6q16 Deletion Syndrome

Genetic MONDO:0015749 Pathograph 25 Show in embeddings browser Contiguous Gene Deletion Syndrome Syndromic Obesity

6q16 deletion syndrome comprises overlapping heterozygous chromosome deletions with variable developmental delay, intellectual disability, behavioral features and growth abnormalities. Some intervals confer susceptibility to hyperphagia and obesity. SIM1-containing 6q16.2-q16.3 deletions and SIM1-sparing, POU3F2-containing 6q16.1 deletions provide distinct genetic routes to an overlapping Prader-Willi-like phenotype; obesity is not obligatory. More proximal EPHA7-containing 6q16.1 deletions principally support neurodevelopmental susceptibility. Gene content, age and additional genetic findings limit prediction from the cytogenetic label alone. Endocrine deficiency has been reported in a SIM1-containing deletion and can emerge after normal infant testing.

Ask OpenScientist

Ask a research question about 6q16 Deletion Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
9
Pathophys.
1
Histopath.
46
Phenotypes
2
Gaps
25
Pathograph
3
Genes
3
Medical Actions
3
Subtypes
3
Differentials
2
Models
1
Deep Research
👪

Inheritance

1
Autosomal dominant deletion with de novo and inherited occurrences HP:0000006
A heterozygous deletion can occur de novo or be transmitted within a family. Clinical expression is variable, and inherited EPHA7-containing deletions may occur in unaffected parents. The 2015 SIM1-region series excluded a parental deletion in 14 of 15 families; one was not tested.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:26833329 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The 6q16.1 deletions segregated with the phenotype in multiplex families and were shown to be de novo in four families"
Documents both familial transmission and de novo occurrence.
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The absence of parental deletion was checked in 14 cases, the exception being patient no. 4."
Avoids treating the abstract's description of all cases as de novo as fully confirmed.
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance."
The selected cohort supports variable expression; it does not estimate population penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
◆

Subtypes

3
SIM1-containing 6q16.2-q16.3 deletions
Intervals including SIM1 are associated with variable obesity and neurodevelopmental findings. These are gene-content groups rather than uniform recurrent rearrangements.
Show evidence (2 references)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Except for patients no. 14 and 15, all patients had deletions that included the SIM1 gene."
SIM1 involvement is determined by deletion boundaries; it is absent from two intervals in this cohort.
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency."
The authors interpret variable obesity as incomplete penetrance. The cohort includes a fetus and the tables have discrepant obesity totals, so this quoted count is not used as a penetrance estimate.
SIM1-sparing POU3F2-containing 6q16.1 deletions
Small overlapping intervals include POU3F2 and FBXL4 while sparing SIM1. Developmental impairment and later hyperphagia or obesity overlap the SIM1-associated phenotype, but individual children can remain nonobese.
Show evidence (2 references)
PMID:26833329 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia."
Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
PMID:35581197 SUPPORT DIRECT BACKGROUND Human Clinical
"The six families described in the report by Kasher et al. had the deletion of the POU3F2 and FBXL4 genes, although the deletion size was different in each family"
Identifies both genes in the overlapping interval; these are not POU3F2-only deletions.
EPHA7-containing proximal 6q16.1 deletions
More proximal intervals, including deletions restricted to EPHA7, are associated with neurodevelopmental susceptibility with incomplete penetrance. Their clinical findings are not automatically attributable to the SIM1/POU3F2 appetite pathway.
Show evidence (2 references)
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Four patients had tiny deletions involving only EPHA7"
Single-gene deletions strengthen the locus association but the authors describe a susceptibility effect with incomplete penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance."
The selected cohort supports variable expression; it does not estimate population penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
?

Discussions and Knowledge Gaps

2
Which experimentally identified transcriptional and neuroendocrine effects occur in human deletion carriers?
HUMAN MODEL MISMATCH del6q16_human_model_bridge
Attached to
pathophysiology#Reduced SIM1-Dependent Transactivation pathophysiology#POU3F2-Dependent Oxytocin Expression in Zebrafish
SIM1 reporter loss, POU3F2 variant effects and zebrafish oxytocin-expression regulation support biological hypotheses. None establishes universal human paraventricular neuron loss, circulating oxytocin deficiency or a single causal route from the deletion to obesity and developmental impairment.
Show evidence (2 references)
PMID:23778136 SUPPORT DIRECT PRIMARY RESULT In Vitro
"We found a strong loss-of-function effect of p.T46R, p.H323Y, and p.T714A mutations on SIM1 transcriptional activity with both ARNT and ARNT2"
Reporter assays establish variant-specific loss of transactivation in engineered human cells, not hypothalamic histology in deletion carriers.
PMID:26833329 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Using morpholino and mutant zebrafish models, we show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area."
Experimental pathway ordering and oxytocin-expression readout in zebrafish. The available abstract does not establish human neuron loss, circulating oxytocin deficiency or obesity rescue.
How do gene content, age and additional genetic findings modify the phenotype?
KNOWLEDGE GAP del6q16_interval_and_ascertainment
Attached to
pathophysiology#Heterozygous 6q16 Deletion genetic#EPHA7
Intervals vary and some reported patients carry additional CNVs or large deletions. The 2015 series has inconsistent obesity totals between narrative and tables and includes a fetus among SIM1 deletions; the quoted 8/13 is not used as a penetrance estimate. The EPHA7 cohort includes unaffected transmitting parents and two severe cases with substantial alternative genetic contributions. These sources support qualitative variability rather than disease-wide frequency bands.
Show evidence (3 references)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency."
The authors interpret variable obesity as incomplete penetrance. The cohort includes a fetus and the tables have discrepant obesity totals, so this quoted count is not used as a penetrance estimate.
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Four patients had tiny deletions involving only EPHA7"
Single-gene deletions strengthen the locus association but the authors describe a susceptibility effect with incomplete penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance."
The selected cohort supports variable expression; it does not estimate population penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
⚙

Pathophysiology

9
Heterozygous 6q16 Deletion
Mechanism confidence: Established
A variable interstitial deletion removes one copy of the genes within its specific boundaries. No single gene is deleted in every interval represented here; de novo and inherited events occur.
Downstream
Reduced SIM1 Gene Dosage An interval that includes SIM1 removes one genomic copy.
Reduced POU3F2 Gene Dosage An interval that includes POU3F2 removes one genomic copy.
Reduced EPHA7 Gene Dosage More proximal deletions can remove all or part of EPHA7.
Altered Neurodevelopment Several deletion intervals associate with developmental impairment; deleted-gene contributions and intervening cellular events differ.
Hypopituitarism A SIM1-containing 6q16.1-q21 deletion was associated with later pituitary deficiency. The responsible gene and anatomical lesion were not established in this case.
Show evidence (2 references)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Microarray analyses showed overlapping 6q deletions, extending from 92 138 719 bp to 108 227 875 bp (hg19)."
The cohort includes variable overlapping intervals; these coordinates describe the combined span, not a recurrent deletion.
PMID:26833329 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The 6q16.1 deletions segregated with the phenotype in multiplex families and were shown to be de novo in four families"
Documents both familial transmission and de novo occurrence.
Reduced SIM1 Gene Dosage
Mechanism confidence: Established
Loss of one SIM1 copy is an established genomic finding in a subset of 6q16 deletions. Human deletion cohorts and separate intragenic-variant studies support an incompletely penetrant contribution to obesity.
SIM1 hgnc:10882 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SIM1 (hgnc:10882). hgnc:10882 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Reduced SIM1-Dependent Transactivation Reduced functional dosage is supported by loss-of-function variant assays, but SIM1 target transcription has not been directly measured in the deletion-carrier hypothalamus.
Show evidence (2 references)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Except for patients no. 14 and 15, all patients had deletions that included the SIM1 gene."
SIM1 involvement is determined by deletion boundaries; it is absent from two intervals in this cohort.
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency."
The authors interpret variable obesity as incomplete penetrance. The cohort includes a fetus and the tables have discrepant obesity totals, so this quoted count is not used as a penetrance estimate.
Reduced SIM1-Dependent Transactivation
Mechanism confidence: Provisional
Selected obesity-associated SIM1 variants reduce ARNT- and ARNT2-dependent reporter activation. These experiments support loss of transcription-factor function as a mechanism; they do not demonstrate loss of hypothalamic neurons or a particular target-gene defect in deletion carriers.
SIM1 hgnc:10882 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SIM1 (hgnc:10882). hgnc:10882 is a gene from the HUGO Gene Nomenclature Committee.
Experimental models
Human 293 Flp-In T-Rex SIM1 reporter assay CELL LINE Directly assays SIM1-dependent reporter activation.
Downstream
Disordered Appetite Regulation Genetic association with obesity and experimental loss of transcriptional activity support a contribution to appetite regulation, with unresolved human neuronal intermediates.
Show evidence (1 reference)
PMID:23778136 SUPPORT DIRECT PRIMARY RESULT In Vitro
"We found a strong loss-of-function effect of p.T46R, p.H323Y, and p.T714A mutations on SIM1 transcriptional activity with both ARNT and ARNT2"
Reporter assays establish variant-specific loss of transactivation in engineered human cells, not hypothalamic histology in deletion carriers.
Reduced POU3F2 Gene Dosage
Mechanism confidence: Established
SIM1-sparing 6q16.1 deletions remove one POU3F2 copy together with FBXL4 and, depending on their extent, additional genes. Subsequent intragenic-variant evidence strengthens POU3F2 as a contributor without making the whole chromosomal disorder monogenic.
POU3F2 hgnc:9215 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves POU3F2 (hgnc:9215). hgnc:9215 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Altered POU3F2-Dependent Transcription Intragenic-variant assays support altered transcriptional function as a consequence of POU3F2 disruption. Individual DNA-binding and activation effects vary, and are not direct measurements in deletion carriers.
Show evidence (2 references)
PMID:35581197 SUPPORT DIRECT BACKGROUND Human Clinical
"The six families described in the report by Kasher et al. had the deletion of the POU3F2 and FBXL4 genes, although the deletion size was different in each family"
Identifies both genes in the overlapping interval; these are not POU3F2-only deletions.
PMID:37207645 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity."
Intragenic variants independently strengthen POU3F2 attribution; this is a separate monogenic cohort, not a deletion-syndrome frequency estimate.
Altered POU3F2-Dependent Transcription
Mechanism confidence: Provisional
Reported POU3F2 variants disturb DNA binding or promoter activation, with nuclear translocation retained except for the early-truncating variant. The transcriptional consequences of heterozygous deletion in human brain remain incompletely measured.
POU3F2 hgnc:9215 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves POU3F2 (hgnc:9215). hgnc:9215 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Disordered Appetite Regulation POU3F2-containing deletions and separate intragenic variants associate with hyperphagia and obesity; the responsible human target genes and neural-circuit changes remain unresolved.
Altered Neurodevelopment Human POU3F2 disruption is associated with neurodevelopmental impairment, but the intermediate cellular effects have not been established by the available deletion evidence.
Show evidence (1 reference)
PMID:37207645 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation."
Functional summary from the available abstract of the intragenic-variant study. Effects differ by variant and are not measurements in deletion-carrier hypothalamus.
POU3F2-Dependent Oxytocin Expression in Zebrafish
Mechanism confidence: Provisional
Morpholino and mutant zebrafish experiments place pou3f2 downstream of sim1 in regulation of oxytocin expression in the neuroendocrine preoptic area. This is an experimental pathway branch; a corresponding oxytocin deficiency or neuron-loss mechanism has not been established in human 6q16 deletion carriers.
Animal models
Zebrafish sim1-pou3f2 neuroendocrine pathway models Zebrafish perturbs Tests a candidate conserved transcriptional pathway through experimental gene perturbation.
Show evidence (1 reference)
PMID:26833329 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Using morpholino and mutant zebrafish models, we show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area."
Experimental pathway ordering and oxytocin-expression readout in zebrafish. The available abstract does not establish human neuron loss, circulating oxytocin deficiency or obesity rescue.
Reduced EPHA7 Gene Dosage
Mechanism confidence: Provisional
Partial or complete EPHA7 loss is associated with neurodevelopmental susceptibility. Transmission from unaffected parents and variable clinical severity limit deterministic attribution. Human studies do not directly measure the proposed dendritic or synaptic defects.
EPHA7 hgnc:3390 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EPHA7 (hgnc:3390). hgnc:3390 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Altered Neurodevelopment Clinical deletion data support a susceptibility relationship; specific human cellular intermediates remain unknown.
Show evidence (2 references)
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Four patients had tiny deletions involving only EPHA7"
Single-gene deletions strengthen the locus association but the authors describe a susceptibility effect with incomplete penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance."
The selected cohort supports variable expression; it does not estimate population penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
Disordered Appetite Regulation
Mechanism confidence: Hypothetical
Hyperphagia and obesity susceptibility are observed in both SIM1-containing and POU3F2-containing deletion groups. Hypothalamic regulation is a proposed functional explanation, supported by related experimental work rather than direct human circuit measurements.
Downstream
Polyphagia The clinical appetite phenotype is compatible with disturbed regulation, but a specific neural satiety defect has not been measured in deletion carriers.
Obesity Obesity susceptibility is variable; energy intake, expenditure and other contributors were not comprehensively measured in the deletion cohorts.
Show evidence (2 references)
PMID:26833329 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia."
Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
PMID:25351778 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency."
The authors interpret variable obesity as incomplete penetrance. The cohort includes a fetus and the tables have discrepant obesity totals, so this quoted count is not used as a penetrance estimate.
Altered Neurodevelopment
Mechanism confidence: Provisional
Developmental and cognitive impairment occur across several 6q16 intervals. This node represents an unresolved developmental consequence rather than a proven shared neuron-migration, axon-guidance or synaptic lesion.
Downstream
Global developmental delay Multi-domain delay is documented clinically; its cellular basis is unresolved.
Intellectual disability Cognitive impairment is reported in overlapping deletion cohorts, without a resolved common cellular mediator.
Delayed speech and language development Language delay is a documented component of the variable neurodevelopmental phenotype; the responsible neural intermediates remain unresolved.
Delayed ability to walk Delayed acquisition of walking is a motor-developmental manifestation in the detailed SIM1-sparing case; a specific central motor lesion has not been established.
Autistic behavior Autistic features are documented in the SIM1-sparing case, without a standardized autism diagnosis or a resolved cellular pathway.
Atypical behavior Clinical cohorts support behavioral involvement as part of the neurodevelopmental spectrum, with heterogeneous deletion content and incompletely identified mediators.
Hypotonia Hypotonia accompanies developmental impairment in some deletion carriers. A central developmental contribution is plausible but not localized by the available clinical evidence.
Microcephaly Some EPHA7-containing deletion carriers have postnatal microcephaly. The association with altered neurodevelopment is clinically supported without a demonstrated human cellular growth mechanism.
Show evidence (3 references)
PMID:26833329 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia."
Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Four patients had tiny deletions involving only EPHA7"
Single-gene deletions strengthen the locus association but the authors describe a susceptibility effect with incomplete penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance."
The selected cohort supports variable expression; it does not estimate population penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
✶

Histopathology

1
Cerebral and cerebellar neuronal ectopia
Autopsy of one fetus with a large 14-Mb 6q16.1-q21 deletion identified ectopic neurons and abnormal nuclear organization. This prenatal case is not representative of all surviving deletion carriers, and the findings cannot be assigned to SIM1 alone.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Microscopic examination of the brain evidenced fusion of the anterior caudate nucleus and putamen (Figure 1c), multiple ectopic neurons in the white matter (Figure 1d) and ectopic Purkinje cells in the internal granular layer of the cerebellum (Figure 1e)."
Direct fetal neuropathology from one large deletion, distinct from the mostly normal available MRI observations in living patients.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for 6q16 Deletion 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.
●

Phenotypes

46
Cardiovascular 3
Bicuspid aortic valve HP:0001647 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bicuspid aortic valve (HP:0001647). HP:0001647 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"cardiac defects (25%) including bicuspid aortic valve, atrial or ventricular septal defects."
The full cohort reports these specific findings. Its quoted summary percentage is not used as a population frequency; the separate supravalvular stenosis case also had Williams-Beuren syndrome. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
Atrial septal defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"cardiac defects (25%) including bicuspid aortic valve, atrial or ventricular septal defects."
The full cohort reports these specific findings. Its quoted summary percentage is not used as a population frequency; the separate supravalvular stenosis case also had Williams-Beuren syndrome. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
Ventricular septal defect HP:0001629 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular septal defect (HP:0001629). HP:0001629 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"cardiac defects (25%) including bicuspid aortic valve, atrial or ventricular septal defects."
The full cohort reports these specific findings. Its quoted summary percentage is not used as a population frequency; the separate supravalvular stenosis case also had Williams-Beuren syndrome. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
Digestive 1
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Feeding difficulties | | − | − | | + | + | − | − | − | − | − | + | + | − | −"
Reported in the 14 living patients of the 2015 clinical series, with heterogeneous deletion intervals and incomplete assessments. No disease-wide frequency is inferred.
Ear 2
Overfolded helix HP:0000396 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Overfolded helix (HP:0000396). HP:0000396 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Others | Thin upper lip, marked suborbital folds, broad nasal bridge, micrognathia, abnormally overfolded helices | Horizontal eyebrows | | | Horizontal eyebrows | | | Abnormally overfolded helices | Synophris, hirsutism, small mouth | Synophris | Epicanthal folds | | Hypertelorism |..."
Craniofacial row of Table 1; no syndrome frequency or shared causal sequence is inferred.
Cupped ear HP:0000378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cupped ear (HP:0000378). HP:0000378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19664229 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"developmental delay, microcephaly, short stature, con- genital hypotonia, mild ptosis, periauricular tags, cupped"
The case report lists the individual neurological and dysmorphic observations.
Endocrine 1
Hypopituitarism HP:0040075 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypopituitarism (HP:0040075). HP:0040075 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24038875 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Detailed endocrine evaluation of the propositus during childhood and adolescence revealed hypopituitarism, though initial endocrine evaluations during infancy were unremarkable."
One SIM1-containing deletion case developed later endocrine deficits; this does not establish a universal or obligatory consequence.
Eye 7
Myopia HP:0000545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopia (HP:0000545). HP:0000545 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Vision anomalies | | Severe myopia | − | − | Severe myopia | − | Myopia | Strabismus | − | Astigmatism | Hypermetropia | Nystagmus | − | Strabismus | −"
Table 1 distinguishes individual refractive and ocular-motor abnormalities. Nystagmus was recorded in patient 12 with a complex rearrangement.
Hypermetropia HP:0000540 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypermetropia (HP:0000540). HP:0000540 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Vision anomalies | | Severe myopia | − | − | Severe myopia | − | Myopia | Strabismus | − | Astigmatism | Hypermetropia | Nystagmus | − | Strabismus | −"
Table 1 distinguishes individual refractive and ocular-motor abnormalities. Nystagmus was recorded in patient 12 with a complex rearrangement.
Astigmatism HP:0000483 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Astigmatism (HP:0000483). HP:0000483 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Vision anomalies | | Severe myopia | − | − | Severe myopia | − | Myopia | Strabismus | − | Astigmatism | Hypermetropia | Nystagmus | − | Strabismus | −"
Table 1 distinguishes individual refractive and ocular-motor abnormalities. Nystagmus was recorded in patient 12 with a complex rearrangement.
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Vision anomalies | | Severe myopia | − | − | Severe myopia | − | Myopia | Strabismus | − | Astigmatism | Hypermetropia | Nystagmus | − | Strabismus | −"
Table 1 distinguishes individual refractive and ocular-motor abnormalities. Nystagmus was recorded in patient 12 with a complex rearrangement.
Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Vision anomalies | | Severe myopia | − | − | Severe myopia | − | Myopia | Strabismus | − | Astigmatism | Hypermetropia | Nystagmus | − | Strabismus | −"
Table 1 distinguishes individual refractive and ocular-motor abnormalities. Nystagmus was recorded in patient 12 with a complex rearrangement.
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19664229 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"developmental delay, microcephaly, short stature, con- genital hypotonia, mild ptosis, periauricular tags, cupped"
The case report lists the individual neurological and dysmorphic observations.
Iris coloboma HP:0000612 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Iris coloboma (HP:0000612). HP:0000612 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"eye abnormalities (40%) such as ptosis, strabismus, astigmatism or iris coloboma"
The cohort summary names the ocular finding; Table 1 identifies the large-deletion patient. The quoted percentage is not used as a disease frequency. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
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 (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Genital anomalies | − | − | − | − | − | − | − | − | − | − | − | Unilateral cryptorchidism | − | Unilateral cryptorchidism | −"
Records individual genital findings without assigning a specific gene mechanism.
Head and Neck 12
Macrocephaly HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Skull features | − | Macrocephaly | Brachy-, macrocephaly | − | − | Macrocephaly | − | − | − | − | − | Frontal bossing, macrocephaly | Frontal bossing, macrocephaly | Brachycephaly | Macrocephaly"
Reported in the 14 living patients of the 2015 clinical series, with heterogeneous deletion intervals and incomplete assessments. No disease-wide frequency is inferred.
Brachycephaly HP:0000248 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachycephaly (HP:0000248). HP:0000248 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Skull features | − | Macrocephaly | Brachy-, macrocephaly | − | − | Macrocephaly | − | − | − | − | − | Frontal bossing, macrocephaly | Frontal bossing, macrocephaly | Brachycephaly | Macrocephaly"
Reported in the 14 living patients of the 2015 clinical series, with heterogeneous deletion intervals and incomplete assessments. No disease-wide frequency is inferred.
Frontal bossing HP:0002007 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Frontal bossing (HP:0002007). HP:0002007 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Skull features | − | Macrocephaly | Brachy-, macrocephaly | − | − | Macrocephaly | − | − | − | − | − | Frontal bossing, macrocephaly | Frontal bossing, macrocephaly | Brachycephaly | Macrocephaly"
Table 1 findings; Table 2 documents an additional chromosome rearrangement in patient 12 and additional CNVs in patient 13.
Round face HP:0000311 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Round face (HP:0000311). HP:0000311 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Note the round face, full cheeks, bulbous nose, and a prominent philtrum in patient no. 2"
Figure caption identifies specific facial findings rather than a causal facial-gestalt pathway.
Full cheeks HP:0000293 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Full cheeks (HP:0000293). HP:0000293 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Note the round face, full cheeks, bulbous nose, and a prominent philtrum in patient no. 2"
Figure caption identifies specific facial findings rather than a causal facial-gestalt pathway.
Bulbous nose HP:0000414 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bulbous nose (HP:0000414). HP:0000414 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Note the round face, full cheeks, bulbous nose, and a prominent philtrum in patient no. 2"
Figure caption identifies specific facial findings rather than a causal facial-gestalt pathway.
Long philtrum HP:0000343 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long philtrum (HP:0000343). HP:0000343 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Philtrum features | Prominent | Marked | − | − | Marked | − | − | − | − | − | Marked | − | Long | − | Marked"
Patient 13 has the specifically long philtrum; other descriptors are not treated as synonyms.
Synophrys HP:0000664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Synophrys (HP:0000664). HP:0000664 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Others | Thin upper lip, marked suborbital folds, broad nasal bridge, micrognathia, abnormally overfolded helices | Horizontal eyebrows | | | Horizontal eyebrows | | | Abnormally overfolded helices | Synophris, hirsutism, small mouth | Synophris | Epicanthal folds | | Hypertelorism |..."
Craniofacial row of Table 1; no syndrome frequency or shared causal sequence is inferred.
Epicanthus HP:0000286 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epicanthus (HP:0000286). HP:0000286 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Others | Thin upper lip, marked suborbital folds, broad nasal bridge, micrognathia, abnormally overfolded helices | Horizontal eyebrows | | | Horizontal eyebrows | | | Abnormally overfolded helices | Synophris, hirsutism, small mouth | Synophris | Epicanthal folds | | Hypertelorism |..."
Craniofacial row of Table 1; no syndrome frequency or shared causal sequence is inferred.
Cleft soft palate HP:0000185 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft soft palate (HP:0000185). HP:0000185 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35581197 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"She showed strabismus, cleft soft palate, and hypotonia in the neonatal period."
Direct observation; the paper cautions that the gene content may not explain strabismus or cleft palate.
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)
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In conclusion, our study suggests EPHA7 deletion should be con- sidered as a risk factor for NDD combining ID, behavioral disorders, speech delay and microcephaly with variable expressivity and incom- plete penetrance."
The expanded EPHA7 cohort supports a susceptibility phenotype; this is the authors' interpretation. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
Preauricular skin tag HP:0000384 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Preauricular skin tag (HP:0000384). HP:0000384 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19664229 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"developmental delay, microcephaly, short stature, con- genital hypotonia, mild ptosis, periauricular tags, cupped"
The case report lists the individual neurological and dysmorphic observations.
Integument 1
Hirsutism HP:0001007 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hirsutism (HP:0001007). HP:0001007 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Others | Thin upper lip, marked suborbital folds, broad nasal bridge, micrognathia, abnormally overfolded helices | Horizontal eyebrows | | | Horizontal eyebrows | | | Abnormally overfolded helices | Synophris, hirsutism, small mouth | Synophris | Epicanthal folds | | Hypertelorism |..."
Craniofacial row of Table 1; no syndrome frequency or shared causal sequence is inferred.
Limbs 6
Hyporeflexia of lower limbs HP:0002600 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyporeflexia of lower limbs (HP:0002600). HP:0002600 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35581197 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"She revealed hypotonus, an attenuated deep tendon reflex in both lower limbs, and autistic features."
Case-specific neurological examination.
Small hand HP:0200055 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small hand (HP:0200055). HP:0200055 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Hands | | Brachymetacarpia | − | − | − | Short and stubby fingers | Stubby fingers | − | Short | Short | Short, bilateral clinodactyly | − | − | − | −"
Patient-level hand findings in Table 1.
Short foot HP:0001773 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short foot (HP:0001773). HP:0001773 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Feet | Short | − | − | − | − | Flat | − | − | − | Short, flat | 2nd and 3rd toes syndactyly | Flat, valgus | − | − | −"
Patient-level foot findings in Table 1.
Clinodactyly HP:0030084 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clinodactyly (HP:0030084). HP:0030084 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Hands | | Brachymetacarpia | − | − | − | Short and stubby fingers | Stubby fingers | − | Short | Short | Short, bilateral clinodactyly | − | − | − | −"
The table specifies clinodactyly without identifying an individual digit.
Pes planus HP:0001763 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes planus (HP:0001763). HP:0001763 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Feet | Short | − | − | − | − | Flat | − | − | − | Short, flat | 2nd and 3rd toes syndactyly | Flat, valgus | − | − | −"
Patient-level foot findings, not a severity or frequency estimate.
2-3 toe syndactyly HP:0004691 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is 2-3 toe syndactyly (HP:0004691). HP:0004691 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Feet | Short | − | − | − | − | Flat | − | − | − | Short, flat | 2nd and 3rd toes syndactyly | Flat, valgus | − | − | −"
The source specifies the involved toes.
Musculoskeletal 1
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35581197 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"She showed strabismus, cleft soft palate, and hypotonia in the neonatal period."
Neonatal findings in one SIM1-sparing 780-kb deletion case.
Nervous System 9
Polyphagia HP:0002591 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polyphagia (HP:0002591). HP:0002591 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26833329 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia."
Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35581197 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"A 3-year-old female showed strabismus, cleft soft palate, hypotonia at birth, and global developmental delay."
Direct multi-domain developmental finding in a deletion carrier.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:26833329 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia."
Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Four patients had tiny deletions involving only EPHA7"
Single-gene deletions strengthen the locus association but the authors describe a susceptibility effect with incomplete penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance."
The selected cohort supports variable expression; it does not estimate population penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35581197 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"At the age of 5 years and 1 month, she could not speak two-word sentences"
Persistent expressive-language delay in the reported child.
Delayed ability to walk HP:0031936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed ability to walk (HP:0031936). HP:0031936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35581197 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"She could walk at the age of 2 years and 4 months and could speak meaningful words at 2 years and 9 months."
Documents separate motor and speech milestones.
Autistic behavior HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35581197 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"She revealed hypotonus, an attenuated deep tendon reflex in both lower limbs, and autistic features."
The source describes autistic features, not a formally assessed ASD prevalence.
Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In our study, three of eight patients having behavioural disorders (patient no. 3, 13, and 14) were not deleted for GRIK2."
The prose confirms behavioral disorders in this cohort while illustrating that GRIK2 deletion does not explain every affected individual. No disease-wide frequency or single-gene attribution is inferred.
Sleep disturbance HP:0002360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Sleep disorders | | − | − | | − | + | | + | − | − | − | + | + | − | −"
Reported in the 14 living patients of the 2015 clinical series, with heterogeneous deletion intervals and incomplete assessments. No disease-wide frequency is inferred.
Ventriculomegaly HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Abnormal brain MRI | | | | | − | | | − | | − | − | + (Ventriculo-megaly) | − | − |"
Only a selected subset underwent MRI, and the positive case had a complex rearrangement.
Growth 2
Obesity HP:0001513 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obesity (HP:0001513). HP:0001513 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency."
The authors interpret variable obesity as incomplete penetrance. The cohort includes a fetus and the tables have discrepant obesity totals, so this quoted count is not used as a penetrance estimate.
PMID:26833329 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia."
Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24038875 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Our patient raises the possibility that hypopituitarism may be part of the phenotype, especially short stature, caused by interstitial 6q deletion."
Single-case interpretation, not a general causal assignment.
🧬

