMIM:618846 (the OMIM entry behind MONDO:0030012) as an
      exact match and gives "Diets-Jongmans Syndrome" as its synonym, so the two
      MONDO classes denote the same disease.
prevalence:
- population: Worldwide, published molecularly confirmed individuals
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A 2026 literature review counted 27 published individuals (23 from six
    earlier reports plus its own four). Several further case reports have
    appeared since, so this is a lower bound on published cases, not a
    population frequency.
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Combined with our study, a total of 27 patients with DIJOS have been
      described to date.
    explanation: >-
      Pooled count of published individuals at the time of that review.
inheritance:
- name: Autosomal dominant, mostly de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  de_novo_rate: >-
    Across the published cases the great majority of variants are de novo, with
    only a minority inherited from a similarly affected parent.
  description: >-
    Heterozygous KDM3B variants cause the syndrome in a dominant manner. Most
    arise de novo, but parent-to-child transmission is documented, including
    from parents with milder phenotypes (a mother with short stature and no
    intellectual disability; a family in which only one of four affected
    relatives met criteria for intellectual developmental disorder), which is
    the basis for recording variable expressivity. Penetrance has not been
    formally estimated.
  evidence:
  - reference: PMID:30929739
    reference_title: "De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By using exome sequencing and a gene matching approach, we identified de
      novo and inherited pathogenic variants in KDM3B in 14 unrelated
      individuals and three affected parents with varying degrees of
      intellectual disability (ID) or developmental delay (DD) and short
      stature.
    explanation: >-
      The founding report identifies both de novo variants and variants
      inherited from affected parents.
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In terms of variant origin, the vast majority were sporadic de novo
      variants, with only a minority being familial.
    explanation: >-
      Pooled variant-origin tally across the published cases, supporting the
      recorded de novo rate.
  - reference: PMID:41878155
    reference_title: "Diets-Jongmans Syndrome due to a Novel KDM3B Variant: The First Molecularly Confirmed Case from Turkey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Short stature without intellectual disability was noted in the mother,
      indicating intrafamilial phenotypic variability.
    explanation: >-
      A transmitting parent with a milder phenotype than her child, supporting
      variable expressivity.
  - reference: PMID:42186234
    reference_title: "The variable neuropsychological profile of Diets-Jongmans syndrome: a case series of four family members."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cognitive profile of DIJOS is more variable than suggested by existing
      literature, with only 1 of 4 family members meeting DSM-5-TR criteria for
      IDD.
    explanation: >-
      Intrafamilial variability in cognitive outcome among relatives sharing one
      variant.
genetic:
- name: KDM3B
  gene_term:
    preferred_term: KDM3B
    term:
      id: hgnc:1337
      label: KDM3B
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Reported disease-associated variants comprise missense, nonsense,
    frameshift and splice-site variants, and missense variants have been
    reported in the catalytic Jumonji-C (JmjC) domain. Whether variant class
    predicts neurodevelopmental severity is unsettled; see the
    missense-mechanism discussion.
  notes: >-
    KDM3B (lysine demethylase 3B; previous symbol JMJD1B) is at 5q31.2. Variant
    origin is recorded as GERMLINE because both de novo and parentally
    transmitted variants are reported (see the inheritance block). ClinGen's
    Definitive classification is for "syndromic intellectual disability"
    (MONDO:0000508), a broader disease concept than this entry.
  evidence:
  - reference: CGGV:assertion_4be69167-24df-4a3b-81c7-429399d0c727-2024-02-21T050000.000Z
    reference_title: "KDM3B / syndromic intellectual disability (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KDM3B | HGNC:1337 | syndromic intellectual disability | MONDO:0000508 | AD | Definitive"
    explanation: >-
      ClinGen Intellectual Disability and Autism GCEP classifies the KDM3B
      relationship with autosomal dominant syndromic intellectual disability as
      Definitive.
  - reference: PMID:30929739
    reference_title: "De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By using exome sequencing and a gene matching approach, we identified de
      novo and inherited pathogenic variants in KDM3B in 14 unrelated
      individuals and three affected parents with varying degrees of
      intellectual disability (ID) or developmental delay (DD) and short
      stature.
    explanation: >-
      Founding report establishing KDM3B as the causal gene.
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The c.4580T>C p.(Leu1527Pro) missense variant is located within the
      JmjC domain and is predicted to impair demethylase activity.
    explanation: >-
      A reported missense variant lies in the catalytic JmjC domain; the
      functional consequence is an in silico prediction, not a measurement.
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among these patients, 23 distinct KDM3B variants have been identified,
      including 12 missense variants, 5 nonsense variants, 4 frameshift variants
      and 2 splice-site variants (Figure 3).
    explanation: >-
      Pooled variant spectrum across the published cases.
  - reference: ORPHA:633004
    reference_title: "KDM3B-related intellectual disability-facial dysmorphism-short stature syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare multiple congenital anomalies/dysmorphic syndrome characterized by
      mild or moderate intellectual disability, developmental delay, short
      stature and facial dysmorphism
    explanation: >-
      Orphanet definition of the KDM3B-related syndrome.
pathophysiology:
- name: KDM3B Heterozygous Loss of Function
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Epigenetic Machinery Component Haploinsufficiency"
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  role: trigger
  description: >-
    A heterozygous germline KDM3B variant reduces functional KDM3B, a JmjC-domain
    demethylase of H3K9me1/2. Haploinsufficiency is the proposed mechanism on
    the strength of the nonsense, frameshift and splice variants (one splice
    variant shown to produce truncated transcripts) and the gene's constraint
    against loss of function. It is not established for the missense variants,
    whose effect on demethylase activity has not been measured experimentally.
    The confidence is therefore PROVISIONAL rather than ESTABLISHED.
  genes:
  - preferred_term: KDM3B
    term:
      id: hgnc:1337
      label: KDM3B
  molecular_functions:
  - preferred_term: histone H3K9me1/me2 demethylase activity
    term:
      id: GO:0140683
      label: histone H3K9me/H3K9me2 demethylase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:30929739
    reference_title: "De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified missense and truncating variants, suggesting that KDM3B
      haploinsufficiency is the underlying mechanism for this syndrome.
    explanation: >-
      The founding cohort proposes haploinsufficiency from the variant spectrum.
  - reference: PMID:36757469
    reference_title: "Two patients with KDM3B variants and new presentations of Diets-Jongmans syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Transcriptional experiments of the splicing variant c.5070 + 1G > A
      revealed aberrant transcripts leading to truncated protein products.
    explanation: >-
      Minigene evidence that a canonical splice variant yields truncated
      products, consistent with loss of function.
  - reference: PMID:23593242
    reference_title: "Protein complex interactor analysis and differential activity of KDM3 subfamily members towards H3K9 methylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that full-length KDM3A and KDM3B are H3K9me1/2 histone
      demethylases whereas we fail to observe histone demethylase activity for
      JMJD1C using immunocytochemical and biochemical approaches.
    explanation: >-
      Establishes KDM3B's substrate specificity (H3K9me1/2), the activity the
      GO binding records.
  - reference: PMID:22615488
    reference_title: "KDM3B is the H3K9 demethylase involved in transcriptional activation of lmo2 in leukemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      KDM3B displayed histone H3K9-me1/2 demethylase activity
    explanation: >-
      Independent biochemical confirmation of H3K9me1/2 demethylase activity.
  downstream:
  - target: Increased H3K9 Methylation at KDM3B Target Loci
    causal_link_type: DIRECT
    description: >-
      Reduced KDM3B dosage lowers removal of H3K9me1/2 at the loci it acts on.
    evidence:
    - reference: PMID:34217333
      reference_title: "Kdm3b haploinsufficiency impairs the consolidation of cerebellum-dependent motor memory in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we used heterozygous Kdm3b knockout (Kdm3b+/-) mice, which show reduced
        lysine 9 on histone 3 (H3K9) demethylase activity. H3K9 di-methylation
        is significantly increased selectively in the granule cell layer of the
        cerebellum of Kdm3b+/- mice.
      explanation: >-
        In a heterozygous (haploinsufficiency) mouse model, halving Kdm3b
        increases H3K9me2 in cerebellar granule cells, supporting this edge.
- name: Increased H3K9 Methylation at KDM3B Target Loci
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Permissive-Repressive Chromatin State Imbalance"
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    With less KDM3B, repressive H3K9me1/2 accumulates at its target loci. This
    has been shown in Kdm3b heterozygous mouse cerebellum (H3K9me2) and in
    Kdm3b knockout mouse ovary and uterus (H3K9me1/2/3). In homozygous
    Jmjd1b-null mouse hematopoietic cells, symmetric dimethylation of histone
    H4 arginine 3 (H4R3me2s) also fails to be removed at a distinct set of
    genes. The state has not been measured in cells or tissue from people
    with the syndrome.
  cell_types:
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  biological_processes:
  - preferred_term: epigenetic regulation of gene expression
    term:
      id: GO:0040029
      label: epigenetic regulation of gene expression
    modifier: ABNORMAL
  evidence:
  - reference: PMID:25892958
    reference_title: "The histone H3K9 demethylase Kdm3b is required for somatic growth and female reproductive function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      these female reproductive phenotypes were associated with significantly
      increased levels of H3K9me1/2/3 in the ovary and uterus.
    explanation: >-
      Kdm3b loss raises H3K9 methylation in vivo in the tissues examined.
  - reference: PMID:29641999
    reference_title: "JMJD1B Demethylates H4R3me2s and H3K9me2 to Facilitate Gene Expression for Development of Hematopoietic Stem and Progenitor Cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      knockout of JMJD1B blocks demethylation of H4R3me2s and/or H3K9me2 at
      distinct clusters of genes and impairs the activation of genes important
      for HSPC differentiation and development.
    explanation: >-
      In homozygous knockout hematopoietic cells, loss of JMJD1B (KDM3B)
      leaves H3K9me2 and H4R3me2s in place at specific gene clusters.
  downstream:
  - target: Altered Expression of Plasticity-Related Genes
    causal_link_type: DIRECT
    description: >-
      H3K9me2 is a repressive mark; its accumulation is expected to lower
      activation of KDM3B target genes. Shown for plasticity-related genes in
      heterozygous mouse cerebellum.
  - target: Reduced Circulating IGF-1
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In Kdm3b knockout mice, loss of Kdm3b lowers renal IGFBP-3 expression and
      circulating IGF-1. The chromatin intermediates between Kdm3b loss and
      reduced IGFBP-3 expression were not characterized.
  - target: Impaired Hematopoietic Stem and Progenitor Cell Differentiation
    causal_link_type: DIRECT
    description: >-
      In homozygous Jmjd1b-null mice, failure to demethylate H4R3me2s and/or
      H3K9me2 blocks activation of genes needed for hematopoietic stem and
      progenitor cell differentiation.
    evidence:
    - reference: PMID:29641999
      reference_title: "JMJD1B Demethylates H4R3me2s and H3K9me2 to Facilitate Gene Expression for Development of Hematopoietic Stem and Progenitor Cells."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        knockout of JMJD1B blocks demethylation of H4R3me2s and/or H3K9me2 at
        distinct clusters of genes and impairs the activation of genes important
        for HSPC differentiation and development.
      explanation: >-
        Links the chromatin-state change to the hematopoietic differentiation
        defect in the knockout.
- name: Altered Expression of Plasticity-Related Genes
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Dysregulated Neurodevelopmental Transcriptional Program"
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    In Kdm3b heterozygous mouse cerebellum, RNA-seq showed altered expression of
    several plasticity-related genes. Which KDM3B target genes are dysregulated
    in the developing human brain is unknown.
  cell_types:
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  evidence:
  - reference: PMID:34217333
    reference_title: "Kdm3b haploinsufficiency impairs the consolidation of cerebellum-dependent motor memory in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      RNA-seq analyses revealed that the expression levels of several
      plasticity-related genes were altered in the mutant cerebellum.
    explanation: >-
      Transcriptional consequence in the heterozygous haploinsufficiency model.
  downstream:
  - target: Impaired Memory Consolidation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The authors connect active histone-methylation regulation to cerebellar
      memory consolidation; which altered genes mediate the deficit was not
      determined.
    evidence:
    - reference: PMID:34217333
      reference_title: "Kdm3b haploinsufficiency impairs the consolidation of cerebellum-dependent motor memory in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our study suggests that active regulation of histone methylation is
        critical for the consolidation of cerebellar motor memory.
      explanation: >-
        The authors' conclusion linking the chromatin and transcriptional
        changes to the memory phenotype.
- name: Impaired Memory Consolidation
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Impaired Neuronal Maturation, Plasticity, and Postnatal Neurogenesis"
  biological_scale: ORGANISM
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Kdm3b heterozygous mice have normal basal oculomotor performance and normal
    acquisition of cerebellum-dependent optokinetic learning but fail to
    consolidate the memory. This is the only neural-plasticity phenotype
    reported for a Kdm3b haploinsufficiency model. Its relevance to the human
    intellectual disability and developmental delay is an inference, and the
    edges from this node to those phenotypes carry no direct evidence.
  biological_processes:
  - preferred_term: motor learning
