WAPL-Related Developmental Disorder

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Mappings

MONDO

MONDO:0012830 chromosome 10q23 deletion syndrome Not Yet Curated

Related, not equivalent. MONDO:0012830 is the recurrent contiguous-gene 10q22.3q23.3 microdeletion entity; this dismech entry is the monogenic WAPL disorder, which PMID:42431198 nominates as the phenotypic driver within that deletion interval. The deletion entity is additionally recorded as a subtype of this entry.

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Inheritance

1

Autosomal dominant inheritance HP:0000006

All reported affected individuals carry a single damaging WAPL allele: either a heterozygous sequence variant or a heterozygous deletion of the 10q22.3q23.2 interval containing WAPL, supporting autosomal-dominant inheritance. Protein-truncating variants and deletions act through reduced dosage; the functional mechanism of each predicted damaging missense allele remains unresolved.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:42431198 SUPPORT Human Clinical

"phenotyping individuals with heterozygous predicted damaging variants in WAPL (n = 27)"

States that the disease-associated WAPL genotype in the human cohort is heterozygous, i.e. a monoallelic (dominant) mechanism.

PMID:42431198 SUPPORT Human Clinical

"large, recurrent 10q22.3q23.2 (10q) deletions encompassing WAPL"

Supports monoallelic copy loss for the deletion subtype.

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Subtypes

2

WAPL sequence-variant subtype (heterozygous damaging WAPL variant)

Individuals with a heterozygous predicted damaging sequence variant in WAPL and no deletion of the surrounding 10q22.3q23.2 interval. This is the subtype that establishes WAPL as a Mendelian disease gene; 27 such individuals were phenotyped in the defining report.

Show evidence (1 reference)

PMID:42431198 SUPPORT Human Clinical

"We explored the relevance of cohesin release factors in Mendelian disease by phenotyping individuals with heterozygous predicted damaging variants in WAPL (n = 27), PDS5A (n = 8), and PDS5B (n = 8)"

Defines the sequence-variant cohort and its size, and states that the variants are heterozygous.

10q22.3q23.2 contiguous-gene deletion subtype (WAPL-containing) MONDO:0012830

Individuals with a large recurrent deletion of 10q22.3q23.2, generated by non-allelic homologous recombination between the flanking low-copy repeats LCR3 and LCR4, which removes WAPL together with roughly 30 neighbouring genes. Clinically this subtype adds features that the source literature attributes to other genes in the interval (cardiac defects, congenital breast aplasia, cerebellar anomalies, macrocephaly) on top of the developmental delay shared with the sequence-variant subtype.

Show evidence (2 references)

PMID:42431198 SUPPORT Human Clinical

"Similarities between individuals with damaging WAPL variants and those with large, recurrent 10q22.3q23.2 (10q) deletions encompassing WAPL nominate WAPL as a driver gene within this genomic disorder region."

Establishes the deletion group as clinically overlapping with, and mechanistically linked to, the monogenic WAPL group.

PMID:17436248 SUPPORT Human Clinical

"Our data provide evidence that the 10q22-q23 genomic region harbors one or more genes important for cognitive and behavioral development and that recurrent deletions affecting this interval define a novel genomic disorder."

Original delineation of the recurrent 10q22-q23 deletion as a genomic disorder, i.e. the entity within which WAPL was later nominated as driver.

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Mechanistic Hypotheses

3

Altered genome folding as a route to transcriptional dysregulation

altered_genome_folding_to_transcription EMERGING

Evidence balance 1 support

WAPL loss produces extended loops, altered TAD contacts, promoter-enhancer loop disruption, and transcriptional changes, but the general causal route from three-dimensional folding to gene expression remains unresolved.

Pathograph links

Extended Chromatin Loops and Altered Genome Folding -> Transcriptional Dysregulation INDIRECT UNKNOWN INTERMEDIATES WAPL-deficient cells show both altered loop/TAD contacts and differential expression, but the source explicitly leaves the general causal relation unresolved; this is therefore an emerging, indirect disease model.

Show evidence (1 reference)

PMID:28475897 SUPPORT In Vitro

"The formation of loops and TADs has been suggested to be linked to gene expression ... although the causal relationship between them has remained unresolved."

The source explicitly defines the relationship as unresolved.

Neural transcriptional dysregulation as a route to developmental disability

transcriptional_dysregulation_to_neurodevelopment EMERGING

Evidence balance 1 support

WAPL dosage reduction dysregulates transcription in neural models and the human disorder is neurodevelopmental, but the responsible effector genes and tissue-level intermediates have not been identified.

Pathograph links

Transcriptional Dysregulation -> Impaired Neurodevelopment INDIRECT UNKNOWN INTERMEDIATES Which dysregulated genes mediate the neurodevelopmental outcome has not been established; the link is asserted at the level of a shared transcriptomic signature in neural cells, not of an identified effector.

Impaired Neurodevelopment -> Developmental Delay and Intellectual Disability INDIRECT UNKNOWN INTERMEDIATES The clinical endpoint of the neurodevelopmental disturbance.

Show evidence (1 reference)

PMID:36449618 SUPPORT Model Organism

"Here, we show dysregulation of >1000 genes in WaplΔ/+ embryonic mouse brain."

Provides brain-specific model evidence without proving the human route.

Candidate neighbouring-gene effects in the recurrent deletion

deletion_interval_candidate_gene_effects EMERGING

Evidence balance 1 support

NRG3 is proposed for breast aplasia and BMPR1A/GRID1 for cardiac findings; these are candidate attributions rather than demonstrated causal routes.

Pathograph links

Contiguous Loss of Neighbouring Genes -> Congenital Breast Aplasia INDIRECT UNKNOWN INTERMEDIATES The deletion literature nominates NRG3 as a candidate for congenital breast aplasia, but does not establish the causal variant-to-organ route.

Show evidence (1 reference)

PMID:21248748 SUPPORT Human Clinical

"For congenital breast aplasia, the NRG3 gene, known to be involved in early mammary gland development in mice, is a putative candidate gene."

Explicitly supports only a candidate relationship.

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Discussions and Knowledge Gaps

5

What is the organ-system-level phenotypic spectrum, allelic spectrum, and frequency breakdown of the 27-individual WAPL cohort?

CURATION TODO OPEN wapl_full_text_curation

PMID:42431198 was published online ahead of print on 2026-07-10 and is cached as abstract only. The original framing of this discussion - that the detail had to wait for the PMC deposit - was wrong: the same study is openly available as a medRxiv preprint, DOI:10.64898/2026.02.23.26346364, which is now fetched and cited here. From that full text the entry has since gained per-feature frequency bands for the sequence-variant cohort (n = 25 phenotyped), the clubfoot and cardiac malformation phenotypes, and the DNA methylation episignature diagnostic entry. What genuinely remains blocked is case-level detail. The preprint states that Table 1, Table S4, Fig. 2 and Fig. S12 have had case-level data - including age, sex, phenotype and photographs - removed per medRxiv guidelines. So a per-individual `variants:` block and the facial-gestalt description still cannot be curated from any currently available source, and the peer-reviewed full text remains the route to them.

Concretely, what is still outstanding: (1) a `variants:` block, blocked on the redacted case-level tables; (2) facial-gestalt detail, blocked the same way - note the preprint explicitly reports that no typical set of facial features is shared across individuals, so a gestalt may not exist to curate; (3) a re-check of whether the subtype split used here matches the published nosology. Re-run `just fetch-reference PMID:42431198` after the PMC deposit for (1) and (2).

Show evidence (1 reference)

PMID:42431198 SUPPORT Human Clinical

"We identified a WAPL-related disorder featuring developmental delay, intellectual disability, and risk of other developmental anomalies."

The abstract-level statement that is currently the whole of the available clinical description, which is what makes full-text re-curation necessary.

What additional phenotypes and frequency bands does ORPHA:276413 record for the recurrent 10q22.3q23.3 deletion subtype?

CURATION TODO OPEN wapl_10q_deletion_orphanet_phenotypes

The deletion subtype here is grounded on MONDO:0012830, whose Orphanet source record (ORPHA:276413) enumerates features this entry does not capture - among them hypertelorism/hypotelorism, low-set ears, flat nasal bridge, cleft palate, arachnodactyly, joint hyperlaxity, feeding difficulties and failure to thrive - together with HPO-coded frequency bands. None of those features is quotable from any reference currently cached for this entry, so they are omitted rather than asserted without evidence. Scope note: this is now a gap in the *feature list*, not in frequency data as such. The deletion arm does carry frequency bands, derived from the delineating study's own 41-carrier rCNV cohort and its 27-case literature review rather than from Orphanet - facial dysmorphism 20%, cardiovascular 12%, atypical behaviour 12%, clubfoot 22%. Those are preferable here anyway, because they are same-source and same-analysis as the sequence-variant bands and so support the equivalent-prevalence comparison the driver-gene argument rests on. What ORPHA:276413 would still add is the long tail of dysmorphic and growth features listed above, which no cached source supports.

Blocked, not merely undone. `just refresh-orphadata` currently fails with a checksum mismatch on `en_product1.xml` against the pin in `data/orphadata/MANIFEST.yaml`, so `just structured-rebuild-orphanet --id 276413` cannot produce `references_cache/ORPHA_276413.md`. Re-pinning the Orphadata snapshot is a repo-wide operation (it would rebuild all committed `ORPHA_*.md` files) and belongs in its own change, not in a single disorder curation. Once the snapshot is re-pinned, rebuild ORPHA:276413 and mine its `## Phenotypes` table for the deletion subtype.

Are PDS5A and PDS5B Mendelian disease genes, and if so what phenotypes do they cause?

KNOWLEDGE GAP OPEN wapl_pds5a_pds5b_validity

Attached to

pathophysiology#Impaired Cohesin Release from Chromatin

PDS5A and PDS5B are WAPL's binding partners and, with WAPL, control chromatin loop length, so they are strong biological candidates for a parallel disorder. Eight individuals with damaging variants in each were phenotyped and did show features of developmental disorders, yet neither cohort statistics nor phenotyping produced a specific association. It is therefore unresolved whether these are genuine but low-penetrance or heterogeneous disease genes, whether the cohorts were simply too small, or whether the variants are tolerated. The preprint full text has since been read, and it does not resolve the question - but it does sharpen it in two ways, so this gap is no longer "waiting on the full text". First, the negative result is not that the carriers were unaffected: every PDS5A/PDS5B subject had neurodevelopmental and/or neurological features, and what failed was the coalescence of those features into a defined syndrome. Second, PDS5A and PDS5B truncating variants were pooled with WAPL in Analysis 1 of the methylation work, and that combined analysis did yield a cohesin-release-factor-deficiency episignature - which is suggestive of a shared molecular consequence, but cannot be attributed to PDS5A/PDS5B individually from a pooled classifier. Neither observation changes relationship_type: UNKNOWN, which remains the correct call.

Proposed experiments

Powered PDS5A and PDS5B variant cohort with repeated association statistics

exp_pds5_matchmaking_cohort

Assemble larger international PDS5A and PDS5B variant cohorts through matchmaking platforms and repeat the phenotype-association statistics with adequate power.

Isogenic PDS5A/PDS5B iPSC and induced-neuron transcriptomic comparison

exp_pds5_isogenic_ipsc_transcriptomics

Apply the same isogenic iPSC and induced-neuron CRISPR and transcriptomic pipeline used for WAPL to PDS5A and PDS5B knockouts, and test whether their differentially expressed gene sets overlap the WAPL signature.

Show evidence (4 references)

PMID:42431198 SUPPORT Human Clinical

"While individuals with PDS5A or PDS5B variants exhibited features of developmental disorders, neither cohort-based statistics nor subject phenotyping associated these genes with specific phenotypes."

States the unresolved association directly.