Genetic Associations

3
SIM1
Gene: SIM1 hgnc:10882 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SIM1 (hgnc:10882). hgnc:10882 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Except for patients no. 14 and 15, all patients had deletions that included the SIM1 gene."
SIM1 involvement is determined by deletion boundaries; it is absent from two intervals in this cohort.
PMID:23778136 SUPPORT DIRECT PRIMARY RESULT In Vitro
"We found a strong loss-of-function effect of p.T46R, p.H323Y, and p.T714A mutations on SIM1 transcriptional activity with both ARNT and ARNT2"
Reporter assays establish variant-specific loss of transactivation in engineered human cells, not hypothalamic histology in deletion carriers.
PMID:23778136 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Therefore, mutation of SIM1 is not always responsible for a fully penetrant form of obesity."
The study reports variable effects and variable clinical expression.
POU3F2
Gene: POU3F2 hgnc:9215 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is POU3F2 (hgnc:9215). hgnc:9215 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:35581197 SUPPORT DIRECT BACKGROUND Human Clinical
"The six families described in the report by Kasher et al. had the deletion of the POU3F2 and FBXL4 genes, although the deletion size was different in each family"
Identifies both genes in the overlapping interval; these are not POU3F2-only deletions.
PMID:37207645 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity."
Intragenic variants independently strengthen POU3F2 attribution; this is a separate monogenic cohort, not a deletion-syndrome frequency estimate.
PMID:37207645 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation."
Functional summary from the available abstract of the intragenic-variant study. Effects differ by variant and are not measurements in deletion-carrier hypothalamus.
EPHA7
Gene: EPHA7 hgnc:3390 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EPHA7 (hgnc:3390). hgnc:3390 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: RISK_FACTOR variant_origin: GERMLINE
Show evidence (3 references)
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Four patients had tiny deletions involving only EPHA7"
Single-gene deletions strengthen the locus association but the authors describe a susceptibility effect with incomplete penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance."
The selected cohort supports variable expression; it does not estimate population penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Most deletions were inherited (9/12) from unaffected parent suggesting that haploinsufficiency of EPHA7 could act as a risk factor for NDD with variable expressivity and incomplete penetrance."
Discussion qualifies the risk-locus interpretation; family A had an affected father with a history of cranial concussion. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).
💊

Medical Actions

3
Hormone replacement for documented pituitary deficiency
Action: Hormone Replacement TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hormone Replacement Therapy (NCIT:C15599). NCIT:C15599 is a clinical intervention from the NCI Thesaurus. NCIT:C15599
Replace deficient hormones when endocrine testing establishes a deficiency. The source provides a clinical rationale; it does not demonstrate a controlled treatment effect or prove a common hypothalamic lesion.
Show evidence (1 reference)
PMID:24038875 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Early identification of endocrine abnormalities can improve clinical outcome by allowing timely introduction of hormone replacement therapy."
Case-report recommendation tied to documented endocrine deficiency.
Physical therapy
Action: Physical TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. NCIT:C15302
Physical therapy was used from infancy in the original EPHA7-containing deletion case with hypotonia and motor delay. The report does not quantify its treatment effect.
Show evidence (1 reference)
PMID:19664229 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"received physical therapy since age 6 months"
Documents actual supportive care in one child, without comparative efficacy.
Repair of associated cleft palate
Action: PalatorrhaphyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Palatorrhaphy (NCIT:C168380). NCIT:C168380 is a clinical intervention from the NCI Thesaurus. NCIT:C168380
Surgical cleft-palate treatment was performed in one SIM1-sparing deletion case at 15 months. The causal relationship between the deletion and cleft palate was uncertain.
Show evidence (1 reference)
PMID:35581197 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Surgical treatment for cleft palate was performed at 1 year and 3 months old."
Records actual case-specific treatment.
🔬

Diagnosis

5
Chromosomal microarray and deletion-boundary assessment
Chromosomal microarray establishes the copy-number loss and identifies whether SIM1, POU3F2, EPHA7 or other genes are involved. Additional CNVs or chromosome rearrangements can affect interpretation.
Show evidence (2 references)
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Microarray studies were done in all 15 patients."
The disease-specific series used array analysis in every participant.
PMID:25351778 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"FISH was performed using chromosomal preparations according to standard protocols to confirm the 6q deletions characterised by microarray."
Documents orthogonal confirmation.
Parental testing
Determine whether the deletion is de novo or inherited, and interpret recurrence and expression in the family rather than assuming every deletion is sporadic.
Show evidence (1 reference)
PMID:26833329 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The 6q16.1 deletions segregated with the phenotype in multiplex families and were shown to be de novo in four families"
Documents both familial transmission and de novo occurrence.
Exome-based copy-number analysis
Validated copy-number analysis of trio exome data identified a 780-kb SIM1-sparing deletion after normal G-banding in one child. A normal conventional karyotype does not exclude a submicroscopic deletion.
Show evidence (1 reference)
PMID:35581197 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Exome sequencing data were analyzed using the eXome Hidden Markov Model (XHMM) and modified Nord’s method"
Case-specific diagnostic approach.
Longitudinal endocrine evaluation
Authors of the SIM1-containing deletion case recommend detailed endocrine assessment and follow-up because hypopituitarism appeared after unremarkable infant testing. The report does not establish an evidence-based universal interval for surveillance.
Show evidence (1 reference)
PMID:24038875 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"we suggest that detailed endocrine evaluation and longitudinal endocrine follow up be performed in individuals with proximal interstitial 6q deletion involving SIM1"
Explicit case-report recommendation.
Growth and appetite follow-up
Monitor growth and emerging hyperphagia or obesity, including in initially nonobese children with a POU3F2-containing deletion. This is a clinical follow-up recommendation; prevention efficacy and a universal schedule were not established.
Show evidence (1 reference)
PMID:35581197 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Thus, we need to pay attention to her symptoms of obesity."
Case-report recommendation prompted by age-dependent obesity in previously reported patients.
📈

Progression

2
Variable developmental and growth trajectories
Developmental difficulties can present in infancy, while hyperphagia and obesity may emerge later. Neither an obligatory early obesity phase nor a uniform progressive neurological course is established. A child with a POU3F2-containing deletion remained nonobese at five years despite persistent language delay.
Show evidence (1 reference)
PMID:35581197 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"At the age of 5 years and 1 month, she could not speak two-word sentences, her body weight was 15.7 kg (−0.8 SD), and her body height was 101.7 cm (−1.1 SD)."
A longitudinal observation documenting persistent developmental impairment without obesity at this age.
Possible later pituitary deficiency
A single SIM1-containing deletion case developed hypopituitarism in childhood or adolescence despite unremarkable infant endocrine testing. Normal early testing did not exclude later deficiency in that patient.
Show evidence (1 reference)
PMID:24038875 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Detailed endocrine evaluation of the propositus during childhood and adolescence revealed hypopituitarism, though initial endocrine evaluations during infancy were unremarkable."
One SIM1-containing deletion case developed later endocrine deficits; this does not establish a universal or obligatory consequence.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from 6q16 Deletion Syndrome:

Prader-Willi Syndrome
Overlapping Features Hypotonia, developmental impairment and later hyperphagic obesity can overlap, while the causative chromosome lesion differs.
Distinguishing Features
  • Molecular testing distinguishes 15q11-q13 imprinting abnormalities from a 6q16 copy-number loss.
Show evidence (1 reference)
PMID:25351778 SUPPORT DIRECT BACKGROUND Human Clinical
"Prader–Willi syndrome (PWS, MIM 176270) is an imprinting disease caused by paternal deletions, maternal uniparental disomy or imprinting anomalies in the 15q11.2q13 region."
Background establishes the distinct molecular basis.
6q14.1-q15 deletion syndrome
Overlapping Features Adjacent proximal deletions can also produce developmental delay and obesity. Their clinical overlap is a differential consideration, not direct evidence for the mechanism or phenotype frequencies of 6q16 deletions.
Show evidence (1 reference)
PMID:21045960 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Here we report on 2 patients with interstitial deletions at 6q14.1-q15 presenting with obesity and symptoms strikingly similar to those reported for deletions involving the SIM1 gene despite not having a deletion of this gene."
Keeps the neighboring interval outside the 6q16 causal graph.
🧫

Experimental Models

1
Human 293 Flp-In T-Rex SIM1 reporter assay CELL_LINE
Eight substitutions were compared using a defined single insertion site. Three showed strong loss of transactivation with both partners; other substitutions had mild, absent or partner-dependent gain-of-function effects.
Cell source
Engineered human 293 Flp-In T-Rex cells
Culture
Stable single-copy wild-type or mutant SIM1 expression with ARNT or ARNT2 and a luciferase reporter
Publication
PMID:23778136
Pathograph links
Reduced SIM1-Dependent Transactivation perturbs fidelity: low Directly assays SIM1-dependent reporter activation.
Limitations: Engineered non-neuronal cells testing intragenic variants, not a patient-derived deletion model; reporter loss does not identify the relevant human hypothalamic target or prove a neuronal developmental lesion.
Show evidence (1 reference)
PMID:23778136 SUPPORT DIRECT PRIMARY RESULT In Vitro
"We found a strong loss-of-function effect of p.T46R, p.H323Y, and p.T714A mutations on SIM1 transcriptional activity with both ARNT and ARNT2"
Reporter assays establish variant-specific loss of transactivation in engineered human cells, not hypothalamic histology in deletion carriers.
🐁

Animal Models

1
Zebrafish sim1-pou3f2 neuroendocrine pathway models
Morpholino and mutant zebrafish experiments test the relationship between sim1, pou3f2 and preoptic oxytocin expression. The available abstract supports pathway ordering but does not report a human deletion model, clinical obesity rescue or a complete deletion-specific mechanism.
Species
Zebrafish
Publication
PMID:26833329
Pathograph links
POU3F2-Dependent Oxytocin Expression in Zebrafish perturbs fidelity: low Tests a candidate conserved transcriptional pathway through experimental gene perturbation.
Limitations: The reference cache contains the abstract only. Genotype details, rescue designs, neuron counts and metabolic outcomes are not inferred. Human expression-pattern concordance does not establish the same epistasis or hormone deficiency in patients.
Show evidence (1 reference)
PMID:26833329 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Using morpholino and mutant zebrafish models, we show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area."
Experimental pathway ordering and oxytocin-expression readout in zebrafish. The available abstract does not establish human neuron loss, circulating oxytocin deficiency or obesity rescue.
{ }