    term:
      id: GO:0061743
      label: motor learning
    modifier: DECREASED
  - preferred_term: memory
    term:
      id: GO:0007613
      label: memory
    modifier: DECREASED
  evidence:
  - reference: PMID:34217333
    reference_title: "Kdm3b haploinsufficiency impairs the consolidation of cerebellum-dependent motor memory in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In the cerebellum-dependent optokinetic response (OKR) learning, Kdm3b+/-
      mice show deficits in memory consolidation, whereas they are normal in
      basal oculomotor performance and OKR acquisition.
    explanation: >-
      Direct behavioral evidence of the plasticity deficit in the
      haploinsufficiency model.
  downstream:
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred by analogy with the module chain; no study links the mouse
      memory-consolidation deficit to the human cognitive phenotype.
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred by analogy with the module chain; not directly tested.
  - target: Delayed speech and language development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred by analogy with the module chain; not directly tested.
  - target: Motor delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred; the mouse deficit is in cerebellar motor-memory consolidation,
      whereas the human phenotype is delayed motor milestones.
- name: Reduced Circulating IGF-1
  biological_scale: ORGANISM
  mechanism_confidence: HYPOTHETICAL
  description: >-
    In Kdm3b knockout mice, loss of Kdm3b reduces renal IGFBP-3 expression and
    circulating IGFBP-3, which accelerates IGF-1 degradation and lowers
    circulating IGF-1, with restricted postnatal growth. A later review
    proposes this as the explanation for the short stature of people with KDM3B
    variants; it has not been demonstrated in patients. This mouse mechanism is
    IGF-1 loss through IGFBP-3, not growth hormone deficiency; growth hormone
    deficiency, documented in one individual, is recorded separately as a
    phenotype.
  biological_processes:
  - preferred_term: insulin-like growth factor receptor signaling pathway
    term:
      id: GO:0048009
      label: insulin-like growth factor receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:25892958
    reference_title: "The histone H3K9 demethylase Kdm3b is required for somatic growth and female reproductive function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found that Kdm3b ablation decreased IGFBP-3 expressed in the kidney by
      53% and significantly reduced IGFBP-3 in the blood, which caused an
      accelerated degradation of IGF-1 and a 36% decrease in circulating IGF-1
      concentration.
    explanation: >-
      Mouse knockout evidence for the IGFBP-3/IGF-1 mechanism.
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Notably, postnatal somatic growth restriction in Kdm3b-null mice is
      closely associated with reduced levels of insulin-like growth factor
      binding protein-3 (IGFBP-3) in the kidney and blood, as well as reduced
      serum insulin-like growth factor-1 (IGF-1).
    explanation: >-
      The review restates the mouse IGFBP-3/IGF-1 result as the proposed
      explanation for short stature in this syndrome; the quoted sentence
      describes knockout mice, not patients, so the human claim follows only
      by extrapolation.
  downstream:
  - target: Short stature
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Lower circulating IGF-1 restricts postnatal somatic growth in the mouse;
      proposed, not demonstrated, as the cause of human short stature.
    evidence:
    - reference: PMID:25892958
      reference_title: "The histone H3K9 demethylase Kdm3b is required for somatic growth and female reproductive function."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These results demonstrate that Kdm3b-mediated H3K9 demethylation plays
        essential roles in maintenance of the circulating IGF-1, postnatal
        somatic growth, circulating 17beta-estradiol, and female reproductive
        function.
      explanation: >-
        Mouse evidence connecting Kdm3b-dependent IGF-1 maintenance to
        postnatal growth.
- name: Impaired Hematopoietic Stem and Progenitor Cell Differentiation
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Homozygous Jmjd1b (Kdm3b) knockout mice fail to activate genes needed for
    hematopoietic stem and progenitor cell differentiation and show leukocytosis,
    mild anemia and granulocytosis, which the authors correlate with
    myelodysplastic syndrome. This is a homozygous-null phenotype. It has not
    been shown in heterozygous animals or in people with the syndrome, and it is
    deliberately not connected to the leukemia, lymphoma or neutropenia
    phenotypes, whose relationship to germline KDM3B variants is unestablished
    (see the cancer-predisposition discussion).
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: hematopoietic progenitor cell differentiation
    term:
      id: GO:0002244
      label: hematopoietic progenitor cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:29641999
    reference_title: "JMJD1B Demethylates H4R3me2s and H3K9me2 to Facilitate Gene Expression for Development of Hematopoietic Stem and Progenitor Cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consequently, JMJD1B-/- mice show defects in hematopoiesis.
    explanation: >-
      Homozygous knockout evidence for the hematopoietic defect.
  - reference: PMID:29641999
    reference_title: "JMJD1B Demethylates H4R3me2s and H3K9me2 to Facilitate Gene Expression for Development of Hematopoietic Stem and Progenitor Cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consequently, JMJD1B−/− mice displayed abnormal phenotypes in the
      hematopoietic system, which are correlated with myelodysplastic syndrome
      (MDS), including leukocytosis, mild anemia, and granulocytosis.
    explanation: >-
      Describes the blood-count phenotype of the null mice and its resemblance
      to myelodysplastic syndrome.
phenotypes:
- category: Neurodevelopmental
  name: Global developmental delay
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
    onset:
      onset_category: INFANTILE
  frequency: VERY_FREQUENT
  description: >-
    Developmental delay or intellectual disability was present in 16 of 17
    founding individuals and in 22 of 27 pooled published individuals. Later
    reports include individuals with normal or only mildly impaired
    neurodevelopment.
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Intellectual disability or developmental delay | 1/4 | 16/17 | 0/1 | 1/1 | 2/2 | 1/1 | 1/1 | 22/27 (81.5%)
    explanation: >-
      Pooled frequency (Table 3 of the review): 16 of 17 founding individuals
      and 22 of 27 published individuals.
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unlike other patients with DIJOS who presented with growth retardation,
      mild to moderate intellectual developmental disorder and facial
      dysmorphism, our patients mainly presented with growth retardation, while
      their neurodevelopment was either normal or mildly impaired.
    explanation: >-
      Shows that developmental delay is not universal.
- category: Neurodevelopmental
  name: Intellectual disability
  phenotype_term:
    preferred_term: Intellectual disability, mild to moderate
    term:
      id: HP:0001249
      label: Intellectual disability
  description: >-
    Intellectual disability, where present, is characteristically mild to
    moderate. Affected relatives in one family scored mostly within normal
    limits on intelligence measures, with weaknesses in working memory and
    executive function. No published source scores intellectual disability
    separately from developmental delay: both the founding cohort and Table 3
    of the 2026 case series and literature review count the two together, so
    the pooled figure is carried by the developmental delay phenotype and no
    frequency band is assigned here.
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The core phenotypes include mild-to-moderate intellectual disability or
      developmental delay, predominantly affecting motor and language function,
      facial dysmorphism (long ears, broad nasal tip, low columella, thin lips
      and wide mouth), growth retardation, and neonatal feeding difficulties.
    explanation: >-
      Intellectual disability in this syndrome is characteristically mild to
      moderate.
  - reference: PMID:42186234
    reference_title: "The variable neuropsychological profile of Diets-Jongmans syndrome: a case series of four family members."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Scores on intelligence measures for Cases 1-3 (aged 19, 21, and 46) ranged
      from Below Average to Average, though were predominantly within normative
      limits.
    explanation: >-
      Some affected relatives do not have intellectual disability.
- category: Neurodevelopmental
  name: Delayed speech and language development
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
    onset:
      onset_category: INFANTILE
  description: >-
    The developmental delay of the syndrome predominantly affects motor and
    language function.
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The core phenotypes include mild-to-moderate intellectual disability or
      developmental delay, predominantly affecting motor and language function,
      facial dysmorphism (long ears, broad nasal tip, low columella, thin lips
      and wide mouth), growth retardation, and neonatal feeding difficulties.
    explanation: >-
      The developmental delay predominantly affects motor and language
      function.
- category: Neurodevelopmental
  name: Motor delay
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
    onset:
      onset_category: INFANTILE
  frequency: FREQUENT
  description: >-
    Motor delay was reported in all 17 founding individuals and in 19 of 27
    pooled published individuals (70.4%).
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Motor delay | 0/4 | 17/17 | 1/1 | 1/1 | 0/2 | 0/1 | 0/1 | 19/27 (70.4%)
    explanation: >-
      Pooled frequency (Table 3 of the review), FREQUENT band.
- category: Neurodevelopmental
  name: Specific learning disability
  phenotype_term:
    preferred_term: Learning difficulties
    term:
      id: HP:0001328
      label: Specific learning disability
  description: >-
    Learning difficulties were present in all four members of one family with
    the syndrome, including three who did not meet criteria for intellectual
    developmental disorder.
  evidence:
  - reference: PMID:42186234
    reference_title: "The variable neuropsychological profile of Diets-Jongmans syndrome: a case series of four family members."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All cases presented with learning difficulties, mental health symptoms,
      and features of autism spectrum disorder and attention-deficit
      hyperactivity disorder.
    explanation: >-
      Learning difficulties in every affected family member.
- category: Behavioral
  name: Attention deficit hyperactivity disorder
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  frequency: OCCASIONAL
  description: >-
    ADHD was diagnosed in 4 of 17 founding individuals and in 5 of 27 pooled
    published individuals (18.5%).
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      ADHD | 1/4 | 4/17 | 0/1 | 0/1 | 0/2 | 0/1 | 0/1 | 5/27 (18.5%)
    explanation: >-
      Pooled frequency (Table 3 of the review): 4 of 17 founding individuals
      and 5 of 27 published individuals, the OCCASIONAL band.
  - reference: PMID:42186234
    reference_title: "The variable neuropsychological profile of Diets-Jongmans syndrome: a case series of four family members."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All cases presented with learning difficulties, mental health symptoms,
      and features of autism spectrum disorder and attention-deficit
      hyperactivity disorder.
    explanation: >-
      ADHD features in all four members of one affected family.
- category: Behavioral
  name: Autistic behavior
  phenotype_term:
    preferred_term: Autism spectrum disorder
    term:
      id: HP:0000729
      label: Autistic behavior
  frequency: OCCASIONAL
  description: >-
    Autism spectrum disorder was diagnosed in 3 of 17 founding individuals and
    in 4 of 27 pooled published individuals (14.8%); autistic features are the
    presenting complaint in several later case reports.
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Autism spectrum disorder | 0/4 | 3/17 | 0/1 | 1/1 | 0/2 | 0/1 | 0/1 | 4/27 (14.8%)
    explanation: >-
      Pooled frequency (Table 3 of the review): 3 of 17 founding individuals
      and 4 of 27 published individuals, the OCCASIONAL band.
  - reference: PMID:41408900
    reference_title: "Novel KDM3B Variants in Two Chinese Patients With Global Developmental Delay and Autism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report on two unrelated patients with global developmental delay
      and autistic features
    explanation: >-
      Autistic features in two further unrelated individuals.
  - reference: PMID:41914422
    reference_title: "[A case report of Diets-Jongmans syndrome caused by a KDM3B gene variant]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 5-year-3-month-old boy presented with intellectual disability, autism
      spectrum disorder, short stature, long ears, large auricles, a broad nasal
      tip, a pointed chin, and cryptorchidism.
    explanation: >-
      A further case report with autism spectrum disorder.
- category: Neurologic
  name: Seizure
  phenotype_term:
    preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  frequency: OCCASIONAL
  description: >-
    Epilepsy was present in 3 of 17 founding individuals and in 3 of 27 pooled
    published individuals (11.1%).
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Epilepsy | 0/4 | 3/17 | 0/1 | 0/1 | 0/2 | 0/1 | 0/1 | 3/27 (11.1%)
    explanation: >-
      Pooled frequency (Table 3 of the review): 3 of 17 founding individuals
      and 3 of 27 published individuals, the OCCASIONAL band.
- category: Neurologic
  name: Hypotonia
  phenotype_term:
    preferred_term: Childhood hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
    onset:
      onset_category: CHILDHOOD
  frequency: OCCASIONAL
  description: >-
    Childhood hypotonia was reported in 5 of 17 founding individuals and in 6
    of 27 pooled published individuals (22.2%).
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Childhood hypotonia | 0/4 | 5/17 | 0/1 | 0/1 | 0/2 | 0/1 | 1/1 | 6/27 (22.2%)
    explanation: >-
      Pooled frequency (Table 3 of the review): 5 of 17 founding individuals
      and 6 of 27 published individuals, the OCCASIONAL band.
- category: Growth
  name: Short stature
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: FREQUENT
  description: >-
    Height below -2 SD in 8 of 17 founding individuals and in 15 of 27 pooled
    published individuals (55.6%). In some later reports growth restriction is
    the predominant feature, with normal or mildly impaired neurodevelopment.
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Height (−2 sd) | 4/4 | 8/17 | 1/1 | 1/1 | 0/2 | 0/1 | 1/1 | 15/27 (55.6%)
    explanation: >-
      Pooled frequency (Table 3 of the review): height below -2 SD in 8 of 17
      founding individuals and 15 of 27 published individuals, the FREQUENT
      band.
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      our patients mainly presented with growth retardation, while their
      neurodevelopment was either normal or mildly impaired
    explanation: >-
      Growth restriction can be the leading feature.
- category: Growth
  name: Decreased body weight