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"every subject had neurodevelopmental and/or neurological features"

Shows the carriers were not unaffected, which is what makes this a genuine open question rather than a negative result. PARTIAL because it supports the existence of a phenotype while leaving the gene-disease association unresolved.

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"Analysis 1 combined truncating variants"

Records that PDS5A and PDS5B were pooled with WAPL in the episignature analysis that succeeded, so the positive methylation result cannot be apportioned to them individually.

+ 1 more reference

Does the mouse Wapl dosage-liability threshold, which lies below heterozygosity, actually describe the human dose-response, and does it predict that severely hypomorphic or biallelic human WAPL genotypes are non-viable?

HUMAN MODEL MISMATCH OPEN wapl_mouse_dosage_threshold_translation

The dosage-series evidence is retained in the animal model rather than as a human causal-graph node because it exists only in mouse. Every reported human is heterozygous, so the 25%-residual arm - birth defects and postnatal lethality - has no human counterpart and its translational validity is untested. The mismatch is mechanistically meaningful in two directions: if the human curve is shifted, apparently mild human heterozygotes could still harbour subclinical cohesin-folding defects; and if it holds, human sub-heterozygous WAPL genotypes would be expected to present as pregnancy loss or lethal congenital anomaly rather than as this neurodevelopmental disorder, which would systematically hide them from neurodevelopmental cohorts.

Proposed experiments

Search perinatal-loss and lethal-anomaly cohorts for sub-heterozygous WAPL genotypes

exp_wapl_perinatal_loss_cohort_search

Search prenatal and perinatal-loss and lethal-congenital-anomaly sequencing cohorts for biallelic or severely hypomorphic WAPL genotypes, which the mouse data predict should exist there and nowhere else.

Residual WAPL protein and cohesin residence time in human heterozygote cells

exp_wapl_human_residual_dosage_assay

Quantify residual WAPL protein and cohesin residence time in cells from human heterozygotes and relate them to phenotype severity, to place human carriers on the mouse dose-response curve directly.

Show evidence (1 reference)

PMID:42431198 SUPPORT Model Organism

"Mice with 50% Wapl expression exhibited mild deficits of growth and learning/memory, whereas those with 25% residual Wapl displayed birth defects and postnatal lethality, revealing a dosage liability threshold below the level of heterozygosity."

The model-organism result whose human translation is the open question.

Should a MONDO term be requested for the monogenic WAPL-related developmental disorder, distinct from MONDO:0012830 (the contiguous-gene 10q deletion)?

CURATION TODO OPEN wapl_mondo_term_request

`disease_term` is currently omitted because no MONDO class exists for the monogenic entity. MONDO:0012830 is deliberately not reused, since conflating a single-gene disorder with the deletion syndrome that contains it is exactly the named-entity-confusion failure mode the curation SOP warns about. Once the full text and additional cases are published, a MONDO new-term request would let this entry carry a proper `disease_term` and would let the deletion/sequence-variant distinction be represented in the ontology rather than only in dismech.

Show evidence (1 reference)

PMID:42431198 SUPPORT Human Clinical

"In summary, we delineated a genetic condition caused by cohesin release factor deficiency, nominated WAPL as a driver gene within a genomic disorder region, and further illuminated dosage sensitivity of human cohesin."

The publication delineating a distinct genetic condition, which is the basis on which a new MONDO class would be requested.

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Pathophysiology

9

Heterozygous Damaging WAPL Sequence Variant

Mechanism confidence: Established

The proximal lesion of the sequence-variant subtype: a single heterozygous predicted damaging variant in WAPL, with the surrounding 10q22.3q23.2 interval intact. This is the genotype that isolates WAPL from the other genes in the deletion interval and so establishes it as a Mendelian disease gene in its own right.

WAPL hgnc:23293

Downstream

WAPL Deficiency Predicted loss-of-function and damaging missense variants are grouped as cohesin-release-factor deficiency by the defining study. The precise functional effect of each missense allele has not been established.

Show evidence (1 reference)

PMID:42431198 SUPPORT Human Clinical

"We explored the relevance of cohesin release factors in Mendelian disease by phenotyping individuals with heterozygous predicted damaging variants in WAPL (n = 27), PDS5A (n = 8), and PDS5B (n = 8)"

Directly supports the heterozygous WAPL sequence-variant lesion and cohort.

Recurrent 10q22.3q23.2 Deletion

Mechanism confidence: Established

Non-allelic homologous recombination between the paralogous low-copy repeats LCR3 and LCR4 removes a multi-megabase interval of 10q22.3q23.2 containing roughly 30 genes, WAPL among them. The deletion is the historical entry point to this disorder: it was recognised as a genomic disorder associated with cognitive and behavioural abnormalities two decades before the driver gene was identified.

WAPL hgnc:23293

Downstream

WAPL Deficiency The deletion removes one copy of WAPL, producing the same reduced-dosage state as a damaging sequence variant. Clinical similarity between the two groups is the basis of the driver-gene nomination. Note that the deletion also removes roughly 30 other genes, so it is not reducible to this edge - the deletion-only features curated on the 10q Deletion subtype are attributed elsewhere in the interval.

Contiguous Loss of Neighbouring Genes The same LCR3-4 event removes roughly 30 other genes, so the deletion has a second, WAPL-independent arm. This edge exists so that the deletion-only features are routed through the pathograph rather than attributed by prose alone.

Show evidence (1 reference)

PMID:17436248 SUPPORT Human Clinical

"in the other two families, the breakpoints are within paralogous LCRs, removing approximately 7.2 Mb and 32 genes"

Documents the low-copy-repeat-mediated recurrent breakpoints and the contiguous-gene extent of the deletion.

Contiguous Loss of Neighbouring Genes

Mechanism confidence: Provisional

The WAPL-independent arm of the contiguous-gene deletion. Alongside WAPL, the LCR3-4 interval carries roughly 30 genes, and the deletion literature proposes specific candidates for the deletion-only features: NRG3 for congenital breast aplasia, on the basis of its role in early mammary gland development in mice; and BMPR1A and GRID1 for the cardiac defects, on the basis of their association with cardiac structure and function. These candidate attributions are the reason those phenotypes are curated on the 10q Deletion subtype and explicitly NOT on WAPL. Note that cardiac malformation also occurs in WAPL sequence-variant carriers who have no deletion, so the cardiac phenotype is likely to have contributions from both arms; breast aplasia has no sequence-variant counterpart.

Candidate neighbouring-gene effects in the recurrent deletion

NRG3 hgnc:7999 BMPR1A hgnc:1076 GRID1 hgnc:4575

Downstream

Congenital Breast Aplasia The deletion literature nominates NRG3 as a candidate for congenital breast aplasia, but does not establish the causal variant-to-organ route.

Hamartomatous Polyposis The deletion removes BMPR1A, an established juvenile-polyposis gene; the clinical deletion report documents severe juvenile polyposis. The edge is indirect because the intervening tissue pathogenesis is not represented.

Show evidence (4 references)

PMID:21248748 SUPPORT Human Clinical

"For congenital breast aplasia, the NRG3 gene, known to be involved in early mammary gland development in mice, is a putative candidate gene."

Names NRG3 as the candidate for the breast-aplasia feature, which is what keeps that phenotype off WAPL.

PMID:21248748 SUPPORT Human Clinical

"For cardiac defects, BMPR1A and GRID1 are putative candidate genes because of their association with cardiac structure and function."

Names BMPR1A and GRID1 as the candidates for the cardiac feature. Recorded at PROVISIONAL confidence because the source proposes them as putative candidates rather than demonstrating causation.

PMID:31561016 SUPPORT Human Clinical

"More specifically, point mutations and structural abnormalities in BMPR1A lead to a highly penetrant yet variable phenotype of JPS."

The strongest link in this node, and the reason it is not merely speculative: BMPR1A is an established juvenile-polyposis gene in which structural loss is itself pathogenic, so its inclusion in the deleted interval predicts a cancer-predisposition phenotype independently of any candidate-gene reasoning about the deletion.

+ 1 more reference

WAPL Deficiency

Mechanism confidence: Provisional

The convergence point of the two lesions: reduced WAPL dosage after a deletion or protein-truncating variant, and predicted impaired function for damaging missense variants. The isogenic experiment directly establishes haploinsufficiency only for engineered frameshift and deletion models; the functional effect of each clinical missense allele remains unresolved.

WAPL hgnc:23293

Downstream

Impaired Cohesin Release from Chromatin Halving WAPL dosage reduces the cohesin-unloading activity available to remove cohesin rings from DNA.

Show evidence (1 reference)

PMID:42431198 SUPPORT In Vitro

"Transcriptomics identified significant overlap between WAPL haploinsufficiency and 10q deletion differentially expressed genes."

Names WAPL haploinsufficiency as the engineered loss-of-function state and shows that it recapitulates the transcriptional consequence of the whole deletion.

Impaired Cohesin Release from Chromatin

Mechanism confidence: Established

WAPL is cohesin's DNA release factor: it opens the exit gate at the SMC3-RAD21 interface and unlocks cohesin from a state in which it is stably bound to chromatin. Loss of WAPL activity abolishes cohesin turnover, so cohesin remains loaded and its residence time on DNA increases. This is the core biochemical consequence expected from WAPL deficiency and is established from cell-biological loss-of-function work that predates the clinical entity. Direct release assays have not been reported for every clinical missense allele.

sister chromatid cohesion GO:0007062 ⚠ ABNORMAL

cohesin unloader activity GO:0140670 ↓ DECREASED

cohesin complex GO:0008278

Downstream

Extended Chromatin Loops and Altered Genome Folding Because cohesin is not released, loop extrusion continues past its normal stopping points and loops become longer.

Show evidence (3 references)

PMID:17113138 SUPPORT In Vitro

"Our data indicate that Wapl is required to unlock cohesin from a particular state in which it is stably bound to chromatin."

Establishes the molecular function that is reduced in this disorder: WAPL-dependent release of cohesin from chromatin.

PMID:17113138 SUPPORT In Vitro

"Wapl depletion also increases the residence time of cohesin on chromatin in interphase."

Shows the direct consequence of reduced WAPL activity in interphase, the cell-cycle phase relevant to transcriptional regulation in developing tissue.

PMID:17113138 SUPPORT In Vitro

"its depletion blocks cohesin dissociation from chromosomes during the early stages of mitosis and prevents the resolution of sister chromatids until anaphase"

Direct support for the `sister chromatid cohesion / ABNORMAL` descriptor on this node: loss of WAPL leaves sister chromatids unresolved until anaphase, which is the mitotic readout of failed cohesin release.

Extended Chromatin Loops and Altered Genome Folding

Mechanism confidence: Established

Cohesin structures interphase chromosomes by processively enlarging chromatin loops until it is stopped at CTCF sites or released by WAPL. When WAPL activity is reduced, loops extend well beyond their normal length, cohesin accumulates in axial vermicelli-like positions, interactions between neighbouring topologically associating domains increase, and loops form between incorrectly oriented CTCF sites. The three-dimensional genome therefore folds abnormally.

Altered genome folding as a route to transcriptional dysregulation

chromatin looping GO:0140588 ⚠ ABNORMAL chromatin organization GO:0006325 ⚠ ABNORMAL

Experimental models

WAPL-knockout human HAP1 Hi-C model CELL LINE Provides the direct experimental demonstration that loss of WAPL lengthens chromatin loops and increases inter-TAD contact.

Downstream

Transcriptional Dysregulation WAPL-deficient cells show both altered loop/TAD contacts and differential expression, but the source explicitly leaves the general causal relation unresolved; this is therefore an emerging, indirect disease model.

Show evidence (3 references)

PMID:28475897 SUPPORT In Vitro

"WAPL restricts this loop extension and also prevents looping between incorrectly oriented CTCF sites."

States the normal restraining function of WAPL on loop length and CTCF directionality, whose loss defines this node.