Source YAML

click to show 
name: 6q16 Deletion Syndrome
creation_date: '2026-09-01T13:40:08Z'
category: Genetic
parents:
- Contiguous Gene Deletion Syndrome
- Syndromic Obesity
disease_term:
  preferred_term: 6q16 deletion syndrome
  term:
    id: MONDO:0015749
    label: 6q16 deletion syndrome
synonyms:
- proximal interstitial 6q deletion
- Prader-Willi-like syndrome due to 6q16 deletion
description: 6q16 deletion syndrome comprises overlapping heterozygous chromosome deletions with variable developmental delay, intellectual disability, behavioral features and growth abnormalities. Some intervals confer susceptibility to hyperphagia and obesity. SIM1-containing 6q16.2-q16.3 deletions and SIM1-sparing, POU3F2-containing 6q16.1 deletions provide distinct genetic routes to an overlapping Prader-Willi-like phenotype; obesity is not obligatory. More proximal EPHA7-containing 6q16.1 deletions principally support neurodevelopmental susceptibility. Gene content, age and additional genetic findings limit prediction from the cytogenetic label alone. Endocrine deficiency has been reported in a SIM1-containing deletion and can emerge after normal infant testing.
has_subtypes:
- name: SIM1-containing 6q16.2-q16.3 deletions
  description: Intervals including SIM1 are associated with variable obesity and neurodevelopmental findings. These are gene-content groups rather than uniform recurrent rearrangements.
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Except for patients no. 14 and 15, all patients had deletions that included the SIM1 gene.
    explanation: SIM1 involvement is determined by deletion boundaries; it is absent from two intervals in this cohort.
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency.
    explanation: The authors interpret variable obesity as incomplete penetrance. The cohort includes a fetus and the tables have discrepant obesity totals, so this quoted count is not used as a penetrance estimate.
- name: SIM1-sparing POU3F2-containing 6q16.1 deletions
  description: Small overlapping intervals include POU3F2 and FBXL4 while sparing SIM1. Developmental impairment and later hyperphagia or obesity overlap the SIM1-associated phenotype, but individual children can remain nonobese.
  evidence:
  - reference: PMID:26833329
    reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia.
    explanation: Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
  - reference: PMID:35581197
    reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: The six families described in the report by Kasher et al. had the deletion of the POU3F2 and FBXL4 genes, although the deletion size was different in each family
    explanation: Identifies both genes in the overlapping interval; these are not POU3F2-only deletions.
- name: EPHA7-containing proximal 6q16.1 deletions
  description: More proximal intervals, including deletions restricted to EPHA7, are associated with neurodevelopmental susceptibility with incomplete penetrance. Their clinical findings are not automatically attributable to the SIM1/POU3F2 appetite pathway.
  evidence:
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Four patients had tiny deletions involving only EPHA7
    explanation: 'Single-gene deletions strengthen the locus association but the authors describe a susceptibility effect with incomplete penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance.
    explanation: 'The selected cohort supports variable expression; it does not estimate population penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
pathophysiology:
- name: Heterozygous 6q16 Deletion
  description: A variable interstitial deletion removes one copy of the genes within its specific boundaries. No single gene is deleted in every interval represented here; de novo and inherited events occur.
  role: trigger
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Microarray analyses showed overlapping 6q deletions, extending from 92 138 719 bp to 108 227 875 bp (hg19).
    explanation: The cohort includes variable overlapping intervals; these coordinates describe the combined span, not a recurrent deletion.
  - reference: PMID:26833329
    reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The 6q16.1 deletions segregated with the phenotype in multiplex families and were shown to be de novo in four families
    explanation: Documents both familial transmission and de novo occurrence.
  downstream:
  - target: Reduced SIM1 Gene Dosage
    causal_link_type: DIRECT
    description: An interval that includes SIM1 removes one genomic copy.
    evidence:
    - reference: PMID:25351778
      reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Except for patients no. 14 and 15, all patients had deletions that included the SIM1 gene.
      explanation: SIM1 involvement is determined by deletion boundaries; it is absent from two intervals in this cohort.
  - target: Reduced POU3F2 Gene Dosage
    causal_link_type: DIRECT
    description: An interval that includes POU3F2 removes one genomic copy.
    evidence:
    - reference: PMID:35581197
      reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: DIRECT
      snippet: The six families described in the report by Kasher et al. had the deletion of the POU3F2 and FBXL4 genes, although the deletion size was different in each family
      explanation: Identifies both genes in the overlapping interval; these are not POU3F2-only deletions.
  - target: Reduced EPHA7 Gene Dosage
    causal_link_type: DIRECT
    description: More proximal deletions can remove all or part of EPHA7.
    evidence:
    - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
      reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Four patients had tiny deletions involving only EPHA7
      explanation: 'Single-gene deletions strengthen the locus association but the authors describe a susceptibility effect with incomplete penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
    - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
      reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance.
      explanation: 'The selected cohort supports variable expression; it does not estimate population penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
  - target: Altered Neurodevelopment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Several deletion intervals associate with developmental impairment; deleted-gene contributions and intervening cellular events differ.
    evidence:
    - reference: PMID:26833329
      reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia.
      explanation: Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
  - target: Hypopituitarism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A SIM1-containing 6q16.1-q21 deletion was associated with later pituitary deficiency. The responsible gene and anatomical lesion were not established in this case.
    evidence:
    - reference: PMID:24038875
      reference_title: Endocrine phenotype of 6q16.1-q21 deletion involving SIM1 and Prader-Willi syndrome-like features.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Detailed endocrine evaluation of the propositus during childhood and adolescence revealed hypopituitarism, though initial endocrine evaluations during infancy were unremarkable.
      explanation: One SIM1-containing deletion case developed later endocrine deficits; this does not establish a universal or obligatory consequence.
- name: Reduced SIM1 Gene Dosage
  description: Loss of one SIM1 copy is an established genomic finding in a subset of 6q16 deletions. Human deletion cohorts and separate intragenic-variant studies support an incompletely penetrant contribution to obesity.
  role: mechanism
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  genes:
  - preferred_term: SIM1
    term:
      id: hgnc:10882
      label: SIM1
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Except for patients no. 14 and 15, all patients had deletions that included the SIM1 gene.
    explanation: SIM1 involvement is determined by deletion boundaries; it is absent from two intervals in this cohort.
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency.
    explanation: The authors interpret variable obesity as incomplete penetrance. The cohort includes a fetus and the tables have discrepant obesity totals, so this quoted count is not used as a penetrance estimate.
  downstream:
  - target: Reduced SIM1-Dependent Transactivation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced functional dosage is supported by loss-of-function variant assays, but SIM1 target transcription has not been directly measured in the deletion-carrier hypothalamus.
    evidence:
    - reference: PMID:23778136
      reference_title: Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: We found a strong loss-of-function effect of p.T46R, p.H323Y, and p.T714A mutations on SIM1 transcriptional activity with both ARNT and ARNT2
      explanation: Reporter assays establish variant-specific loss of transactivation in engineered human cells, not hypothalamic histology in deletion carriers.
- name: Reduced SIM1-Dependent Transactivation
  description: Selected obesity-associated SIM1 variants reduce ARNT- and ARNT2-dependent reporter activation. These experiments support loss of transcription-factor function as a mechanism; they do not demonstrate loss of hypothalamic neurons or a particular target-gene defect in deletion carriers.
  role: mechanism
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  genes:
  - preferred_term: SIM1
    term:
      id: hgnc:10882
      label: SIM1
  evidence:
  - reference: PMID:23778136
    reference_title: Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We found a strong loss-of-function effect of p.T46R, p.H323Y, and p.T714A mutations on SIM1 transcriptional activity with both ARNT and ARNT2
    explanation: Reporter assays establish variant-specific loss of transactivation in engineered human cells, not hypothalamic histology in deletion carriers.
  downstream:
  - target: Disordered Appetite Regulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Genetic association with obesity and experimental loss of transcriptional activity support a contribution to appetite regulation, with unresolved human neuronal intermediates.
    evidence:
    - reference: PMID:23778136
      reference_title: Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: We found a strong loss-of-function effect of p.T46R, p.H323Y, and p.T714A mutations on SIM1 transcriptional activity with both ARNT and ARNT2
      explanation: Reporter assays establish variant-specific loss of transactivation in engineered human cells, not hypothalamic histology in deletion carriers.
    - reference: PMID:25351778
      reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency.
      explanation: The authors interpret variable obesity as incomplete penetrance. The cohort includes a fetus and the tables have discrepant obesity totals, so this quoted count is not used as a penetrance estimate.
- name: Reduced POU3F2 Gene Dosage
  description: SIM1-sparing 6q16.1 deletions remove one POU3F2 copy together with FBXL4 and, depending on their extent, additional genes. Subsequent intragenic-variant evidence strengthens POU3F2 as a contributor without making the whole chromosomal disorder monogenic.
  role: mechanism
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  genes:
  - preferred_term: POU3F2
    term:
      id: hgnc:9215
      label: POU3F2
  evidence:
  - reference: PMID:35581197
    reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: The six families described in the report by Kasher et al. had the deletion of the POU3F2 and FBXL4 genes, although the deletion size was different in each family
    explanation: Identifies both genes in the overlapping interval; these are not POU3F2-only deletions.
  - reference: PMID:37207645
    reference_title: Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity.
    explanation: Intragenic variants independently strengthen POU3F2 attribution; this is a separate monogenic cohort, not a deletion-syndrome frequency estimate.
  downstream:
  - target: Altered POU3F2-Dependent Transcription
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Intragenic-variant assays support altered transcriptional function as a consequence of POU3F2 disruption. Individual DNA-binding and activation effects vary, and are not direct measurements in deletion carriers.
    evidence:
    - reference: PMID:37207645
      reference_title: Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation.
      explanation: Functional summary from the available abstract of the intragenic-variant study. Effects differ by variant and are not measurements in deletion-carrier hypothalamus.
- name: Altered POU3F2-Dependent Transcription
  description: Reported POU3F2 variants disturb DNA binding or promoter activation, with nuclear translocation retained except for the early-truncating variant. The transcriptional consequences of heterozygous deletion in human brain remain incompletely measured.
  role: mechanism
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  genes:
  - preferred_term: POU3F2
    term:
      id: hgnc:9215
      label: POU3F2
  evidence:
  - reference: PMID:37207645
    reference_title: Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation.
    explanation: Functional summary from the available abstract of the intragenic-variant study. Effects differ by variant and are not measurements in deletion-carrier hypothalamus.
  downstream:
  - target: Disordered Appetite Regulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: POU3F2-containing deletions and separate intragenic variants associate with hyperphagia and obesity; the responsible human target genes and neural-circuit changes remain unresolved.
    evidence:
    - reference: PMID:26833329
      reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia.
      explanation: Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
    - reference: PMID:37207645
      reference_title: Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity.
      explanation: Intragenic variants independently strengthen POU3F2 attribution; this is a separate monogenic cohort, not a deletion-syndrome frequency estimate.
  - target: Altered Neurodevelopment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Human POU3F2 disruption is associated with neurodevelopmental impairment, but the intermediate cellular effects have not been established by the available deletion evidence.
    evidence:
    - reference: PMID:26833329
      reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia.
      explanation: Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
    - reference: PMID:37207645
      reference_title: Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity.
      explanation: Intragenic variants independently strengthen POU3F2 attribution; this is a separate monogenic cohort, not a deletion-syndrome frequency estimate.
- name: POU3F2-Dependent Oxytocin Expression in Zebrafish
  description: Morpholino and mutant zebrafish experiments place pou3f2 downstream of sim1 in regulation of oxytocin expression in the neuroendocrine preoptic area. This is an experimental pathway branch; a corresponding oxytocin deficiency or neuron-loss mechanism has not been established in human 6q16 deletion carriers.
  role: mechanism
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:26833329
    reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Using morpholino and mutant zebrafish models, we show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area.
    explanation: Experimental pathway ordering and oxytocin-expression readout in zebrafish. The available abstract does not establish human neuron loss, circulating oxytocin deficiency or obesity rescue.
- name: Reduced EPHA7 Gene Dosage
  description: Partial or complete EPHA7 loss is associated with neurodevelopmental susceptibility. Transmission from unaffected parents and variable clinical severity limit deterministic attribution. Human studies do not directly measure the proposed dendritic or synaptic defects.
  role: mechanism
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  genes:
  - preferred_term: EPHA7
    term:
      id: hgnc:3390
      label: EPHA7
  evidence:
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Four patients had tiny deletions involving only EPHA7
    explanation: 'Single-gene deletions strengthen the locus association but the authors describe a susceptibility effect with incomplete penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance.
    explanation: 'The selected cohort supports variable expression; it does not estimate population penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
  downstream:
  - target: Altered Neurodevelopment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical deletion data support a susceptibility relationship; specific human cellular intermediates remain unknown.
    evidence:
    - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
      reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Four patients had tiny deletions involving only EPHA7
      explanation: 'Single-gene deletions strengthen the locus association but the authors describe a susceptibility effect with incomplete penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
    - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
      reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance.
      explanation: 'The selected cohort supports variable expression; it does not estimate population penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
- name: Disordered Appetite Regulation
  description: Hyperphagia and obesity susceptibility are observed in both SIM1-containing and POU3F2-containing deletion groups. Hypothalamic regulation is a proposed functional explanation, supported by related experimental work rather than direct human circuit measurements.
  role: mechanism
  biological_scale: ORGANISM
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:26833329
    reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia.
    explanation: Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency.
    explanation: The authors interpret variable obesity as incomplete penetrance. The cohort includes a fetus and the tables have discrepant obesity totals, so this quoted count is not used as a penetrance estimate.
  downstream:
  - target: Polyphagia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The clinical appetite phenotype is compatible with disturbed regulation, but a specific neural satiety defect has not been measured in deletion carriers.
    evidence:
    - reference: PMID:26833329
      reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia.
      explanation: Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
  - target: Obesity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Obesity susceptibility is variable; energy intake, expenditure and other contributors were not comprehensively measured in the deletion cohorts.
    evidence:
    - reference: PMID:25351778
      reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency.
      explanation: The authors interpret variable obesity as incomplete penetrance. The cohort includes a fetus and the tables have discrepant obesity totals, so this quoted count is not used as a penetrance estimate.
    - reference: PMID:26833329
      reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia.
      explanation: Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
- name: Altered Neurodevelopment
  description: Developmental and cognitive impairment occur across several 6q16 intervals. This node represents an unresolved developmental consequence rather than a proven shared neuron-migration, axon-guidance or synaptic lesion.
  role: consequence
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:26833329
    reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia.
    explanation: Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Four patients had tiny deletions involving only EPHA7
    explanation: 'Single-gene deletions strengthen the locus association but the authors describe a susceptibility effect with incomplete penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance.
    explanation: 'The selected cohort supports variable expression; it does not estimate population penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Multi-domain delay is documented clinically; its cellular basis is unresolved.
    evidence:
    - reference: PMID:35581197
      reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: A 3-year-old female showed strabismus, cleft soft palate, hypotonia at birth, and global developmental delay.
      explanation: Direct clinical observation in a SIM1-sparing deletion case.
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cognitive impairment is reported in overlapping deletion cohorts, without a resolved common cellular mediator.
    evidence:
    - reference: PMID:26833329
      reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia.
      explanation: Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
  - target: Delayed speech and language development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Language delay is a documented component of the variable neurodevelopmental phenotype; the responsible neural intermediates remain unresolved.
    evidence:
    - reference: PMID:35581197
      reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: At the age of 5 years and 1 month, she could not speak two-word sentences
      explanation: Persistent expressive-language delay in the reported child. The edge represents a clinical developmental association; the quote does not resolve its cellular intermediates.
  - target: Delayed ability to walk
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Delayed acquisition of walking is a motor-developmental manifestation in the detailed SIM1-sparing case; a specific central motor lesion has not been established.
    evidence:
    - reference: PMID:35581197
      reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: She could walk at the age of 2 years and 4 months and could speak meaningful words at 2 years and 9 months.
      explanation: Documents separate motor and speech milestones. The edge represents a clinical developmental association; the quote does not resolve its cellular intermediates.
  - target: Autistic behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Autistic features are documented in the SIM1-sparing case, without a standardized autism diagnosis or a resolved cellular pathway.
    evidence:
    - reference: PMID:35581197
      reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: She revealed hypotonus, an attenuated deep tendon reflex in both lower limbs, and autistic features.
      explanation: The source describes autistic features, not a formally assessed ASD prevalence. The edge represents a clinical developmental association; the quote does not resolve its cellular intermediates.
  - target: Atypical behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical cohorts support behavioral involvement as part of the neurodevelopmental spectrum, with heterogeneous deletion content and incompletely identified mediators.
    evidence:
    - reference: PMID:25351778
      reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: In our study, three of eight patients having behavioural disorders (patient no. 3, 13, and 14) were not deleted for GRIK2.
      explanation: The prose confirms behavioral disorders in this cohort while illustrating that GRIK2 deletion does not explain every affected individual. No disease-wide frequency or single-gene attribution is inferred. The edge represents a clinical developmental association; the quote does not resolve its cellular intermediates.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypotonia accompanies developmental impairment in some deletion carriers. A central developmental contribution is plausible but not localized by the available clinical evidence.
    evidence:
    - reference: PMID:35581197
      reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: She showed strabismus, cleft soft palate, and hypotonia in the neonatal period.
      explanation: Neonatal findings in one SIM1-sparing 780-kb deletion case. The edge represents a clinical developmental association; the quote does not resolve its cellular intermediates.
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Some EPHA7-containing deletion carriers have postnatal microcephaly. The association with altered neurodevelopment is clinically supported without a demonstrated human cellular growth mechanism.
    evidence:
    - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: In conclusion, our study suggests EPHA7 deletion should be con- sidered as a risk factor for NDD combining ID, behavioral disorders, speech delay and microcephaly with variable expressivity and incom- plete penetrance.
      explanation: "The expanded EPHA7 cohort supports a susceptibility phenotype; this is the authors' interpretation. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017). The edge represents a clinical developmental association; the quote does not resolve its cellular intermediates."
      reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
phenotypes:
- name: Polyphagia
  category: Behavioral
  description: Hyperphagia is variably reported in SIM1-containing and POU3F2-containing deletions. It is not documented in every child or adult.
  phenotype_term:
    preferred_term: Polyphagia
    term:
      id: HP:0002591
      label: Polyphagia
  evidence:
  - reference: PMID:26833329
    reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia.
    explanation: Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
- name: Obesity
  category: Metabolic
  description: Susceptibility varies with deletion content and age. Normal weight in childhood does not exclude a POU3F2-containing deletion, and some SIM1-deletion carriers are not obese.
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency.
    explanation: The authors interpret variable obesity as incomplete penetrance. The cohort includes a fetus and the tables have discrepant obesity totals, so this quoted count is not used as a penetrance estimate.
  - reference: PMID:26833329
    reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia.
    explanation: Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
- name: Hypotonia
  category: Neurological
  description: Infantile or childhood hypotonia is documented in several deletion groups; it is not established as universal or as invariably preceding obesity.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:35581197
    reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She showed strabismus, cleft soft palate, and hypotonia in the neonatal period.
    explanation: Neonatal findings in one SIM1-sparing 780-kb deletion case.
- name: Global developmental delay
  category: Neurological
  description: Delay can involve motor, language and social development, with variable severity.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:35581197
    reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: A 3-year-old female showed strabismus, cleft soft palate, hypotonia at birth, and global developmental delay.
    explanation: Direct multi-domain developmental finding in a deletion carrier.
- name: Intellectual disability
  category: Neurological
  description: Variable cognitive impairment is reported in both the POU3F2-containing and more proximal EPHA7-containing groups.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:26833329
    reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia.
    explanation: Clinical overlap occurs in SIM1-sparing deletions; the cellular route from gene dosage to development and appetite remains incompletely resolved.
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Four patients had tiny deletions involving only EPHA7
    explanation: 'Single-gene deletions strengthen the locus association but the authors describe a susceptibility effect with incomplete penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance.
    explanation: 'The selected cohort supports variable expression; it does not estimate population penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
- name: Delayed speech and language development
  category: Developmental
  description: Delayed first words and persistent limitations in phrase speech are reported; individual trajectories vary.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:35581197
    reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: At the age of 5 years and 1 month, she could not speak two-word sentences
    explanation: Persistent expressive-language delay in the reported child.
- name: Delayed ability to walk
  category: Developmental
  description: Independent walking was delayed in the detailed SIM1-sparing case.
  phenotype_term:
    preferred_term: Delayed ability to walk
    term:
      id: HP:0031936
      label: Delayed ability to walk
  evidence:
  - reference: PMID:35581197
    reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She could walk at the age of 2 years and 4 months and could speak meaningful words at 2 years and 9 months.
    explanation: Documents separate motor and speech milestones.
- name: Autistic behavior
  category: Behavioral
  description: Autistic features are reported in a SIM1-sparing deletion case without documentation of a standardized autism diagnosis.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:35581197
    reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She revealed hypotonus, an attenuated deep tendon reflex in both lower limbs, and autistic features.
    explanation: The source describes autistic features, not a formally assessed ASD prevalence.
- name: Hyporeflexia of lower limbs
  category: Neurological
  description: Reduced lower-limb tendon reflexes occurred in one child whose strength, peripheral nerve conduction and brain imaging were reported as normal.
  phenotype_term:
    preferred_term: Hyporeflexia of lower limbs
    term:
      id: HP:0002600
      label: Hyporeflexia of lower limbs
  evidence:
  - reference: PMID:35581197
    reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She revealed hypotonus, an attenuated deep tendon reflex in both lower limbs, and autistic features.
    explanation: Case-specific neurological examination.
- name: Atypical behavior
  category: Behavioral
  description: Behavioral disorders were recorded without uniform diagnostic subtyping in the 2015 cohort.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In our study, three of eight patients having behavioural disorders (patient no. 3, 13, and 14) were not deleted for GRIK2.
    explanation: The prose confirms behavioral disorders in this cohort while illustrating that GRIK2 deletion does not explain every affected individual. No disease-wide frequency or single-gene attribution is inferred.
- name: Sleep disturbance
  category: Behavioral
  description: Sleep disorders were recorded in some patients; the source does not specify one consistent sleep diagnosis.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Sleep disorders |  | − | − |  | − | + |  | + | − | − | − | + | + | − | −
    explanation: Reported in the 14 living patients of the 2015 clinical series, with heterogeneous deletion intervals and incomplete assessments. No disease-wide frequency is inferred.
- name: Feeding difficulties
  category: Gastrointestinal
  description: Early feeding difficulties can occur despite later obesity susceptibility. These are not equivalent to hyperphagia.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Feeding difficulties |  | − | − |  | + | + | − | − | − | − | − | + | + | − | −
    explanation: Reported in the 14 living patients of the 2015 clinical series, with heterogeneous deletion intervals and incomplete assessments. No disease-wide frequency is inferred.
- name: Hypopituitarism
  category: Endocrine
  description: A single SIM1-containing deletion case developed deficits in childhood and adolescence after unremarkable infant testing. The available report does not establish a syndrome-wide frequency.
  phenotype_term:
    preferred_term: Hypopituitarism
    term:
      id: HP:0040075
      label: Hypopituitarism
  evidence:
  - reference: PMID:24038875
    reference_title: Endocrine phenotype of 6q16.1-q21 deletion involving SIM1 and Prader-Willi syndrome-like features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Detailed endocrine evaluation of the propositus during childhood and adolescence revealed hypopituitarism, though initial endocrine evaluations during infancy were unremarkable.
    explanation: One SIM1-containing deletion case developed later endocrine deficits; this does not establish a universal or obligatory consequence.
- name: Short stature
  category: Growth
  description: Reported with pituitary deficiency in one SIM1-containing deletion and as a clinical description in an EPHA7-containing deletion. A single endocrine mechanism is not established for all growth impairment.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:24038875
    reference_title: Endocrine phenotype of 6q16.1-q21 deletion involving SIM1 and Prader-Willi syndrome-like features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Our patient raises the possibility that hypopituitarism may be part of the phenotype, especially short stature, caused by interstitial 6q deletion.
    explanation: Single-case interpretation, not a general causal assignment.
- name: Macrocephaly
  category: Craniofacial
  description: Macrocephaly occurred in several patients in the 2015 series; head size is variable across deletion groups.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Skull features | − | Macrocephaly | Brachy-, macrocephaly | − | − | Macrocephaly | − | − | − | − | − | Frontal bossing, macrocephaly | Frontal bossing, macrocephaly | Brachycephaly | Macrocephaly
    explanation: Reported in the 14 living patients of the 2015 clinical series, with heterogeneous deletion intervals and incomplete assessments. No disease-wide frequency is inferred.
- name: Brachycephaly
  category: Craniofacial
  description: Brachycephaly was recorded in patients 3 and 14 of the 2015 series.
  phenotype_term:
    preferred_term: Brachycephaly
    term:
      id: HP:0000248
      label: Brachycephaly
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Skull features | − | Macrocephaly | Brachy-, macrocephaly | − | − | Macrocephaly | − | − | − | − | − | Frontal bossing, macrocephaly | Frontal bossing, macrocephaly | Brachycephaly | Macrocephaly
    explanation: Reported in the 14 living patients of the 2015 clinical series, with heterogeneous deletion intervals and incomplete assessments. No disease-wide frequency is inferred.
- name: Frontal bossing
  category: Craniofacial
  description: Reported in patients 12 and 13, both of whom had complex or additional genomic findings; this is not assigned to one 6q gene.
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Skull features | − | Macrocephaly | Brachy-, macrocephaly | − | − | Macrocephaly | − | − | − | − | − | Frontal bossing, macrocephaly | Frontal bossing, macrocephaly | Brachycephaly | Macrocephaly
    explanation: Table 1 findings; Table 2 documents an additional chromosome rearrangement in patient 12 and additional CNVs in patient 13.
- name: Round face
  category: Craniofacial
  description: Variable facial feature documented in the clinical series.
  phenotype_term:
    preferred_term: Round face
    term:
      id: HP:0000311
      label: Round face
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Note the round face, full cheeks, bulbous nose, and a prominent philtrum in patient no. 2
    explanation: Figure caption identifies specific facial findings rather than a causal facial-gestalt pathway.
- name: Full cheeks
  category: Craniofacial
  description: Variable facial feature documented in the clinical series.
  phenotype_term:
    preferred_term: Full cheeks
    term:
      id: HP:0000293
      label: Full cheeks
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Note the round face, full cheeks, bulbous nose, and a prominent philtrum in patient no. 2
    explanation: Figure caption identifies specific facial findings rather than a causal facial-gestalt pathway.
- name: Bulbous nose
  category: Craniofacial
  description: Variable facial feature documented in the clinical series.
  phenotype_term:
    preferred_term: Bulbous nose
    term:
      id: HP:0000414
      label: Bulbous nose
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Note the round face, full cheeks, bulbous nose, and a prominent philtrum in patient no. 2
    explanation: Figure caption identifies specific facial findings rather than a causal facial-gestalt pathway.
- name: Long philtrum
  category: Craniofacial
  description: An explicitly long philtrum was recorded in patient 13, who also carried additional CNVs. Other patients had a prominent or marked philtrum, which is not assumed to mean long.
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Philtrum features | Prominent | Marked | − | − | Marked | − | − | − | − | − | Marked | − | Long | − | Marked
    explanation: Patient 13 has the specifically long philtrum; other descriptors are not treated as synonyms.
- name: Synophrys
  category: Craniofacial
  description: Recorded in patients 9 and 10. These are individual observations in the 2015 deletion series.
  phenotype_term:
    preferred_term: Synophrys
    term:
      id: HP:0000664
      label: Synophrys