  phenotype_term:
    preferred_term: Low weight for age
    term:
      id: HP:0004325
      label: Decreased body weight
  frequency: FREQUENT
  description: >-
    Weight below -2 SD in 16 of 27 pooled published individuals (59.3%).
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Weight (−2 sd) | 4/4 | 11/17 | 1/1 | 0/1 | 0/2 | 0/1 | 0/1 | 16/27 (59.3%)
    explanation: >-
      Pooled frequency (Table 3 of the review), FREQUENT band.
- category: Endocrine
  name: Growth hormone deficiency
  phenotype_term:
    preferred_term: Growth hormone deficiency
    term:
      id: HP:0000824
      label: Decreased response to growth hormone stimulation test
  description: >-
    Growth hormone deficiency confirmed by two stimulation tests has been
    documented in one individual with the syndrome. Its frequency across the
    syndrome is unknown.
  evidence:
  - reference: PMID:41878155
    reference_title: "Diets-Jongmans Syndrome due to a Novel KDM3B Variant: The First Molecularly Confirmed Case from Turkey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biochemical evaluation revealed growth hormone deficiency, which was
      confirmed by two stimulation tests.
    explanation: >-
      Documents growth hormone deficiency confirmed by two stimulation tests in
      an individual with molecularly confirmed Diets-Jongmans syndrome.
- category: Neurologic
  name: Microcephaly
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  description: >-
    Reported in individual case reports, including the youngest reported
    affected male.
  evidence:
  - reference: PMID:41239187
    reference_title: "A Novel De Novo KDM3B Variant in the Youngest Reported Male Patient With Diets-Jongmans Syndrome and Facial Asymmetry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a seven-month-old male patient evaluated for small stature, microcephaly,
      facial asymmetry, and mild gross motor delays
    explanation: >-
      Microcephaly in an infant with the syndrome.
- category: Gastrointestinal
  name: Feeding difficulties in infancy
  phenotype_term:
    preferred_term: Neonatal feeding difficulties
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
    onset:
      onset_category: NEONATAL
  frequency: FREQUENT
  description: >-
    Neonatal feeding difficulties in 9 of 17 founding individuals and in 14 of
    27 pooled published individuals (51.9%), and in all four individuals of a
    later series, where they preceded growth restriction.
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Neonatal feeding difficulties | 4/4 | 9/17 | 0/1 | 1/1 | 0/2 | 0/1 | 0/1 | 14/27 (51.9%)
    explanation: >-
      Pooled frequency (Table 3 of the review): 9 of 17 founding individuals
      and 14 of 27 published individuals, the FREQUENT band.
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      feeding difficulties were present in all of them, followed by the growth
      retardation.
    explanation: >-
      Feeding difficulties in all four individuals of a later series, before
      the growth restriction.
- category: Musculoskeletal
  name: Joint hypermobility
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  description: >-
    Joint hypermobility is one of the shared features reported in the founding
    cohort; no published count is available in a source this entry can quote.
  evidence:
  - reference: PMID:30929739
    reference_title: "De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individuals share additional phenotypic features that include feeding
      difficulties in infancy, joint hypermobility, and characteristic facial
      features such as a wide mouth, a pointed chin, long ears, and a low
      columella.
    explanation: >-
      Joint hypermobility is one of the shared features of the founding cohort.
- category: Otologic
  name: Hearing impairment
  phenotype_term:
    preferred_term: Hearing loss
    term:
      id: HP:0000365
      label: Hearing impairment
  frequency: OCCASIONAL
  description: >-
    Hearing loss in 4 of 17 founding individuals and in 4 of 27 pooled
    published individuals (14.8%); deafness in one of two later-reported
    individuals.
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Hearing loss | 0/4 | 4/17 | 0/1 | 0/1 | 0/2 | 0/1 | 0/1 | 4/27 (14.8%)
    explanation: >-
      Pooled frequency (Table 3 of the review): 4 of 17 founding individuals
      and 4 of 27 published individuals, the OCCASIONAL band.
  - reference: PMID:41408900
    reference_title: "Novel KDM3B Variants in Two Chinese Patients With Global Developmental Delay and Autism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinically, Patient 1 had severe developmental retardation, deafness and
      autistic tilt, whereas Patient 2 had milder retardation and autistic
      behaviours with normal hearing.
    explanation: >-
      A later case with deafness.
- category: Craniofacial
  name: Broad nasal tip
  phenotype_term:
    preferred_term: Broad nasal tip
    term:
      id: HP:0000455
      label: Broad nasal tip
  description: >-
    One of the recurrent facial features of the syndrome. Hybrid
    facial-recognition analysis showed that affected individuals' faces cluster
    significantly compared with controls with other intellectual-disability
    syndromes.
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The core phenotypes include mild-to-moderate intellectual disability or
      developmental delay, predominantly affecting motor and language function,
      facial dysmorphism (long ears, broad nasal tip, low columella, thin lips
      and wide mouth), growth retardation, and neonatal feeding difficulties.
    explanation: >-
      A broad nasal tip is one of the recurrent facial features of the
      syndrome.
  - reference: PMID:30929739
    reference_title: "De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By using a hybrid facial-recognition model, we show that individuals with
      a pathogenic variant in KDM3B have a facial gestalt, and that they show
      significant facial similarity compared to control individuals with ID.
    explanation: >-
      The facial features form a recognizable gestalt.
- category: Craniofacial
  name: Wide mouth
  phenotype_term:
    preferred_term: Wide mouth
    term:
      id: HP:0000154
      label: Wide mouth
  description: >-
    One of the characteristic facial features of the founding cohort.
  evidence:
  - reference: PMID:30929739
    reference_title: "De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individuals share additional phenotypic features that include feeding
      difficulties in infancy, joint hypermobility, and characteristic facial
      features such as a wide mouth, a pointed chin, long ears, and a low
      columella.
    explanation: >-
      A wide mouth is among the characteristic facial features of the founding
      cohort.
- category: Craniofacial
  name: Thin upper lip vermilion
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  description: >-
    One of the recurrent facial features of the syndrome.
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The disorder is characterized by developmental delay, mild-to-moderate
      intellectual disability and facial dysmorphism, which includes
      macrostomia, pointed chin, long ears, broad nasal bridge and thin upper
      vermilion.
    explanation: >-
      A thin upper vermilion is one of the recurrent facial features of the
      syndrome.
- category: Craniofacial
  name: Pointed chin
  phenotype_term:
    preferred_term: Pointed chin
    term:
      id: HP:0000307
      label: Pointed chin
  description: >-
    One of the characteristic facial features of the founding cohort.
  evidence:
  - reference: PMID:30929739
    reference_title: "De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individuals share additional phenotypic features that include feeding
      difficulties in infancy, joint hypermobility, and characteristic facial
      features such as a wide mouth, a pointed chin, long ears, and a low
      columella.
    explanation: >-
      A pointed chin is among the characteristic facial features of the
      founding cohort.
- category: Craniofacial
  name: Long ear
  phenotype_term:
    preferred_term: Long ears
    term:
      id: HP:0400004
      label: Long ear
  description: >-
    One of the characteristic facial features of the founding cohort.
  evidence:
  - reference: PMID:30929739
    reference_title: "De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individuals share additional phenotypic features that include feeding
      difficulties in infancy, joint hypermobility, and characteristic facial
      features such as a wide mouth, a pointed chin, long ears, and a low
      columella.
    explanation: >-
      Long ears are among the characteristic facial features of the founding
      cohort.
- category: Craniofacial
  name: Low hanging columella
  phenotype_term:
    preferred_term: Low-hanging columella
    term:
      id: HP:0009765
      label: Low hanging columella
  description: >-
    One of the characteristic facial features of the founding cohort.
  evidence:
  - reference: PMID:30929739
    reference_title: "De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individuals share additional phenotypic features that include feeding
      difficulties in infancy, joint hypermobility, and characteristic facial
      features such as a wide mouth, a pointed chin, long ears, and a low
      columella.
    explanation: >-
      A low columella is among the characteristic facial features of the
      founding cohort.
- category: Congenital anomaly
  name: Umbilical hernia
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  frequency: OCCASIONAL
  description: >-
    Two of 17 founding individuals and 3 of 27 pooled published individuals
    (11.1%).
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Umbilical hernia | 0/4 | 2/17 | 0/1 | 0/1 | 1/2 | 0/1 | 0/1 | 3/27 (11.1%)
    explanation: >-
      Pooled frequency (Table 3 of the review): 2 of 17 founding individuals
      and 3 of 27 published individuals, the OCCASIONAL band.
- category: Congenital anomaly
  name: Inguinal hernia
  phenotype_term:
    preferred_term: Inguinal hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  frequency: OCCASIONAL
  description: >-
    Two of 17 founding individuals and 2 of 27 pooled published individuals
    (7.4%).
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Inguinal hernia | 0/4 | 2/17 | 0/1 | 0/1 | 0/2 | 0/1 | 0/1 | 2/27 (7.4%)
    explanation: >-
      Pooled frequency (Table 3 of the review): 2 of 17 founding individuals
      and 2 of 27 published individuals, the OCCASIONAL band.
- category: Congenital anomaly
  name: Congenital diaphragmatic hernia
  phenotype_term:
    preferred_term: Diaphragmatic hernia
    term:
      id: HP:0000776
      label: Congenital diaphragmatic hernia
    onset:
      onset_category: CONGENITAL
  description: >-
    Listed among the variable congenital anomalies of the syndrome.
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Additional variable features encompass autism-spectrum disorder,
      attention-deficit hyperactivity disorder (ADHD), and congenital
      diaphragmatic, umbilical or inguinal hernias
    explanation: >-
      The review lists congenital diaphragmatic hernia among the variable
      features of the syndrome.
- category: Genitourinary
  name: Cryptorchidism
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  description: >-
    One of 17 founding individuals and 1 of 27 pooled published individuals
    (3.7%), and in a later case report.
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Cryptorchidism | 0/4 | 1/17 | 0/1 | 0/1 | 0/2 | 0/1 | 0/1 | 1/27 (3.7%)
    explanation: >-
      Pooled frequency (Table 3 of the review): 1 of 17 founding individuals
      and 1 of 27 published individuals.
  - reference: PMID:41914422
    reference_title: "[A case report of Diets-Jongmans syndrome caused by a KDM3B gene variant]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 5-year-3-month-old boy presented with intellectual disability, autism
      spectrum disorder, short stature, long ears, large auricles, a broad nasal
      tip, a pointed chin, and cryptorchidism.
    explanation: >-
      Cryptorchidism in a later case.
- category: Cardiovascular
  name: Cardiomyopathy
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  description: >-
    Reported in one of two individuals in a single report. The abstract does
    not say which individual had cardiomyopathy; it describes the second
    (p.Arg943Gln) as presenting with palpitations, shortness of breath and
    pitting edema. Attribution to the syndrome rests on this one report.
  evidence:
  - reference: PMID:36757469
    reference_title: "Two patients with KDM3B variants and new presentations of Diets-Jongmans syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neutropenia and cardiomyopathy are newly found presentations of
      Diets-Jongmans syndrome.
    explanation: >-
      Single-case report of cardiomyopathy.
- category: Hematologic
  name: Transient neutropenia
  phenotype_term:
    preferred_term: Transient neutropenia
    term:
      id: HP:0410255
      label: Transiently decreased total neutrophil count
  description: >-
    Transient neutropenia in one individual with a de novo splice variant, who
    presented with recurrent upper respiratory tract infections. Single report.
  evidence:
  - reference: PMID:36757469
    reference_title: "Two patients with KDM3B variants and new presentations of Diets-Jongmans syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients had additional clinical presentations, and patient 1 had
      transient neutropenia.
    explanation: >-
      Single-case report of transient neutropenia.
- category: Neoplasm
  name: Acute myeloid leukemia
  phenotype_term:
    preferred_term: Acute myeloid leukemia
    term:
      id: HP:0004808
      label: Acute myeloid leukemia
    onset:
      onset_category: CHILDHOOD
  description: >-
    One individual in the founding cohort developed acute myeloid leukemia in
    childhood. That individual was ascertained through a childhood cancer
    predisposition study, so the observation cannot be used to estimate risk;
    see the cancer-predisposition discussion.
  evidence:
  - reference: PMID:30929739
    reference_title: "De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, two individuals developed cancer, acute myeloid leukemia and
      Hodgkin lymphoma, in childhood.
    explanation: >-
      One of the two childhood cancers in the founding cohort was acute myeloid
      leukemia.
- category: Neoplasm
  name: Hodgkin lymphoma
  phenotype_term:
    preferred_term: Hodgkin lymphoma
    term:
      id: HP:0012189
      label: Hodgkin lymphoma
    onset:
      onset_category: CHILDHOOD
  description: >-
    One individual in the founding cohort developed Hodgkin lymphoma in
    childhood. Ascertained through the same childhood cancer predisposition
    study; causality is unestablished.
  evidence:
  - reference: PMID:30929739
    reference_title: "De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, two individuals developed cancer, acute myeloid leukemia and
      Hodgkin lymphoma, in childhood.
    explanation: >-
      The other childhood cancer in the founding cohort was Hodgkin
      lymphoma.
treatments:
- name: Recombinant human growth hormone
  description: >-
    Recombinant human growth hormone has been given to one individual with the
    syndrome, whose height moved from below -3 SD to between -1 and -2 SD over
    about six years, with IGF-1, thyroid function and glucose remaining within
    normal ranges on monitoring. The treating authors describe the effect as
    partially promoting growth and do not report growth hormone deficiency in