PMID:28475897 SUPPORT In Vitro

"WAPL deficiency led to the extension of chromatin loops and strongly increased interaction frequencies between nearby TADs"

Direct experimental demonstration in WAPL-knockout human cells that loops lengthen and inter-TAD insulation is degraded.

PMID:29217591 SUPPORT In Vitro

"In the absence of WAPL and PDS5 proteins, cohesin forms extended loops, presumably by passing CTCF sites, accumulates in axial chromosomal positions (vermicelli), and condenses chromosomes."

Independent replication of the extended-loop phenotype, and the link to the PDS5 binding partners that are the other two cohesin release factor genes examined in the clinical study.

Transcriptional Dysregulation

Mechanism confidence: Established

Cohesin shapes gene expression through three-dimensional chromosome folding, so a folding defect is read out as a transcriptional one. In isogenic human iPSCs and induced neurons, CRISPR-engineered WAPL truncating variants and engineered 10q deletion produced significantly overlapping sets of differentially expressed genes - the direct molecular evidence that the monogenic and contiguous-gene lesions converge on a shared transcriptional consequence in a neural lineage.

Neural transcriptional dysregulation as a route to developmental disability

induced neuron CL:0000540 induced pluripotent stem cell CL:0002248

regulation of transcription by RNA polymerase II GO:0006357 ↕ DYSREGULATED

Experimental models

Isogenic WAPL-truncating and 10q-deletion human iPSC and induced-neuron model IPSC DERIVED MODEL The model provides the transcriptional read-out that WAPL haploinsufficiency and 10q deletion converge on shared gene-expression changes in a human neural lineage.

Downstream

Impaired Neurodevelopment Which dysregulated genes mediate the neurodevelopmental outcome has not been established; the link is asserted at the level of a shared transcriptomic signature in neural cells, not of an identified effector.

Show evidence (6 references)

PMID:42431198 SUPPORT In Vitro

"Transcriptomics identified significant overlap between WAPL haploinsufficiency and 10q deletion differentially expressed genes."

Shows that the two genotypes converge transcriptionally in an isogenic human neural model, which is the mechanistic core of the driver-gene claim.

PMID:42431198 SUPPORT Other

"Cohesin orchestrates gene expression via three-dimensional chromosome folding."

States the general principle linking the folding defect above to the transcriptional defect at this node.

PMID:33318687 SUPPORT In Vitro

"Paradoxically, stabilization of cohesin binding, following WAPL ablation, results in depletion of cohesin from these cell-type-specific regions, loss of gene expression and differentiation."

Supplies the missing step between the folding defect and the transcriptional one, and corrects an intuition the loop-extension model invites: because WAPL-driven turnover is what frees cohesin for reloading, losing WAPL does not simply leave cohesin in place - it strips cohesin from cell-type-specific regulatory sites. That is why a release-factor defect reads out as loss of cell-type-specific gene expression rather than as generic chromatin compaction.

+ 3 more references

Impaired Neurodevelopment

Mechanism confidence: Provisional

The tissue least able to tolerate cohesin-release dysfunction appears to be the developing nervous system, mirroring the other cohesinopathies. Human evidence for this node is inferential (the clinical phenotype is neurodevelopmental and the transcriptomic model system is neuronal); direct human neuropathology has not been reported.

Neural transcriptional dysregulation as a route to developmental disability

neuron CL:0000540

nervous system development GO:0007399 ⚠ ABNORMAL

Downstream

Developmental Delay and Intellectual Disability The clinical endpoint of the neurodevelopmental disturbance.

Show evidence (1 reference)

PMID:42431198 SUPPORT In Vitro

"We used CRISPR to generate truncating variants in WAPL and 10q deletion or duplication in human induced pluripotent stem cells (iPSCs) and induced neurons."

Establishes that the modelled cell type is neuronal, which is why the transcriptional consequence is interpreted as neurodevelopmental. Marked PARTIAL because the paper does not report a human neuroanatomical or neuropathological phenotype.

Developmental Delay and Intellectual Disability

Mechanism confidence: Established

The organism-level output of the cascade: a developmental disorder whose consistent features are developmental delay and intellectual disability, with an added risk of other developmental anomalies. In the contiguous-gene subtype the delay is described as predominantly affecting speech.

Show evidence (1 reference)

PMID:42431198 SUPPORT Human Clinical

"We identified a WAPL-related disorder featuring developmental delay, intellectual disability, and risk of other developmental anomalies."

The defining clinical statement of the disorder.

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Pathograph

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

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Phenotypes

20

Breast 1

Congenital Breast Aplasia HP:0100783

Show evidence (1 reference)

PMID:21248748 SUPPORT Human Clinical

"For congenital breast aplasia, the NRG3 gene, known to be involved in early mammary gland development in mice, is a putative candidate gene."

Supports the feature and records its attribution to NRG3 rather than WAPL.

Cardiovascular 2

Cardiovascular Abnormality (WAPL Variant) OCCASIONAL Abnormality of the cardiovascular system HP:0001626

Show evidence (1 reference)

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"clubfoot (n = 4), cardiac (n = 7)), and variable neurological features (n = 14; including 4 with"

7 of 25 phenotyped individuals (28%) supports the OCCASIONAL band, in a cohort ascertained on WAPL sequence variants rather than 10q deletions.

Cardiovascular Abnormality (10q Deletion) OCCASIONAL Abnormality of the cardiovascular system HP:0001626

Show evidence (2 references)

PMID:21248748 SUPPORT Human Clinical

"For cardiac defects, BMPR1A and GRID1 are putative candidate genes because of their association with cardiac structure and function."

Supports both the occurrence of cardiac defects in this deletion and their attribution to genes other than WAPL.

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"the cardiovascular system (n = 5; 12%)"

Frequency evidence. 5 of the 41 rCNV deletion carriers (12%) carried the identically bound cardiovascular-system parent, placing this feature in the OCCASIONAL band (5-29%).

Digestive 1

Hamartomatous Polyposis HP:0004390

Onset: YOUNG ADULT

Frequency is deliberately omitted: the source reports a single case and explicitly argues that juvenile polyps have never previously been reported in this deletion because the deletion is now diagnosed by CNV array years before the digestive phenotype appears. That is an ascertainment argument for under-reporting, not a frequency estimate, so no band can be derived. The interval is labelled 10q22.3q23.1 (7 Mb) in this source and 10q22.3q23.2 elsewhere in the entry - see the entry notes on source-inherited cytoband labelling.

Show evidence (2 references)

PMID:31561016 SUPPORT Human Clinical

"We present the case of a young adult harboring this recurrent deletion, in a context of intellectual disability, ventricular septal defect and severe juvenile polyposis syndrome diagnosed at the age of 25 years, requiring a surgical preventive colectomy."

The index observation linking the recurrent deletion to juvenile polyposis, alongside the intellectual disability and cardiac defect that are already curated on this subtype. Onset is recorded as YOUNG_ADULT because that is the age at diagnosis in the only reported case.

PMID:31561016 SUPPORT Human Clinical

"This observation highlights the importance of an active digestive surveillance of patients with 10q22.3q23.1 deletion."

The surveillance recommendation, which is the actionable consequence of this phenotype and the reason it is curated despite resting on a single reported case.

Head and Neck 4

Craniofacial Dysmorphism FREQUENT Abnormal facial shape HP:0001999

Show evidence (1 reference)

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"craniofacial dysmorphism (n = 15 ) ... although some facial features were shared by multiple ... there is not a typical set of features across all ... individuals."

15 of 25 phenotyped individuals (60%) supports the FREQUENT band, and the same sentence carries the caveat that the features do not coalesce into a single gestalt.

Decreased Head Circumference OCCASIONAL HP:0040195

Contrast with the 10q Deletion subtype, where macrocephaly - the opposite direction - is the reported head-size finding. The two are curated on different subtypes and are not reconciled by any current source.

Show evidence (1 reference)

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"hypotonia, 2 with small head circumference)."

2 of 25 (8%) supports the OCCASIONAL band (5-29%).

Macrocephaly HP:0000256

Show evidence (1 reference)

PMID:21248748 SUPPORT Human Clinical

"In addition, macrocephaly, mild facial dysmorphisms, cerebellar anomalies, cardiac defects and congenital breast aplasia were observed."

Lists macrocephaly among the features of the LCR3-4 deletion cohort.

Abnormality of the Face (10q Deletion) OCCASIONAL HP:0000271

Show evidence (3 references)

PMID:21248748 SUPPORT Human Clinical

"Reciprocal deletions lead to speech and language delay, mild facial dysmorphisms and, in some individuals, to cerebellar, breast developmental and cardiac defects."

Summarises the deletion phenotype including mild facial dysmorphism.

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"abnormality of the face (n = 8; 20%)"

Frequency evidence. 8 of the 41 rCNV deletion carriers (20%) carried an HPO term for abnormality of the face, which places the identically bound phenotype in the OCCASIONAL band (5-29%).

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"Our analysis identified 41 carriers of the canonical"

Establishes the denominator (41 deletion carriers ascertained from the cross-disorder rCNV microarray dataset) against which the 20% is computed.

Limbs 2

Talipes Equinovarus OCCASIONAL HP:0001762

Show evidence (2 references)

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"clubfoot (n = 4), cardiac (n = 7)), and variable neurological features (n = 14; including 4 with"

4 of 25 phenotyped individuals (16%) supports the OCCASIONAL band.

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"intellectual disability, and risk of other developmental anomalies including clubfoot."

The preprint abstract names clubfoot specifically, where the ahead-of-print journal abstract says only "other developmental anomalies".

Talipes Equinovarus (10q Deletion) OCCASIONAL HP:0001762

Show evidence (2 references)

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"musculoskeletal abnormalities (including clubfoot in 6 individuals)"

6 of the 27 published deletion cases (22%) supports the OCCASIONAL band (5-29%).

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"we performed a literature review and identified 27 published cases of the"

Establishes the denominator for this band - the 27 published deletion cases, a different cohort from the 41 rCNV carriers used for the other deletion-arm bands.

Musculoskeletal 1

Hypotonia OCCASIONAL HP:0001252

Show evidence (2 references)

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"variable neurological features (n = 14; including 4 with"

Opens the enumeration of the neurological aggregate; the count of 4 is attached to hypotonia in the continuation quoted below.

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"hypotonia, 2 with small head circumference)."

Completes the sentence and names hypotonia as the feature carrying the count of 4. 4 of 25 (16%) supports the OCCASIONAL band (5-29%), the same count and band used for clubfoot. The two quotes are given separately because the sentence spans a page-layout line break in the source.

Nervous System 9

Global Developmental Delay VERY_FREQUENT HP:0001263

The frequency band is derived from the medRxiv preprint of the defining study (DOI:10.64898/2026.02.23.26346364), which reports the per-feature counts the ahead-of-print abstract omits: 21 of 25 phenotyped individuals (84%). Developmental delay and intellectual disability are counted together in that source, so the same denominator and band apply to both.

Show evidence (3 references)

PMID:42431198 SUPPORT Human Clinical

"We identified a WAPL-related disorder featuring developmental delay, intellectual disability, and risk of other developmental anomalies."

Names developmental delay as a core feature of the newly delineated disorder.

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"developmental delay/intellectual disability is present in most (n = 21)"

Quantitative support for the VERY_FREQUENT band. The preprint of the same study reports 21 affected individuals out of the 25 with detailed phenotype information (84%), which falls in the 80-99% band.

PMID:21248748 SUPPORT Human Clinical

"Most of the individuals with the LCR3-4 deletion had developmental delay, mainly affecting speech."

Supports developmental delay and its speech-predominant presentation in the deletion subtype.