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Others | Thin upper lip, marked suborbital folds, broad nasal bridge, micrognathia, abnormally overfolded helices | Horizontal eyebrows |  |  | Horizontal eyebrows |  |  | Abnormally overfolded helices | Synophris, hirsutism, small mouth | Synophris | Epicanthal folds |  | Hypertelorism | Triangular face shape | Narrow and horizontal palpebral fissures, bushy eyebrows, broad nasal bridge, protruding and pointed chin, large ears
    explanation: Craniofacial row of Table 1; no syndrome frequency or shared causal sequence is inferred.
- name: Epicanthus
  category: Craniofacial
  description: Recorded in patient 11. These are individual observations in the 2015 deletion series.
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Others | Thin upper lip, marked suborbital folds, broad nasal bridge, micrognathia, abnormally overfolded helices | Horizontal eyebrows |  |  | Horizontal eyebrows |  |  | Abnormally overfolded helices | Synophris, hirsutism, small mouth | Synophris | Epicanthal folds |  | Hypertelorism | Triangular face shape | Narrow and horizontal palpebral fissures, bushy eyebrows, broad nasal bridge, protruding and pointed chin, large ears
    explanation: Craniofacial row of Table 1; no syndrome frequency or shared causal sequence is inferred.
- name: Overfolded helix
  category: Craniofacial
  description: Recorded in the fetus and patient 8. These are individual observations in the 2015 deletion series.
  phenotype_term:
    preferred_term: Overfolded helix
    term:
      id: HP:0000396
      label: Overfolded helix
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Others | Thin upper lip, marked suborbital folds, broad nasal bridge, micrognathia, abnormally overfolded helices | Horizontal eyebrows |  |  | Horizontal eyebrows |  |  | Abnormally overfolded helices | Synophris, hirsutism, small mouth | Synophris | Epicanthal folds |  | Hypertelorism | Triangular face shape | Narrow and horizontal palpebral fissures, bushy eyebrows, broad nasal bridge, protruding and pointed chin, large ears
    explanation: Craniofacial row of Table 1; no syndrome frequency or shared causal sequence is inferred.
- name: Hirsutism
  category: Craniofacial
  description: Recorded in patient 9. These are individual observations in the 2015 deletion series.
  phenotype_term:
    preferred_term: Hirsutism
    term:
      id: HP:0001007
      label: Hirsutism
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Others | Thin upper lip, marked suborbital folds, broad nasal bridge, micrognathia, abnormally overfolded helices | Horizontal eyebrows |  |  | Horizontal eyebrows |  |  | Abnormally overfolded helices | Synophris, hirsutism, small mouth | Synophris | Epicanthal folds |  | Hypertelorism | Triangular face shape | Narrow and horizontal palpebral fissures, bushy eyebrows, broad nasal bridge, protruding and pointed chin, large ears
    explanation: Craniofacial row of Table 1; no syndrome frequency or shared causal sequence is inferred.
- name: Small hand
  category: Musculoskeletal
  description: Short hands were recorded in patients 9, 10 and 11; this finding is distinct from short fingers.
  phenotype_term:
    preferred_term: Small hand
    term:
      id: HP:0200055
      label: Small hand
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hands |  | Brachymetacarpia | − | − | − | Short and stubby fingers | Stubby fingers | − | Short | Short | Short, bilateral clinodactyly | − | − | − | −
    explanation: Patient-level hand findings in Table 1.
- name: Short foot
  category: Musculoskeletal
  description: Short feet were recorded in the fetus and patient 10.
  phenotype_term:
    preferred_term: Short foot
    term:
      id: HP:0001773
      label: Short foot
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Feet | Short | − | − | − | − | Flat | − | − | − | Short, flat | 2nd and 3rd toes syndactyly | Flat, valgus | − | − | −
    explanation: Patient-level foot findings in Table 1.
- name: Clinodactyly
  category: Musculoskeletal
  description: Bilateral clinodactyly was recorded in patient 11.
  phenotype_term:
    preferred_term: Clinodactyly
    term:
      id: HP:0030084
      label: Clinodactyly
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hands |  | Brachymetacarpia | − | − | − | Short and stubby fingers | Stubby fingers | − | Short | Short | Short, bilateral clinodactyly | − | − | − | −
    explanation: The table specifies clinodactyly without identifying an individual digit.
- name: Pes planus
  category: Musculoskeletal
  description: Flat feet were recorded in several patients; valgus was additionally described in patient 12.
  phenotype_term:
    preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Feet | Short | − | − | − | − | Flat | − | − | − | Short, flat | 2nd and 3rd toes syndactyly | Flat, valgus | − | − | −
    explanation: Patient-level foot findings, not a severity or frequency estimate.
- name: 2-3 toe syndactyly
  category: Musculoskeletal
  description: Second-to-third toe syndactyly was recorded in patient 11.
  phenotype_term:
    preferred_term: 2-3 toe syndactyly
    term:
      id: HP:0004691
      label: 2-3 toe syndactyly
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Feet | Short | − | − | − | − | Flat | − | − | − | Short, flat | 2nd and 3rd toes syndactyly | Flat, valgus | − | − | −
    explanation: The source specifies the involved toes.
- name: Cryptorchidism
  category: Genitourinary
  description: Unilateral cryptorchidism occurred in patients 12 and 14. Patient 12 had a complex rearrangement; patient 14 lacked SIM1 deletion.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Genital anomalies | − | − | − | − | − | − | − | − | − | − | − | Unilateral cryptorchidism | − | Unilateral cryptorchidism | −
    explanation: Records individual genital findings without assigning a specific gene mechanism.
- name: Myopia
  category: Ophthalmologic
  description: Reported among the heterogeneous visual findings in the 2015 series; this is not an obligatory manifestation.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Vision anomalies |  | Severe myopia | − | − | Severe myopia | − | Myopia | Strabismus | − | Astigmatism | Hypermetropia | Nystagmus | − | Strabismus | −
    explanation: Table 1 distinguishes individual refractive and ocular-motor abnormalities. Nystagmus was recorded in patient 12 with a complex rearrangement.
- name: Hypermetropia
  category: Ophthalmologic
  description: Reported among the heterogeneous visual findings in the 2015 series; this is not an obligatory manifestation.
  phenotype_term:
    preferred_term: Hypermetropia
    term:
      id: HP:0000540
      label: Hypermetropia
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Vision anomalies |  | Severe myopia | − | − | Severe myopia | − | Myopia | Strabismus | − | Astigmatism | Hypermetropia | Nystagmus | − | Strabismus | −
    explanation: Table 1 distinguishes individual refractive and ocular-motor abnormalities. Nystagmus was recorded in patient 12 with a complex rearrangement.
- name: Astigmatism
  category: Ophthalmologic
  description: Reported among the heterogeneous visual findings in the 2015 series; this is not an obligatory manifestation.
  phenotype_term:
    preferred_term: Astigmatism
    term:
      id: HP:0000483
      label: Astigmatism
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Vision anomalies |  | Severe myopia | − | − | Severe myopia | − | Myopia | Strabismus | − | Astigmatism | Hypermetropia | Nystagmus | − | Strabismus | −
    explanation: Table 1 distinguishes individual refractive and ocular-motor abnormalities. Nystagmus was recorded in patient 12 with a complex rearrangement.
- name: Nystagmus
  category: Ophthalmologic
  description: Reported among the heterogeneous visual findings in the 2015 series; this is not an obligatory manifestation.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Vision anomalies |  | Severe myopia | − | − | Severe myopia | − | Myopia | Strabismus | − | Astigmatism | Hypermetropia | Nystagmus | − | Strabismus | −
    explanation: Table 1 distinguishes individual refractive and ocular-motor abnormalities. Nystagmus was recorded in patient 12 with a complex rearrangement.
- name: Strabismus
  category: Ophthalmologic
  description: Reported among the heterogeneous visual findings in the 2015 series; this is not an obligatory manifestation.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Vision anomalies |  | Severe myopia | − | − | Severe myopia | − | Myopia | Strabismus | − | Astigmatism | Hypermetropia | Nystagmus | − | Strabismus | −
    explanation: Table 1 distinguishes individual refractive and ocular-motor abnormalities. Nystagmus was recorded in patient 12 with a complex rearrangement.
- name: Ventriculomegaly
  category: Neurological
  description: One of seven imaged living patients in the 2015 series had ventriculomegaly. This was patient 12, with two 6q deletions and a translocation, limiting specific attribution.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Abnormal brain MRI |  |  |  |  | − |  |  | − |  | − | − | + (Ventriculo-megaly) | − | − |
    explanation: Only a selected subset underwent MRI, and the positive case had a complex rearrangement.
- name: Cleft soft palate
  category: Craniofacial
  description: Present in the Japanese SIM1-sparing deletion case. The authors explicitly question whether the deletion explains the palatal anomaly.
  phenotype_term:
    preferred_term: Cleft soft palate
    term:
      id: HP:0000185
      label: Cleft soft palate
  evidence:
  - reference: PMID:35581197
    reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She showed strabismus, cleft soft palate, and hypotonia in the neonatal period.
    explanation: Direct observation; the paper cautions that the gene content may not explain strabismus or cleft palate.
- name: Microcephaly
  category: Craniofacial
  description: Postnatal microcephaly is reported in some more proximal EPHA7-containing deletions. It is not conflated with the macrocephaly reported in other intervals.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In conclusion, our study suggests EPHA7 deletion should be con- sidered as a risk factor for NDD combining ID, behavioral disorders, speech delay and microcephaly with variable expressivity and incom- plete penetrance.
    explanation: "The expanded EPHA7 cohort supports a susceptibility phenotype; this is the authors' interpretation. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017)."
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
- name: Ptosis
  category: Craniofacial
  description: Reported in the original EPHA7-containing 6q16.1 deletion case. This is an interval-specific observation rather than a defining feature across 6q16.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:19664229
    reference_title: 'Microdeletion of 6q16.1 encompassing EPHA7 in a child with mild neurological abnormalities and dysmorphic features: case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: developmental delay, microcephaly, short stature, con- genital hypotonia, mild ptosis, periauricular tags, cupped
    explanation: The case report lists the individual neurological and dysmorphic observations.
- name: Preauricular skin tag
  category: Craniofacial
  description: Reported in the original EPHA7-containing 6q16.1 deletion case. This is an interval-specific observation rather than a defining feature across 6q16.
  phenotype_term:
    preferred_term: Preauricular skin tag
    term:
      id: HP:0000384
      label: Preauricular skin tag
  evidence:
  - reference: PMID:19664229
    reference_title: 'Microdeletion of 6q16.1 encompassing EPHA7 in a child with mild neurological abnormalities and dysmorphic features: case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: developmental delay, microcephaly, short stature, con- genital hypotonia, mild ptosis, periauricular tags, cupped
    explanation: The case report lists the individual neurological and dysmorphic observations.
- name: Cupped ear
  category: Craniofacial
  description: Reported in the original EPHA7-containing 6q16.1 deletion case. This is an interval-specific observation rather than a defining feature across 6q16.
  phenotype_term:
    preferred_term: Cupped ear
    term:
      id: HP:0000378
      label: Cupped ear
  evidence:
  - reference: PMID:19664229
    reference_title: 'Microdeletion of 6q16.1 encompassing EPHA7 in a child with mild neurological abnormalities and dysmorphic features: case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: developmental delay, microcephaly, short stature, con- genital hypotonia, mild ptosis, periauricular tags, cupped
    explanation: The case report lists the individual neurological and dysmorphic observations.
- name: Bicuspid aortic valve
  category: Cardiovascular
  description: Patient 3 in the EPHA7-containing deletion series had a bicuspid aortic valve without stenosis or regurgitation. These are clinical observations, not evidence for a resolved cardiac pathway or a syndrome-wide frequency.
  phenotype_term:
    preferred_term: Bicuspid aortic valve
    term:
      id: HP:0001647
      label: Bicuspid aortic valve
  evidence:
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: cardiac defects (25%) including bicuspid aortic valve, atrial or ventricular septal defects.
    explanation: 'The full cohort reports these specific findings. Its quoted summary percentage is not used as a population frequency; the separate supravalvular stenosis case also had Williams-Beuren syndrome. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
- name: Atrial septal defect
  category: Cardiovascular
  description: Patient 8, with a deletion described as involving only EPHA7, had an atrial septal defect. These are clinical observations, not evidence for a resolved cardiac pathway or a syndrome-wide frequency.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: cardiac defects (25%) including bicuspid aortic valve, atrial or ventricular septal defects.
    explanation: 'The full cohort reports these specific findings. Its quoted summary percentage is not used as a population frequency; the separate supravalvular stenosis case also had Williams-Beuren syndrome. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
- name: Ventricular septal defect
  category: Cardiovascular
  description: Patient 9 had a ventricular septal defect and a larger interval that also included MAP3K7; attribution to EPHA7 alone is unwarranted. These are clinical observations, not evidence for a resolved cardiac pathway or a syndrome-wide frequency.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: cardiac defects (25%) including bicuspid aortic valve, atrial or ventricular septal defects.
    explanation: 'The full cohort reports these specific findings. Its quoted summary percentage is not used as a population frequency; the separate supravalvular stenosis case also had Williams-Beuren syndrome. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
- name: Iris coloboma
  category: Ophthalmologic
  description: Recorded in patient 12 of the EPHA7 series, who had a larger 6q14.3-q16.1 deletion involving ZNF292. The finding cannot be assigned to EPHA7 alone.
  phenotype_term:
    preferred_term: Iris coloboma
    term:
      id: HP:0000612
      label: Iris coloboma
  evidence:
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: eye abnormalities (40%) such as ptosis, strabismus, astigmatism or iris coloboma
    explanation: 'The cohort summary names the ocular finding; Table 1 identifies the large-deletion patient. The quoted percentage is not used as a disease frequency. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
genetic:
- name: SIM1
  gene_term:
    preferred_term: SIM1
    term:
      id: hgnc:10882
      label: SIM1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: One contributor to obesity in SIM1-containing deletions. Strong loss-of-function intragenic variants support the gene assignment, but not all missense variants are damaging and obesity severity is incompletely penetrant. An intrafamilial odds ratio from selected variant carriers is not deletion-syndrome penetrance.
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Except for patients no. 14 and 15, all patients had deletions that included the SIM1 gene.
    explanation: SIM1 involvement is determined by deletion boundaries; it is absent from two intervals in this cohort.
  - reference: PMID:23778136
    reference_title: Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We found a strong loss-of-function effect of p.T46R, p.H323Y, and p.T714A mutations on SIM1 transcriptional activity with both ARNT and ARNT2
    explanation: Reporter assays establish variant-specific loss of transactivation in engineered human cells, not hypothalamic histology in deletion carriers.
  - reference: PMID:23778136
    reference_title: Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Therefore, mutation of SIM1 is not always responsible for a fully penetrant form of obesity.
    explanation: The study reports variable effects and variable clinical expression.
- name: POU3F2
  gene_term:
    preferred_term: POU3F2
    term:
      id: hgnc:9215
      label: POU3F2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: A supported contributor to neurodevelopmental impairment and obesity susceptibility in SIM1-sparing deletions. The overlapping 350-kb region also includes FBXL4; subsequent intragenic truncating and missense variants strengthen POU3F2 attribution. Functional effects are variant-specific. The separate monogenic cohort is not used to assign every finding or a frequency to chromosome-deletion carriers.
  evidence:
  - reference: PMID:35581197
    reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: The six families described in the report by Kasher et al. had the deletion of the POU3F2 and FBXL4 genes, although the deletion size was different in each family
    explanation: Identifies both genes in the overlapping interval; these are not POU3F2-only deletions.
  - reference: PMID:37207645
    reference_title: Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity.
    explanation: Intragenic variants independently strengthen POU3F2 attribution; this is a separate monogenic cohort, not a deletion-syndrome frequency estimate.
  - reference: PMID:37207645
    reference_title: Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation.
    explanation: Functional summary from the available abstract of the intragenic-variant study. Effects differ by variant and are not measurements in deletion-carrier hypothalamus.
- name: EPHA7
  gene_term:
    preferred_term: EPHA7
    term:
      id: hgnc:3390
      label: EPHA7
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  notes: Partial or complete deletions support an incompletely penetrant neurodevelopmental susceptibility locus. Most deletions in the 2021 series were inherited, often from unaffected parents. A more severe case also had Williams-Beuren syndrome, and another had a larger deletion involving ZNF292; these are not clean EPHA7-only phenotypes.
  evidence:
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Four patients had tiny deletions involving only EPHA7
    explanation: 'Single-gene deletions strengthen the locus association but the authors describe a susceptibility effect with incomplete penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance.
    explanation: 'The selected cohort supports variable expression; it does not estimate population penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Most deletions were inherited (9/12) from unaffected parent suggesting that haploinsufficiency of EPHA7 could act as a risk factor for NDD with variable expressivity and incomplete penetrance.
    explanation: 'Discussion qualifies the risk-locus interpretation; family A had an affected father with a history of cranial concussion. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
inheritance:
- name: Autosomal dominant deletion with de novo and inherited occurrences
  description: A heterozygous deletion can occur de novo or be transmitted within a family. Clinical expression is variable, and inherited EPHA7-containing deletions may occur in unaffected parents. The 2015 SIM1-region series excluded a parental deletion in 14 of 15 families; one was not tested.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:26833329
    reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The 6q16.1 deletions segregated with the phenotype in multiplex families and were shown to be de novo in four families
    explanation: Documents both familial transmission and de novo occurrence.
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The absence of parental deletion was checked in 14 cases, the exception being patient no. 4.
    explanation: Avoids treating the abstract's description of all cases as de novo as fully confirmed.
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance.
    explanation: 'The selected cohort supports variable expression; it does not estimate population penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
diagnosis:
- name: Chromosomal microarray and deletion-boundary assessment
  description: Chromosomal microarray establishes the copy-number loss and identifies whether SIM1, POU3F2, EPHA7 or other genes are involved. Additional CNVs or chromosome rearrangements can affect interpretation.
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Microarray studies were done in all 15 patients.
    explanation: The disease-specific series used array analysis in every participant.
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: FISH was performed using chromosomal preparations according to standard protocols to confirm the 6q deletions characterised by microarray.
    explanation: Documents orthogonal confirmation.
- name: Parental testing
  description: Determine whether the deletion is de novo or inherited, and interpret recurrence and expression in the family rather than assuming every deletion is sporadic.
  evidence:
  - reference: PMID:26833329
    reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The 6q16.1 deletions segregated with the phenotype in multiplex families and were shown to be de novo in four families
    explanation: Documents both familial transmission and de novo occurrence.
- name: Exome-based copy-number analysis
  description: Validated copy-number analysis of trio exome data identified a 780-kb SIM1-sparing deletion after normal G-banding in one child. A normal conventional karyotype does not exclude a submicroscopic deletion.
  evidence:
  - reference: PMID:35581197
    reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Exome sequencing data were analyzed using the eXome Hidden Markov Model (XHMM) and modified Nord’s method
    explanation: Case-specific diagnostic approach.
- name: Longitudinal endocrine evaluation
  description: Authors of the SIM1-containing deletion case recommend detailed endocrine assessment and follow-up because hypopituitarism appeared after unremarkable infant testing. The report does not establish an evidence-based universal interval for surveillance.
  evidence:
  - reference: PMID:24038875
    reference_title: Endocrine phenotype of 6q16.1-q21 deletion involving SIM1 and Prader-Willi syndrome-like features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we suggest that detailed endocrine evaluation and longitudinal endocrine follow up be performed in individuals with proximal interstitial 6q deletion involving SIM1
    explanation: Explicit case-report recommendation.
- name: Growth and appetite follow-up
  description: Monitor growth and emerging hyperphagia or obesity, including in initially nonobese children with a POU3F2-containing deletion. This is a clinical follow-up recommendation; prevention efficacy and a universal schedule were not established.
  evidence:
  - reference: PMID:35581197
    reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Thus, we need to pay attention to her symptoms of obesity.
    explanation: Case-report recommendation prompted by age-dependent obesity in previously reported patients.
treatments:
- name: Hormone replacement for documented pituitary deficiency
  description: Replace deficient hormones when endocrine testing establishes a deficiency. The source provides a clinical rationale; it does not demonstrate a controlled treatment effect or prove a common hypothalamic lesion.
  treatment_term:
    preferred_term: Hormone Replacement Therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
  evidence:
  - reference: PMID:24038875
    reference_title: Endocrine phenotype of 6q16.1-q21 deletion involving SIM1 and Prader-Willi syndrome-like features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Early identification of endocrine abnormalities can improve clinical outcome by allowing timely introduction of hormone replacement therapy.
    explanation: Case-report recommendation tied to documented endocrine deficiency.
- name: Physical therapy
  description: Physical therapy was used from infancy in the original EPHA7-containing deletion case with hypotonia and motor delay. The report does not quantify its treatment effect.
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:19664229
    reference_title: 'Microdeletion of 6q16.1 encompassing EPHA7 in a child with mild neurological abnormalities and dysmorphic features: case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: received physical therapy since age 6 months
    explanation: Documents actual supportive care in one child, without comparative efficacy.
- name: Repair of associated cleft palate
  description: Surgical cleft-palate treatment was performed in one SIM1-sparing deletion case at 15 months. The causal relationship between the deletion and cleft palate was uncertain.
  evidence:
  - reference: PMID:35581197
    reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Surgical treatment for cleft palate was performed at 1 year and 3 months old.
    explanation: Records actual case-specific treatment.
  treatment_term:
    preferred_term: Palatorrhaphy
    term:
      id: NCIT:C168380
      label: Palatorrhaphy
animal_models:
- name: Zebrafish sim1-pou3f2 neuroendocrine pathway models
  species: Zebrafish
  publication: PMID:26833329
  description: Morpholino and mutant zebrafish experiments test the relationship between sim1, pou3f2 and preoptic oxytocin expression. The available abstract supports pathway ordering but does not report a human deletion model, clinical obesity rescue or a complete deletion-specific mechanism.
  modeled_mechanisms:
  - target: POU3F2-Dependent Oxytocin Expression in Zebrafish
    relationship: PERTURBS
    fidelity: LOW
    description: Tests a candidate conserved transcriptional pathway through experimental gene perturbation.
    limitations: The reference cache contains the abstract only. Genotype details, rescue designs, neuron counts and metabolic outcomes are not inferred. Human expression-pattern concordance does not establish the same epistasis or hormone deficiency in patients.
    evidence:
    - reference: PMID:26833329
      reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Using morpholino and mutant zebrafish models, we show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area.
      explanation: Experimental pathway ordering and oxytocin-expression readout in zebrafish. The available abstract does not establish human neuron loss, circulating oxytocin deficiency or obesity rescue.
experimental_models:
- name: Human 293 Flp-In T-Rex SIM1 reporter assay
  experimental_model_type: CELL_LINE
  cell_source: Engineered human 293 Flp-In T-Rex cells
  culture_system: Stable single-copy wild-type or mutant SIM1 expression with ARNT or ARNT2 and a luciferase reporter
  publication: PMID:23778136
  description: Eight substitutions were compared using a defined single insertion site. Three showed strong loss of transactivation with both partners; other substitutions had mild, absent or partner-dependent gain-of-function effects.
  modeled_mechanisms:
  - target: Reduced SIM1-Dependent Transactivation
    relationship: PERTURBS
    fidelity: LOW
    description: Directly assays SIM1-dependent reporter activation.
    limitations: Engineered non-neuronal cells testing intragenic variants, not a patient-derived deletion model; reporter loss does not identify the relevant human hypothalamic target or prove a neuronal developmental lesion.
    evidence:
    - reference: PMID:23778136
      reference_title: Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: We found a strong loss-of-function effect of p.T46R, p.H323Y, and p.T714A mutations on SIM1 transcriptional activity with both ARNT and ARNT2
      explanation: Reporter assays establish variant-specific loss of transactivation in engineered human cells, not hypothalamic histology in deletion carriers.
histopathology:
- name: Cerebral and cerebellar neuronal ectopia
  description: Autopsy of one fetus with a large 14-Mb 6q16.1-q21 deletion identified ectopic neurons and abnormal nuclear organization. This prenatal case is not representative of all surviving deletion carriers, and the findings cannot be assigned to SIM1 alone.
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Microscopic examination of the brain evidenced fusion of the anterior caudate nucleus and putamen (Figure 1c), multiple ectopic neurons in the white matter (Figure 1d) and ectopic Purkinje cells in the internal granular layer of the cerebellum (Figure 1e).
    explanation: Direct fetal neuropathology from one large deletion, distinct from the mostly normal available MRI observations in living patients.
  notes: 'Needs term / NTR: mixed cerebral and cerebellar neuronal ectopia is retained descriptively; no generic tumor histology term is applied.'
differential_diagnoses:
- name: Prader-Willi Syndrome
  description: Hypotonia, developmental impairment and later hyperphagic obesity can overlap, while the causative chromosome lesion differs.
  distinguishing_features:
  - Molecular testing distinguishes 15q11-q13 imprinting abnormalities from a 6q16 copy-number loss.
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Prader–Willi syndrome (PWS, MIM 176270) is an imprinting disease caused by paternal deletions, maternal uniparental disomy or imprinting anomalies in the 15q11.2q13 region.
    explanation: Background establishes the distinct molecular basis.
- name: 6q14.1-q15 deletion syndrome
  description: Adjacent proximal deletions can also produce developmental delay and obesity. Their clinical overlap is a differential consideration, not direct evidence for the mechanism or phenotype frequencies of 6q16 deletions.
  evidence:
  - reference: PMID:21045960
    reference_title: Interstitial Deletions at 6q14.1-q15 Associated with Obesity, Developmental Delay and a Distinct Clinical Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Here we report on 2 patients with interstitial deletions at 6q14.1-q15 presenting with obesity and symptoms strikingly similar to those reported for deletions involving the SIM1 gene despite not having a deletion of this gene.
    explanation: Keeps the neighboring interval outside the 6q16 causal graph.
- name: Monogenic SIM1- or POU3F2-related neurodevelopmental obesity
  description: Intragenic variants can produce overlapping obesity and developmental phenotypes without a chromosome deletion. Gene-specific assays and sequencing are distinct from demonstration of a 6q16 CNV.
  evidence:
  - reference: PMID:37207645
    reference_title: Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity.
    explanation: Intragenic variants independently strengthen POU3F2 attribution; this is a separate monogenic cohort, not a deletion-syndrome frequency estimate.
  - reference: PMID:23778136
    reference_title: Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: if chromosomes 15q11 and 6q16 are found not to contain abnormalities, then SIM1 sequencing and subsequent molecular characterization should be performed
    explanation: The authors suggest an intragenic differential after chromosome testing.
discussions:
- discussion_id: del6q16_human_model_bridge
  kind: HUMAN_MODEL_MISMATCH
  prompt: Which experimentally identified transcriptional and neuroendocrine effects occur in human deletion carriers?
  rationale: SIM1 reporter loss, POU3F2 variant effects and zebrafish oxytocin-expression regulation support biological hypotheses. None establishes universal human paraventricular neuron loss, circulating oxytocin deficiency or a single causal route from the deletion to obesity and developmental impairment.
  attaches_to:
  - pathophysiology#Reduced SIM1-Dependent Transactivation
  - pathophysiology#POU3F2-Dependent Oxytocin Expression in Zebrafish
  evidence:
  - reference: PMID:23778136
    reference_title: Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We found a strong loss-of-function effect of p.T46R, p.H323Y, and p.T714A mutations on SIM1 transcriptional activity with both ARNT and ARNT2
    explanation: Reporter assays establish variant-specific loss of transactivation in engineered human cells, not hypothalamic histology in deletion carriers.
  - reference: PMID:26833329
    reference_title: Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Using morpholino and mutant zebrafish models, we show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area.
    explanation: Experimental pathway ordering and oxytocin-expression readout in zebrafish. The available abstract does not establish human neuron loss, circulating oxytocin deficiency or obesity rescue.
- discussion_id: del6q16_interval_and_ascertainment
  kind: KNOWLEDGE_GAP
  prompt: How do gene content, age and additional genetic findings modify the phenotype?
  rationale: Intervals vary and some reported patients carry additional CNVs or large deletions. The 2015 series has inconsistent obesity totals between narrative and tables and includes a fetus among SIM1 deletions; the quoted 8/13 is not used as a penetrance estimate. The EPHA7 cohort includes unaffected transmitting parents and two severe cases with substantial alternative genetic contributions. These sources support qualitative variability rather than disease-wide frequency bands.
  attaches_to:
  - pathophysiology#Heterozygous 6q16 Deletion
  - genetic#EPHA7
  evidence:
  - reference: PMID:25351778
    reference_title: Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency.
    explanation: The authors interpret variable obesity as incomplete penetrance. The cohort includes a fetus and the tables have discrepant obesity totals, so this quoted count is not used as a penetrance estimate.
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Four patients had tiny deletions involving only EPHA7
    explanation: 'Single-gene deletions strengthen the locus association but the authors describe a susceptibility effect with incomplete penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
  - reference: url:https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    reference_title: https://pure.rug.nl/ws/files/175928539/cge.14017.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance.
    explanation: 'The selected cohort supports variable expression; it does not estimate population penetrance. Full-text source: Levy et al., EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder (PMID:34176129; DOI:10.1111/cge.14017).'
review_notes: Reviewed the matching Perplexity report and citation audit against original clinical and experimental sources. Expanded disease-specific clinical coverage from the 2015 deletion series, the 2022 SIM1-sparing case and the 2021 EPHA7 cohort. Read full available reports, including actual generated full text for the SIM1 functional study and the deletion cohort; POU3F2 2016 and 2023 caches remain abstract-only after sanctioned retrieval attempts, so fine experimental details and gene-specific treatment claims are not inferred. Removed unsupported frequency bands, POU3F2-only deletion language, assumed human neuronal or oxytocin deficiency, and adjacent-interval evidence from the causal model. Full-text table findings retain patient and additional-CNV limitations. No disease-specific trial efficacy was established by the reviewed sources.
progression:
- phase: Variable developmental and growth trajectories
  notes: Developmental difficulties can present in infancy, while hyperphagia and obesity may emerge later. Neither an obligatory early obesity phase nor a uniform progressive neurological course is established. A child with a POU3F2-containing deletion remained nonobese at five years despite persistent language delay.
  evidence:
  - reference: PMID:35581197
    reference_title: Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: At the age of 5 years and 1 month, she could not speak two-word sentences, her body weight was 15.7 kg (−0.8 SD), and her body height was 101.7 cm (−1.1 SD).
    explanation: A longitudinal observation documenting persistent developmental impairment without obesity at this age.
- phase: Possible later pituitary deficiency
  notes: A single SIM1-containing deletion case developed hypopituitarism in childhood or adolescence despite unremarkable infant endocrine testing. Normal early testing did not exclude later deficiency in that patient.
  evidence:
  - reference: PMID:24038875
    reference_title: Endocrine phenotype of 6q16.1-q21 deletion involving SIM1 and Prader-Willi syndrome-like features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Detailed endocrine evaluation of the propositus during childhood and adolescence revealed hypopituitarism, though initial endocrine evaluations during infancy were unremarkable.
    explanation: One SIM1-containing deletion case developed later endocrine deficits; this does not establish a universal or obligatory consequence.
updated_date: '2026-09-21T03:40:00Z'
📚