    this individual, so the indication was short stature rather than a
    documented hormone deficit; growth hormone deficiency in this syndrome,
    documented in two other individuals, is recorded separately as a phenotype.
    The treating authors caution that, because KDM3B has been linked to
    myelodysplastic syndrome and acute myeloid leukemia, the potential
    oncogenic risk of growth hormone must be weighed; no guideline addresses
    this. Evidence is a single treated case.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: recombinant human growth hormone therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
    therapeutic_agent:
    - preferred_term: somatropin
      term:
        id: NCIT:C837
        label: Somatropin
  target_mechanisms:
  - target: Short stature
    description: >-
      Growth-promoting therapy aimed at the short stature; one treated case.
    evidence:
    - reference: PMID:41898828
      reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        One patient treated with recombinant human growth hormone (rhGH) showed
        improvement in growth.
      explanation: >-
        Single-case evidence of growth response.
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient treated with recombinant human growth hormone (rhGH) showed
      improvement in growth.
    explanation: >-
      Growth response in one treated individual.
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For the first time, we demonstrate that rhGH therapy can partially
      promote growth, providing novel evidence for genetic counseling.
    explanation: >-
      The treating authors characterize the effect as partial growth promotion,
      not as replacement of a documented growth hormone deficit.
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the potential oncogenic risk of rhGH must be carefully weighed
    explanation: >-
      The treating authors' caution about growth hormone given KDM3B's links
      to myeloid neoplasia.
- name: Early developmental rehabilitation
  description: >-
    Management is supportive and multidisciplinary; early referral to
    rehabilitation services with individualized programs for cognitive and
    motor deficits is recommended. No disease-specific therapy exists.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: developmental rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  target_mechanisms:
  - target: Global developmental delay
    description: >-
      Supportive therapy for developmental delay.
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Children with developmental delay should be referred early to
      rehabilitation services.
    explanation: >-
      Management recommendation from the most recent case series and review.
discussions:
- discussion_id: dijos_cancer_predisposition
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Do germline KDM3B variants predispose to childhood hematologic malignancy,
    and should people with Diets-Jongmans syndrome have any cancer surveillance?
  attaches_to:
  - phenotypes#Acute myeloid leukemia
  - phenotypes#Hodgkin lymphoma
  - pathophysiology#Impaired Hematopoietic Stem and Progenitor Cell Differentiation
  rationale: >-
    Two of the 17 founding individuals had a childhood hematologic malignancy,
    but both were recruited through a childhood cancer predisposition exome
    study, which introduces ascertainment bias. None of the later case reports
    and series cited in this entry (about ten further individuals) describes a
    malignancy, though follow-up in them is short. Separately,
    KDM3B lies in the 5q31 region lost in myeloid neoplasms and was proposed as
    a candidate somatic tumor suppressor there, and homozygous Kdm3b-null mice
    have hematopoietic abnormalities resembling myelodysplastic syndrome. The
    somatic evidence is not uniformly tumor-suppressive: in other leukemia cell
    work KDM3B activates the LMO2 oncogene and represses differentiation. None
    of this somatic or homozygous-model evidence establishes that a single
    germline loss-of-function allele raises cancer risk, and no surveillance
    guideline addresses the syndrome. One later report cites the leukemia
    association when weighing growth hormone therapy.
  proposed_experiments:
  - experiment_id: exp_dijos_malignancy_incidence_cohort
    name: Malignancy incidence in individuals ascertained for developmental phenotypes
    description: >-
      Follow individuals with DIJOS ascertained through developmental or
      growth referral (not through cancer studies) and compare observed with
      expected childhood hematologic malignancy incidence.
  - experiment_id: exp_kdm3b_heterozygous_hematopoiesis
    name: Hematopoiesis in Kdm3b heterozygous mice
    description: >-
      Test whether heterozygous, rather than homozygous-null, Kdm3b mice
      develop myelodysplasia-like changes or leukemia with aging or
      cooperating lesions.
  evidence:
  - reference: PMID:29351919
    reference_title: "High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, we identified two genes, KDM3B and TYK2, which are possibly
      involved in genetic cancer predisposition.
    explanation: >-
      The childhood cancer predisposition exome study through which the two
      affected individuals were ascertained proposes KDM3B only as a possible
      predisposition gene.
  - reference: PMID:11687974
    reference_title: "A novel nuclear protein, 5qNCA (LOC51780) is a candidate for the myeloid leukemia tumor suppressor gene on chromosome 5 band q31."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We propose 5qNCA is a good candidate for the del(5q) tumor suppressor gene
      based on its predicted function and growth suppressive activities
    explanation: >-
      Somatic context only. 5qNCA is the former name of KDM3B; proposed as a
      5q31 myeloid tumor suppressor candidate from somatic deletion mapping and
      cell-line growth suppression, not from germline data.
  - reference: PMID:21536236
    reference_title: "A cryptic deletion in 5q31.2 provides further evidence for a minimally deleted region in myelodysplastic syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      suggests that the proximal boundary of the common deleted region may lie
      within the KDM3B gene
    explanation: >-
      Somatic context only: a myelodysplastic-syndrome case with a cryptic 5q31.2
      deletion places the deleted-region boundary within KDM3B.
  - reference: PMID:28540746
    reference_title: "KDM3B shows tumor-suppressive activity and transcriptionally regulates HOXA1 through retinoic acid response elements in acute myeloid leukemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Collectively, we found that KDM3B exhibits potential tumor-suppressive
      activity and transcriptionally modulates HOXA1 expression via RARE in AML.
    explanation: >-
      Somatic/cell-line context only: KDM3B shows tumor-suppressive activity in
      AML cell lines.
  - reference: PMID:22615488
    reference_title: "KDM3B is the H3K9 demethylase involved in transcriptional activation of lmo2 in leukemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The combined results of this study provide evidence that the H3K9-me1/2
      demethylase KDM3B might play a role in leukemogenesis via activation of
      lmo2
    explanation: >-
      Somatic/cell-line context: here KDM3B acts in a leukemia-promoting
      direction, supporting the rationale's statement that its somatic role is
      not uniformly tumor-suppressive.
  - reference: PMID:29641999
    reference_title: "JMJD1B Demethylates H4R3me2s and H3K9me2 to Facilitate Gene Expression for Development of Hematopoietic Stem and Progenitor Cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results suggest that JMJD1B might be a tumor suppressor gene and
      contribute to MDS through regulation of the H4R3me2s marker to regulate
      gene expression.
    explanation: >-
      Homozygous knockout mouse evidence that the authors interpret as a
      tumor-suppressor role in myelodysplastic syndrome.
- discussion_id: dijos_missense_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do the disease-associated KDM3B missense variants reduce demethylase
    activity (haploinsufficiency-equivalent), or act by another mechanism, and
    does variant class predict neurodevelopmental severity?
  attaches_to:
  - pathophysiology#KDM3B Heterozygous Loss of Function
  - genetic#KDM3B
  rationale: >-
    Haploinsufficiency is inferred from truncating and splice variants. About
    half of reported variants are missense, and their effect on demethylase
    activity has not been measured: the one reported assessment of a missense
    variant is an in silico structural prediction. A later review suggests that
    truncating variants may be associated with milder neurodevelopmental
    involvement than missense variants, which would imply that some missense
    variants act other than by simple loss of function, but that observation
    rests on small numbers.
  proposed_experiments:
  - experiment_id: exp_kdm3b_missense_demethylase_assay
    name: Demethylase activity of patient missense variants
    description: >-
      Measure H3K9me1/2 (and H4R3me2s) demethylase activity and protein
      stability of each reported missense variant against wild type at matched
      expression levels.
  evidence:
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Experimental validation is required to confirm the predicted local
      conformational changes and their functional implications for KDM3B
      enzymatic activity.
    explanation: >-
      The only reported assessment of a disease-associated missense variant is
      an in silico structural prediction, which its authors state needs
      experimental validation.
  - reference: PMID:41898828
    reference_title: "De Novo Heterozygous KDM3B Variants Expand the Mutational Spectrum of Diets-Jongmans Syndrome: Case Series and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This finding suggests that LOF variants may confer a relatively milder
      neurodevelopmental phenotype
    explanation: >-
      Tentative genotype-phenotype suggestion from pooled small numbers.
- discussion_id: dijos_mouse_to_human_neurodevelopment
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Is the cerebellar motor-memory consolidation deficit of Kdm3b heterozygous
    mice a valid model of the developmental delay and intellectual disability
    of Diets-Jongmans syndrome?
  attaches_to:
  - pathophysiology#Altered Expression of Plasticity-Related Genes
  - pathophysiology#Impaired Memory Consolidation
  rationale: >-
    The heterozygous mouse is the right genetic model for a haploinsufficiency
    disorder, and it shows increased H3K9me2 and altered plasticity-gene
    expression in the cerebellum. But its phenotype is a selective deficit in
    consolidating one cerebellum-dependent memory, with normal acquisition and
    basal performance, whereas the human syndrome is global developmental and
    language delay beginning in infancy. No developmental, cortical or
    language-relevant phenotype has been reported in the mouse, and no
    patient-derived neural cells have been studied.
  proposed_experiments:
  - experiment_id: exp_kdm3b_patient_ipsc_neurons
    name: Patient-derived neuronal chromatin and transcriptome profiling
    description: >-
      Profile H3K9me2 and gene expression in iPSC-derived cortical neurons from
      individuals with truncating and missense KDM3B variants against isogenic
      corrected controls.
  evidence:
  - reference: PMID:34217333
    reference_title: "Kdm3b haploinsufficiency impairs the consolidation of cerebellum-dependent motor memory in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In the cerebellum-dependent optokinetic response (OKR) learning, Kdm3b+/-
      mice show deficits in memory consolidation, whereas they are normal in
      basal oculomotor performance and OKR acquisition.
    explanation: >-
      The mouse phenotype is narrow and adult-behavioral, unlike the human
      developmental phenotype.
animal_models:
- name: Kdm3b heterozygous knockout mouse
  species: Mouse
  genotype: Kdm3b+/-
  publication: PMID:34217333
  modeled_mechanisms:
  - target: Increased H3K9 Methylation at KDM3B Target Loci
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Heterozygous loss raises H3K9me2 in cerebellar granule cells, matching
      the dosage of the human disorder.
    limitations: >-
      Measured in adult cerebellum only; the developing brain and other
      regions were not examined.
    evidence:
    - reference: PMID:34217333
      reference_title: "Kdm3b haploinsufficiency impairs the consolidation of cerebellum-dependent motor memory in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        H3K9 di-methylation is significantly increased selectively in the
        granule cell layer of the cerebellum of Kdm3b+/- mice.
      explanation: >-
        Supports the model as informative for the chromatin-state node.
  - target: Impaired Memory Consolidation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Deficit in consolidation of cerebellum-dependent optokinetic memory.
    limitations: >-
      A selective adult memory-consolidation deficit, not the global
      developmental and language delay of the human syndrome.
    evidence:
    - reference: PMID:34217333
      reference_title: "Kdm3b haploinsufficiency impairs the consolidation of cerebellum-dependent motor memory in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In the cerebellum-dependent optokinetic response (OKR) learning,
        Kdm3b+/- mice show deficits in memory consolidation, whereas they are
        normal in basal oculomotor performance and OKR acquisition.
      explanation: >-
        The behavioral phenotype of the model.
- name: Kdm3b knockout mouse (growth)
  species: Mouse
  genotype: Kdm3b knockout (Kdm3bKO)
  publication: PMID:25892958
  modeled_mechanisms:
  - target: Reduced Circulating IGF-1
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: ORGANISM
    description: >-
      Kdm3b ablation reduces IGFBP-3 and circulating IGF-1 with restricted
      postnatal growth.
    limitations: >-
      A knockout rather than a heterozygous model, and IGF-1 has not been
      measured systematically in patients, so whether the same mechanism
      underlies human short stature is untested.
    evidence:
    - reference: PMID:25892958
      reference_title: "The histone H3K9 demethylase Kdm3b is required for somatic growth and female reproductive function."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we generated Kdm3b knockout (Kdm3bKO) mice and observed restricted
        postnatal growth and female infertility in these mice.
      explanation: >-
        The knockout shows the growth phenotype.
- name: Jmjd1b knockout mouse (hematopoiesis)
  species: Mouse
  genotype: Jmjd1b-/-
  publication: PMID:29641999
  modeled_mechanisms:
  - target: Impaired Hematopoietic Stem and Progenitor Cell Differentiation
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: ORGANISM
    description: >-
      Homozygous null mice show hematopoietic defects resembling
      myelodysplastic syndrome.
    limitations: >-
      Homozygous-null genotype; people with the syndrome are heterozygous, and
      no hematopoietic phenotype has been described in heterozygous mice.
    evidence:
    - reference: PMID:29641999
      reference_title: "JMJD1B Demethylates H4R3me2s and H3K9me2 to Facilitate Gene Expression for Development of Hematopoietic Stem and Progenitor Cells."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Consequently, JMJD1B-/- mice show defects in hematopoiesis.
      explanation: >-
        The knockout shows the hematopoietic defect.
📚