Intellectual Disability VERY_FREQUENT HP:0001249

Show evidence (3 references)

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"mild-moderate developmental delay/intellectual disability is present in most (n = 21)"

Quantitative support for the VERY_FREQUENT band (21 of 25 phenotyped individuals, 84%) and for the mild-to-moderate severity qualifier, both stated in the same sentence. The band is not narrowed further because the source counts developmental delay and intellectual disability jointly.

PMID:42431198 SUPPORT Human Clinical

"We identified a WAPL-related disorder featuring developmental delay, intellectual disability, and risk of other developmental anomalies."

Names intellectual disability as a core feature.

PMID:17436248 SUPPORT Human Clinical

"rearrangements in this region are associated with behavioral and neurodevelopmental abnormalities, including cognitive impairment, autism, hyperactivity, and possibly psychiatric disease"

Independent, earlier support for cognitive impairment in the contiguous-gene deletion subtype.

Behavioral Abnormality FREQUENT Atypical behavior HP:0000708

Show evidence (1 reference)

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"Many subjects also have behavioral features (n = 11), organ malformation"

11 of 25 phenotyped individuals (44%) supports the FREQUENT band.

Neurological Abnormality Abnormality of the nervous system HP:0000707

Show evidence (2 references)

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"variable neurological features (n = 14; including 4 with"

14 of 25 phenotyped individuals had neurological features beyond the developmental-delay core, supporting the association (the count is kept in prose rather than as a frequency band - see the description).

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"and neurological issues are each present in about half of subjects."

Independent corroboration from the figure legend, phrased qualitatively as "about half" - consistent with the 14/25 count.

Delayed Speech and Language Development HP:0000750

Attributed to the deletion subtype only. The abstract of the defining WAPL paper does not break the 27-individual sequence-variant cohort down by speech versus global delay.

Show evidence (1 reference)

PMID:21248748 SUPPORT Human Clinical

"Most of the individuals with the LCR3-4 deletion had developmental delay, mainly affecting speech."

Directly supports speech-predominant delay in the deletion subtype.

Autism HP:0000717

Deliberately unbanded. The rCNV deletion cohort codes behaviour only at the aggregate HPO level (atypical behavior, 5 of 41), and that count cannot be apportioned between autism and hyperactivity. The aggregate is banded on the separate Atypical Behavior phenotype below.

Show evidence (1 reference)

PMID:17436248 SUPPORT Human Clinical

"rearrangements in this region are associated with behavioral and neurodevelopmental abnormalities, including cognitive impairment, autism, hyperactivity, and possibly psychiatric disease"

Names autism among the behavioural features of the deletion.

Hyperactivity HP:0000752

Deliberately unbanded, for the same reason as Autism above: the rCNV cohort reports behaviour only as an aggregate.

Show evidence (1 reference)

PMID:17436248 SUPPORT Human Clinical

"rearrangements in this region are associated with behavioral and neurodevelopmental abnormalities, including cognitive impairment, autism, hyperactivity, and possibly psychiatric disease"

Names hyperactivity among the behavioural features of the deletion. The bound term is HP:0000752 Hyperactivity, an exact match for the reported feature; a formal ADHD diagnosis (HP:0007018) is not asserted by the source and is deliberately not used.

Atypical Behavior (10q Deletion) OCCASIONAL HP:0000708

The comparable sequence-variant figure is 11 of 25 (44%, FREQUENT) on the Behavioral Abnormality phenotype. The two arms are not directly comparable - the deletion count comes from HPO-coded microarray-referral records and the sequence-variant count from direct clinical phenotyping - so the difference should not be read as a dosage effect.

Show evidence (2 references)

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"and atypical behavior (n = 5)"

5 of the 41 rCNV deletion carriers (12%) supports the OCCASIONAL band (5-29%).

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"Our analysis identified 41 carriers of the canonical"

Establishes the 41-carrier denominator for the deletion-arm bands.

Cerebellar Anomalies Abnormal cerebellum morphology HP:0001317

Show evidence (1 reference)

PMID:21248748 SUPPORT Human Clinical

"In addition, macrocephaly, mild facial dysmorphisms, cerebellar anomalies, cardiac defects and congenital breast aplasia were observed."

Lists cerebellar anomalies among the deletion features.

🧬

Genetic Associations

3

WAPL (Heterozygous predicted damaging WAPL variants, and heterozygous deletion of WAPL within the recurrent 10q22.3q23.2 interval, cause a developmental disorder characterised by developmental delay and intellectual disability. WAPL encodes cohesin's DNA release factor; this is the first cohesin release factor to be associated with Mendelian disease.)

Gene: WAPL hgnc:23293 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:42431198 SUPPORT Human Clinical

"In summary, we delineated a genetic condition caused by cohesin release factor deficiency, nominated WAPL as a driver gene within a genomic disorder region, and further illuminated dosage sensitivity of human cohesin."

The authors' own summary of the gene-disease claim.

PDS5A (Eight individuals with heterozygous predicted damaging PDS5A variants were phenotyped in the same study. They exhibited features of developmental disorders, but neither cohort-based statistics nor subject phenotyping associated PDS5A with specific phenotypes. PDS5A is therefore recorded as investigated and unconfirmed, not as a disease gene.)

Gene: PDS5A hgnc:29088 relationship_type: UNKNOWN variant_origin: GERMLINE

Show evidence (1 reference)

PMID:42431198 SUPPORT Human Clinical

"While individuals with PDS5A or PDS5B variants exhibited features of developmental disorders, neither cohort-based statistics nor subject phenotyping associated these genes with specific phenotypes."

Explicitly declines to establish a gene-disease association for PDS5A, which is why the relationship type is UNKNOWN.

PDS5B (As for PDS5A, eight individuals with heterozygous predicted damaging PDS5B variants were phenotyped without a specific phenotype association emerging. PDS5B is a WAPL binding partner and, with PDS5A, controls loop length together with WAPL, so it remains a strong biological candidate awaiting additional cases.)

Gene: PDS5B hgnc:20418 relationship_type: UNKNOWN variant_origin: GERMLINE

Show evidence (2 references)

PMID:42431198 SUPPORT Human Clinical

"While individuals with PDS5A or PDS5B variants exhibited features of developmental disorders, neither cohort-based statistics nor subject phenotyping associated these genes with specific phenotypes."

Same negative-association statement as for PDS5A.

PMID:29217591 SUPPORT In Vitro

"the cohesin unloading factor WAPL and its PDS5 binding partners control the length of loops"

Biological rationale for treating PDS5A/PDS5B as candidate genes in the same mechanism, independent of the currently unestablished clinical association.

🗃️

External Assertions

1

OMIM 10q22.3q23.3 microdeletion syndrome identifier

OMIM related identifier OMIM:612242

OMIM identifier for the recurrent 10q22.3q23.3 deletion syndrome, recorded as a related external identifier for the contiguous-gene subtype. There is no OMIM phenotype entry for the monogenic WAPL disorder at curation time.

💊

Medical Actions

1

Digestive surveillance for 10q deletion carriers

Category: Monitoring Action: clinical evaluation Ontology label: Clinical Evaluation NCIT:C124351

Active digestive surveillance is recommended for carriers of the recurrent 10q22.3q23.1/10q22.3q23.2 deletion because the interval includes BMPR1A and a reported adult developed severe juvenile polyposis. The manifestation being surveilled for is the hamartomatous polyposis curated in the `phenotypes` section (HP:0004390); this is detection, not treatment, so the action carries no `target_phenotypes` link. This recommendation applies to the contiguous-deletion subtype, not to isolated WAPL variants; the source does not specify a surveillance modality or interval.

Show evidence (1 reference)

PMID:31561016 SUPPORT Human Clinical

"This observation highlights the importance of an active digestive surveillance of patients with 10q22.3q23.1 deletion."

Directly supports surveillance limited to deletion carriers.

🔬

Diagnosis

3

Molecular identification of a damaging WAPL sequence variant

The sequence-variant subtype is defined by a heterozygous predicted damaging WAPL variant. The cited cohort does not establish a preferred clinical assay or validated variant-classification algorithm, so no specific sequencing platform is asserted here.

Show evidence (1 reference)

PMID:42431198 SUPPORT Human Clinical

"phenotyping individuals with heterozygous predicted damaging variants in WAPL (n = 27)"

Establishes that the diagnostic finding is a heterozygous predicted damaging WAPL sequence variant.

Chromosomal microarray for the recurrent 10q22.3q23.2 deletion

The contiguous-gene subtype is detected by chromosomal microarray as a recurrent copy-number loss between the low-copy repeats LCR3 and LCR4. Because the breakpoints are LCR-mediated, the deletion is recurrent and of reproducible size, which is what makes it a classical genomic disorder.

Show evidence (1 reference)

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"We screened our cross-disorder rare copy number variant (rCNV) microarray dataset ... Our analysis identified 41 carriers of the canonical ... 10q22.3q23.2 deletion"

Directly documents detection of the canonical deletion in a microarray dataset.

Investigational DNA methylation episignature analysis

EpiSign analysis of peripheral blood DNA identified a cohesin release factor deficiency-associated methylation episignature, and a second signature combining WAPL sequence-variant and 10q deletion samples. Both classifiers showed high specificity against other episignature disorders, including Cornelia de Lange syndrome, whose overall methylation pattern these profiles do NOT mimic - so the episignature is not simply a cohesinopathy readout. The small research analyses do not establish a clinically validated diagnostic assay. The important bound is that the study did not find a methylation signature for WAPL sequence variants alone (the left-out sample clustered with cases in 0 of 8 leave-one-out iterations of that analysis). This assay therefore cannot currently be used to reclassify an isolated WAPL variant of uncertain significance; the reported profiles apply only to the combined and release-factor-wide research groupings.

Show evidence (4 references)

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"we identified an overall cohesin release factor deficiency -associated DNA"

Establishes that a methylation episignature exists for cohesin release factor deficiency as a group. The sentence is split across a page-layout line break in the source, so its continuation is quoted as the next evidence item rather than joined here.

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"methylation signature and a DNA methylation signature combining WAPL SNV and 10q del"

Completes the preceding quote and establishes the second, combined sequence-variant-plus-deletion signature.

DOI:10.64898/2026.02.23.26346364 Preprint · not peer-reviewed SUPPORT Human Clinical

"We did not identify a DNA methylation signature for WAPL SNVs alone."

The explicit negative result that bounds the assay's diagnostic use. Recorded as PARTIAL because it supports the existence of the episignature workup while refuting its applicability to isolated WAPL sequence variants.

+ 1 more reference

📊

Prevalence

2

Worldwide reported literature

Cases In Literature Ultra Rare

No population-based prevalence estimate exists for the monogenic disorder, which was first delineated in 2026. The only defensible measure is the published case count: 27 individuals with heterozygous predicted damaging WAPL sequence variants in the defining report.

Show evidence (1 reference)

PMID:42431198 SUPPORT Human Clinical

"phenotyping individuals with heterozygous predicted damaging variants in WAPL (n = 27)"

Provides the published worldwide case count for the sequence-variant subtype, supporting an ultra-rare classification.

Worldwide reported literature (10q22.3q23.2 deletion subtype)

Cases In Literature Ultra Rare

The recurrent LCR3-4 deletion is explicitly described as rare in the delineating cohort study, which assembled only eight deletions (five of them the recurrent LCR3-4 type) alongside six duplications.

Show evidence (1 reference)

PMID:21248748 SUPPORT Human Clinical

"The genomic architecture of the 10q22q23 region is characterised by two low-copy repeats (LCRs3 and 4), and deletions in this region appear to be rare."

States directly that deletions of this interval are rare, and gives the LCR architecture that makes them recurrent.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from WAPL-Related Developmental Disorder:

Cornelia de Lange Syndrome

Overlapping Features The archetypal cohesinopathy, caused mainly by NIPBL (the cohesin loader) and by cohesin subunit genes. It sits on the opposite side of the same cohesin cycle from WAPL: loading versus release. The methylation results and opposing mouse dosage effects support keeping the entities distinct rather than treating WAPL deficiency as an untyped Cornelia de Lange syndrome.