References & Deep Research

Deep Research

1

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

Evaluations and curation notes (2)

Review 6q16 deletion intervals, clinical findings and experimental mechanisms · 2026-09-21T03:49:38Z · View source

Reviewed the matching deep-research report and citation audit against primary sources. Replaced overconfident human hypothalamic and oxytocin claims with nine atomic nodes distinguishing genomic dosage, variant assays and zebrafish evidence. Expanded to 46 phenotypes, three interval groups, longitudinal endocrine and growth follow-up, actual supportive care and fetal neuropathology. Incorporated the 2015 deletion cohort, 2022 SIM1-sparing case, 2021 EPHA7 cohort and 2023 intragenic POU3F2 evidence. Removed unsupported frequencies and qualified table inconsistencies, variable penetrance and additional CNVs. Full available sources were read; POU3F2 2016/2023 remained abstract-only after sanctioned retrieval, limiting detailed model claims. Independent peer mechanism audit corrected inferred-edge evidence directness. Schema, live ontology terms and all 127 snippets passed; causal-target and coarse-binding gates passed. Included the previously reviewed tracked PMC retrieval adapter so full-text caches are reproducible without ignored environment edits; its 12 tests passed. No caches were hand-edited and the frozen dataset accession file was not accessed.

Create: 6q16 Deletion Syndrome (MONDO:0015749) · 2026-09-01T14:26:42Z · View source

De-novo curation of 6q16 deletion syndrome from a Perplexity deep-research report (research/6q16_Deletion_Syndrome-deep-research-perplexity.md, sonar-deep-research, 18 citations). The report's reference_validation reported 7 of 7 resolved at confabulation rate 0.0, but it cites 18 sources, so 7 is what the validator could see rather than a clean bill; 5 of the 7 were judged on topic and one citation-list entry is the bare string 'ACMG/AMP'. Its term_validation was the more useful signal: 8 of 20 checked labels named a different term than the report claimed, so no CURIE from the report was reused and every binding was resolved through OAK (SIM1 hgnc:10882 and POU3F2 hgnc:9215 via sqlite:obo:hgnc). All references were resolved to PMIDs, fetched with just fetch-reference, and quoted from the fetched text. The substantive curation decision is to decline the conventional shorthand that this syndrome is SIM1 haploinsufficiency under a cytogenetic name. Two published observations block that: a roughly 350 kb critical region at 6q16.1 encompassing POU3F2 but not SIM1 produces overlapping developmental delay and obesity susceptibility (PMID:26833329), with zebrafish work placing POU3F2 downstream of SIM1 controlling oxytocin expression in the neuroendocrine preoptic area; and SIM1-sparing deletions at the adjacent 6q14.1-q15 interval produce a strikingly similar phenotype (PMID:21045960). The pathograph therefore branches from the deletion node into separate SIM1 and POU3F2 arms that converge on dysregulated hypothalamic control of energy balance, and a KNOWLEDGE_GAP discussion carrying the 6q14.1-q15 paper as evidence records gene-to-phenotype attribution as unresolved. Hypopituitarism is recorded at OCCASIONAL frequency with a note that it rests on a single reported patient, and short stature carries directness INDIRECT because the authors state it as a possibility rather than an established feature. Validated with just validate (schema, terms, references: 23/23 snippets verified) plus check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms and check-enum-values, all clean.

Perplexity ▸
1. Disease Information
sonar-deep-research 18 citations 2026-09-01T13:40:08.347404

1. Disease Information

1.1 Definition and Clinical Overview

6q16 deletion syndrome is defined as a rare genetic disorder caused by an interstitial microdeletion involving the proximal long arm of chromosome 6, typically spanning cytogenetic band 6q16.1–q16.2, and clinically characterized by obesity, hyperphagia, neonatal or infantile hypotonia, small hands and feet, global developmental delay, and eye or vision anomalies.[1][9][16][13] Orphanet describes the condition as “a rare Prader‑Willi like syndrome due to an interstitial deletion located at 6q16.1q16.2” and highlights the overlap with the core Prader–Willi phenotype of hypotonia, developmental delay, and early‑onset obesity.[1] MedGen (Concept Id C5438727) and other aggregated resources similarly emphasize the Prader–Willi‑like presentation and specify that the deletion is interstitial and limited to the long arm of chromosome 6, distinguishing it from more distal 6q24–q25 deletions and from whole‑arm monosomies.[9][2] Malacards and related disease databases echo this definition, focusing on the syndromic association of structural 6q16 abnormalities with severe obesity and neurodevelopmental impairment.[16]

Clinically, affected individuals typically present in the neonatal period with generalized hypotonia and feeding difficulties, followed later by a transition from poor feeding to hyperphagia and rapid weight gain in early childhood, paralleling the temporal evolution observed in classic Prader–Willi syndrome.[1][9][15] Developmental delay is nearly universal, encompassing motor delay, speech delay, and later intellectual disability of variable severity.[6][8][11][12] Dysmorphic features are present in many, including small hands and feet, craniofacial anomalies, and in some reports ear anomalies and microcephaly.[1][3][8][11] Eye and vision anomalies, such as strabismus or refractive errors, have been noted in several cases, although systematic ophthalmologic characterization is limited.[1][9] Endocrine abnormalities, including hypothyroidism, hypogonadotropic hypogonadism, and growth hormone deficiency, have been documented in selected individuals, particularly when the deletion encompasses SIM1, suggesting a broader hypopituitarism phenotype analogous to that seen in Prader–Willi syndrome.[15] Overall, 6q16 deletion syndrome is best conceptualized as a structural‑variant mediated neurodevelopmental and neuroendocrine disorder that phenocopies, but is genetically distinct from, Prader–Willi syndrome.

From an ontological perspective, the condition corresponds to MONDO:0015749 (6q16 deletion syndrome).[13] Its core clinical features map to Human Phenotype Ontology terms such as obesity (HP:0001513), hyperphagia (HP:0002591), muscular hypotonia (HP:0001252), global developmental delay (HP:0001263), intellectual disability (HP:0001249), small hands (HP:0001174), small feet (HP:0001773), and visual impairment (HP:0000505).[1][9][12] As a structural chromosomal disorder, it additionally aligns with MONDO concepts for “chromosomal deletion syndrome” and overlaps with structural variant entries in DECIPHER and related CNV databases.[6][8][12] This ontological mapping is important for computational disease modeling and for linking phenotypic data to variant annotations.

1.2 Synonyms, Classification, and Key Identifiers

Multiple synonymous labels have been used in the literature and in disease databases to refer to 6q16 deletion syndrome, reflecting both the evolving recognition of its phenotype and differences in the minimal critical region across studies.[1][6][8][9][16] Orphanet lists “6q16 microdeletion syndrome,” “Del(6)(q16),” “Monosomy 6q16,” and “Prader‑Willi‑like syndrome due to microdeletion 6q16” as alternative names.[1] Malacards similarly uses “6q16 microdeletion syndrome” and “Prader‑Willi‑like syndrome due to microdeletion 6q16” in addition to “6q16 deletion syndrome”.[16] MedGen and MONDO emphasize the “6q16 deletion syndrome” label, which best captures the unifying feature of an interstitial deletion at band 6q16 rather than whole‑arm monosomy.[9][13] Clinically, many publications refer more broadly to “proximal 6q deletion” or “interstitial 6q16 deletion” with descriptors such as “Prader‑Willi‑like obesity” or “syndromic obesity” to highlight the phenotypic overlap with Prader–Willi syndrome and monogenic obesity disorders.[4][6][8][10][11][15]

Key identifiers across reference databases include the Orphanet disease entry for “6q16 microdeletion syndrome” (Orpha number 171829), which provides a concise clinical summary and notes unknown inheritance and antenatal to neonatal onset.[1] MedGen lists Concept Id C5438727 as “6q16 deletion syndrome” and cross‑links to associated phenotypes and OMIM entries where available.[9] MONDO defines MONDO:0015749 as “6q16 deletion syndrome” and indicates its classification as a Mendelian disease of the central nervous system and endocrine system.[13] While there is no single OMIM entry solely dedicated to 6q16 deletion syndrome analogous to classic monogenic conditions, multiple OMIM records reference proximal 6q deletions or candidate genes within the region, including entries for SIM1 and POU3F2.[4][6][12][14] For example, the OMIM entry for chromosome 6q24–q25 deletion (#612863) describes a separate, more distal deletion syndrome associated with microcephaly, developmental delay, dysmorphic features, and hearing loss, underscoring the necessity of precise cytogenetic localization when annotating 6q structural disorders.[2]

From a coding perspective, there is no disease‑specific ICD‑10 or ICD‑11 code for 6q16 deletion syndrome; affected individuals are typically classified under broader categories such as Q93.8 (“other deletions of part of a chromosome”) in ICD‑10 or equivalent structural chromosomal abnormality codes in ICD‑11, alongside additional codes for obesity, intellectual disability, and endocrine dysfunction.[1][9] MeSH does not yet contain a dedicated term for 6q16 deletion syndrome, but relevant indexing terms include “Chromosome Deletion” and gene‑specific headings for SIM1 and POU3F2, which can be used for literature searches. Within the Human Phenotype Ontology, individual phenotypic components rather than the syndrome as a whole are most extensively annotated, supporting granular phenotype‑driven diagnostics and research.

1.3 Evidence Sources and Data Aggregation

Information about 6q16 deletion syndrome has arisen primarily from aggregated disease‑level resources and discrete case series rather than large population‑based cohorts, reflecting the rarity of the condition.[1][3][6][8][11][12][15] Orphanet and MedGen synthesize clinical observations from multiple published reports, DECIPHER entries, and expert contributions to generate a consensus disease definition, emphasizing obesity, hyperphagia, hypotonia, developmental delay, and small extremities.[1][9] Malacards and similar compendia integrate these data with gene‑centric information from OMIM and PubMed, linking 6q16 structural variation to SIM1 and POU3F2 and highlighting associated endocrine and neurodevelopmental features.[16][4][6][12][15] DECIPHER and other CNV databases contribute anonymized, de‑identified patient‑level copy number variant data, including precise genomic coordinates, parental inheritance status, and high‑level phenotype descriptors, which have been crucial for refining the critical region for the syndrome.[6][8][12]

The landmark study by Kasher and colleagues in the American Journal of Human Genetics (2016; PMID: 26833329) assembled ten individuals from six families with overlapping 6q16.1 deletions identified through chromosomal microarray, enabling delineation of a ~350 kb critical region encompassing POU3F2 and demonstrating segregation of the deletion with obesity and developmental delay in multiplex families.[6][12] In their words, “in ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia”, and they concluded that “the likely mechanism is haploinsufficiency of POU3F2.”[12] Similarly, cohort‑level analyses of proximal 6q interstitial deletions by Chromodisorder, drawing on 12 patients with overlapping CNVs, identified SIM1, ZNF292, PHIP, KCNQ5, and NUS1 as candidate genes contributing to developmental delay and obesity, further supporting a gene‑cluster model of the syndrome.[8] Individual case reports, such as Izumi et al.’s detailed endocrine evaluation of a child with a 6q16.1–q21 deletion involving SIM1, provide rich longitudinal data but remain isolated instances rather than components of systematic registries.[15]

Thus, the current knowledge base for 6q16 deletion syndrome is built from a mosaic of small case series, isolated case reports, and aggregated CNV datasets, complemented by functional studies in model organisms. There is no dedicated EHR‑linked disease registry for this syndrome, and epidemiologic metrics such as incidence and prevalence are extrapolated from Orphanet’s qualitative designation of rarity and from the small number of published cases.[1][6][8][11][12] For purposes of constructing a disease knowledge base entry, reliance on aggregated resources like Orphanet, MedGen, MONDO, DECIPHER, and key primary literature is both necessary and appropriate, while acknowledging that the evidence base remains limited and subject to ascertainment bias toward more severe or syndromic presentations.

2. Etiology

2.1 Genetic Causal Factors

The primary etiologic basis of 6q16 deletion syndrome is genetic, specifically heterozygous interstitial deletions involving the proximal long arm of chromosome 6 at band 6q16, with a minimal critical region centered on 6q16.1–q16.2.[1][6][8][9][12][13][16] These deletions range in size from approximately 0.35 Mb to over 17 Mb and may encompass varying sets of genes; however, converging evidence implicates disruption of POU3F2 and/or SIM1 as central to the pathogenesis of the core neurodevelopmental and metabolic features.[4][6][8][11][12][14][15] Kasher et al. reported overlapping 6q16.1 deletions of 1–1.2 Mb (chr6: 99,218,535–100,260,996 in hg19) in several families, identifying a ~350 kb critical interval including POU3F2 and FBXL4 and demonstrating that deletions encompassing POU3F2 but not SIM1 were sufficient to cause developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia.[6][12] The deletion in one family encompassed nine known protein‑coding genes—POU3F2, FBXL4, FAXC, COQ3, PNISR, USP45, TSTD3, CCNC, and PRDM13—yet comparative analyses narrowed the phenotype to POU3F2/FBXL4, with functional arguments favoring POU3F2 haploinsufficiency as the principal driver of neurodevelopmental and metabolic manifestations.[6]

Independent evidence implicating SIM1 comes from both structural variants and intragenic mutations. Bonnefond et al. (2013; PMID: 23778136) demonstrated that rare, heterozygous loss‑of‑function mutations in SIM1 (including missense variants such as p.T46R, p.H323Y, and p.T714A) significantly increased intra‑familial risk of severe obesity and, in some carriers, Prader–Willi‑like features, thereby establishing a “firm link between SIM1 loss of function and severe obesity associated with, or independent of, Prader‑Willi‑like features.”[4] They noted that “in humans, abnormalities in chromosome 6q16, a region that includes SIM1, were reported in obese children with a Prader‑Willi‑like syndrome; however, SIM1 involvement in obesity has never been conclusively demonstrated,” and their work filled this gap by integrating sequencing and functional assays.[4] Complementing this, Izumi et al. described a child with a proximal interstitial 6q16.1–q21 deletion including SIM1 who exhibited Prader–Willi–like obesity and evolving hypopituitarism, suggesting that SIM1 haploinsufficiency contributes not only to hyperphagia and obesity but also to pituitary hormone deficiencies.[15]

The Chromodisorder cohort of 12 patients with proximal 6q interstitial deletions further supports a multi‑gene etiologic model. Patients with deletions including SIM1 were more likely to exhibit obesity and Prader–Willi‑like features, while overlapping deletions implicating PHIP and ZNF292 were associated with neurodevelopmental delay and intellectual disability.[8] The authors proposed that haploinsufficiency of PHIP contributes to the neurodevelopmental delay observed in three patients, and that ZNF292 loss is related to intellectual developmental disorder, both augmenting the phenotype beyond pure hypothalamic obesity.[8] Additional candidate genes such as KCNQ5 (linked to intellectual developmental disorder) and NUS1 (associated with neurodevelopmental disorders) may further modify the severity and spectrum of manifestations.[8]

Collectively, these data indicate that 6q16 deletion syndrome arises from germline, typically heterozygous structural deletions (copy number losses) at 6q16 that either directly remove or disrupt regulatory elements for SIM1 and/or POU3F2 and potentially co‑delete other neurodevelopmental genes such as PHIP and ZNF292.[1][4][6][8][11][12][14][15][16] The mechanism is largely one of haploinsufficiency—a reduction in dosage of dosage‑sensitive transcription factors and signaling proteins critical for hypothalamic development and function—rather than gain‑of‑function or dominant‑negative effects.[6][12][14][15] The deletions are germline and constitutional, present in all tissues, and can be either de novo or inherited, with de novo occurrences common in simplex cases and inherited deletions observed in multiplex families with segregating obesity and developmental delay.[6][12][8] There is no evidence that somatic 6q16 deletions play a role in acquired pediatric obesity syndromes, and the condition is not known to be caused by environmental insults.

2.2 Risk Factors

Given the strong structural genetic basis of 6q16 deletion syndrome, the primary risk factor for developing the condition is the presence of a heterozygous pathogenic 6q16 deletion, particularly those encompassing SIM1 and/or POU3F2.[1][4][6][8][12][14][15][16] For individuals with an inherited deletion, risk is effectively determined by Mendelian segregation from a parent carrying the deletion; for de novo cases, risk pertains to parental germline mutational events, which are not easily quantifiable at the individual level. Beyond the structural deletion itself, intragenic variants within SIM1 and POU3F2 represent additional genetic risk factors for phenotypes overlapping with or embedded within the broader deletion syndrome. Bonnefond et al. identified rare SIM1 missense variants with strong loss‑of‑function effects that were associated with “high intra‑family risk for obesity” but not necessarily developmental delay, suggesting that SIM1 variation defines a broader monogenic obesity risk spectrum that may intersect with 6q16 deletion syndrome in some families.[4] Schönauer et al. (2023) reported monoallelic intragenic POU3F2 variants that recapitulate the neurodevelopmental delay and hyperphagic obesity seen in 6q16.1 deletions, thereby “confirming the gene’s candidacy in 6q16.1 deletions” and indicating that pathogenic POU3F2 variation constitutes a risk factor independent of large deletions.[14]

At the level of gene networks, co‑deletion or pathogenic variation in genes such as PHIP, ZNF292, KCNQ5, and NUS1 may act as modifier risk factors, intensifying neurodevelopmental impairment, behavioral abnormalities, and cognitive deficits.[8] For example, PHIP haploinsufficiency is suggested to cause Chung–Jansen syndrome, characterized by global developmental delay, impaired intellectual development, behavioral abnormalities, dysmorphic features, and obesity, and its inclusion in 6q16 deletions likely increases risk for a more severe or complex phenotype.[8] ZNF292 haploinsufficiency is related to intellectual developmental disorder and may enhance the severity of cognitive impairment when co‑deleted with SIM1 or POU3F2.[8] Thus, the risk architecture within 6q16 deletions is polygenic at the CNV level, with SIM1 and POU3F2 contributing core features and additional genes modulating expressivity.

Environmental risk factors for obesity and developmental phenotypes—such as high‑calorie diets, sedentary lifestyle, and social adversity—are likely to influence the severity of obesity and behavioral manifestations, but there is currently no specific evidence that they alter the penetrance of the core syndrome; they rather act as non‑specific modifiers of weight trajectory and adaptive functioning.[1][4][6][8][12][15] Sex, age, and family history can modulate presentation; for instance, some reports suggest a slight male predominance among published cases, although small sample sizes preclude firm conclusions.[6][8][11][12] Family history of obesity or neurodevelopmental disorders may reflect shared genetic CNV burden or polygenic background, but again data are sparse. There are no documented environmental toxins, occupational exposures, or infectious agents that specifically increase risk of germline 6q16 deletions.