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 (1)

Create: Diets-Jongmans_Syndrome · 2026-09-23T20:05:24Z · View source

Created the Diets-Jongmans syndrome (MONDO:0030012, KDM3B) entry as a single Disease. Deep research: one report. Falcon was requested and returned HTTP 402 (out of credits); the claude_code fallback produced research/Diets-Jongmans_Syndrome-deep-research-claude_code.md (frontmatter records requested_provider falcon, fell_back true). The run exited before writing its validation sections because OLS timed out during term validation, so both were added afterwards with just validate-research-reference and just validate-research-terms. Reference validation: 13/13 references resolved, 6 of 7 quotes found; the one not found is a paraphrase of a PMID:30929739 sentence ("13/14 had high CADD scores"), so the report needs review. Term validation: 53/55 resolved, 0 unresolved, 8 CURIEs named as a different term (HP:0011342, HP:0000824, HP:0009884, HP:0011832, HP:0001696, HP:0012156, NCIT:C1691, and MONDO:0030012 with a prose label). None of the mislabelled CURIEs was used; every binding was looked up in the term caches or OLS. just preflight-dr returned PASS (KDM3B mentioned 47 times, OMIM 618846 matches). Sources: the phenotype baseline is the founding 17-individual cohort (PMID:30929739, full text cached, Table 2 frequencies) plus the pooled 27-individual review (PMID:41898828, Table 3). No GeneReviews chapter exists (just check-genereviews --online: NO_CHAPTER). Structured sources: ClinGen CGGV Definitive for KDM3B with syndromic intellectual disability (MONDO:0000508, broader than this entry), and Orphanet ORPHA:633004. The CGGV cache was built with --csv-only from the ClinGen gene-validity CSV downloaded on 2026-09-23, whose sha256 differs from the manifest pin (snapshot 2026-08-13); the cache header therefore carries the manifest's 2026-08-13 date. The KDM3B row's classification date is 2024-02-21, so the row predates both snapshots. ClinGen has no dosage-sensitivity curation for KDM3B. Mechanism: KDM3B loss of function (PROVISIONAL, because missense effect is unassayed) -> increased H3K9me1/2 (Kdm3b+/- cerebellum, PMID:34217333; Kdm3b knockout ovary/uterus, PMID:25892958) -> altered plasticity-gene expression -> impaired memory consolidation, conforming to epigenetic_machinery_neurodevelopmental_dysregulation at four nodes. The last node's edges to intellectual disability, developmental delay, speech and motor delay are marked as inference with no evidence. Growth branch via reduced IGF-1 (Kdm3b knockout mouse) to short stature. Hematopoietic branch (Jmjd1b-/- mouse, PMID:29641999) is left unconnected to the AML, Hodgkin lymphoma and neutropenia phenotypes. Germline versus somatic: AML (age 13) and Hodgkin lymphoma (age 17) are recorded as phenotypes because individuals with the syndrome were reported with them, but the founding authors note both were ascertained through a childhood cancer predisposition study. The 5q31 somatic tumor-suppressor literature (PMID:11687974, PMID:21536236, PMID:28540746, PMID:22615488) is confined to an OPEN_QUESTION discussion. Two further discussions record the missense-mechanism gap and the mouse-to-human neurodevelopment mismatch. Ontology note: MONDO has a second class for the same disease, MONDO:0858999 (from ORPHA:633004), recorded as a skos:exactMatch mapping. Searches run on 2026-09-23 and recorded in notes: PubMed "5q31.2 AND deletion AND (intellectual OR developmental) AND KDM3B" returned 0 records; "KDM3B AND (episignature OR DNA methylation signature)" returned 2, neither about the syndrome. Validation: just validate, count-verified-snippets (96/96), validate-terms, check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-environmental-evidence, check-enum-values, check-coarse-phenotypes, check-reference-titles, list-gene-term-mismatches, pytest tests/test_data.py -k Diets, and validate-disorders.

Claude Code ▸
Diets-Jongmans Syndrome (DIJOS) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 4 citations 2026-09-23T19:22:28.765818

Diets-Jongmans Syndrome (DIJOS) — Comprehensive Research Report

1. Disease Information

Overview. Diets-Jongmans syndrome (DIJOS) is a rare, autosomal dominant neurodevelopmental/malformation syndrome caused by heterozygous pathogenic variants in KDM3B (lysine demethylase 3B, chromosome 5q31.2). It is characterized by mild-to-moderate intellectual disability/developmental delay, short stature, neonatal feeding difficulties, and a recognizable facial gestalt (long ears, broad/prominent nasal tip with low columella, thin upper lip, wide mouth, pointed chin). It was first delineated as a discrete syndrome by Diets, van der Donk, Baltrunaite et al. in the American Journal of Human Genetics in 2019 (PMID:30929739), using trio exome sequencing, GeneMatcher-facilitated international collaboration, and computational facial-recognition analysis (Face2Gene/Clinical Face Phenotype Space) to establish gestalt validity.

Key identifiers: - OMIM: #618846 — DIETS-JONGMANS SYNDROME; DIJOS (omim.org/entry/618846) - Gene OMIM: KDM3B, #609373 - MONDO: MONDO:0030012 (confirmed via GenCC submission, consistent with the MONDO ID supplied in the research request) - Orphanet: ORPHA:633004 — "KDM3B-related intellectual disability-facial dysmorphism-short stature syndrome" (orpha.net/en/disease/detail/633004) - MedGen: C5394263 (ncbi.nlm.nih.gov/medgen/1714920) - HGNC (gene): HGNC:1337 (KDM3B; previous symbols C5orf7, JMJD1B) - GeneCC/ClinGen: Definitive gene-disease relationship, "Syndromic intellectual disability" (MONDO:0000508), Intellectual Disability and Autism GCEP, curated 2024-02-21 (search.clinicalgenome.org/kb/genes/HGNC:1337); GenCC entry independently lists KDM3B–Diets-Jongmans syndrome (MONDO:0030012) as Definitive, autosomal dominant, submitted by Ambry Genetics, evaluated 2024-04-03. - No GeneReviews chapter currently exists* for this condition (searched; not found as of this report). GTR lists the condition under C5394263.

Synonyms: "KDM3B-related intellectual disability-facial dysmorphism-short stature syndrome" (Orphanet's working name); no other widely used alternate names were found. Caution: an AI-generated web summary encountered during this search expanded "DIJOS" as an acronym for "developmental delay, intellectual disability, joint contractures... immunodeficiency... short stature" — this expansion could not be traced to any primary source (OMIM, the 2019 AJHG paper, or Orphanet) and should be treated as unverified/likely fabricated rather than used in curation.

Evidence base composition: The evidence base is aggregated disease-level literature (case series and case reports pooled across cohorts), not a single large EHR-derived or registry cohort. As of this search, published literature totals roughly 27+ molecularly confirmed individuals across the 2019 founding cohort (17 individuals, PMID:30929739) plus at least 9 subsequently published individuals in independent case reports/series (see §9 for citations), so no large single denominator exists — frequencies below are cohort-level percentages from the cited sources, not population data.

2. Etiology

Disease causal factor: Purely genetic — heterozygous (predominantly de novo) pathogenic/likely pathogenic variants in KDM3B. No infectious, toxic, or purely environmental cause is described.

Genetic risk factors: - Heterozygous missense, nonsense, frameshift, and splice-site variants in KDM3B, clustering in/near the zinc-finger DNA-binding domain and the C-terminal catalytic Jumonji-C (JmjC) domain (PMID:30929739). - KDM3B is highly constrained against loss-of-function variation: original 2019 report cites ExAC pLI = 1.00 and Z-score = 4.99 (missense constraint); ClinGen's current summary similarly reports pLI ≈ 1.0 and a low LOEUF (~0.12), consistent with strong haploinsufficiency intolerance (ClinGen KDM3B page). - No modifier genes have been formally identified; a co-occurring SIN3A variant was reported alongside a KDM3B variant in one atypical pulmonary-hypertension case (PMID:38314229), but this is a single dual-diagnosis observation, not an established modifier relationship.

Environmental risk factors: None established; this is a monogenic disorder.

Protective factors: None reported in the literature to date.

Gene-environment interactions: Not described. The single case with rhGH (recombinant human growth hormone) exposure (PMC13025784) is a treatment-response observation, not a G×E etiologic interaction.

3. Phenotypes

Developmental / Cognitive

  • Intellectual disability / developmental delay — present in 16/17 (94.1%) of the founding cohort (PMID:30929739); pooled across later literature (27 patients, PMC13025784) 81.5%. Predominantly mild (47.1%) to mild-moderate (23.5%); severe ID is uncommon. Speech/language delay is typically more pronounced than motor delay.
  • HP:0001249 (Intellectual disability); HP:0011342 (Mild intellectual disability); HP:0001263 (Global developmental delay); HP:0000750 (Delayed speech and language development)
  • Motor delay — 70.4% (pooled, PMC13025784).
  • HP:0001270 (Motor delay)
  • Childhood hypotonia — 38.5% (PMID:30929739).
  • HP:0001252 (Hypotonia)
  • Behavioral problems — 53.3%; ADHD 18.5–26.7%; autism spectrum disorder 14.8–20%. A 2025 report of two Chinese patients specifically highlights autistic features and global developmental delay as presenting complaints (PMID:41408900).
  • HP:0000708 (Behavioral abnormality); HP:0007018 (Attention deficit hyperactivity disorder); HP:0000717 (Autism)
  • Epilepsy — 20% (two transient cases) (PMID:30929739).
  • HP:0001250 (Seizure)
  • Variable neuropsychological profile within families — a 2026 case series of four family members carrying the same variant reported a "variable neuropsychological profile," i.e., marked intrafamilial variability in cognitive presentation despite an identical KDM3B variant (Archives of Clinical Neuropsychology, PMID:42186234; full abstract text could not be retrieved due to access restrictions — treat as a lead pending direct verification).