Show evidence (2 references)

PMID:42431198 SUPPORT Human Clinical

"Genes encoding cohesin and cohesin loaders have been associated with Mendelian disorders, whereas genes encoding cohesin release factors, including WAPL and its binding partners PDS5A and PDS5B, have not."

Places WAPL-related disorder beside the already-known cohesin and cohesin-loader disorders, of which Cornelia de Lange syndrome is the prototype.

PMID:36449618 SUPPORT Model Organism

"Since WAPL and NIPBL have opposite effects on cohesin's association with DNA, we asked whether decreasing Wapl dosage could correct phenotypes seen in Nipbl+/- mice. Gene expression and embryonic growth are partially corrected, but perinatal lethality is not."

Establishes the relationship between the two disorders as genuinely antagonistic rather than merely adjacent: lowering Wapl partially rescues the CdLS model. That the rescue is only partial - perinatal lethality persists - is why the two remain distinct entities and why this is a differential rather than a shared mechanism. Note the counterintuitive direction: reduced WAPL is the lesion in this disorder but a partial corrective in the loader disorder.

10q22.3q23.3 microduplication syndrome

Overlapping Features The reciprocal duplication of the same LCR3-4 interval. It has its own MONDO identity (MONDO:0017180) and a distinct, more variably penetrant presentation - speech and motor delay with a broad forehead, deep-set eyes, upslanting palpebral fissures, a smooth philtrum and a thin upper lip - and duplications have also been found in healthy family members. It is a different dosage direction and is deliberately not modelled as a subtype here.

Show evidence (2 references)

PMID:21248748 SUPPORT Human Clinical

"Duplications between LCRs3 and 4 are associated with variable phenotypic penetrance."

Distinguishes the reciprocal duplication by its variable penetrance.

PMID:21248748 SUPPORT Human Clinical

"Probands had speech and/or motor delays and dysmorphisms including a broad forehead, deep-set eyes, upslanting palpebral fissures, a smooth philtrum and a thin upper lip."

Supports the detailed reciprocal-duplication phenotype used in the differential.

🧫

Experimental Models

2

Isogenic WAPL-truncating and 10q-deletion human iPSC and induced-neuron model IPSC_DERIVED_MODEL

CRISPR-engineered human induced pluripotent stem cells and induced neurons carrying either WAPL truncating variants or an engineered 10q22.3q23.2 deletion (or the reciprocal duplication) in an otherwise isogenic background. Transcriptomic comparison of the two genotypes is the experiment that links the monogenic lesion to the genomic disorder: their differentially expressed gene sets overlap significantly.

Organism

human NCBITaxon:9606

Culture

Isogenic iPSC lines differentiated to induced neurons, profiled by transcriptomics

Publication

PMID:42431198

Pathograph links

Transcriptional Dysregulation The model provides the transcriptional read-out that WAPL haploinsufficiency and 10q deletion converge on shared gene-expression changes in a human neural lineage.

Show evidence (1 reference)

PMID:42431198 SUPPORT In Vitro

"Transcriptomics identified significant overlap between WAPL haploinsufficiency and 10q deletion differentially expressed genes."

Links this model system to the Transcriptional Dysregulation node it supports.

Findings

WAPL haploinsufficiency and 10q22.3q23.2 deletion produce significantly overlapping differentially expressed gene sets in isogenic human iPSCs and induced neurons.

"Transcriptomics identified significant overlap between WAPL haploinsufficiency and 10q deletion differentially expressed genes."

Show evidence (1 reference)

PMID:42431198 SUPPORT In Vitro

"Transcriptomics identified significant overlap between WAPL haploinsufficiency and 10q deletion differentially expressed genes."

The sentence reporting this finding.

Show evidence (2 references)

PMID:42431198 SUPPORT In Vitro

"We used CRISPR to generate truncating variants in WAPL and 10q deletion or duplication in human induced pluripotent stem cells (iPSCs) and induced neurons."

Describes the engineered genotypes and cell systems of the model.

PMID:42431198 SUPPORT In Vitro

"Transcriptomics identified significant overlap between WAPL haploinsufficiency and 10q deletion differentially expressed genes."

The model's key finding.

WAPL-knockout human HAP1 Hi-C model CELL_LINE

CRISPR WAPL-knockout HAP1 cells profiled by Hi-C, the system in which the chromosome-folding consequences of losing cohesin release were first resolved genome-wide. Not a disease model in itself, but the source of the mechanistic node linking WAPL loss to extended chromatin loops and degraded TAD insulation.

Organism

human NCBITaxon:9606

Cell source

HAP1 near-haploid human cell line

Culture

Genome-wide chromosome conformation capture (Hi-C) and CTCF/SMC1 ChIP-seq

Publication

PMID:28475897

Pathograph links

Extended Chromatin Loops and Altered Genome Folding Provides the direct experimental demonstration that loss of WAPL lengthens chromatin loops and increases inter-TAD contact.

Show evidence (1 reference)

PMID:28475897 SUPPORT In Vitro

"WAPL deficiency led to the extension of chromatin loops and strongly increased interaction frequencies between nearby TADs"

The Hi-C result from this model that the pathophysiology node rests on.

Show evidence (1 reference)

PMID:28475897 SUPPORT In Vitro

"we generated WAPL knockout HAP1 cells using CRISPR technology"

Describes the model system.

🐁

Animal Models

1

Wapl hypomorphic mouse dosage series

A graded Wapl-dosage mouse series is the in vivo arm of the defining study and is the source of the dosage-liability-threshold claim. Mice retaining about half of normal Wapl expression show mild growth and learning/memory deficits. Mice retaining only a quarter show birth defects and die after birth. Translation of that mouse dose-response to humans remains explicitly unresolved in the HUMAN_MODEL_MISMATCH discussion.

Species

Mus musculus

Genotype

Wapl hypomorphic allelic series (approximately 50% and 25% residual Wapl expression)

Genes

WAPL hgnc:23293

Show evidence (1 reference)

PMID:42431198 SUPPORT Model Organism

"Mice with 50% Wapl expression exhibited mild deficits of growth and learning/memory, whereas those with 25% residual Wapl displayed birth defects and postnatal lethality, revealing a dosage liability threshold below the level of heterozygosity."

Describes the model, both dosage arms, and the threshold inference.

{ }

Source YAML

click to show

name: WAPL-Related Developmental Disorder
creation_date: "2026-07-12T21:00:00Z"
category: Mendelian
description: >-
  WAPL-related developmental disorder is a recently delineated, ultra-rare
  neurodevelopmental condition caused by heterozygous damaging variants in WAPL,
  the gene encoding cohesin's DNA release (unloading) factor. Cohesin is a
  ring-shaped complex that organises the genome into chromatin loops and
  topologically associating domains; loading of cohesin onto DNA by NIPBL/MAU2
  and release of cohesin from DNA by WAPL together set the residence time of
  cohesin on chromatin and hence the size and dynamics of loops. Genes encoding
  cohesin subunits and the cohesin loader had already been associated with the
  cohesinopathies (most prominently Cornelia de Lange syndrome), but until 2026
  no cohesin release factor had been linked to a Mendelian disease. Phenotyping
  of 27 individuals with heterozygous predicted damaging WAPL variants defined a
  disorder whose core is developmental delay and intellectual disability, with an
  additional risk of other developmental anomalies. The same work nominated WAPL
  as a phenotypic driver gene inside the recurrent, low-copy-repeat-mediated
  10q22.3q23.2 deletion region, on the basis of clinical similarity between the
  two groups and of overlapping transcriptomic consequences of WAPL
  haploinsufficiency and 10q deletion in isogenic human iPSCs and induced
  neurons. Mouse dosage series place the liability threshold below
  heterozygosity: 50% Wapl expression produces mild growth and learning/memory
  deficits, whereas 25% residual Wapl produces birth defects and postnatal
  lethality.
notes: >-
  Scope and naming. This entry is the monogenic WAPL entity. The recurrent
  10q22.3q23.2 (LCR3-4) deletion is curated here as a contiguous-gene subtype
  rather than as a separate disease page, because the defining publication
  (PMID:42431198) nominates WAPL as the phenotypic driver within that interval
  and the two presentations are argued to be mechanistically continuous. Claims
  that are specific to the deletion and that the source literature attributes to
  other genes in the interval (for example congenital breast aplasia, for which
  PMID:21248748 proposes NRG3, and cardiac defects, for which it proposes BMPR1A
  and GRID1) are curated on the deletion subtype and are explicitly NOT
  attributed to WAPL.

  Named-entity-confusion preflight. No MONDO term exists for the monogenic
  WAPL-related disorder. `runoak -i sqlite:obo:mondo search "l~WAPL"` returns no
  hits, so `disease_term` is deliberately omitted pending ontology coverage
  rather than being back-filled with a near-miss term. In particular
  MONDO:0012830 (chromosome 10q23 deletion syndrome / 10q22.3q23.3 microdeletion
  syndrome; Orphanet:276413, OMIM:612242) is NOT used as the `disease_term`,
  because it denotes the contiguous-gene deletion entity and not the single-gene
  disorder; it is recorded instead as a `skos:relatedMatch` mapping and as the
  subtype grounding. MONDO:0017180 is the reciprocal duplication syndrome and is
  out of scope here.

  Evidence limits. PMID:42431198 was published online ahead of print on
  2026-07-10 and is cached as abstract only (`content_type: abstract_only`). The
  same study is, however, openly available as a medRxiv preprint
  (DOI:10.64898/2026.02.23.26346364, posted 2026-02-28, recorded as the "Update
  of" record in the PubMed entry), which is cached here as full text and is the
  source of every per-feature count in this entry. Phenotype `frequency:` bands
  for the sequence-variant subtype are derived from that preprint's denominator
  of 25 phenotyped individuals (of 27 ascertained), not from the 27-individual
  headline figure, and each band cites the count that supports it per
  docs/frequency-evidence-guidelines.md.

  What the preprint does NOT provide is case-level data: it states that Table 1,
  Table S4, Fig. 2 and Fig. S12 have had age, sex, phenotype and photographs
  removed per medRxiv guidelines. Detailed variant-level curation (`variants:`)
  and facial-gestalt findings therefore still await the peer-reviewed full text
  and remain tracked as an open discussion below, as does the PDS5A/PDS5B
  question.

  Cytoband coordinates. Both `10q22.3q23.2` and `10q22.3q23.3` appear in this
  entry, and the inconsistency is inherited from the sources rather than
  introduced here. PMID:21248748 describes the whole surveyed interval as
  `10q22.3q23.3` while placing the recurrent LCR3-4 rearrangements at
  `10q22.3q23.2`; MONDO:0012830 and Orphanet:276413 name the entity with the
  wider `10q22.3q23.3` label; the 2026 WAPL study uses `10q22.3q23.2` for the
  recurrent LCR3-4 deletion it studies. This entry uses `10q22.3q23.2` for the
  recurrent LCR3-4 deletion itself and retains `10q22.3q23.3` only where it is
  the name of an external record. The two are not competing claims about
  different deletions.

  Deliberate non-claims. (1) PDS5A and PDS5B are curated with
  `relationship_type: UNKNOWN`; the source explicitly states that neither
  cohort-based statistics nor subject phenotyping associated these genes with
  specific phenotypes, so they are recorded as investigated-but-unconfirmed
  rather than as disease genes. (2) No disease-modifying or WAPL-specific
  therapy has been reported, and generic developmental supportive care is not
  sourced to any WAPL publication. The sole management entry is active digestive
  surveillance explicitly recommended for the BMPR1A-containing deletion
  subtype; it does not apply to isolated WAPL variants. (3) The
  mouse dosage-threshold result is curated as MODEL_ORGANISM evidence and is
  paired with a HUMAN_MODEL_MISMATCH discussion, because the human cohort is
  entirely heterozygous and the severe (25% residual Wapl) arm has no human
  counterpart.