2.3 Protective Factors

Specific genetic protective factors for 6q16 deletion syndrome are not currently defined, largely because the condition arises from relatively large, rare deletions that either occur or do not occur, rather than from common risk alleles subject to genetic balancing.[1][6][8][12][13][16] It is conceivable that favorable polygenic background for leanness or cognitive resilience could attenuate the severity of obesity and intellectual disability in carriers, but no systematic studies have explored this possibility. Similarly, allelic variation in genes downstream of SIM1 and POU3F2—such as those in oxytocin signaling pathways—could theoretically modulate phenotype, but evidence is lacking.[12][14]

Environmental and lifestyle factors that mitigate obesity and improve neurodevelopmental outcomes constitute practical protective factors for individuals with 6q16 deletions. Early, structured nutritional counseling, strict caloric control, and promotion of physical activity may reduce the degree of obesity and its cardiometabolic sequelae, echoing strategies used in Prader–Willi syndrome, though again formal studies in 6q16 deletion cohorts are not available.[1][4][15] Intensive early intervention services, including physical, speech, and occupational therapy, can partially ameliorate developmental delay and maximize functional outcomes, representing secondary and tertiary protective factors that act downstream of the genetic lesion.[6][8][11][12] Supportive psychosocial environments and consistent behavioral management may reduce the impact of hyperphagia‑driven behavioral issues and improve adaptive behaviors.

2.4 Gene–Environment Interactions

To date, there are no dedicated gene–environment interaction (GxE) studies for 6q16 deletion syndrome, and no entries in specialized GxE databases linking 6q16 CNVs with environmental exposures.[1][4][6][8][12][15][16] Nevertheless, extrapolating from broader obesity and neurodevelopmental research, one can posit that the structural deletion creates a strong genetic predisposition to hyperphagia and obesity by disrupting hypothalamic circuits responsible for energy homeostasis, while environmental factors such as diet and activity patterns modulate the expression of this predisposition. Bonnefond et al. explicitly noted that SIM1 loss‑of‑function variants confer increased intra‑family risk for obesity, implying that variation in shared family environment interacts with the genetic lesion to determine whether carriers develop severe obesity or milder phenotypes.[4] They observed that SIM1 variants with mild or no effects on transcriptional activity were not associated with obesity within families, while variants with strong functional impairment were associated with severe obesity, underscoring that functional dosage interacts with environmental context.

Similarly, Kasher et al. reported variable susceptibility to obesity among carriers of POU3F2‑encompassing deletions, indicating that while the deletion predisposes to obesity and hyperphagia, not all carriers develop extreme obesity, suggesting modifying effects of environment and possibly polygenic background.[6][12] Their zebrafish models showed that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area, providing a mechanistic basis for gene–environment interactions wherein oxytocin‑mediated regulation of satiety may be particularly sensitive to environmental feeding patterns.[12] In practical terms, individuals with 6q16 deletion syndrome likely have a lower threshold for developing severe obesity when exposed to obesogenic environments, meaning that environmental modification can have a disproportionately beneficial effect relative to individuals without the genetic lesion.

In summary, while explicit GxE studies are absent, the clinical and functional data support a model in which 6q16 deletions define a high‑penetrance genetic predisposition to hyperphagic obesity and neurodevelopmental impairment, with environmental factors predominantly modulating the quantitative severity of obesity and psychosocial outcomes rather than determining disease presence or absence.[1][4][6][8][12][15][16] Ontologically, this can be framed using GO terms such as “response to food” (GO:0032094), “feeding behavior” (GO:0007631), and “regulation of appetite” and linked to environmental exposures like high‑fat diet (CHEBI terms for lipids), although these remain theoretical constructs in this specific syndrome.

3. Phenotypes

3.1 Core Prader–Willi-like Features

The clinical phenotype of 6q16 deletion syndrome is dominated by features that closely resemble Prader–Willi syndrome, forming the core syndrome definition used in Orphanet, MedGen, and Malacards.[1][9][16][13] Obesity is a cardinal feature, typically severe and of early onset, with many individuals developing marked weight gain in early childhood associated with hyperphagia and food‑seeking behaviors.[1][4][6][8][12][15] Hyperphagia—defined as abnormally increased appetite and food intake—is explicitly described in Orphanet and in Kasher’s series as a consistent component of the syndrome, though its onset can vary and is often preceded by a neonatal period of feeding difficulties and poor weight gain.[1][6][12] From an HPO perspective, obesity corresponds to HP:0001513 and hyperphagia to HP:0002591, both of which have severe impact on quality of life due to increased risk of cardiometabolic disease, reduced mobility, and significant psychosocial challenges.

Hypotonia is typically present from the neonatal period, manifesting as generalized muscle weakness, poor suck, and delayed motor milestones.[1][3][8][9][11][15] Orphanet and MedGen list hypotonia as a core feature, and multiple case reports describe infants with proximal 6q deletions as “floppy,” requiring feeding support and delayed in rolling and sitting.[1][3][9][11][15] HPO term muscular hypotonia (HP:0001252) accurately captures this presentation. Hypotonia directly impairs quality of life by delaying motor development, increasing risk of feeding difficulties, and necessitating physical therapy.

Small hands and feet are reported as characteristic dysmorphic features, mirroring the “acromicria” noted in Prader–Willi syndrome.[1][9][16] Orphanet emphasizes small hands and feet as part of the syndrome definition, with HPO terms small hand (HP:0001174) and small foot (HP:0001773).[1] These features may not in themselves cause functional impairment but serve as physical clues to the diagnosis. Eye and vision anomalies, including strabismus or refractive errors, are noted in aggregated descriptions but have not been systematically characterized; they map to HPO terms such as visual impairment (HP:0000505) and strabismus (HP:0000486).[1][9]

The age of onset of these core phenotypes is primarily antenatal to neonatal for hypotonia and developmental delay, and early childhood for obesity and hyperphagia.[1][3][6][9][11][12][15] Symptom severity is generally moderate to severe, particularly for obesity and developmental delay, though some variability exists, especially in POU3F2‑only deletions.[6][12][14] Progression is chronic and lifelong, with obesity and neurodevelopmental impairments persisting and often worsening over time, whereas hypotonia may partially improve as muscle strength and motor skills develop.[1][6][8][11][12][15] The frequency of these core phenotypes among affected individuals appears high; developmental delay is present in essentially all reported cases, obesity in the majority of adolescents and adults, hyperphagia in most, hypotonia in nearly all neonates, and small hands/feet in a large subset, though precise percentages are not available due to small sample sizes.[1][3][6][8][9][11][12][15]

Quality of life is substantially impacted by these features. Severe obesity leads to increased risk of type 2 diabetes, cardiovascular disease, sleep apnea, and orthopedic complications, while hyperphagia and food preoccupation can cause significant family stress and social difficulties.[4][6][8][12][15] Developmental delay and intellectual disability impair educational attainment and independence. Hypotonia in infancy complicates feeding and caregiving. Thus, 6q16 deletion syndrome is a high‑burden condition despite its rarity.

3.2 Neurodevelopmental and Cognitive Phenotypes

Neurodevelopmental impairment is a central component of 6q16 deletion syndrome, reflecting both cortical and subcortical brain involvement, particularly in the hypothalamus.[3][6][8][11][12][14][15] Kasher et al. described “variable developmental delay, intellectual disability” in all ten individuals with 6q16.1 deletions, noting that the severity ranged from mild learning difficulties to more profound intellectual disability.[6][12] Traylor et al., in an earlier report of a child with a microdeletion at 6q16.1 encompassing EPHA7, highlighted “mental retardation, ear anomalies, hypotonia, and postnatal growth retardation” as recurrent features among reported 6q deletion patients, indicating that intellectual disability is a general hallmark of proximal 6q structural disorders.[3] The Chromodisorder cohort found that all 12 patients exhibited developmental delay, with extent significantly varying, reinforcing that global developmental delay (HP:0001263) and intellectual disability (HP:0001249) are universal but variable components of the syndrome.[8]

Speech and language delays are commonly noted, with late onset of first words and impaired expressive language. While specific HPO terms such as speech delay (HP:0000750) and language development delay (HP:0002463) are applicable, the literature seldom quantifies these domains separately from global cognitive measures.[6][8][11][12] Motor delays, including delayed walking and poor coordination, are frequent and map to HPO developmental motor milestone delay (HP:0001270).[3][6][8][11][12] Learning difficulties and behavioral problems in school settings have been described, consistent with moderate intellectual disability and possible attention or executive function deficits.[6][8][11][12][14]

Schonauer et al.’s study of monoallelic intragenic POU3F2 variants provides particularly clear evidence that disruptions in this gene cause neurodevelopmental delay and cognitive impairments analogous to those seen in 6q16.1 deletions, thus reinforcing that POU3F2 haploinsufficiency is mechanistically tied to neurodevelopmental phenotypes.[14] Their findings indicate that POU3F2 variants alone, without larger deletions, can result in global developmental delay and learning difficulties, supporting an HPO mapping to global developmental delay and intellectual disability.

The age of onset for neurodevelopmental phenotypes is typically infancy, as delays in achieving motor and language milestones become apparent within the first year or two of life.[3][6][8][11][12][14][15] Severity is variable, with some individuals achieving near‑normal cognitive functioning with supportive interventions, while others remain significantly impaired.[6][8][11][12] Progression is relatively stable once developmental trajectories are established; there is no evidence of neurodegenerative course but rather a static or slowly improving profile constrained by early brain developmental disturbances.[6][8][11][12][15] Quality of life impacts are substantial, affecting educational attainment, employment possibilities, social relationships, and independence in adulthood.

3.3 Growth, Craniofacial, and Musculoskeletal Features

Growth abnormalities, craniofacial features, and musculoskeletal manifestations provide additional phenotypic clues to 6q16 deletion syndrome. Postnatal growth retardation has been reported in several patients with proximal 6q deletions, including the child with an EPHA7‑encompassing deletion described by Traylor et al., who exhibited postnatal growth retardation in addition to hypotonia and intellectual disability.[3] Conversely, obesity in later childhood often shifts height‑adjusted weight status dramatically upward, complicating interpretation of height growth patterns.[1][4][6][8][11][12][15] Izumi et al. described short stature in their SIM1‑deleted propositus, plausibly linked to hypopituitarism and growth hormone deficiency, indicating that growth hormone axis dysfunction can contribute to reduced height despite obesity.[15] HPO terms short stature (HP:0004322) and postnatal growth retardation (HP:0008897) are therefore relevant.

Craniofacial dysmorphisms are variably described, including broad nasal bridge, downslanting palpebral fissures, ear anomalies, and sometimes microcephaly.[3][6][8][11][12] The OMIM entry for 6q24–q25 deletion (#612863), although more distal, mentions microcephaly, developmental delay, dysmorphic features, and hearing loss, underscoring that structural 6q deletions often carry craniofacial dysmorphisms.[2] In the Kasher cohort, detailed dysmorphologic descriptions indicate subtle facial differences but are not pathognomonic.[6][12] HPO terms such as facial dysmorphism (HP:0001999), ear malformation (HP:0000369), and microcephaly (HP:0000252) apply where present.

Musculoskeletal features include hypotonia‑related joint laxity and delayed motor skill acquisition, as noted previously.[1][3][8][11][15] Small hands and feet (HP:0001174 and HP:0001773) reflect skeletal growth differences, possibly related to endocrine abnormalities and altered growth factor signaling.[1][9][16][15] There is limited data on scoliosis, joint contractures, or other orthopedic complications, though obesity‑related mechanical strain may contribute to musculoskeletal discomfort. Musculoskeletal phenotypes are typically congenital or early‑onset and remain relatively stable, with hypotonia improving somewhat as muscle strength develops.

Quality of life impacts from growth and musculoskeletal features include difficulties with fine motor tasks, physical endurance limitations, and psychosocial effects of short stature and dysmorphic facial features, which can contribute to social stigma or bullying in school settings.[3][6][8][11][12][15] However, these impacts are often overshadowed by the more severe challenges posed by obesity and intellectual disability.

3.4 Endocrine and Metabolic Phenotypes

Endocrine phenotypes in 6q16 deletion syndrome are increasingly recognized but remain less well characterized than in classic Prader–Willi syndrome. Izumi et al.’s detailed report of a child with a proximal interstitial 6q16.1–q21 deletion involving SIM1 provides the most comprehensive endocrine profile.[15] They note that “proximal interstitial 6q deletion involving Single‑minded 1 (SIM1) gene causes a syndromic form of obesity mimicking Prader‑Willi syndrome,” and that “in addition to obesity, Prader‑Willi syndrome includes several other endocrinopathies, such as hypothyroidism, growth hormone deficiency, and hypogonadotropic hypogonadism.”[15] Their longitudinal endocrine evaluation revealed that while initial assessments during infancy were unremarkable, the propositus later developed hypopituitarism, including deficiencies in growth hormone and thyroid hormone, as well as hypogonadotropic hypogonadism, indicating that pituitary hormone deficits may emerge over time.[15] They conclude that “our patient raises the possibility that hypopituitarism may be part of the phenotype… caused by interstitial 6q deletion” and emphasize the importance of longitudinal endocrine follow‑up.[15]

These findings suggest that 6q16 deletions involving SIM1 can produce a broader endocrine syndrome akin to Prader–Willi, encompassing hypothyroidism (HP:0000821), growth hormone deficiency (HP:0000824), and hypogonadotropic hypogonadism (HP:0000008), in addition to obesity and hyperphagia.[15] SIM1 plays “an important role in the development of neuroendocrine lineage cells,” as Izumi et al. point out, implicating SIM1 haploinsufficiency directly in the pathophysiology of pituitary hormone deficits.[15] Kasher et al. mention endocrine features more briefly but acknowledge that the POU3F2–SIM1 pathway is important for hypothalamic development and function, which inherently includes neuroendocrine regulation.[6][12] Zebrafish models show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area, indicating that oxytocin‑mediated regulation of feeding and social behaviors may be disrupted in the syndrome.[12]

Metabolic phenotypes include dyslipidemia, insulin resistance, and type 2 diabetes mellitus, which are common sequelae of severe obesity but have not been systematically catalogued in small 6q16 cohorts.[4][6][8][12][15] Nevertheless, given the severity of obesity and hyperphagia described, it is plausible that many affected individuals develop metabolic syndrome, with HPO terms such as hyperlipidemia (HP:0003077) and insulin resistance (HP:0000855) applicable. Endocrine and metabolic abnormalities typically emerge in late childhood or adolescence as obesity worsens and pituitary deficits become clinically apparent.[15] Their severity is variable and may be mitigated by timely hormone replacement therapy and lifestyle interventions.[15] Quality of life impacts include fatigue, reduced physical capacity, sexual maturation delays, and increased morbidity from cardiovascular and endocrine complications.

3.5 Behavioral and Psychiatric Phenotypes

Behavioral abnormalities and psychiatric features have been noted in individuals with 6q16 deletions and related CNVs, though detailed psychiatric assessments are rare. Hyperphagia is behaviorally expressed as food‑seeking, hoarding, and difficulty adhering to dietary restrictions, paralleling behavioral challenges in Prader–Willi syndrome.[1][4][6][8][12][15] In the Chromodisorder cohort, PHIP‑related Chung–Jansen syndrome was described as involving “behavioral abnormalities, dysmorphic features, and obesity” in addition to developmental delay, and PHIP haploinsufficiency was suggested to contribute to behavioral phenotypes in patients whose 6q deletions encompassed this gene.[8] Behavioral abnormalities in this context may include attention deficits, impulsivity, and social difficulties; corresponding HPO terms could include abnormal behavior (HP:0000708), attention deficit hyperactivity disorder (HP:0007018), and autistic behavior (HP:0000729), though explicit autism diagnoses are rarely reported.

Some individuals with proximal 6q deletions exhibit irritability, tantrums, or mood lability, possibly linked to hypothalamic and limbic dysregulation, but systematic psychiatric characterization is lacking.[6][8][11][12][15] Sleep disturbances, including insomnia or fragmented sleep, are plausible given hypothalamic involvement and obesity‑related sleep apnea, but again data are limited. Overall, behavioral and psychiatric phenotypes are secondary yet important components of quality of life, affecting family dynamics, educational support needs, and long‑term psychosocial adaptation.

3.6 Laboratory and Imaging Findings

Laboratory findings in 6q16 deletion syndrome primarily reflect endocrine and metabolic abnormalities. Izumi et al. reported pituitary hormone testing that eventually revealed growth hormone deficiency, hypothyroidism, and hypogonadotropic hypogonadism, underscoring the value of comprehensive pituitary hormone panels in suspected cases.[15] HPO terms for abnormal hormone levels, such as decreased serum IGF‑1 (HP:0008267), low thyroxine (HP:0003200), and low gonadotropins (HP:0002920), may apply. Standard metabolic labs may reveal hyperlipidemia, elevated fasting glucose, or impaired glucose tolerance, but these have not been systematically detailed in the small case literature.[4][6][8][12][15]

Neuroimaging findings are underreported; few studies include brain MRI or CT descriptions. Given the hypothalamic–pituitary axis involvement inferred from endocrine abnormalities and gene function, subtle hypothalamic or pituitary structural changes may be present, but documentation is sparse.[12][15] In model organisms, mutant zebrafish have shown altered hypothalamic neuroendocrine preoptic area development with reduced oxytocin expression, supporting the notion that structural and functional hypothalamic abnormalities exist in human carriers.[12] Formal HPO terms such as abnormal brain MRI (HP:0000488) and pituitary hypoplasia (HP:0003189) could be considered where imaging data support them.

Standard chromosomal microarray and karyotyping are laboratory cornerstones for diagnosis and are discussed under diagnostics.[6][8][11][12][15] No specific circulating biomarkers unique to 6q16 deletion syndrome have been identified beyond endocrine hormones; there are currently no FDA‑approved diagnostic biomarkers distinct from genetic testing.

4. Genetic and Molecular Information

4.1 Chromosomal Architecture of 6q16 Deletions

The chromosomal architecture of 6q16 deletions in this syndrome is characterized by heterozygous, interstitial copy number losses spanning proximal 6q, with breakpoints that vary among individuals but share overlapping segments in 6q16.1–q16.2.[1][6][8][9][11][12][13][16] Kasher et al. defined a 1–1.2 Mb deletion on chromosome 6q16.1–q16.2 (chr6: 99,218,535–100,260,996 in hg19) in one family (DECIPHER: 265018) and noted overlap among deletions in ten individuals, enabling delineation of a ~350 kb critical region containing POU3F2 and FBXL4.[6][12] This region lies in cytogenetic band 6q16.1, and deletions may be simple deletions with no additional structural rearrangements, or part of larger deletions extending into adjacent bands (e.g., 6q13–q22).[6][8][11][12]

Donahue et al. reported a patient with a 17.31 Mb interstitial deletion of 6q16.3–6q22.31, who exhibited a “unique constellation of 6q‑ features,” including neurodevelopmental delay and obesity, emphasizing that larger deletions spanning multiple bands can produce broader phenotypes while still retaining the core 6q16‑related features.[11] Chromodisorder’s cohort of 12 patients included deletions at various proximal 6q locations, including 6q13, 6q16, and 6q22, with overlapping regions implicating key genes such as SIM1, ZNF292, PHIP, KCNQ5, and NUS1.[8] Their analysis identified SIM1‑containing deletions in patients with obesity and Prader–Willi‑like features, PHIP‑containing deletions in those with Chung–Jansen syndrome‑like phenotypes, and ZNF292‑containing deletions in those with intellectual developmental disorder.[8]

From a genomic structural perspective, these deletions likely result from non‑allelic homologous recombination or other mechanisms of structural variation, but specific breakpoint mechanisms are seldom characterized at nucleotide resolution.[6][8][11][12] The deletions are detectable by chromosomal microarray and may be visible on high‑resolution karyotyping when large. They are autosomal and not associated with sex chromosomes. dbVar and DECIPHER entries provide coordinate‑level information and structural classification (e.g., “loss” CNVs), supporting annotation in genomic databases.

4.2 Causal and Candidate Genes: SIM1, POU3F2, and Others

The etiological core of 6q16 deletion syndrome resides in genes crucial for hypothalamic development and neuroendocrine regulation, notably SIM1 and POU3F2.[4][6][8][12][14][15] SIM1 (Single‑minded homolog 1) encodes a transcription factor expressed in the developing hypothalamus and is essential for differentiation of paraventricular nucleus neurons that regulate appetite and energy homeostasis.[4][15] Mouse models with Sim1 haploinsufficiency exhibit “hyperphagic obesity and developmental abnormalities of the brain,” providing strong mechanistic support for SIM1’s role in obesity and neurodevelopment.[4] Bonnefond et al. showed that “Sim1 haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain,” and that in humans, SIM1 loss‑of‑function mutations cause severe obesity with or without Prader–Willi‑like features.[4] Izumi et al. extended these findings to structural deletions, demonstrating that proximal interstitial 6q deletions involving SIM1 produce syndromic obesity mimicking Prader–Willi syndrome and associated hypopituitarism.[15]

POU3F2 (also known as BRN2, N‑OCT3, or OCT7) encodes a proneuronal transcription factor in the POU family, with important roles in hypothalamic development, cortical neuron differentiation, and neuroendocrine function.[6][12][14] Kasher et al. identified POU3F2 as the prime candidate gene within the 6q16.1 critical region, noting that “analysis of the deletions revealed a ~350 kb critical region on chromosome 6q16.1 that encompasses a gene for proneuronal transcription factor POU3F2, which is important for hypothalamic development and function,” and demonstrating in zebrafish that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area.[12] They concluded that “the likely mechanism is haploinsufficiency of POU3F2,” implicating reduced dosage of this transcription factor in developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia.[6][12] Schönauer et al. (2023) provided independent confirmation by showing that monoallelic intragenic POU3F2 variants cause neurodevelopmental delay and hyperphagic obesity, thus “confirming the gene’s candidacy in 6q16.1 deletions.”[14]

Other genes within proximal 6q that contribute to or modify the phenotype include PHIP (pleckstrin homology domain interacting protein), associated with Chung–Jansen syndrome and characterized by global developmental delay, intellectual disability, behavioral abnormalities, dysmorphic features, and obesity.[8] Chromodisorder’s authors suggested that PHIP haploinsufficiency contributes to the neurodevelopmental delay observed in three patients whose deletions included this gene.[8] ZNF292 is linked to intellectual developmental disorder and may enhance cognitive impairment when co‑deleted.[8] KCNQ5, a potassium voltage‑gated channel, has loss‑of‑function variants associated with intellectual developmental disorder and may contribute to developmental delay when deleted.[8] NUS1 has been related to a pathogenic mechanism for intellectual developmental disorder, and its deletion may worsen neurodevelopmental phenotypes.[8] Additional genes such as FBXL4 (linked elsewhere to mitochondrial disease), COQ3 (involved in coenzyme Q biosynthesis), PNISR, USP45, TSTD3, CCNC, and PRDM13 are present in some deletions but their specific contributions to the 6q16 deletion phenotype are less well defined.[6][12]

From a gene ontology perspective, SIM1 and POU3F2 are annotated with biological processes such as “hypothalamus development” (GO:0021854), “regulation of transcription, DNA‑templated” (GO:0006355), and “neurogenesis” (GO:0022008).[4][6][12][14][15] They are expressed in hypothalamic neurons (CL terms for hypothalamic neuroendocrine cells, e.g., CL:0000393) and linked to anatomical structures like the hypothalamus (UBERON:0001898) and pituitary gland (UBERON:0000007).[12][15] PHIP, ZNF292, and NUS1 are associated with generic neurodevelopmental processes and synaptic function. These ontological links support mechanistic descriptions in knowledge bases.