Growth

  • Short stature — ~50–55.6% of patients (<-2 to -2.5 SD), with height <-1.5 SD in 68.8% (PMID:30929739; PMC13025784).
  • HP:0004322 (Short stature)
  • Low birth weight / postnatal growth restriction — 59.3% pooled (PMC13025784); one recent 4-patient case series found growth retardation to be the predominant/sole clinical feature with minimal neurodevelopmental involvement, expanding phenotypic heterogeneity (PMC13025784, MDPI Genes 2026, doi:10.3390/genes17030294).
  • HP:0001518 (Small for gestational age); HP:0004325 (Decreased body weight)
  • Growth hormone deficiency — documented and biochemically confirmed (stimulation testing) in at least two independently reported cases (PMC13025784; Turkish case, PMID:41878155/PMC13008413), described as "rarely reported" previously.
  • HP:0000824 (Growth hormone deficiency)
  • Microcephaly-range head circumference reduction — reported in the Turkish case (head circumference SDS -3.96) (PMC13008413).
  • HP:0000252 (Microcephaly)

Feeding / Gastrointestinal

  • Neonatal feeding difficulties — 51.9–60% (PMID:30929739; PMC13025784).
  • HP:0011968 (Feeding difficulties)
  • Umbilical/inguinal hernia — 12.5% each; diaphragmatic hernia — 12.5% (PMID:30929739).
  • HP:0001537 (Umbilical hernia); HP:0000023 (Inguinal hernia); HP:0000776 (Congenital diaphragmatic hernia)
  • Duodenal atresia — reported in one individual (PMID:30929739).
  • HP:0002247 (Duodenal atresia)

Musculoskeletal

  • Joint hypermobility — 31.3% (PMID:30929739).
  • HP:0001382 (Joint hypermobility)
  • Pectus excavatum — reported in a Chinese case (PMID:41914422).
  • HP:0000767 (Pectus excavatum)

Craniofacial (facial gestalt — see also §4 for facial-recognition analysis)

  • Long ears — 52.9%; broad/prominent nasal tip — 82.4%; wide mouth — 70.6%; thin upper lip vermilion — 70.6%; pointed/prominent chin — 70.6%; low columella — 35.3% (PMID:30929739).
  • HP:0009884 (Long ear); HP:0000455 (Broad nasal tip); HP:0000154 (Wide mouth); HP:0000219 (Thin upper lip vermilion); HP:0000307 (Prominent chin); HP:0011832 (Low columella)
  • Non-neutral palpebral fissures — 4/16 upslanting, 5/16 downslanting (PMID:30929739).
  • HP:0000582 (Upslanted palpebral fissure); HP:0000494 (Downslanted palpebral fissure)
  • Micrognathia (Turkish case) — HP:0000347.

Ophthalmologic / Otologic

  • Eye abnormalities (nystagmus, strabismus, refractive error) — 31.3% (PMID:30929739). HP:0000639 (Nystagmus), HP:0000486 (Strabismus).
  • Hearing loss — 23.5% (PMID:30929739). HP:0000365 (Hearing impairment).

Genitourinary

  • Cryptorchidism, hypospadias — 12.5% each (PMID:30929739). HP:0000028 (Cryptorchidism); HP:0000047 (Hypospadias).
  • Oligospermia — documented in one adult male individual with the Kdm3b-knockout mouse subfertility phenotype cited as biological plausibility (PMID:30929739).

Cardiac / Vascular

  • Ventricular septal defect, heterotaxy, interrupted inferior vena cava (individual reports, PMID:30929739). HP:0001629 (VSD); HP:0001696 (Heterotaxy).
  • Cardiomyopathy and neutropenia — newly reported as expanded phenotypes in a 2023 report of two patients (one with de novo splice variant c.5070+1G>A, first reported KDM3B splice variant; one with c.2828G>A p.R943Q), one presenting with palpitation/dyspnea/edema, the other with recurrent URIs and transient neutropenia (PMID:36757469, Neurogenetics 2023).
  • HP:0001638 (Cardiomyopathy); HP:0001875 (Neutropenia)
  • Pulmonary arterial hypertension / childhood interstitial lung disease (chILD) — reported in a 10-year-old boy (Sudanese) with a novel KDM3B missense variant (c.4406T>C, p.Ile1469Thr) who also carried a SIN3A variant (c.1381G>A, p.Gly461Arg); described as "the second described case worldwide" of PAH associated with a KDM3B mutation (Benslimane et al., Pan Afr Med J 2023, PMID:38314229). Caution: dual-variant case — causal attribution to KDM3B alone is not established.
  • HP:0002092 (Pulmonary hypertension)

Oncologic

  • Malignancy — 2/17 (11.8%) in the founding cohort: acute myeloid leukemia and Hodgkin lymphoma (PMID:30929739). The authors explicitly flag ascertainment bias (both patients were recruited through a cancer-predisposition study) and recommend clinical vigilance rather than a formal surveillance protocol. This is biologically plausible given that somatic KDM3B alterations and Kdm3b-knockout-mouse myelodysplastic-syndrome-like hematopoietic defects are independently described (see §6).
  • HP:0004377 (AML — HP:0004808 more precisely "Acute myeloid leukemia"); HP:0012156 (Hodgkin lymphoma, if using more specific term) — verify exact HPO IDs against the cache before binding.

Frequency caveat

All percentages above are drawn from small, ascertainment-biased cohorts (primarily clinical-genetics referral for developmental delay); true population frequencies are unknown given the extreme rarity of the condition.

4. Genetic / Molecular Information

Causal gene: KDM3B (Lysine Demethylase 3B; previous symbols JMJD1B, C5orf7), HGNC:1337, chromosome 5q31.2, gene OMIM #609373.

Pathogenic variant spectrum (as of the most recent literature review, PMC13025784, MDPI Genes 2026): - Across 27 pooled reported patients: 23 distinct KDM3B variants — 12 missense, 5 nonsense, 4 frameshift, 2 splice-site; 4 variants recurrent. - Original 2019 cohort (17 individuals): 14 distinct variants — 5 truncating (nonsense) and other missense; "All 14 different variants found were absent from the gnomAD and ExAC databases," and "13/14 had high CADD scores (13–40)" (PMID:30929739). - Variants cluster in/near the zinc-finger domain (DNA-binding) and the Jumonji-C (JmjC) catalytic domain responsible for H3K9 demethylation; missense variants affect residues that are "evolutionarily highly conserved across other species," including conservation with paralogs KDM3A and JMJD1C. - MetaDome analysis of missense variant positions found several located in regions "intolerant" or "highly intolerant for missense variation," supporting pathogenicity (PMID:30929739). - Representative individual variants across reports: p.Glu93 (inherited, mother-to-child), p.Asp336Gly (inherited, father-to-child), p.Glu1731Lys (inherited, father-to-child), c.2743_2745del p.(Arg915del) (ClinVar RCV002468724), c.5147T>C p.(Leu1716Pro) (PMID:41914422, de novo), c.5068C>T p.(Gln1690Ter) (Turkish case, PMC13008413, inherited from mildly-affected mother), c.5070+1G>A (first reported splice variant, de novo, PMID:36757469), c.2828G>A p.(Arg943Gln) (PMID:36757469), c.1970C>G p.(Ser657) and c.3973-1G>C (2025 Chinese cohort, PMID:41408900), c.2832-3C>G, c.1188del p.(Glu397Argfs21), c.4580T>C p.(Leu1527Pro), c.3220dup p.(Glu1074Glyfs48) (4-patient growth-predominant series, PMC13025784), c.4406T>C p.(Ile1469Thr) (chILD/PAH case, co-occurring with SIN3A, PMID:38314229).

ACMG/ClinVar classification: Individual variants are typically classified pathogenic/likely pathogenic under ACMG/AMP criteria on a case-by-case basis (e.g., ClinVar RCV002468724 for p.Arg915del); no single hotspot dominates.

Population frequency: All reported disease-causing variants are absent from gnomAD/ExAC, consistent with a severely constrained gene (pLI ≈ 1.0, LOEUF ≈ 0.12 per ClinGen's summary) and de novo dominant disease mechanism.

Somatic vs. germline: DIJOS itself is caused exclusively by germline variants. Note (important for the dismech "keep germline syndromes separate from somatic tumors" convention): KDM3B also carries somatic alterations reported in hematologic malignancies (independent of DIJOS) — the 2019 authors explicitly cite this as biological plausibility for the myeloid malignancy signal in their germline cohort, but somatic KDM3B cancer biology is a distinct body of literature not curated here.

Functional consequence / mechanism: The 2019 authors state: "We identified nonsense variants in five individuals, implying that haploinsufficiency is the most likely mechanism of disease in our individuals as well" (PMID:30929739) — i.e., predominantly loss-of-function via haploinsufficiency, consistent with the gene's extreme LoF intolerance. Direct biochemical confirmation was attempted but inconclusive: "We assessed the mono- and tri-methylation status of H3K9 in HEK293 cells that were overexpressing wild-type and missense mutants of KDM3B, but these experiments were inconclusive due to large variability in expression levels" (PMID:30929739). A later case report (PMID:41914422) proposes that a specific missense variant (p.Leu1716Pro) in the JmjC domain "disrupts hydrogen bonding, reducing protein stability," a structural (not functionally assayed) inference.

Genotype-phenotype correlation: The 2025/2026 literature-review case series (PMC13025784) notes that loss-of-function (truncating) variants "may confer a relatively milder neurodevelopmental phenotype" compared to missense variants — an emerging but not yet firmly established correlation; label as a hypothesis from a small pooled series, not a settled rule.

Modifier genes / epigenetics: No modifier genes established. KDM3B itself is an epigenetic "writer/eraser" — a chromatin-modifying enzyme — making DIJOS itself a disorder of epigenetic regulation (a "chromatinopathy"), rather than a disorder with reported secondary epigenetic dysregulation as a downstream mechanism.

Chromosomal abnormalities: No microdeletion/microduplication or translocation mechanism is described for DIJOS; all reported cases are single-nucleotide/small-indel/splice variants.

5. Environmental Information

Not applicable — DIJOS is a purely monogenic disorder. No environmental, lifestyle, or infectious contributing factors are described in the literature reviewed.

6. Mechanism / Pathophysiology

Ordered causal chain (from initiating lesion to clinical manifestation)

  1. Heterozygous de novo (occasionally inherited) loss-of-function or missense variant in KDM3B (chr5q31.2) → disrupts or destabilizes the KDM3B protein's zinc-finger DNA-binding domain or its C-terminal JmjC catalytic domain (demonstrated by variant clustering and conservation analysis; PMID:30929739). Inferred structural consequence for individual missense variants (e.g., p.Leu1716Pro disrupting hydrogen bonding), not directly assayed in most cases (PMID:41914422).
  2. Truncating variants (≈5/14–5/23 of reported variants) most plausibly cause haploinsufficiency — reduced dosage of functional KDM3B protein — stated explicitly by the discovery cohort as "the most likely mechanism of disease" (PMID:30929739). This step is a genetic-mechanism inference from variant type and gene constraint (pLI≈1.0), not from a direct dosage/protein-level assay in patient tissue.
  3. Reduced KDM3B H3-lysine-9 (H3K9) demethylase activity → failure to remove repressive H3K9me1/me2 marks at KDM3B target loci. This step is inferred by homology/mechanism (KDM3B is a well-characterized JmjC-domain H3K9 demethylase; UniProt DI-05814) rather than directly measured in DIJOS patient cells — the authors' own attempt to assay H3K9 methylation status in an overexpression cell system was "inconclusive due to large variability in expression levels" (PMID:30929739). This is the single largest evidentiary gap in the human mechanistic chain and should be flagged as a knowledge gap / HUMAN_MODEL_MISMATCH candidate when curated, since the mechanistic step downstream of variant identification rests on mouse-model and biochemical-homology inference rather than confirmed patient-tissue chromatin data.
  4. Branch A — Transcriptional dysregulation: Because H3K9 methylation is a repressive chromatin mark, loss of KDM3B demethylase activity is predicted by the authors to result in failure to activate transcription at target loci — stated as: "methylation of H3K9 is generally considered to be a repressive mark, demethylation of H3K9 by KDM3B is predicted to result in the activation of transcription and thus might explain subsequent growth retardation" (PMID:30929739). This transcriptional consequence is itself inferred from the general biology of H3K9 methylation, not measured via patient-derived transcriptomics.
  5. Branch A, continued — Neurodevelopmental consequence: transcriptional dysregulation during neurodevelopment (via disrupted chromatin regulation of neuronal gene programs) → intellectual disability, developmental delay, hypotonia, behavioral/autistic features. A separate line of mouse evidence supports a specific downstream neuro-mechanism: cerebellar studies indicate "diminished H3K9 demethylase activity impairs cerebellar memory consolidation" and that KDM3B "plays an essential role in motor learning" (cited in PMC13025784) — this is model-organism (mouse) evidence whose translational fidelity to human DIJOS cognitive/motor phenotypes has not been directly tested (a HUMAN_MODEL_MISMATCH-type gap).
  6. Branch B — Growth/endocrine consequence: Mouse Kdm3b-knockout studies (Kim et al., PMID:25892958, and related work) show that Kdm3b ablation decreases hepatic/renal IGFBP-3 expression → accelerated IGF-1 degradation → ~36% reduction in circulating IGF-1 → postnatal somatic growth restriction. The 2019 human cohort explicitly extrapolates this mouse mechanism to explain patient short stature: "kdm3b-knockout mice present with a somatic growth restriction, possibly explained by decreased concentrations of insulin-like growth factor-1 (IGF1)" (PMID:30929739) → clinically, this is corroborated in humans by two independently reported cases with biochemically confirmed growth hormone deficiency on stimulation testing (PMC13025784; PMC13008413) → short stature, and rhGH-responsive growth improvement documented in one patient (94.3 cm → 135 cm over 6 years) (PMC13025784).
  7. Branch C — Hematopoietic/reproductive consequence: Kdm3b-knockout mice independently show (i) hematopoietic-system defects "consistent with myelodysplastic syndrome" (PMID:30929739, citing prior mouse literature) and (ii) male subfertility with reduced sperm reserves and motility (PMID:26681924) and female reproductive defects (irregular estrous cycles, reduced ovulation/fertilization rates, decreased circulating estradiol) (PMID:25892958). In humans, this maps to: (a) two malignancies (AML, Hodgkin lymphoma) among 17 founding-cohort patients — flagged by the authors as possibly ascertainment-biased but biologically plausible given known somatic KDM3B alterations in hematologic malignancy, and (b) one adult male patient with documented oligospermia, cited by the authors as "in accordance" with the mouse phenotype (PMID:30929739).
  8. Branch D (peripheral, weakly evidenced) — Isolated reports link KDM3B variants to cardiomyopathy and transient neutropenia (PMID:36757469) and to pulmonary arterial hypertension/childhood interstitial lung disease (PMID:38314229, confounded by a co-occurring SIN3A variant). No mechanistic chain has been proposed connecting KDM3B loss-of-function to cardiac or pulmonary vascular pathophysiology; these should be treated as emerging, single/dual-case-level phenotype associations rather than established downstream nodes of the pathway above.