  Structured sources. No ORPHA, ClinGen gene-disease validity, or ClinGen dosage
  record exists for WAPL *as a monogenic disease gene* at curation time; that
  gene-disease relationship rests entirely on the 2026 primary report. This is
  narrower than an absence of Orphanet coverage for the whole entry: ORPHA:276413
  does exist for the contiguous-gene 10q deletion subtype (= MONDO:0012830,
  OMIM:612242) and carries a phenotype table with frequency bands that would
  enrich that subtype. It is not cited here only because the pinned Orphadata
  snapshot in `data/orphadata/MANIFEST.yaml` no longer matches upstream -
  `just refresh-orphadata` fails with a checksum mismatch on `en_product1.xml` -
  so `references_cache/ORPHA_276413.md` cannot be generated without re-pinning
  the snapshot, which is a repo-wide change out of scope for this entry. Mining
  ORPHA:276413 for the deletion-subtype phenotypes is tracked as an open
  discussion below.
parents:
- Neurodevelopmental Disorder
- cohesinopathy
- syndromic intellectual disability
- Genetic Disease
synonyms:
- WAPL-related neurodevelopmental disorder
- WAPL haploinsufficiency
- cohesin release factor deficiency
- WAPL-related disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0012830
      label: chromosome 10q23 deletion syndrome
    mapping_predicate: skos:relatedMatch
    mapping_source: MONDO
    mapping_justification: >-
      Related, not equivalent. MONDO:0012830 is the recurrent contiguous-gene
      10q22.3q23.3 microdeletion entity; this dismech entry is the monogenic
      WAPL disorder, which PMID:42431198 nominates as the phenotypic driver
      within that deletion interval. The deletion entity is additionally
      recorded as a subtype of this entry.
external_assertions:
- name: OMIM 10q22.3q23.3 microdeletion syndrome identifier
  source: OMIM
  assertion_type: related_identifier
  external_id: OMIM:612242
  description: >-
    OMIM identifier for the recurrent 10q22.3q23.3 deletion syndrome, recorded
    as a related external identifier for the contiguous-gene subtype. There is
    no OMIM phenotype entry for the monogenic WAPL disorder at curation time.
has_subtypes:
- name: WAPL Variant
  display_name: WAPL sequence-variant subtype (heterozygous damaging WAPL variant)
  description: >-
    Individuals with a heterozygous predicted damaging sequence variant in WAPL
    and no deletion of the surrounding 10q22.3q23.2 interval. This is the
    subtype that establishes WAPL as a Mendelian disease gene; 27 such
    individuals were phenotyped in the defining report.
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We explored the relevance of cohesin release factors in Mendelian disease
      by phenotyping individuals with heterozygous predicted damaging variants
      in WAPL (n = 27), PDS5A (n = 8), and PDS5B (n = 8)
    explanation: >-
      Defines the sequence-variant cohort and its size, and states that the
      variants are heterozygous.
- name: 10q Deletion
  display_name: 10q22.3q23.2 contiguous-gene deletion subtype (WAPL-containing)
  subtype_term:
    preferred_term: 10q22.3q23.2 recurrent deletion syndrome
    term:
      id: MONDO:0012830
      label: chromosome 10q23 deletion syndrome
  description: >-
    Individuals with a large recurrent deletion of 10q22.3q23.2, generated by
    non-allelic homologous recombination between the flanking low-copy repeats
    LCR3 and LCR4, which removes WAPL together with roughly 30 neighbouring
    genes. Clinically this subtype adds features that the source literature
    attributes to other genes in the interval (cardiac defects, congenital
    breast aplasia, cerebellar anomalies, macrocephaly) on top of the
    developmental delay shared with the sequence-variant subtype.
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similarities between individuals with damaging WAPL variants and those
      with large, recurrent 10q22.3q23.2 (10q) deletions encompassing WAPL
      nominate WAPL as a driver gene within this genomic disorder region.
    explanation: >-
      Establishes the deletion group as clinically overlapping with, and
      mechanistically linked to, the monogenic WAPL group.
  - reference: PMID:17436248
    reference_title: "Recurrent 10q22-q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data provide evidence that the 10q22-q23 genomic region harbors one or
      more genes important for cognitive and behavioral development and that
      recurrent deletions affecting this interval define a novel genomic
      disorder.
    explanation: >-
      Original delineation of the recurrent 10q22-q23 deletion as a genomic
      disorder, i.e. the entity within which WAPL was later nominated as driver.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    All reported affected individuals carry a single damaging WAPL allele:
    either a heterozygous sequence variant or a heterozygous deletion of the
    10q22.3q23.2 interval containing WAPL, supporting autosomal-dominant
    inheritance. Protein-truncating variants and deletions act through reduced
    dosage; the functional mechanism of each predicted damaging missense allele
    remains unresolved.
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      phenotyping individuals with heterozygous predicted damaging variants in
      WAPL (n = 27)
    explanation: >-
      States that the disease-associated WAPL genotype in the human cohort is
      heterozygous, i.e. a monoallelic (dominant) mechanism.
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      large, recurrent 10q22.3q23.2 (10q) deletions encompassing WAPL
    explanation: Supports monoallelic copy loss for the deletion subtype.
prevalence:
- population: Worldwide reported literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based prevalence estimate exists for the monogenic disorder,
    which was first delineated in 2026. The only defensible measure is the
    published case count: 27 individuals with heterozygous predicted damaging
    WAPL sequence variants in the defining report.
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      phenotyping individuals with heterozygous predicted damaging variants in
      WAPL (n = 27)
    explanation: >-
      Provides the published worldwide case count for the sequence-variant
      subtype, supporting an ultra-rare classification.
- population: Worldwide reported literature (10q22.3q23.2 deletion subtype)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The recurrent LCR3-4 deletion is explicitly described as rare in the
    delineating cohort study, which assembled only eight deletions (five of them
    the recurrent LCR3-4 type) alongside six duplications.
  evidence:
  - reference: PMID:21248748
    reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The genomic architecture of the 10q22q23 region is characterised by two
      low-copy repeats (LCRs3 and 4), and deletions in this region appear to be
      rare.
    explanation: >-
      States directly that deletions of this interval are rare, and gives the
      LCR architecture that makes them recurrent.
pathophysiology:
- name: Heterozygous Damaging WAPL Sequence Variant
  biological_scale: MOLECULAR
  subtypes:
  - WAPL Variant
  description: >-
    The proximal lesion of the sequence-variant subtype: a single heterozygous
    predicted damaging variant in WAPL, with the surrounding 10q22.3q23.2
    interval intact. This is the genotype that isolates WAPL from the other
    genes in the deletion interval and so establishes it as a Mendelian disease
    gene in its own right.
  gene:
    preferred_term: WAPL
    term:
      id: hgnc:23293
      label: WAPL
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We explored the relevance of cohesin release factors in Mendelian disease
      by phenotyping individuals with heterozygous predicted damaging variants
      in WAPL (n = 27), PDS5A (n = 8), and PDS5B (n = 8)
    explanation: >-
      Directly supports the heterozygous WAPL sequence-variant lesion and cohort.
  downstream:
  - target: WAPL Deficiency
    causal_link_type: DIRECT
    description: >-
      Predicted loss-of-function and damaging missense variants are grouped as
      cohesin-release-factor deficiency by the defining study. The precise
      functional effect of each missense allele has not been established.
    evidence:
    - reference: PMID:42431198
      reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In summary, we delineated a genetic condition caused by cohesin release
        factor deficiency
      explanation: >-
        Supports a deficiency state for the sequence-variant disorder while the
        description preserves uncertainty about individual missense alleles.
- name: Recurrent 10q22.3q23.2 Deletion
  biological_scale: MOLECULAR
  subtypes:
  - 10q Deletion
  description: >-
    Non-allelic homologous recombination between the paralogous low-copy repeats
    LCR3 and LCR4 removes a multi-megabase interval of 10q22.3q23.2 containing
    roughly 30 genes, WAPL among them. The deletion is the historical entry
    point to this disorder: it was recognised as a genomic disorder associated
    with cognitive and behavioural abnormalities two decades before the driver
    gene was identified.
  genes:
  - preferred_term: WAPL
    term:
      id: hgnc:23293
      label: WAPL
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:17436248
    reference_title: "Recurrent 10q22-q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in the other two families, the breakpoints are within paralogous LCRs,
      removing approximately 7.2 Mb and 32 genes
    explanation: >-
      Documents the low-copy-repeat-mediated recurrent breakpoints and the
      contiguous-gene extent of the deletion.
  downstream:
  - target: WAPL Deficiency
    causal_link_type: DIRECT
    description: >-
      The deletion removes one copy of WAPL, producing the same reduced-dosage
      state as a damaging sequence variant. Clinical similarity between the two
      groups is the basis of the driver-gene nomination. Note that the deletion
      also removes roughly 30 other genes, so it is not reducible to this edge -
      the deletion-only features curated on the 10q Deletion subtype are
      attributed elsewhere in the interval.
    evidence:
    - reference: PMID:42431198
      reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Similarities between individuals with damaging WAPL variants and those
        with large, recurrent 10q22.3q23.2 (10q) deletions encompassing WAPL
        nominate WAPL as a driver gene within this genomic disorder region.
      explanation: >-
        States the inference that connects the contiguous-gene deletion to the
        monogenic lesion.
  - target: Contiguous Loss of Neighbouring Genes
    causal_link_type: DIRECT
    description: >-
      The same LCR3-4 event removes roughly 30 other genes, so the deletion has
      a second, WAPL-independent arm. This edge exists so that the
      deletion-only features are routed through the pathograph rather than
      attributed by prose alone.
    evidence:
    - reference: PMID:17436248
      reference_title: "Recurrent 10q22-q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        in the other two families, the breakpoints are within paralogous LCRs,
        removing approximately 7.2 Mb and 32 genes
      explanation: Directly supports simultaneous loss of the neighbouring-gene interval.
- name: Contiguous Loss of Neighbouring Genes
  biological_scale: MOLECULAR
  subtypes:
  - 10q Deletion
  description: >-
    The WAPL-independent arm of the contiguous-gene deletion. Alongside WAPL,
    the LCR3-4 interval carries roughly 30 genes, and the deletion literature
    proposes specific candidates for the deletion-only features: NRG3 for
    congenital breast aplasia, on the basis of its role in early mammary gland
    development in mice; and BMPR1A and GRID1 for the cardiac defects, on the
    basis of their association with cardiac structure and function. These
    candidate attributions are the reason those phenotypes are curated on the
    10q Deletion subtype and explicitly NOT on WAPL. Note that cardiac
    malformation also occurs in WAPL sequence-variant carriers who have no
    deletion, so the cardiac phenotype is likely to have contributions from both
    arms; breast aplasia has no sequence-variant counterpart.
  genes:
  - preferred_term: NRG3
    term:
      id: hgnc:7999
      label: NRG3
  - preferred_term: BMPR1A
    term:
      id: hgnc:1076
      label: BMPR1A
  - preferred_term: GRID1
    term:
      id: hgnc:4575
      label: GRID1
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:21248748
    reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For congenital breast aplasia, the NRG3 gene, known to be involved in
      early mammary gland development in mice, is a putative candidate gene.
    explanation: >-
      Names NRG3 as the candidate for the breast-aplasia feature, which is what
      keeps that phenotype off WAPL.
  - reference: PMID:21248748
    reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For cardiac defects, BMPR1A and GRID1 are putative candidate genes because
      of their association with cardiac structure and function.
    explanation: >-
      Names BMPR1A and GRID1 as the candidates for the cardiac feature. Recorded
      at PROVISIONAL confidence because the source proposes them as putative
      candidates rather than demonstrating causation.
  - reference: PMID:31561016
    reference_title: "Patients with 10q22.3q23.1 recurrent deletion syndrome are at risk for juvenile polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More specifically, point mutations and structural abnormalities in BMPR1A
      lead to a highly penetrant yet variable phenotype of JPS.
    explanation: >-
      The strongest link in this node, and the reason it is not merely
      speculative: BMPR1A is an established juvenile-polyposis gene in which
      structural loss is itself pathogenic, so its inclusion in the deleted
      interval predicts a cancer-predisposition phenotype independently of any
      candidate-gene reasoning about the deletion.
  - reference: PMID:17436248