4.3 Pathogenic Variant Spectrum

The pathogenic variant spectrum underlying 6q16 deletion syndrome encompasses both large structural deletions and smaller intragenic variants in SIM1 and POU3F2.[1][4][6][8][11][12][14][15][16] Structural interstitial deletions at 6q16 are typically categorized as pathogenic or likely pathogenic CNVs under ACMG/AMP guidelines, given their size, gene content, de novo status in many cases, segregation with disease in multiplex families, and overlap with known critical regions.[6][8][11][12] Kasher et al. classified the 6q16.1 deletions as causative for the observed phenotypes based on co‑segregation, absence in parental DNA (in de novo cases), and co‑localization with POU3F2 and other neurodevelopmental genes.[6][12] Chromodisorder’s deletions were also interpreted as pathogenic, with involvement of genes previously linked to intellectual developmental disorder and obesity.[8]

Intragenic SIM1 variants include missense mutations with strong loss‑of‑function effects, such as p.T46R, p.H323Y, and p.T714A, identified by Bonnefond et al.[4] Functional assays showed that these variants significantly reduced SIM1 transcriptional activity, correlating with severe obesity phenotypes and high intra‑family risk for obesity.[4] These variants would be classified as pathogenic or likely pathogenic according to ACMG/AMP, based on functional evidence of loss‑of‑function and segregation with disease.[4] Other SIM1 variants with mild or no functional effects were not associated with obesity and would therefore be classified as variants of uncertain significance (VUS).[4] Intragenic POU3F2 variants described by Schönauer et al., including de novo missense changes, similarly showed disruption of normal gene function and were linked to neurodevelopmental delay and hyperphagic obesity, supporting their classification as pathogenic or likely pathogenic.[14]

Allele frequency data from population databases such as gnomAD are not given explicitly in the cited studies, but the rarity of these variants in general populations and their absence in healthy controls strengthen their pathogenic classification.[4][12][14] The structural deletions are also rare and are absent from large CNV datasets of healthy individuals.[6][8][12] All reported pathogenic variants are germline rather than somatic, present constitutionally in all tissues. Somatic variants in SIM1 or POU3F2 have not been implicated in cancer or other acquired diseases in the context of this syndrome.

4.4 Modifier Genes and Genetic Complexity

Modifier genes within or outside the 6q16 region can influence the severity and spectrum of 6q16 deletion syndrome phenotypes.[6][8][12][14][15] Within the deletion, PHIP and ZNF292 are prime candidates for modifying neurodevelopmental and behavioral outcomes.[8] PHIP haploinsufficiency is thought to contribute to the Chung–Jansen syndrome phenotype, which includes global developmental delay and behavioral abnormalities, and its co‑deletion with SIM1 or POU3F2 may result in more pronounced cognitive and behavioral impairments.[8] ZNF292’s association with intellectual developmental disorder suggests that its co‑deletion amplifies the severity of intellectual disability.[8] KCNQ5 and NUS1 deletion may further modify neurodevelopmental phenotypes through effects on neuronal excitability and synaptic function.[8]

Outside the 6q16 region, polygenic background for obesity and neurodevelopmental traits likely modulates expressivity but is not currently characterized in this syndrome. The presence of intragenic SIM1 or POU3F2 variants alongside structural deletions could theoretically compound phenotypic severity, but such double hits have not been reported.[4][12][14] Genetic anticipation, repeat expansion phenomena, and mitochondrial inheritance do not appear to play roles.

4.5 Structural and Epigenetic Aspects

Epigenetic mechanisms in 6q16 deletion syndrome are less well defined than in classic imprinted disorders like Prader–Willi syndrome, which involves epigenetic silencing of paternal 15q11–q13 alleles.[10][15] 6q16 deletions occur in non‑imprinted regions of chromosome 6 and primarily exert their effect through haploinsufficiency rather than parent‑of‑origin specific expression changes.[1][4][6][8][12][15][16] There is no evidence that 6q16 deletions are subject to parent‑of‑origin effects, although parental inheritance patterns are not extensively documented; where known, deletions can be de novo or inherited from either parent.[6][8][12]

However, the downstream transcriptional effects of SIM1 and POU3F2 haploinsufficiency likely manifest through altered epigenetic landscapes in hypothalamic and cortical neurons, including changes in DNA methylation and histone modifications at target gene promoters, as is typical for transcription factor dysfunction.[12][14][15] Kasher et al.’s demonstration that POU3F2 controls oxytocin expression in the hypothalamic neuroendocrine preoptic area implies altered chromatin states at the oxytocin gene in mutant zebrafish models.[12] While not yet studied in human carriers, analogous epigenetic changes could be hypothesized. No genome‑wide methylation or chromatin profiling studies specific to 6q16 deletion syndrome have been reported, and ENCODE or Roadmap Epigenomics do not have disease‑specific tracks.

At the structural genomic level, some deletions may disrupt topologically associating domains (TADs) and cis‑regulatory architectures, potentially affecting enhancer–promoter interactions for SIM1, POU3F2, and neighboring genes.[6][8][12] The functional impact of TAD disruption has not been systematically examined in this syndrome but represents a plausible mechanism for variable expressivity among deletions of similar size.

5. Environmental Information

5.1 Non-genetic Contributors to Phenotypic Expression

Non‑genetic factors—broadly including diet, physical activity, social environment, and access to medical care—play significant roles in shaping the phenotypic expression of 6q16 deletion syndrome, particularly regarding obesity severity, behavioral manifestations, and adaptive functioning.[1][4][6][8][12][15] The genetic lesion sets a predisposition for hyperphagia and hypothalamic dysregulation, but actual caloric intake and energy expenditure are modifiable by environment. Families who implement strict dietary controls, consistent mealtime routines, and environments with limited access to high‑calorie foods may be able to attenuate the degree of obesity despite persistent hyperphagic drive.[4][6][15] Conversely, highly obesogenic environments exacerbate the weight trajectory and metabolic complications.

Social and educational environments also influence neurodevelopmental outcomes. Early enrollment in developmental intervention programs, inclusive educational settings, and supportive family dynamics can improve language skills, social behavior, and adaptive functioning, mitigating the functional impact of intellectual disability.[6][8][11][12] Behavioral therapy for hyperphagia and associated compulsive behaviors can reduce family stress and improve quality of life. Thus, while environment does not cause or cure the genetic syndrome, it substantially shapes its lived experience.

5.2 Lifestyle and Obesogenic Environment

Lifestyle factors intersect strongly with the obesity phenotype. SIM1 and POU3F2 haploinsufficiency confer a strong drive toward increased food intake and reduced satiety, but the magnitude of weight gain depends on caloric availability and physical activity.[4][6][12][14][15] For example, in the Bonnefond study, SIM1 variant carriers within families showed different obesity severities, suggesting differential lifestyle factors despite shared genetic risk.[4] Approximately, this maps to GO terms for feeding behavior (GO:0007631) and regulation of appetite and satiety, with environment modulating the expression of these processes.

Physical activity levels are particularly important; structured exercise programs can increase energy expenditure and improve cardiometabolic health, though achieving adherence may be challenging given hypotonia and behavioral issues.[1][3][6][8][11][12][15] Sleep hygiene also affects obesity risk, and hypothalamic involvement may predispose to sleep disturbances, further complicating metabolic regulation. No specific data link smoking, alcohol consumption, or occupational exposures to syndrome severity in this rare pediatric‑onset disorder.

5.3 Infectious and Toxic Exposures

There is no evidence that infectious agents or toxic exposures directly cause 6q16 deletions or initiate the syndrome.[1][6][8][12][13][16] Germline structural deletions arise from meiotic recombination errors and are not induced by postnatal exposures. Infections and toxins can, however, aggravate secondary complications, such as respiratory infections exacerbated by obesity‑related sleep apnea or endocrine disturbances. Toxic exposures known to affect neurodevelopment broadly (e.g., lead, alcohol) could theoretically worsen cognitive outcomes in affected children, but no syndrome‑specific data exist.

6. Mechanisms and Pathophysiology

6.1 Hypothalamic Development and Neuroendocrine Circuitry

The central mechanistic theme in 6q16 deletion syndrome is disruption of hypothalamic development and neuroendocrine circuitry due to haploinsufficiency of SIM1 and POU3F2, both transcription factors critical for hypothalamic neuron differentiation.[4][6][12][14][15] SIM1 is expressed in progenitor cells destined for the paraventricular nucleus (PVN) of the hypothalamus, a key region integrating signals for energy homeostasis, stress response, and endocrine regulation.[4][15] Mouse models with Sim1 haploinsufficiency display reduced numbers of PVN neurons, altered neuroanatomy of the hypothalamus, and profound hyperphagic obesity, establishing a causal chain from Sim1 loss to hypothalamic structural abnormalities and then to dysregulated feeding behavior and obesity.[4] Bonnefond et al. cite that “Sim1 haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain,” underscoring the role of SIM1 in hypothalamic development.[4]

In humans, structural deletions involving SIM1 reduce its dosage, leading to impaired development of neuroendocrine lineage cells in the hypothalamus and subsequent deficits in downstream endocrine axes.[15] Izumi et al. highlight that “SIM1 plays an important role in the development of neuroendocrine lineage cells, implicating SIM1 haploinsufficiency in the pathophysiology of hypopituitarism seen in our propositus.”[15] This suggests a mechanistic sequence where SIM1 haploinsufficiency alters hypothalamic neuron differentiation, which in turn disrupts trophic inputs to the pituitary gland, leading to hypopituitarism and deficiencies in growth hormone, thyroid hormone, and gonadotropins.[15] The hypothalamus (UBERON:0001898) and pituitary gland (UBERON:0000007) are thus primary anatomical sites of dysfunction, with relevant GO processes including “hypothalamus development” (GO:0021854), “neuroendocrine cell differentiation” (GO:0030218), and “endocrine system development” (GO:0035270).

POU3F2, as demonstrated by Kasher et al., lies downstream of SIM1 in a conserved molecular pathway controlling oxytocin expression in hypothalamic neuroendocrine neurons.[12] In zebrafish, morpholino and mutant models revealed that POU3F2 deficit reduces oxytocin expression in the hypothalamic neuroendocrine preoptic area, pointing to a SIM1–POU3F2–oxytocin axis essential for proper neuroendocrine regulation of feeding and social behavior.[12] Kasher et al. note that “using morpholino and mutant zebrafish models, we show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area,” and that this molecular pathway is conserved across species, including humans.[12] GO terms such as “oxytocin signaling pathway” and “hormone secretion” (GO:0046879) are relevant here.

In 6q16 deletion syndrome, haploinsufficiency of SIM1 and/or POU3F2 disrupts this pathway, leading to altered oxytocin production and secretion. Oxytocin influences satiety, social bonding, and stress responses; thus, its dysregulation contributes to hyperphagia, obesity, and possibly social and behavioral abnormalities.[12][14] The causal chain can be conceptualized as: structural 6q16 deletion → SIM1/POU3F2 haploinsufficiency → impaired hypothalamic neuron differentiation and oxytocin expression → disordered neuroendocrine signaling (including pituitary trophic control and satiety pathways) → clinical manifestation as hyperphagic obesity, endocrine deficits, and behavioral changes.[4][6][12][14][15]

6.2 Control of Feeding Behavior and Energy Homeostasis

Feeding behavior and energy homeostasis are tightly regulated by hypothalamic circuits, which integrate peripheral signals (leptin, ghrelin, insulin) and central signals (neuropeptides) to control appetite and metabolic rate.[4][6][12][14][15] SIM1 and POU3F2 are integral components of transcriptional networks that establish these circuits. Sim1 haploinsufficient mice exhibit hyperphagia, preferring high‑fat diets, and fail to adjust food intake appropriately to caloric density, leading to obesity.[4] Bonnefond et al. noted parallels in humans with SIM1 loss‑of‑function variants—severe obesity often associated with, or independent of, Prader–Willi‑like features.[4] In 6q16 deletion syndrome, similar mechanisms likely operate, with SIM1 haploinsufficiency impairing PVN neuron function, reducing expression of anorexigenic neuropeptides (e.g., corticotropin‑releasing hormone, thyrotropin‑releasing hormone), and altering responses to leptin, thereby increasing appetite and decreasing satiety.[4][15]

POU3F2’s control of oxytocin expression further modulates feeding behavior.[12][14] Oxytocin has been implicated in satiety and reduction of food intake; thus, decreased oxytocin levels due to POU3F2 haploinsufficiency may enhance hyperphagia and food‑seeking behavior.[12][14] Kasher et al. link POU3F2 haploinsufficiency to susceptibility to obesity and hyperphagia, emphasizing that their work “helps to further delineate the neuro‑endocrine control of energy balance/body mass and demonstrates that this molecular pathway is conserved across multiple species.”[12] Schonauer et al.’s findings that intragenic POU3F2 variants cause hyperphagic obesity corroborate this mechanistic model.[14]

The upstream trigger is reduced transcriptional activity of SIM1 and POU3F2 due to haploinsufficiency; downstream processes include altered neuropeptide expression, impaired integration of peripheral metabolic signals, and behavioral changes in feeding patterns.[4][6][12][14][15] GO processes such as “feeding behavior” (GO:0007631), “regulation of appetite” and “energy homeostasis” (GO:0001932) are thus central to the pathophysiology. Cell types involved include hypothalamic neuropeptidergic neurons (CL:0000393 and related CL terms), oxytocin‑producing neurons, and pituitary endocrine cells.

6.3 Neurodevelopmental Mechanisms Underlying Cognitive Deficits

Intellectual disability and developmental delay in 6q16 deletion syndrome arise from combined effects on cortical and subcortical neurodevelopment, mediated by transcription factors like POU3F2 and possibly other co‑deleted genes.[3][6][8][11][12][14] POU3F2 is expressed in cortical neurons and has been implicated in neuronal differentiation and migration. Haploinsufficiency likely impairs the generation and maturation of specific cortical neuron subtypes, leading to deficits in cognitive processing, language, and executive function.[6][12][14] Schonauer et al.’s demonstration that POU3F2 variants cause neurodevelopmental delay reinforces this idea.[14]

PHIP, ZNF292, and NUS1, when co‑deleted, contribute additional neurodevelopmental pathology. PHIP haploinsufficiency causes Chung–Jansen syndrome with global developmental delay and behavioral abnormalities, likely via disrupted synaptic signaling and neuronal proliferation.[8] ZNF292 and NUS1 are linked to intellectual developmental disorder and may influence chromatin remodeling and neuronal function.[8] KCNQ5 loss affects neuronal excitability, possibly contributing to developmental delay.

The causal chain for cognitive deficits can be summarized as: 6q16 structural deletion → haploinsufficiency of POU3F2 and co‑deleted neurodevelopmental genes → disrupted neuronal differentiation, cortical layering, and synaptic function → global developmental delay and intellectual disability.[3][6][8][11][12][14] GO terms such as “neurogenesis” (GO:0022008), “neuron differentiation” (GO:0030182), and “synapse organization” (GO:0050808) apply. Relevant CL terms include cortical excitatory neurons (CL:0008026) and inhibitory interneurons.

6.4 Endocrine Axis Dysfunction and Pituitary Abnormalities

Endocrine axis dysfunction in 6q16 deletion syndrome reflects impaired hypothalamic control of pituitary hormone secretion due to SIM1 haploinsufficiency and associated hypothalamic neuroendocrine defects.[15] Izumi et al. detail that their propositus developed hypopituitarism during childhood and adolescence, including deficiencies in growth hormone, thyroid hormone, and gonadotropins, despite initial endocrine evaluations in infancy being unremarkable.[15] They suggest that “early identification of endocrine abnormalities can improve clinical outcome by allowing timely introduction of hormone replacement therapy,” and recommend “detailed endocrine evaluation and longitudinal endocrine follow up… in individuals with proximal interstitial 6q deletion involving SIM1.”[15]

Mechanistically, SIM1 haploinsufficiency compromises the differentiation and function of neuroendocrine cells that produce releasing hormones such as GHRH, TRH, and GnRH, leading to reduced stimulation of somatotroph, thyrotroph, and gonadotroph cells in the pituitary.[4][15] This results in decreased secretion of GH, TSH, and LH/FSH, respectively, causing short stature, hypothyroidism, and hypogonadotropic hypogonadism.[15] The causal chain is thus: reduced SIM1 dosage → impaired neuroendocrine cell development → decreased releasing hormone production → pituitary hypofunction → endocrine phenotypes. GO processes such as “hormone secretion” (GO:0046879), “pituitary gland development” (GO:0021983), and “endocrine system development” (GO:0035270) are relevant. CL terms include hypothalamic neuroendocrine cells and pituitary hormone‑producing cells.

6.5 Systems-level Integration and Downstream Pathology

Systems‑level integration reveals that 6q16 deletion syndrome is a multi‑system disorder in which central nervous system developmental abnormalities, hypothalamic and pituitary dysfunction, and peripheral metabolic changes converge to produce the observed clinical phenotype.[1][3][4][6][8][11][12][14][15][16] Upstream mechanisms involve germline structural deletions and transcription factor haploinsufficiency. Midstream mechanisms include hypothalamic neuroendocrine dysregulation, oxytocin signaling changes, and cortical neurodevelopmental deficits. Downstream pathology manifests as hyperphagic obesity, endocrine deficits, intellectual disability, and behavioral abnormalities.

Peripheral tissues affected include adipose tissue (UBERON:0001013), liver, skeletal muscle, and cardiovascular system, which respond to altered hormonal milieu and obesity by developing insulin resistance, dyslipidemia, and increased cardiovascular risk.[4][15] The immune system does not appear to play a primary pathogenic role, although chronic inflammation related to obesity may contribute to cardiometabolic complications. Tissue damage mechanisms such as oxidative stress, ectopic fat deposition, and vascular changes operate downstream but are not unique to this syndrome; they mirror general obesity‑related pathology.

Epigenetic and transcriptional profiling data specific to this syndrome are lacking, but the conserved SIM1–POU3F2–oxytocin pathway suggests that transcriptomic changes in hypothalamus and pituitary would show downregulation of oxytocin, releasing hormones, and other neuropeptides.[12][14][15] Multi‑omics integration has not yet been performed, though in principle such studies could link structural deletions to altered gene expression and hormone levels.

7. Anatomical Structures Affected

7.1 Central Nervous System and Hypothalamus

The central nervous system, particularly the hypothalamus and associated neuroendocrine structures, is the primary anatomical site of dysfunction in 6q16 deletion syndrome.[4][6][12][14][15] The hypothalamus (UBERON:0001898) integrates signals for appetite, endocrine regulation, and autonomic function, and SIM1 and POU3F2 expression in this region is critical for normal development and function.[4][6][12][14][15] Disruption of these genes leads to structural and functional abnormalities in hypothalamic nuclei, especially the paraventricular nucleus, arcuate nucleus, and preoptic area.[4][12][15] Cortical regions involved in cognitive processing and behavior are also affected due to POU3F2‑mediated developmental processes.[6][12][14]

Brain imaging data are sparse, but functional impairment is evident from clinical phenotypes of intellectual disability, behavioral changes, and endocrine dysfunction.[3][6][8][11][12][14][15] The pituitary gland (UBERON:0000007) is a secondary central structure affected through hypothalamic dysregulation, leading to hypopituitarism.[15]

7.2 Endocrine Organs and Metabolic Tissues

Endocrine organs downstream of hypothalamic–pituitary axes, including the thyroid gland (UBERON:0002046), gonads (testis UBERON:0000473; ovary UBERON:0000992), and adrenal glands (UBERON:0002369), may be functionally affected by pituitary hormone deficiencies, though primary structural abnormalities are not reported.[15] Peripheral metabolic tissues such as adipose tissue, liver, and skeletal muscle respond to chronic hormonal and nutritional signals with changes in lipid storage, insulin sensitivity, and metabolic flexibility.[4][15] While not directly structurally altered by the deletion, they are secondary sites of disease manifestations.

7.3 Musculoskeletal and Craniofacial Structures

Musculoskeletal structures involved include skeletal muscles affected by hypotonia, small bones of the hands and feet (phalanges), and craniofacial bones contributing to dysmorphic features.[1][3][6][8][11][15] Small hands and feet reflect altered growth patterns in distal extremity bones, possibly influenced by endocrine factors. Craniofacial anomalies point to disturbed facial development, which may be influenced by global neurodevelopmental and craniofacial gene networks.

7.4 Cellular and Subcellular Localization

At the tissue and cell level, the syndrome primarily affects neuronal cell populations in the hypothalamus and cortex, including neuroendocrine neurons producing oxytocin, vasopressin, and releasing hormones, and cortical projection neurons.[4][6][12][14][15] Relevant Cell Ontology terms include hypothalamic neuroendocrine neurons (CL:0000393) and cortical neurons. Pituitary hormone‑producing cells (somatotrophs, thyrotrophs, gonadotrophs) are secondary targets due to upstream hypothalamic dysfunction.[15]

Subcellularly, SIM1 and POU3F2 proteins localize to the nucleus (GO:0005634) where they regulate transcription, binding to DNA and modulating expression of target genes.[4][6][12][14][15] Altered transcription factor activity affects chromatin states and nuclear transcriptional machinery. Oxytocin is produced in neurosecretory vesicles and released at synaptic terminals and into the bloodstream; its reduction alters synaptic and hormonal signaling.

8. Temporal Development

8.1 Age of Onset and Natural History

The age of onset for 6q16 deletion syndrome is predominantly congenital, with antenatal to neonatal manifestations of hypotonia and developmental delay.[1][3][6][9][11][12][15][16] Orphanet explicitly lists age of onset as antenatal, infancy, and neonatal, reflecting that developmental abnormalities are typically evident early in life.[1] Hypotonia and feeding difficulties are often apparent shortly after birth, with poor suck, low muscle tone, and delayed motor milestones.[1][3][11][15] Global developmental delay becomes increasingly obvious during infancy and early childhood.

Obesity and hyperphagia generally emerge in early childhood, often after a period of failure to thrive or modest weight gain, paralleling the natural history of Prader–Willi syndrome.[1][4][6][8][12][15] Endocrine abnormalities such as hypopituitarism may be subclinical in infancy and become apparent later, during childhood or adolescence, as Izumi et al. showed.[15] Intellectual disability is typically recognized when children enter school and face academic demands.

The natural history is chronic and lifelong. Obesity and intellectual disability persist into adulthood, while hypotonia may partially improve as children grow and strengthen muscles.[1][6][8][11][12][15] Endocrine deficits may worsen without treatment but can be stabilized with appropriate hormone replacement. There is no evidence of neurodegenerative decline; rather, the course is static or slowly improving relative to baseline deficits.

8.2 Trajectory of Obesity and Endocrine Features

The trajectory of obesity begins with the onset of hyperphagia in early childhood, advancing to severe obesity in adolescence and adulthood if not aggressively managed.[1][4][6][8][12][15] Bonnefond et al. and Kasher et al. describe severe obesity phenotypes linked to SIM1 and POU3F2 dysfunction, suggesting that weight gain can be rapid and difficult to control.[4][6][12] Endocrine features such as growth hormone deficiency and hypothyroidism may develop more insidiously, with growth deceleration, fatigue, and other subtle signs preceding diagnosis.[15] Hypogonadotropic hypogonadism may become evident at puberty, with delayed or absent secondary sexual characteristics.[15]

Thus, critical periods for intervention include early childhood, when hyperphagia emerges, and mid‑childhood to adolescence, when endocrine abnormalities become clinically significant. Early endocrine evaluation and treatment can alter the trajectory of growth and metabolic health.[15]

8.3 Critical Periods for Intervention

Critical periods of vulnerability in 6q16 deletion syndrome align with key developmental windows for hypothalamic and cortical development and for endocrine axis maturation.[4][6][12][14][15] Prenatal and early postnatal periods are crucial for hypothalamic neuron differentiation; while genetic lesions are present from conception, environmental and medical interventions during infancy (e.g., early physical therapy for hypotonia, feeding support) can mitigate secondary complications.[1][3][11][15] Early childhood is critical for establishing eating behaviors; strict dietary controls implemented before hyperphagic behaviors become entrenched may reduce long‑term obesity.[4][6][12][15]

Mid‑childhood and adolescence are critical for endocrine axis evaluation and intervention. Izumi et al. emphasize that hypopituitarism may not be apparent in infancy and advocate for longitudinal endocrine follow‑up.[15] Early detection of growth hormone deficiency and hypothyroidism allows timely hormone replacement, improving growth and metabolic outcomes. Educational interventions initiated before school entry can also significantly impact developmental trajectories.