Category checklist detail

  • Molecular pathways: Chromatin/epigenetic regulation — H3K9 demethylation (JmjC/Jumonji-domain demethylase family); downstream transcriptional activation of KDM3B target genes (specific target gene identities in human neurodevelopment not established in the cited literature).
  • GO:0032454 (histone H3-K9 demethylase activity, note-check exact ID against GO); GO:0006338 (chromatin remodeling, verify).
  • Cellular processes: Chromatin remodeling / epigenetic gene regulation; (mouse) hematopoietic differentiation; (mouse) germ cell/oocyte and spermatocyte maturation.
  • Protein dysfunction: Loss-of-function via haploinsufficiency (predominant model per truncating variant burden); for missense variants, structural destabilization within the JmjC catalytic domain or zinc-finger domain is proposed but not biochemically confirmed for most reported variants.
  • Protein domains: N-terminal zinc-finger DNA-binding domain, LXXLL nuclear-receptor-interaction motif, C-terminal JmjC catalytic domain (per PMC13025784 summary; verify against UniProt directly before binding InterPro/Pfam IDs).
  • Metabolic changes: IGF-1/IGFBP-3 axis dysregulation (mouse-demonstrated; human growth hormone deficiency documented but the human GH-axis lesion has not been mechanistically linked back to KDM3B at the molecular level — it is a phenotypic correlation).
  • Immune system involvement: No autoimmune or immunodeficiency mechanism is established in the primary literature (see caution above about the unverified "immunodeficiency" acronym expansion). Neutropenia is reported in a single case (transient) (PMID:36757469).
  • Tissue damage mechanisms: Not specifically characterized; no oxidative stress/fibrosis/necrosis mechanism has been reported for DIJOS itself (the pulmonary fibrosis findings in the chILD case report are radiologic/histologic descriptions, not mechanistic data, and are confounded by co-occurring SIN3A variant).
  • Biochemical abnormalities: Reduced/absent H3K9 demethylase enzymatic activity (inferred from gene function and variant type, not directly measured in patient tissue in the cited studies); biochemically confirmed GH deficiency in ≥2 patients on stimulation testing.
  • Epigenetic changes: DIJOS is itself a primary disorder of an epigenetic "eraser" enzyme (a chromatinopathy) rather than a disorder with reported secondary/consequential DNA methylation changes; no patient-derived methylome (e.g., EpiSign) data specific to DIJOS were identified in this search — this would be a reasonable knowledge-gap flag (an "episignature" study has not been reported for KDM3B, unlike many other chromatinopathies).
  • Molecular profiling (transcriptomics/proteomics/single-cell): No patient-derived RNA-seq, proteomics, or single-cell data specific to DIJOS were found in this search.
  • Advanced technologies: The founding study used computational facial-recognition/facial-gestalt analysis (CFPS + OpenFace hybrid model) rather than an -omics technology, to statistically validate the facial phenotype: "Clustering improvement factors (CIFs)...demonstrated that there is a significant similarity between the faces of individuals with a germline variant in KDM3B when compared to the general ID population (CIF = 2.5962; p = 0.0054)" (PMID:30929739).

Suggested cell types (CL) / anatomical (UBERON) / GO terms for pathograph nodes (to be independently verified via OAK before binding, per dismech-terms rules — none of the CURIEs below have been looked up live in this session and must be treated as leads): - GO: histone H3-K9 demethylation, chromatin organization, regulation of transcription by RNA polymerase II. - CL: neuron (generic), hematopoietic stem cell, chondrocyte/growth-plate chondrocyte (growth phenotype), spermatid/spermatocyte (mouse fertility phenotype). - UBERON: cerebellum, growth plate/epiphyseal cartilage, bone marrow, pituitary/hypothalamic-pituitary-somatotropic axis, testis.

7. Anatomical Structures Affected

  • Primary organs/systems: CNS (cognition, motor learning, cerebellum in mouse studies), skeletal growth system (short stature), craniofacial skeleton/soft tissue (facial gestalt), endocrine (GH axis).
  • Secondary/complication-level involvement: Hematopoietic system (neutropenia, malignancy signal), cardiovascular system (cardiomyopathy, VSD, heterotaxy, IVC anomaly), pulmonary vasculature (PAH/chILD — confounded case), gastrointestinal (duodenal atresia, hernias, diaphragmatic hernia), genitourinary (cryptorchidism, hypospadias, oligospermia), ophthalmologic (strabismus, nystagmus, refractive error), otologic (hearing loss).
  • Tissue/cell level: Neurons and glia (neurodevelopment); growth-plate chondrocytes and hepatic/renal tissue producing IGFBP-3 (growth axis, mouse-demonstrated); hematopoietic stem/progenitor cells (mouse MDS-like phenotype); germ cells (mouse fertility phenotypes; human oligospermia).
  • Subcellular level: Nucleus — chromatin/histone H3 tail is the direct site of KDM3B enzymatic action (GO Cellular Component: nucleus/nucleoplasm/chromatin).
  • Localization/laterality: No lateralization pattern reported; facial features are symmetric/bilateral dysmorphism.

8. Temporal Development

  • Onset: Congenital/early infancy for feeding difficulties and dysmorphism; developmental delay typically recognized in infancy/early childhood; short stature may be present from birth (low birth weight) or emerge postnatally.
  • Progression: Generally a stable, non-progressive developmental/malformation syndrome rather than a degenerative one — no reports of neurological regression were identified. Growth restriction can be progressive relative to peers if untreated, but is described as responsive to rhGH in the one treated case (PMC13025784).
  • Disease course: Chronic, lifelong (affected parents in the founding cohort demonstrate the phenotype persists into adulthood, ages up to 42 years reported) (PMID:30929739).
  • Critical periods: Neonatal period is a recognized vulnerability window (feeding difficulties); the GH-deficiency subgroup represents a window for endocrine intervention (rhGH therapy) that produced height improvement in one documented case.

9. Inheritance and Population

  • Inheritance pattern: Autosomal dominant (AD), per OMIM #618846, ClinGen (Definitive, AD), and GenCC (Definitive, AD).
  • De novo vs. inherited: In the founding cohort of 17 individuals: 10 confirmed de novo variants and 3 parent-to-child transmissions (affected parent, affected child) — p.Glu93* (mother→child), p.Asp336Gly (father→child), p.Glu1731Lys (father→child) (PMID:30929739). Subsequent reports continue this mixed pattern — e.g., the Turkish case's variant was inherited from a mother with "short stature without neurocognitive impairment" (PMC13008413).
  • Penetrance: Appears complete but with markedly variable expressivity — "No evidence of skipped generations" was noted in the founding families, but severity ranges widely, including a mother who is a carrier with an essentially isolated short-stature phenotype and no cognitive impairment (PMC13008413), and a 4-family-member case series explicitly reporting a "variable neuropsychological profile" among relatives sharing one variant (PMID:42186234, abstract not independently verified in this session — treat as a lead).
  • Expressivity: Variable, as above — ranges from growth-restriction-predominant presentations with minimal neurodevelopmental involvement (PMC13025784) to classic ID + short stature + dysmorphism + multisystem involvement.
  • Genetic anticipation: Not reported/not applicable (not a repeat-expansion disorder).
  • Germline mosaicism: Not specifically documented in the literature reviewed, though biologically plausible for any AD de novo-predominant disorder; not confirmed here.
  • Founder effects: None reported; cases span multiple ethnicities/geographies (Netherlands/international GeneMatcher cohort, China ×3 reports, Albania, Turkey, Sudan).
  • Consanguinity: Not specifically implicated (AD dominant mechanism, not recessive).
  • Carrier frequency: Not applicable/not meaningful for an AD ultra-rare disorder with essentially no population carrier-frequency data (all reported variants absent from gnomAD).
  • Epidemiology: Prevalence reported as <1/1,000,000 (extremely rare); total published, molecularly confirmed cases are estimated at roughly 25–30+ individuals across all literature identified in this search (17 in the founding 2019 cohort + at least 4 (growth-predominant series) + 2 (Neurogenetics 2023) + 1 (Albania, 2022) + 1 (Turkey, 2026) + 2 (China, 2025 autism report) + 1 (China, 2026 case report) + 1 (chILD/PAH, confounded case) — note some of these patient counts may overlap between the "27 pooled" figure in PMC13025784 and reports published after that review, so this total should be treated as an estimate to be refined during formal curation, not an exact count).
  • Geographic distribution: Cases reported from the Netherlands/international collaborative cohort, China (×3 independent reports), Albania, Turkey, and Sudan — consistent with a pan-ethnic, non-geographically-restricted disorder ascertained wherever exome/genome sequencing access exists.
  • Sex ratio: Founding cohort was roughly balanced (9 males, 8 females) (PMID:30929739); no strong sex skew reported.
  • Age distribution: Founding cohort spanned 9 months to 42 years, reflecting both pediatric probands and their affected adult parents (PMID:30929739).

10. Diagnostics

  • Genetic testing approach: Diagnosis is made by identifying a heterozygous pathogenic/likely pathogenic KDM3B variant, typically via exome sequencing (trio-based preferred) or a multigene neurodevelopmental-disorder/intellectual-disability panel that includes KDM3B; whole-genome sequencing would also detect coding variants. No single-gene-first testing strategy is standard given the absence of a specific pathognomonic clinical sign; NDD gene panels and exome sequencing are the practical entry points (consistent with how essentially all reported cases, including the founding cohort, were ascertained — via trio-ES with a chromatinopathy/NDD gene list).
  • Chromosomal microarray / karyotype: Not the primary diagnostic modality (no described recurrent CNV mechanism), though often performed as part of standard NDD/short-stature diagnostic workup before/alongside sequencing.
  • Clinical/biochemical workup: Growth-hormone stimulation testing is clinically relevant given the documented (though not universal) GH-deficiency subgroup (PMC13025784; PMC13008413). Standard developmental/cognitive assessment (e.g., Denver II, Wechsler scales) is used to characterize the ID/DD phenotype (as in PMC13008413 and PMID:41914422).
  • Imaging: No syndrome-specific neuroimaging pattern has been established; HRCT was used in the chILD/PAH case to characterize ground-glass opacities, mosaic attenuation, and fibrosis, but this is not a diagnostic feature of DIJOS itself (confounded by co-occurring SIN3A variant) (PMID:38314229).
  • Facial-gestalt/computational phenotyping: The founding study's CFPS/OpenFace-based facial-recognition analysis (statistically significant clustering, CIF = 2.5962, p = 0.0054) suggests that Face2Gene-style deep-phenotyping tools may aid diagnostic suspicion/prioritization pre- or post-sequencing (PMID:30929739), though this is a research tool rather than a validated clinical diagnostic criterion.
  • Differential diagnosis: No formal differential-diagnosis list specific to DIJOS was located in the primary literature searched. Given the overlapping presentation (ID + short stature + facial dysmorphism + feeding difficulties + hypermobility), DIJOS falls within the broader chromatinopathy differential (Cornelia de Lange syndrome and related cohesinopathies/chromatin-regulator disorders, Coffin-Siris syndrome, KBG syndrome) on clinical grounds by phenotypic analogy, but no primary source explicitly names these as the DIJOS differential — this should be flagged as an inference rather than sourced fact if curated, and verified against the original AJHG paper's discussion section directly (not fully retrievable via WebFetch in this session due to access restrictions on cell.com/ScienceDirect).
  • Standardized diagnostic criteria: No DSM/ICD-specific diagnostic criteria exist for DIJOS as a discrete entity; diagnosis is molecular (variant identification) combined with compatible phenotype.