    reference_title: "Recurrent 10q22-q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in the other two families, the breakpoints are within paralogous LCRs,
      removing approximately 7.2 Mb and 32 genes
    explanation: >-
      Establishes the gene content of the interval that this node represents.
  downstream:
  - target: Congenital Breast Aplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - deletion_interval_candidate_gene_effects
    description: >-
      The deletion literature nominates NRG3 as a candidate for congenital
      breast aplasia, but does not establish the causal variant-to-organ route.
    evidence:
    - reference: PMID:21248748
      reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        For congenital breast aplasia, the NRG3 gene, known to be involved in
        early mammary gland development in mice, is a putative candidate gene.
      explanation: >-
        PARTIAL because the source frames the gene-to-malformation link as a
        putative candidate attribution rather than a demonstrated causal chain.
  - target: Hamartomatous Polyposis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The deletion removes BMPR1A, an established juvenile-polyposis gene; the
      clinical deletion report documents severe juvenile polyposis. The edge is
      indirect because the intervening tissue pathogenesis is not represented.
    evidence:
    - reference: PMID:31561016
      reference_title: "Patients with 10q22.3q23.1 recurrent deletion syndrome are at risk for juvenile polyposis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        More specifically, point mutations and structural abnormalities in
        BMPR1A lead to a highly penetrant yet variable phenotype of JPS.
      explanation: Directly links structural BMPR1A loss to juvenile polyposis.
- name: WAPL Deficiency
  biological_scale: MOLECULAR
  description: >-
    The convergence point of the two lesions: reduced WAPL dosage after a
    deletion or protein-truncating variant, and predicted impaired function for
    damaging missense variants. The isogenic experiment directly establishes
    haploinsufficiency only for engineered frameshift and deletion models; the
    functional effect of each clinical missense allele remains unresolved.
  gene:
    preferred_term: WAPL
    term:
      id: hgnc:23293
      label: WAPL
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Transcriptomics identified significant overlap between WAPL
      haploinsufficiency and 10q deletion differentially expressed genes.
    explanation: >-
      Names WAPL haploinsufficiency as the engineered loss-of-function state and
      shows that it recapitulates the transcriptional consequence of the whole deletion.
  downstream:
  - target: Impaired Cohesin Release from Chromatin
    causal_link_type: DIRECT
    description: >-
      Halving WAPL dosage reduces the cohesin-unloading activity available to
      remove cohesin rings from DNA.
    evidence:
    - reference: PMID:17113138
      reference_title: "Wapl controls the dynamic association of cohesin with chromatin."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Our data indicate that Wapl is required to unlock cohesin from a
        particular state in which it is stably bound to chromatin.
      explanation: Establishes the release function impaired when WAPL is deficient.
- name: Impaired Cohesin Release from Chromatin
  biological_scale: MOLECULAR
  description: >-
    WAPL is cohesin's DNA release factor: it opens the exit gate at the
    SMC3-RAD21 interface and unlocks cohesin from a state in which it is stably
    bound to chromatin. Loss of WAPL activity abolishes cohesin turnover, so
    cohesin remains loaded and its residence time on DNA increases. This is the
    core biochemical consequence expected from WAPL deficiency and is
    established from cell-biological loss-of-function work that predates the
    clinical entity. Direct release assays have not been reported for every
    clinical missense allele.
  molecular_functions:
  - preferred_term: cohesin unloader activity
    term:
      id: GO:0140670
      label: cohesin unloader activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: cohesin complex
    term:
      id: GO:0008278
      label: cohesin complex
  biological_processes:
  - preferred_term: sister chromatid cohesion
    term:
      id: GO:0007062
      label: sister chromatid cohesion
    modifier: ABNORMAL
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:17113138
    reference_title: "Wapl controls the dynamic association of cohesin with chromatin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our data indicate that Wapl is required to unlock cohesin from a
      particular state in which it is stably bound to chromatin.
    explanation: >-
      Establishes the molecular function that is reduced in this disorder:
      WAPL-dependent release of cohesin from chromatin.
  - reference: PMID:17113138
    reference_title: "Wapl controls the dynamic association of cohesin with chromatin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Wapl depletion also increases the residence time of cohesin on chromatin
      in interphase.
    explanation: >-
      Shows the direct consequence of reduced WAPL activity in interphase, the
      cell-cycle phase relevant to transcriptional regulation in developing
      tissue.
  - reference: PMID:17113138
    reference_title: "Wapl controls the dynamic association of cohesin with chromatin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      its depletion blocks cohesin dissociation from chromosomes during the
      early stages of mitosis and prevents the resolution of sister chromatids
      until anaphase
    explanation: >-
      Direct support for the `sister chromatid cohesion / ABNORMAL` descriptor
      on this node: loss of WAPL leaves sister chromatids unresolved until
      anaphase, which is the mitotic readout of failed cohesin release.
  downstream:
  - target: Extended Chromatin Loops and Altered Genome Folding
    causal_link_type: DIRECT
    description: >-
      Because cohesin is not released, loop extrusion continues past its normal
      stopping points and loops become longer.
    evidence:
    - reference: PMID:28475897
      reference_title: "The Cohesin Release Factor WAPL Restricts Chromatin Loop Extension."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        WAPL deficiency led to the extension of chromatin loops and strongly
        increased interaction frequencies between nearby TADs
      explanation: Direct WAPL-deficiency experiment supports this edge.
- name: Extended Chromatin Loops and Altered Genome Folding
  biological_scale: MOLECULAR
  description: >-
    Cohesin structures interphase chromosomes by processively enlarging chromatin
    loops until it is stopped at CTCF sites or released by WAPL. When WAPL
    activity is reduced, loops extend well beyond their normal length, cohesin
    accumulates in axial vermicelli-like positions, interactions between
    neighbouring topologically associating domains increase, and loops form
    between incorrectly oriented CTCF sites. The three-dimensional genome
    therefore folds abnormally.
  biological_processes:
  - preferred_term: chromatin looping
    term:
      id: GO:0140588
      label: chromatin looping
    modifier: ABNORMAL
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:28475897
    reference_title: "The Cohesin Release Factor WAPL Restricts Chromatin Loop Extension."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      WAPL restricts this loop extension and also prevents looping between
      incorrectly oriented CTCF sites.
    explanation: >-
      States the normal restraining function of WAPL on loop length and CTCF
      directionality, whose loss defines this node.
  - reference: PMID:28475897
    reference_title: "The Cohesin Release Factor WAPL Restricts Chromatin Loop Extension."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      WAPL deficiency led to the extension of chromatin loops and strongly
      increased interaction frequencies between nearby TADs
    explanation: >-
      Direct experimental demonstration in WAPL-knockout human cells that loops
      lengthen and inter-TAD insulation is degraded.
  - reference: PMID:29217591
    reference_title: "Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In the absence of WAPL and PDS5 proteins, cohesin forms extended loops,
      presumably by passing CTCF sites, accumulates in axial chromosomal
      positions (vermicelli), and condenses chromosomes.
    explanation: >-
      Independent replication of the extended-loop phenotype, and the link to
      the PDS5 binding partners that are the other two cohesin release factor
      genes examined in the clinical study.
  downstream:
  - target: Transcriptional Dysregulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - altered_genome_folding_to_transcription
    description: >-
      WAPL-deficient cells show both altered loop/TAD contacts and differential
      expression, but the source explicitly leaves the general causal relation
      unresolved; this is therefore an emerging, indirect disease model.
    evidence:
    - reference: PMID:28475897
      reference_title: "The Cohesin Release Factor WAPL Restricts Chromatin Loop Extension."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        those TADs that contained differentially expressed genes showed
        significantly stronger interactions ... suggesting that the aberrant
        interaction between TADs can affect the expression of genes within
        these domains.
      explanation: Supports the proposed direction while retaining the authors' suggestive wording.
- name: Transcriptional Dysregulation
  biological_scale: CELLULAR
  description: >-
    Cohesin shapes gene expression through three-dimensional chromosome folding,
    so a folding defect is read out as a transcriptional one. In isogenic human
    iPSCs and induced neurons, CRISPR-engineered WAPL truncating variants and
    engineered 10q deletion produced significantly overlapping sets of
    differentially expressed genes - the direct molecular evidence that the
    monogenic and contiguous-gene lesions converge on a shared transcriptional
    consequence in a neural lineage.
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DYSREGULATED
  cell_types:
  - preferred_term: induced neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: induced pluripotent stem cell
    term:
      id: CL:0002248
      label: pluripotent stem cell
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Transcriptomics identified significant overlap between WAPL
      haploinsufficiency and 10q deletion differentially expressed genes.
    explanation: >-
      Shows that the two genotypes converge transcriptionally in an isogenic
      human neural model, which is the mechanistic core of the driver-gene claim.
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cohesin orchestrates gene expression via three-dimensional chromosome
      folding.
    explanation: >-
      States the general principle linking the folding defect above to the
      transcriptional defect at this node.
  - reference: PMID:33318687
    reference_title: "WAPL maintains a cohesin loading cycle to preserve cell-type-specific distal gene regulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Paradoxically, stabilization of cohesin binding, following WAPL ablation,
      results in depletion of cohesin from these cell-type-specific regions,
      loss of gene expression and differentiation.
    explanation: >-
      Supplies the missing step between the folding defect and the
      transcriptional one, and corrects an intuition the loop-extension model
      invites: because WAPL-driven turnover is what frees cohesin for reloading,
      losing WAPL does not simply leave cohesin in place - it strips cohesin
      from cell-type-specific regulatory sites. That is why a release-factor
      defect reads out as loss of cell-type-specific gene expression rather
      than as generic chromatin compaction.
  - reference: PMID:33318687
    reference_title: "WAPL maintains a cohesin loading cycle to preserve cell-type-specific distal gene regulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Chromosome conformation capture experiments show that cohesin turnover is
      important for maintaining promoter-enhancer loops.
    explanation: >-
      Identifies promoter-enhancer looping as the regulatory structure lost, the
      most plausible proximate mediator of the dysregulated transcription
      curated at this node.
  - reference: PMID:36449618
    reference_title: "Decreasing Wapl dosage partially corrects embryonic growth and brain transcriptome phenotypes in Nipbl(+/-) embryos."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we show dysregulation of >1000 genes in WaplΔ/+ embryonic mouse
      brain.
    explanation: >-
      Independent, and four years earlier, model-organism evidence that WAPL
      heterozygosity alone dysregulates transcription in developing brain -
      obtained without human patients and therefore not circular with the
      clinical delineation. Fenced as MODEL_ORGANISM.
  - reference: PMID:36449618
    reference_title: "Decreasing Wapl dosage partially corrects embryonic growth and brain transcriptome phenotypes in Nipbl(+/-) embryos."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The patterns of dysregulation are highly similar in Wapl and Nipbl
      heterozygotes, suggesting that Wapl mutations may also cause human
      disease.
    explanation: >-
      A prospective prediction that WAPL would prove to be a human disease gene,
      made from the transcriptomic similarity to the Cornelia de Lange model and
      subsequently borne out. Recorded here because it is the mechanistic reason
      the loader and release-factor lesions converge on one phenotype.
  downstream:
  - target: Impaired Neurodevelopment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - transcriptional_dysregulation_to_neurodevelopment
    description: >-
      Which dysregulated genes mediate the neurodevelopmental outcome has not
      been established; the link is asserted at the level of a shared