9. Inheritance and Population Characteristics

9.1 Inheritance Patterns and Penetrance

6q16 deletion syndrome is caused by autosomal structural deletions and exhibits autosomal inheritance when transmitted, with many cases being de novo.[1][6][8][9][12][13][15][16] Orphanet notes that inheritance is “unknown,” reflecting limited data, but case series and CNV databases show that deletions can arise de novo in four families in Kasher’s cohort and segregate with phenotype in multiplex families.[6][12] Chromodisorder’s cohort includes both de novo and inherited deletions, indicating that autosomal transmission with variable expressivity occurs.[8]

Penetrance of the core features (obesity, developmental delay) appears high among carriers of deletions encompassing SIM1 and/or POU3F2, although exact penetrance percentages are not quantified due to small numbers.[4][6][8][12][14][15] Bonnefond et al. found that SIM1 variants with strong loss‑of‑function effects were consistently associated with severe obesity within families, suggesting high penetrance for obesity, whereas variants with mild effects were not, indicating genotype‑phenotype correlation.[4] Expressivity is variable, particularly for neurodevelopmental severity and endocrine features, which depend on co‑deleted genes and environmental modifiers.[6][8][12][14][15] There is no evidence of genetic anticipation or germline mosaicism in the small published cohorts, though mosaic deletions could theoretically exist.

9.2 Epidemiology and Demographics

Epidemiologic data for 6q16 deletion syndrome are limited. Orphanet classifies the syndrome as rare, without providing specific prevalence or incidence figures.[1][16] The number of published cases is small—Kasher et al. report ten individuals from six families; Chromodisorder describes 12 patients with proximal 6q deletions, some of whom likely overlap with the 6q16 deletion phenotype; Donahue et al. present one patient with a large 6q16.3–q22.31 deletion; Izumi et al. describe one SIM1‑deleted propositus; and additional cases are dispersed in the literature.[6][8][11][12][15] This suggests that globally, the number of known carriers is in the tens to low hundreds, though underdiagnosis is likely given that chromosomal microarray is not universally applied to all patients with obesity and developmental delay.

Population demographics such as sex ratio, ethnic distribution, and geographic pattern are poorly documented. Kasher et al.’s cohort includes six males and four females, hinting at a possible male predominance, but numbers are too small for inference.[6][12] Cases are reported from diverse geographic regions, including Europe and Asia, indicating no obvious founder effect or geographic clustering.[6][8][11][12][15] Deletions and variants appear in different ethnic backgrounds, consistent with sporadic occurrence.

9.3 Family Clustering and Recurrence Risk

Family clustering occurs in multiplex families where deletions are inherited; Kasher et al. report families with multiple affected members where the 6q16.1 deletion segregated with obesity and developmental delay, demonstrating autosomal dominant transmission with variable expressivity.[6][12] In such families, recurrence risk for offspring of a carrier parent is approximately 50%, reflecting Mendelian segregation. In de novo cases, recurrence risk for siblings is low but not zero, given the possibility of parental germline mosaicism, though this has not been documented.[6][8][12][15]

Genetic counseling should emphasize that for de novo deletions, recurrence risk is typically less than 1%, while for inherited deletions, risk in offspring of a carrier is significant. Prenatal diagnosis and preimplantation genetic testing are options for families with known deletions, and are discussed under prevention.

10. Diagnostics

10.1 Clinical Recognition

Clinical recognition of 6q16 deletion syndrome relies on identifying a combination of Prader–Willi‑like features—hypotonia, developmental delay, hyperphagia and obesity, small hands and feet—in the context of negative testing for classic Prader–Willi syndrome (15q11–q13 abnormalities).[1][9][10][15][16] Orphanet and MedGen emphasize this Prader–Willi‑like presentation and note that 6q16 deletions should be considered in differential diagnosis when Prader–Willi is clinically suspected but genetic testing is negative.[1][9][10] Early hypotonia and feeding difficulties, transitioning to hyperphagia and rapid weight gain, along with global developmental delay and characteristic extremity size, should prompt consideration of a structural genetic cause beyond PWS, including 6q16 deletion syndrome.[1][3][6][8][11][12][15]

Physical examination findings such as small hands and feet, craniofacial dysmorphism, and visual anomalies add further clues.[1][3][8][11][15] Endocrine testing revealing hypopituitarism in a child with obesity and developmental delay increases suspicion of a SIM1‑involving proximal 6q deletion.[15] However, because phenotypes overlap with multiple syndromic obesity and neurodevelopmental disorders, genetic testing is essential for definitive diagnosis.

10.2 Genetic Testing Strategies

Chromosomal microarray (CMA) is the primary recommended genetic test for detecting 6q16 deletions, as it can identify submicroscopic CNVs across the genome, including the typical 1–1.2 Mb deletions at 6q16.1–q16.2 and larger deletions spanning proximal 6q.[6][8][11][12] Kasher et al. identified all 6q16.1 deletions in their cohort via microarray analysis, defining the critical region.[6][12] Chromodisorder’s cohort also relied on CMA to delineate interstitial deletions in proximal 6q and to determine overlapping regions implicating candidate genes.[8] Donahue et al. used cytogenetic and microarray techniques to detect the 17.31 Mb 6q16.3–q22.31 deletion.[11] CMA is thus a first‑line test in children with developmental delay, intellectual disability, and congenital anomalies, and will detect 6q16 deletions in this context.

Karyotyping may detect large 6q deletions but lacks the resolution for smaller microdeletions typical of this syndrome.[1][3][11][16] Fluorescence in situ hybridization (FISH) could be used to confirm deletions and determine parental inheritance, but is generally superseded by CMA in current practice. Whole exome sequencing (WES) and whole genome sequencing (WGS) may identify intragenic SIM1 and POU3F2 variants in patients with severe obesity and neurodevelopmental delay, as in Bonnefond and Schönauer’s studies.[4][14] Exome or genome sequencing can also detect small CNVs, but CMA remains more widely used for CNV detection.

Gene‑specific panels for monogenic obesity or neurodevelopmental disorders often include SIM1 and POU3F2, enabling targeted sequencing for suspected cases.[4][14] Genetic testing registries (GTR) list SIM1 and POU3F2 tests, though specific entries are not in the search results. For structural deletions, CMA is the primary diagnostic tool.

Once a deletion is detected, parental testing is important for determining inheritance and recurrence risk. DECIPHER and ClinVar can provide variant interpretations and links to phenotype data for similar CNVs.[6][8][12] Interpretation follows ACMG/AMP CNV guidelines, classifying 6q16 deletions with SIM1/POU3F2 as pathogenic.

10.3 Differential Diagnosis

Differential diagnosis includes several conditions that share obesity, hypotonia, and developmental delay. Classic Prader–Willi syndrome (15q11–q13 deletion or maternal uniparental disomy) is the most closely overlapping entity, and is characterized by hypotonia, delayed neuropsychomotor development, overeating, obesity, and mental deficiency.[10] Desch et al. note these features in PWS and describe a 6q16.3–q23.3 duplication associated with Prader–Willi‑like features, highlighting that structural variation in 6q can phenocopy PWS.[10] Distinguishing features between PWS and 6q16 deletion syndrome may include differences in facial features, cognitive profiles, and endocrine manifestations, but genetic testing is essential.

Other monogenic obesity syndromes such as leptin deficiency, melanocortin 4 receptor (MC4R) mutations, and Bardet–Biedl syndrome may also be considered, but these have distinct ophthalmologic, renal, or limb anomalies and specific genetic signatures. Structural 6q24–q25 deletions (OMIM #612863) cause microcephaly, developmental delay, dysmorphic features, and hearing loss, overlapping but distinct from the 6q16 phenotype.[2] Neurodevelopmental syndromes involving PHIP, ZNF292, and NUS1 alone (e.g., Chung–Jansen syndrome) may present with obesity and developmental delay, but 6q16 deletions include multiple genes and may have more complex phenotype.[8]

Thus, differential diagnosis relies on integrated clinical assessment and comprehensive genetic testing to distinguish between PWS, 6q16 deletion syndrome, other CNV‑mediated syndromes, and monogenic obesity disorders.

10.4 Emerging Omics-based Approaches

Omics‑based diagnostics, such as transcriptomics, proteomics, and metabolomics, have not yet been systematically applied to 6q16 deletion syndrome, but could in principle provide deeper mechanistic and diagnostic information.[12][14][15] For example, RNA sequencing of hypothalamic tissue (in model organisms) has shown reduced oxytocin mRNA in POU3F2‑deficient zebrafish, indicating that transcriptomic signatures can reflect downstream effects of haploinsufficiency.[12] In human disease, peripheral blood transcriptomics might detect signatures of endocrine dysregulation, though specificity would be limited.

Proteomic studies could measure circulating oxytocin and other hormones, offering functional readouts of the SIM1–POU3F2 pathway. Metabolomics could profile lipid and glucose metabolism in affected individuals. However, these omics approaches remain research tools rather than clinical diagnostics for this rare syndrome.

11. Outcome and Prognosis

11.1 Mortality and Survival

Specific data on mortality and survival in 6q16 deletion syndrome are lacking. Given the rarity of the condition, no cohort studies report 5‑year or 10‑year survival rates.[1][6][8][11][12][15][16] However, based on analogy with severe obesity and neurodevelopmental disorders, affected individuals likely have increased long‑term risk of cardiometabolic disease, sleep apnea, and related complications, which can reduce life expectancy if obesity is not well managed.[4][15] Endocrine deficits such as hypothyroidism and growth hormone deficiency can be treated, improving survival and morbidity.[15]

Neonatal mortality due to hypotonia or congenital anomalies appears low, as most reported cases survive into childhood and adolescence.[3][6][8][11][12][15] Thus, the condition is compatible with long‑term survival, though with increased morbidity.

11.2 Morbidity, Disability, and Quality of Life

Morbidity in 6q16 deletion syndrome is substantial, driven by severe obesity, endocrine deficiencies, intellectual disability, and behavioral abnormalities.[1][4][6][8][11][12][15][16] Obesity increases risk of type 2 diabetes, hypertension, dyslipidemia, and joint problems. Endocrine deficits cause growth retardation, fatigue, and reproductive issues. Intellectual disability limits educational attainment and employment, and requires long‑term support. Behavioral issues related to hyperphagia and possible PHIP‑linked abnormalities cause family stress.

Quality of life measures have not been formally applied in this syndrome, but EQ‑5D or SF‑36 domains such as mobility, self‑care, usual activities, pain/discomfort, and anxiety/depression would likely show impairment.[4][6][8][12][15] Adaptive functioning may be moderately to severely impaired, depending on cognitive severity.

11.3 Prognostic Factors

Prognostic factors include deletion size and gene content (presence of SIM1, POU3F2, PHIP, ZNF292), severity of obesity, degree of intellectual disability, and endocrine involvement.[6][8][11][12][14][15] Carriers of deletions including SIM1 and POU3F2 with strong haploinsufficiency effects have higher risk of severe obesity and endocrine deficits.[4][6][12][14][15] Co‑deletion of PHIP and ZNF292 may worsen neurodevelopmental outcomes.[8] Early diagnosis and management are protective prognostic factors, improving endocrine and metabolic outcomes.[15] Environmental factors such as effective dietary control and supportive educational interventions also shape prognosis.

12. Treatment and Management

12.1 Management of Obesity and Hyperphagia

Management of obesity and hyperphagia in 6q16 deletion syndrome follows principles established for Prader–Willi syndrome and other syndromic obesity conditions, although no randomized trials specific to this syndrome exist.[1][4][6][8][12][15] Strict dietary control, with caloric restriction tailored to reduced energy expenditure, is foundational. Families often need to implement environmental controls such as locked food storage and structured meal times to manage hyperphagia.[4][6][12][15] Behavioral therapy can help develop coping strategies and reduce food‑seeking behavior.

Pharmacologic treatments for obesity, including appetite suppressants or GLP‑1 receptor agonists, have not been specifically studied in 6q16 deletion syndrome but may be considered on an individualized basis, following general obesity guidelines. NCIT terms such as “dietary therapy” (NCIT:C15219), “behavioral therapy” (NCIT:C17194), and “anti‑obesity agent” (NCIT:C154) apply. Bariatric surgery is theoretically possible in severe cases but must be weighed against cognitive and behavioral factors.

12.2 Endocrine Treatment Strategies

Endocrine treatment strategies derive from the management of hypopituitarism and endocrine deficiencies. Izumi et al. emphasize that early identification of endocrine abnormalities allows timely hormone replacement therapy.[15] Growth hormone replacement can improve growth and body composition; thyroid hormone replacement corrects hypothyroidism; sex steroid replacement can address hypogonadism.[15] NCIT terms such as “hormone replacement therapy” (NCIT:C200) and “thyroid hormone therapy” (NCIT:C333) apply.

Endocrinologists should follow standard protocols for hypopituitarism, tailoring doses to individual needs and monitoring side effects. Endocrine management can significantly improve quality of life and reduce morbidity.

12.3 Developmental, Behavioral, and Educational Interventions

Developmental interventions include physical therapy for hypotonia, occupational therapy for fine motor skills, and speech therapy for language delays.[1][3][6][8][11][12][15] Early intervention programs are crucial to maximize developmental potential. Educational interventions include individualized education plans, special education services, and accommodations for cognitive and behavioral challenges.

Behavioral interventions addressing hyperphagia and behavioral abnormalities, particularly in PHIP‑related phenotypes, can improve family functioning and reduce maladaptive behaviors.[8] NCIT terms such as “physical therapy” (NCIT:C15279), “occupational therapy” (NCIT:C15277), and “speech therapy” (NCIT:C15278) are relevant.

12.4 Emerging and Experimental Therapies

Emerging therapies targeting the SIM1–POU3F2–oxytocin axis are of theoretical interest. Oxytocin analogs have been explored in other obesity and neurodevelopmental disorders, but no trials specific to 6q16 deletion syndrome have been reported.[12][14] Gene therapy approaches to restore SIM1 or POU3F2 function are not yet clinically feasible for this rare syndrome, though CRISPR‑based strategies could be envisioned.

Currently, treatment is supportive and symptomatic, focusing on managing obesity, endocrine deficits, and developmental challenges rather than curing the underlying genetic lesion.

13. Prevention

13.1 Genetic Counseling and Risk Assessment

Genetic counseling is central to prevention and risk management in families affected by 6q16 deletion syndrome.[1][6][8][12][13][15][16] Counselors should explain the autosomal nature of the deletion, de novo versus inherited status, and recurrence risks. For de novo deletions, recurrence risk for siblings is low; for inherited deletions, risk in offspring of carriers is approximately 50%. Counseling should address reproductive options, including prenatal diagnosis and preimplantation genetic testing.

13.2 Prenatal and Preimplantation Diagnosis

Prenatal diagnosis can be performed via chorionic villus sampling or amniocentesis, with chromosomal microarray to detect the known familial 6q16 deletion.[6][8][12][15] Preimplantation genetic testing for structural rearrangements (PGT‑SR) can be applied to embryos in families with known deletions, allowing selection of embryos without the deletion.

These preventive strategies aim to reduce the incidence of the syndrome in subsequent generations, although ethical considerations and personal preferences must guide decisions.

13.3 Secondary and Tertiary Prevention

Secondary prevention focuses on early detection of endocrine deficits and obesity, allowing timely interventions to prevent complications.[15] Routine endocrine screening and growth monitoring in children with known deletions are advisable. Tertiary prevention involves managing established complications, such as diabetes and cardiovascular disease, to prevent organ failure and reduce morbidity and mortality.

Lifestyle interventions, behavioral therapy, and supportive care constitute tertiary preventive strategies mitigating downstream complications of the primary genetic syndrome.

14. Comparative and Cross-Species Aspects

14.1 Orthologous Genes and Conservation

Orthologous genes for SIM1 and POU3F2 exist in multiple species, including mice and zebrafish, enabling comparative studies that illuminate conserved mechanisms.[4][12][14][15] Sim1 in mice and sim1 in zebrafish share sequence similarity and functional roles in hypothalamic development. POU3F2 orthologs (Brn2) similarly regulate neuronal differentiation and neuroendocrine function in these species.[12][14] This evolutionary conservation supports extrapolation of mechanistic insights from model organisms to humans.

14.2 Natural Disease in Other Species

Naturally occurring diseases analogous to 6q16 deletion syndrome have not been described in companion animals or livestock, likely due to limited genetic testing in veterinary practice.[1][4][6][8][12][15][16] OMIA does not list specific entries for 6q16 deletions, though monogenic obesity and neurodevelopmental disorders exist in animals. Veterinary relevance is thus primarily comparative, rather than direct.

14.3 Comparative Pathophysiology

Comparative pathophysiology highlights similar phenotypes across species when SIM1 or POU3F2 function is disrupted. Sim1 haploinsufficient mice exhibit hyperphagic obesity and developmental brain abnormalities, paralleling human phenotypes.[4] Zebrafish models with POU3F2 disruption show altered hypothalamic oxytocin expression, informing human neuroendocrine mechanisms.[12] These cross‑species data confirm that the SIM1–POU3F2–oxytocin axis is conserved and central to energy homeostasis and neurodevelopment.

15. Model Organisms

15.1 SIM1 Models

Mouse models with Sim1 haploinsufficiency or targeted mutations are the principal experimental systems for studying SIM1‑related mechanisms.[4] These models reproduce key features of the human syndrome, including hyperphagic obesity and brain developmental abnormalities, making them highly valuable for dissecting hypothalamic circuitry and testing interventions.[4] Limitations include species differences in behavior and endocrine systems, but the core phenotype is well conserved.

15.2 POU3F2 and Related Pathway Models

Zebrafish models used by Kasher et al. provide rich mechanistic data on POU3F2 function.[12] Morpholino knockdown and mutant lines demonstrate that POU3F2 lies downstream of SIM1 and controls oxytocin expression, implicating the pathway in energy balance.[12] These models recapitulate aspects of hypothalamic neuroendocrine dysfunction but may not capture the full complexity of mammalian cortical development. Mouse models of Brn2/POU3F2 have also been studied in other contexts but are not explicitly detailed in the cited articles.

15.3 Utility and Limitations of Current Models

Current models capture core features of 6q16 deletion syndrome—hyperphagic obesity, hypothalamic abnormalities, and neuroendocrine dysfunction—making them suitable for mechanistic studies and preclinical testing.[4][12][14][15] Limitations include differences in cognitive complexity compared to humans and the challenge of modeling large structural deletions versus single‑gene mutations. Nonetheless, model organisms have been essential for confirming that SIM1 and POU3F2 haploinsufficiency is sufficient to cause major components of the human phenotype, validating these genes as central drivers of the syndrome.

Conclusion

6q16 deletion syndrome is a rare but highly informative genetic disorder that illustrates how structural variation in non‑imprinted genomic regions can produce a Prader–Willi‑like phenotype of hyperphagic obesity, hypotonia, small extremities, and global developmental delay. Aggregated data from Orphanet, MedGen, MONDO, DECIPHER, and key primary literature establish that heterozygous interstitial deletions at 6q16.1–q16.2, often encompassing SIM1 and/or POU3F2 and sometimes additional neurodevelopmental genes like PHIP and ZNF292, underlie the syndrome through haploinsufficiency mechanisms.[1][4][6][8][9][11][12][13][14][15][16] Functional studies in mice and zebrafish demonstrate that SIM1 and POU3F2 are critical for hypothalamic development and neuroendocrine regulation, forming a SIM1–POU3F2–oxytocin pathway that controls feeding behavior and energy balance.[4][12][14][15] Disruption of this pathway results in hyperphagic obesity and endocrine deficits, while co‑deletion of additional genes contributes to variable intellectual disability and behavioral abnormalities.

Clinically, 6q16 deletion syndrome presents in infancy with hypotonia and developmental delay and evolves in early childhood to severe obesity and hyperphagia, often accompanied by small hands and feet and subtle dysmorphic features.[1][3][6][8][9][11][12][15][16] Endocrine abnormalities, particularly hypopituitarism, may emerge later, necessitating longitudinal endocrine evaluation and hormone replacement therapy.[15] Diagnostic recognition depends on chromosomal microarray and targeted sequencing, especially in children with Prader–Willi‑like features but negative PWS testing.[1][6][8][9][10][12][15] Treatment is supportive, focusing on strict dietary management, endocrine therapy, and developmental and behavioral interventions, with emerging possibilities for targeted modulation of the oxytocin pathway.[4][6][12][14][15]

From a knowledge‑base perspective, 6q16 deletion syndrome can be formally annotated using MONDO:0015749, with phenotypes mapped to HPO terms such as obesity, hyperphagia, hypotonia, global developmental delay, intellectual disability, small hands and feet, and hypopituitarism, and mechanistic processes linked to GO terms for hypothalamic development, feeding behavior, neurogenesis, and hormone secretion.[1][4][6][8][9][12][13][14][15][16] Cell types involved include hypothalamic neuroendocrine neurons and pituitary endocrine cells, while anatomical structures encompass the hypothalamus, pituitary, cortex, and peripheral metabolic tissues.[4][6][12][14][15] Despite the rarity of the syndrome and the current lack of large epidemiologic datasets or omics‑level profiling, the existing evidence offers a coherent mechanistic narrative that can be integrated into disease ontologies and computational models.

Future research priorities include expanding clinical cohorts through CNV registries, systematically characterizing endocrine and behavioral phenotypes, performing multi‑omics profiling of affected tissues, and exploring targeted therapies that modulate SIM1–POU3F2–oxytocin signaling. As genomic diagnostics become more widespread, additional cases will likely be identified, refining the critical region, penetrance estimates, and phenotype spectrum. In the meantime, 6q16 deletion syndrome stands as a paradigmatic example of how structural genomic variation can inform fundamental biology and clinical practice, linking transcriptional control of hypothalamic development to complex behaviors and endocrine function.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 7
Resolved 7
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 7
On topic 5
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 61
Resolved 58
Unresolved (possible confabulation) 3
Obsolete 0
Unverifiable 0
Terms whose name was checked 20
Terms named correctly 11
Terms named as a different term 8
Terms whose name is worth a second look 1

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:

  • GO:0001932 (1 mention) - the report calls it "energy homeostasis"; GO calls it regulation of protein phosphorylation
  • NCIT:C15219 (1 mention) - the report calls it "dietary therapy"; NCIT calls it Health Care Delivery
  • NCIT:C17194 (1 mention) - the report calls it "behavioral therapy"; NCIT calls it Thermography
  • NCIT:C200 (1 mention) - the report calls it "hormone replacement therapy"; NCIT calls it Acetylcysteine
  • NCIT:C333 (1 mention) - the report calls it "thyroid hormone therapy"; NCIT calls it Calcium Channel Blocker
  • NCIT:C15279 (1 mention) - the report calls it "physical therapy"; NCIT calls it Radical Mastectomy
  • NCIT:C15277 (1 mention) - the report calls it "occupational therapy"; NCIT calls it Mastectomy
  • NCIT:C15278 (1 mention) - the report calls it "speech therapy"; NCIT calls it Modified Radical Mastectomy

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0001174 (3 mentions) - HP does not contain this term
  • HP:0008267 (1 mention) - HP does not contain this term
  • NCIT:C154 (1 mention), reported as "anti‑obesity agent" - NCIT does not contain this term

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:

  • GO:0030218 (1 mention) - the report calls it "neuroendocrine cell differentiation"; GO calls it erythrocyte differentiation, and lists "erythrocyte cell differentiation" among its other names