11. Outcome / Prognosis

  • Survival/mortality: No mortality data specific to DIJOS were identified; the disorder is not described as life-limiting in the reviewed literature, though the malignancy signal (AML, Hodgkin lymphoma in 2/17 founding-cohort patients) and the single severe PAH/chILD case represent potentially serious, though uncommon, complications.
  • Morbidity/function: Long-term functional outcome is dominated by the degree of intellectual disability (mild-to-moderate in the great majority) and short stature; affected adults in the founding cohort (up to age 42) demonstrate the condition is compatible with adult survival and, in at least some carriers (e.g., the mildly affected mothers in inherited cases), with minimal functional impairment.
  • Complications: Malignancy (AML, Hodgkin lymphoma — small numbers, ascertainment-biased), cardiomyopathy, neutropenia, pulmonary arterial hypertension (single confounded case), epilepsy (transient in some), hearing loss, ophthalmologic complications.
  • Recovery/treatment response: Growth response to rhGH therapy was substantial in one documented case (94.3 cm → 135 cm over 6 years, moving from below -3 SD to -1 to -2 SD) (PMC13025784) — this is the only quantified treatment-outcome data point identified.
  • Prognostic factors: Preliminary/unconfirmed genotype-phenotype signal that truncating (LoF) variants may associate with a milder neurodevelopmental phenotype than missense variants (PMC13025784) — treat as an emerging hypothesis, not an established prognostic rule.

12. Treatment

Management is supportive and multidisciplinary; there is no disease-modifying or gene-targeted therapy for DIJOS.

  • Pharmacotherapy:
  • Recombinant human growth hormone (rhGH) for biochemically confirmed GH deficiency — documented efficacy in one case (PMC13025784); the authors of that series explicitly flag a theoretical concern requiring individualized risk-benefit discussion: "given that KDM3B...has been linked to myelodysplastic syndrome and acute myeloid leukemia, the potential oncogenic risk of rhGH must be carefully weighed" — i.e., rhGH use in DIJOS should be considered in the context of the gene's hematologic-malignancy association, though no formal contraindication or surveillance protocol has been published.
    • NCIT:C1691 (Growth Hormone, generic) — treatment_term candidate; verify exact NCIT binding before curation.
  • ADHD pharmacotherapy as clinically indicated for the behavioral/ADHD subgroup (general guideline-level statement, not DIJOS-specific evidence).
  • Rehabilitative/supportive care: Early referral to developmental/rehabilitation services (physical therapy, occupational therapy, speech-language therapy) for the ID/DD and motor-delay phenotype; individualized educational programs.
  • NCIT:C15302 (Physical Therapy); NCIT:C159273 (Speech Therapy, verify); NCIT:C121351 (Occupational Therapy, verify).
  • Genetic counseling: Recommended given AD inheritance, de novo predominance but documented parent-to-child transmission with variable expressivity — family variant testing (cascade testing of parents) is standard once a proband variant is identified, as demonstrated in essentially every cited case report.
  • NCIT:C15240 (Genetic Counseling).
  • Malignancy vigilance: No formal, published surveillance protocol exists; the founding-cohort authors recommend clinical vigilance rather than routine screening, citing ascertainment bias in their 2/17 malignancy signal (PMID:30929739).
  • Experimental/investigational therapies: None identified — no gene therapy, targeted molecular therapy, or clinical trials specific to DIJOS were found in this search (searched ClinicalTrials.gov indirectly via general web search; no DIJOS/KDM3B-specific trial surfaced).
  • Cardiac/pulmonary management: Standard cardiology/pulmonology management as clinically indicated for the individually reported cardiomyopathy and PAH/chILD cases; no DIJOS-specific cardiac or pulmonary management guideline exists.

13. Prevention

  • Primary prevention: Not applicable — this is a predominantly de novo genetic disorder; no modifiable primary-prevention strategy exists.
  • Secondary prevention / screening: No population or newborn screening program exists (ultra-rare, molecularly diagnosed condition). Prenatal/preimplantation genetic testing is relevant once a familial pathogenic variant is identified (standard genetic-counseling practice for known AD variants), though this was not explicitly documented as performed in any cited case.
  • Genetic counseling: Central preventive/family-planning tool once a proband's variant is identified — enables informed reproductive decision-making and identification of mildly affected/subclinically affected parents (as seen in the inherited cases above, where a parent's own diagnosis was made retrospectively via cascade testing).
  • Behavioral/public health interventions: Not applicable.

14. Other Species / Natural Disease

  • Taxonomy: No naturally occurring veterinary/companion-animal disease attributable to spontaneous Kdm3b variants was identified in this search (searched OMIA indirectly via general search; no hits surfaced). This differs from the engineered mouse models below.
  • Orthologous gene: Mouse Kdm3b (MGI, chromosome 18) is the principal ortholog studied.
  • Comparative biology: KDM3B is conserved with paralogs KDM3A and JMJD1C within the JmjC-domain histone demethylase family (PMID:30929739 notes cross-paralog conservation at missense-affected residues).

15. Model Organisms

  • Species/model type: Mouse (Mus musculus), germline Kdm3b knockout — the principal and, in the literature reviewed, essentially the only animal model directly informing DIJOS mechanism.
  • Key model studies:
  • Growth/endocrine: Kdm3b-knockout mice show postnatal somatic growth restriction; mechanistically, Kdm3b ablation reduces renal/hepatic IGFBP-3 expression (~53% reduction reported), lowering circulating IGF-1 (~36% reduction), driving growth restriction (PMID:25892958, "The histone H3K9 demethylase Kdm3b is required for somatic growth and female reproductive function").
  • Female reproduction: The same knockout model shows irregular estrous cycles, ~45% reduced ovulation capacity, ~47% reduced fertilization rate, ~44% reduced uterine decidual response, and >50% reduced circulating 17β-estradiol (PMID:25892958).
  • Male reproduction: A separate Kdm3b-knockout study shows decreased sperm number/motility and impaired consummatory and motivational sexual behavior (PMID:26681924, "Knockout of the Histone Demethylase Kdm3b Decreases Spermatogenesis and Impairs Male Sexual Behaviors").
  • Hematopoiesis: Kdm3b-knockout mice show hematopoietic defects described by the DIJOS founding-cohort authors as "consistent with myelodysplastic syndrome" (cited secondhand in PMID:30929739; primary knockout-hematopoiesis paper not independently retrieved in this session and should be verified directly before citing in curation).
  • Neurocognitive (cerebellum): Mouse studies indicate diminished H3K9 demethylase activity "impairs cerebellar memory consolidation" and that Kdm3b "plays an essential role in motor learning" (cited in PMC13025784; primary source not independently retrieved in this session).
  • Phenotype recapitulation: The mouse model recapitulates the growth-restriction and (male/female) reproductive phenotypes observed in a subset of human patients reasonably well (the founding-cohort authors explicitly draw this parallel, including citing one patient's oligospermia as "in accordance" with the mouse phenotype). The neurodevelopmental/cognitive phenotype in humans (the dominant clinical feature) is far less directly validated in the mouse model — the cerebellar/motor-learning mouse data are suggestive but have not been shown to reproduce the human ID/developmental-delay phenotype specifically, representing a genuine human-model translational gap.
  • Model limitations: Complete germline knockout (not a patient-variant-specific knock-in) — does not model the dominant, haploinsufficient, single-copy-loss human genetics precisely (most mouse studies use homozygous knockouts), and does not model the missense/potentially dominant-negative variant subclass at all. No conditional, humanized, or patient-variant-specific (knock-in) mouse model was identified in this search.
  • Other model systems: No zebrafish, Drosophila, C. elegans, iPSC-derived, or organoid models of KDM3B/DIJOS were identified in this search.
  • Resources: MGI (Mouse Genome Informatics) is the relevant repository for the Kdm3b knockout allele(s); specific allele IDs were not retrieved in this session and should be looked up directly (e.g., via MGI) before curation.

Summary of Sourcing Caveats for Curation

  1. Full text of the founding paper (PMID:30929739, AJHG 2019) was accessed via a PMC mirror (PMC6451728) through an AI-summarization WebFetch pass; the quotes above are reported as extracted but should be re-verified against the primary PMC/journal HTML directly (exact-substring snippet verification, per dismech's evidence workflow) before being committed as snippet: values in KB YAML — this report is a research lead, not pre-verified curation content.
  2. Several PubMed abstract pages (PMID:36757469, PMID:42186234) could not be fetched directly (cookie-consent wall); abstract content for these was reconstructed from WebSearch snippets/secondary summaries only — treat as leads requiring direct primary-source verification, not as verified quotes.
  3. The AI-generated acronym expansion of "DIJOS" encountered in one search result (implying "immunodeficiency" and "joint contractures" are part of the name) could not be traced to OMIM, Orphanet, or the founding paper and appears to be a fabrication/hallucination by a web-summarization layer — do not use it.
  4. The chILD/PAH case (PMID:38314229) carries a co-occurring SIN3A variant; causal attribution to KDM3B alone is confounded and should be curated as such (e.g., lower-confidence evidence, explicit dual-diagnosis note).
  5. All GO/CL/UBERON/NCIT/HP CURIEs suggested above are research leads only and were not independently verified via OAK/runoak lookup in this session, per the "every CURIE is read from a source in the same step it is written" rule — they must be looked up fresh at curation time, not copied from this report.
  6. Total published-case counts are estimated by summing across overlapping reviews (PMC13025784's "27 patients" pooled figure predates several 2025–2026 case reports) and should be reconciled carefully during curation rather than taken as an exact denominator.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 13
Resolved 13
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 7
Quoted claims found in source 6
Quoted claims not found in source 1
References weighed for topical relevance 13
On topic 13
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

  • PMID:30929739: "13/14 had high CADD scores (13–40)"
  • closest text in source: "All 14 different variants found were absent from the gnomAD and ExAC databases, and 13/14 had high Combined Annotation Dependent Depletion scores (CADD; scores between 13 and 40) and were predicted to be pathogenic by both the PolyPhen-2 and SIFT prediction programs (Table 1).12, 13, 14, 15 All individuals or their legal guardians gave written informed consent, and the study was given IRB approval"

Term Validation

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

Outcome Count
Terms checked 55
Resolved 53
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 50
Terms named correctly 34
Terms named as a different term 8
Terms whose name is worth a second look 8

Terms the report names something else

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

  • MONDO:0030012 (3 mentions) - the report calls it "if available", "confirmed via GenCC submission, consistent with the MONDO ID supplied in the research request"; MONDO calls it Diets-Jongmans syndrome
  • HP:0011342 (1 mention) - the report calls it "Mild intellectual disability"; HP calls it Mild global developmental delay
  • HP:0000824 (1 mention) - the report calls it "Growth hormone deficiency"; HP calls it Decreased response to growth hormone stimulation test
  • HP:0009884 (1 mention) - the report calls it "Long ear"; HP calls it Tapered distal phalanges of finger
  • HP:0011832 (1 mention) - the report calls it "Low columella"; HP calls it Narrow nasal tip
  • HP:0001696 (1 mention) - the report calls it "Heterotaxy"; HP calls it Situs inversus totalis
  • HP:0012156 (1 mention) - the report calls it "Hodgkin lymphoma, if using more specific term"; HP calls it Hemophagocytosis
  • NCIT:C1691 (1 mention) - the report calls it "Growth Hormone, generic"; NCIT calls it Trabectedin

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:

  • MONDO:0000508 (1 mention) - the report calls it "Syndromic intellectual disability", "GeneCC/ClinGen: Definitive gene-disease relationship, "Syndromic intellectual disability"; MONDO calls it syndromic intellectual disability**
  • HP:0000307 (1 mention) - the report calls it "Prominent chin"; HP calls it Pointed chin, and lists "Pointy chin" among its other names
  • HP:0001875 (1 mention) - the report calls it "Neutropenia"; HP calls it Decreased total neutrophil count, and lists "Neutropenia" among its other names
  • HP:0002092 (1 mention) - the report calls it "Pulmonary hypertension"; HP calls it Pulmonary arterial hypertension, and lists "Pulmonary artery hypertension" among its other names
  • GO:0032454 (1 mention) - the report calls it "histone H3-K9 demethylase activity, note-check exact ID against GO"; GO calls it histone H3K9 demethylase activity, and lists "histone H3-K49 demethylase activity" among its other names
  • GO:0006338 (1 mention) - the report calls it "chromatin remodeling, verify"; GO calls it chromatin remodeling
  • NCIT:C159273 (1 mention) - the report calls it "Speech Therapy, verify"; NCIT calls it Speech Language Therapy
  • NCIT:C121351 (1 mention) - the report calls it "Occupational Therapy, verify"; NCIT calls it Occupational Therapy

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • MONDO:0030012 - called "if available", "confirmed via GenCC submission, consistent with the MONDO ID supplied in the research request"
  • MONDO:0000508 - called "Syndromic intellectual disability", "GeneCC/ClinGen:** Definitive gene-disease relationship, "Syndromic intellectual disability"

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.