      transcriptomic signature in neural cells, not of an identified effector.
    evidence:
    - reference: PMID:36449618
      reference_title: "Decreasing Wapl dosage partially corrects embryonic growth and brain transcriptome phenotypes in Nipbl(+/-) embryos."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we show dysregulation of >1000 genes in WaplΔ/+ embryonic mouse
        brain. The patterns of dysregulation are highly similar in Wapl and
        Nipbl heterozygotes, suggesting that Wapl mutations may also cause human
        disease.
      explanation: Embryonic-brain dysregulation supports an emerging neurodevelopmental route, not a resolved human causal chain.
- name: Impaired Neurodevelopment
  biological_scale: TISSUE
  description: >-
    The tissue least able to tolerate cohesin-release dysfunction appears to be
    the developing nervous system, mirroring the other cohesinopathies. Human
    evidence for this node is inferential (the clinical phenotype is
    neurodevelopmental and the transcriptomic model system is neuronal); direct
    human neuropathology has not been reported.
  biological_processes:
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: ABNORMAL
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We used CRISPR to generate truncating variants in WAPL and 10q deletion or
      duplication in human induced pluripotent stem cells (iPSCs) and induced
      neurons.
    explanation: >-
      Establishes that the modelled cell type is neuronal, which is why the
      transcriptional consequence is interpreted as neurodevelopmental. Marked
      PARTIAL because the paper does not report a human neuroanatomical or
      neuropathological phenotype.
  downstream:
  - target: Developmental Delay and Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - transcriptional_dysregulation_to_neurodevelopment
    description: >-
      The clinical endpoint of the neurodevelopmental disturbance.
    evidence:
    - reference: PMID:42431198
      reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified a WAPL-related disorder featuring developmental delay,
        intellectual disability, and risk of other developmental anomalies.
      explanation: Establishes the endpoint; intervening neurodevelopmental mechanisms remain unresolved.
- name: Developmental Delay and Intellectual Disability
  biological_scale: ORGANISM
  description: >-
    The organism-level output of the cascade: a developmental disorder whose
    consistent features are developmental delay and intellectual disability,
    with an added risk of other developmental anomalies. In the contiguous-gene
    subtype the delay is described as predominantly affecting speech.
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a WAPL-related disorder featuring developmental delay,
      intellectual disability, and risk of other developmental anomalies.
    explanation: >-
      The defining clinical statement of the disorder.
mechanistic_hypotheses:
- hypothesis_group_id: altered_genome_folding_to_transcription
  hypothesis_label: Altered genome folding as a route to transcriptional dysregulation
  status: EMERGING
  description: >-
    WAPL loss produces extended loops, altered TAD contacts, promoter-enhancer
    loop disruption, and transcriptional changes, but the general causal route
    from three-dimensional folding to gene expression remains unresolved.
  evidence:
  - reference: PMID:28475897
    reference_title: "The Cohesin Release Factor WAPL Restricts Chromatin Loop Extension."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The formation of loops and TADs has been suggested to be linked to gene
      expression ... although the causal relationship between them has remained
      unresolved.
    explanation: The source explicitly defines the relationship as unresolved.
- hypothesis_group_id: transcriptional_dysregulation_to_neurodevelopment
  hypothesis_label: Neural transcriptional dysregulation as a route to developmental disability
  status: EMERGING
  description: >-
    WAPL dosage reduction dysregulates transcription in neural models and the
    human disorder is neurodevelopmental, but the responsible effector genes and
    tissue-level intermediates have not been identified.
  evidence:
  - reference: PMID:36449618
    reference_title: "Decreasing Wapl dosage partially corrects embryonic growth and brain transcriptome phenotypes in Nipbl(+/-) embryos."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we show dysregulation of >1000 genes in WaplΔ/+ embryonic mouse
      brain.
    explanation: Provides brain-specific model evidence without proving the human route.
- hypothesis_group_id: deletion_interval_candidate_gene_effects
  hypothesis_label: Candidate neighbouring-gene effects in the recurrent deletion
  status: EMERGING
  description: >-
    NRG3 is proposed for breast aplasia and BMPR1A/GRID1 for cardiac findings;
    these are candidate attributions rather than demonstrated causal routes.
  evidence:
  - reference: PMID:21248748
    reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For congenital breast aplasia, the NRG3 gene, known to be involved in
      early mammary gland development in mice, is a putative candidate gene.
    explanation: Explicitly supports only a candidate relationship.
phenotypes:
- category: Neurologic
  name: Global Developmental Delay
  description: >-
    Developmental delay is one of the two defining features of the disorder and
    is present in both the sequence-variant and the deletion subtype. In the
    contiguous-gene deletion cohort it was described as predominantly affecting
    speech.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a WAPL-related disorder featuring developmental delay,
      intellectual disability, and risk of other developmental anomalies.
    explanation: >-
      Names developmental delay as a core feature of the newly delineated
      disorder.
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developmental delay/intellectual disability is present in most (n = 21)
    explanation: >-
      Quantitative support for the VERY_FREQUENT band. The preprint of the same
      study reports 21 affected individuals out of the 25 with detailed
      phenotype information (84%), which falls in the 80-99% band.
  - reference: PMID:21248748
    reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most of the individuals with the LCR3-4 deletion had developmental delay,
      mainly affecting speech.
    explanation: Supports developmental delay and its speech-predominant presentation in the deletion subtype.
  notes: >-
    The frequency band is derived from the medRxiv preprint of the defining
    study (DOI:10.64898/2026.02.23.26346364), which reports the per-feature
    counts the ahead-of-print abstract omits: 21 of 25 phenotyped individuals
    (84%). Developmental delay and intellectual disability are counted together
    in that source, so the same denominator and band apply to both.
- category: Neurologic
  name: Intellectual Disability
  description: >-
    Intellectual disability is the second defining feature of the WAPL-related
    disorder. Cognitive impairment was likewise the presenting concern in the
    original description of the recurrent 10q22-q23 deletion.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: VERY_FREQUENT
  severity: mild to moderate
  diagnostic: true
  evidence:
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild-moderate developmental delay/intellectual disability is present in
      most (n = 21)
    explanation: >-
      Quantitative support for the VERY_FREQUENT band (21 of 25 phenotyped
      individuals, 84%) and for the mild-to-moderate severity qualifier, both
      stated in the same sentence. The band is not narrowed further because the
      source counts developmental delay and intellectual disability jointly.
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a WAPL-related disorder featuring developmental delay,
      intellectual disability, and risk of other developmental anomalies.
    explanation: >-
      Names intellectual disability as a core feature.
  - reference: PMID:17436248
    reference_title: "Recurrent 10q22-q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      rearrangements in this region are associated with behavioral and
      neurodevelopmental abnormalities, including cognitive impairment, autism,
      hyperactivity, and possibly psychiatric disease
    explanation: >-
      Independent, earlier support for cognitive impairment in the
      contiguous-gene deletion subtype.
- category: Craniofacial
  name: Craniofacial Dysmorphism
  subtype: WAPL Variant
  description: >-
    Craniofacial dysmorphism is common in the WAPL sequence-variant cohort but
    is explicitly NOT a recognisable gestalt: the delineating study reports that
    although individual features recur (retrognathia, high columella), no
    typical set of features is shared across all individuals. The phenotype is
    therefore bound to the generic Abnormal facial shape term rather than to any
    specific dysmorphic feature.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  frequency: FREQUENT
  evidence:
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      craniofacial dysmorphism (n = 15 ) ... although some facial features were
      shared by multiple ... there is not a typical set of features across all
      ... individuals.
    explanation: >-
      15 of 25 phenotyped individuals (60%) supports the FREQUENT band, and the
      same sentence carries the caveat that the features do not coalesce into a
      single gestalt.
- category: Behavioral
  name: Behavioral Abnormality
  subtype: WAPL Variant
  description: >-
    Behavioral features were present in a substantial minority of the WAPL
    sequence-variant cohort. The source reports them as an aggregate count
    rather than as named behaviours, so this is curated as a single generic
    behavioral phenotype rather than split into autism, hyperactivity and the
    like, which are asserted only for the deletion subtype.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  frequency: FREQUENT
  evidence:
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many subjects also have behavioral features (n = 11), organ malformation
    explanation: >-
      11 of 25 phenotyped individuals (44%) supports the FREQUENT band.
- category: Musculoskeletal
  name: Talipes Equinovarus
  subtype: WAPL Variant
  description: >-
    Clubfoot is the organ malformation singled out in the study abstract as an
    example of the "other developmental anomalies" that accompany the
    neurodevelopmental core of the WAPL-related disorder.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  frequency: OCCASIONAL
  evidence:
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      clubfoot (n = 4), cardiac (n = 7)), and variable neurological features
      (n = 14; including 4 with
    explanation: >-
      4 of 25 phenotyped individuals (16%) supports the OCCASIONAL band.
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intellectual disability, and risk of other developmental anomalies
      including clubfoot.
    explanation: >-
      The preprint abstract names clubfoot specifically, where the ahead-of-print
      journal abstract says only "other developmental anomalies".
- category: Cardiovascular
  name: Cardiovascular Abnormality (WAPL Variant)
  subtype: WAPL Variant
  description: >-
    Cardiac findings occur in the WAPL sequence-variant cohort in the absence of
    the contiguous deletion. The source reports only an aggregate "cardiac"
    count, so this is bound to the cardiovascular-system parent rather than
    asserted as a structural congenital malformation.
  phenotype_term:
    preferred_term: Abnormality of the cardiovascular system
    term:
      id: HP:0001626
      label: Abnormality of the cardiovascular system
  frequency: OCCASIONAL
  evidence:
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      clubfoot (n = 4), cardiac (n = 7)), and variable neurological features
      (n = 14; including 4 with
    explanation: >-
      7 of 25 phenotyped individuals (28%) supports the OCCASIONAL band, in a
      cohort ascertained on WAPL sequence variants rather than 10q deletions.
- category: Neurologic
  name: Neurological Abnormality
  subtype: WAPL Variant
  description: >-
    Neurological features beyond the developmental-delay core are the
    second-most-frequent finding in the WAPL sequence-variant cohort, reported
    in 14 of 25 phenotyped individuals (56%). The source reports them as a
    single aggregate count of "variable neurological features" and names only
    hypotonia and small head circumference as constituents, so - as with the
    behavioural aggregate - this is curated as one generic nervous-system
    phenotype rather than split into features the source does not enumerate.
    No `frequency:` band is asserted: HP:0000707 is a strict ancestor of
    HP:0001263 (global developmental delay), which is annotated VERY_FREQUENT
    (84%) disease-wide, and under HPO frequency propagation an ancestor term
    cannot be rarer than its descendant. The source's own 14/25 aggregate count
    is therefore recorded in prose only, and the constituents the source names
    - hypotonia (4/25) and decreased head circumference (2/25) - carry their own
    bands below.
  phenotype_term:
    preferred_term: Abnormality of the nervous system
    term:
      id: HP:0000707
      label: Abnormality of the nervous system
  evidence:
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      variable neurological features (n = 14; including 4 with
    explanation: >-
      14 of 25 phenotyped individuals had neurological features beyond the
      developmental-delay core, supporting the association (the count is kept
      in prose rather than as a frequency band - see the description).
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and neurological issues are each present in about half of subjects.
    explanation: >-
      Independent corroboration from the figure legend, phrased qualitatively
      as "about half" - consistent with the 14/25 count.
- category: Neurologic
  name: Hypotonia
  subtype: WAPL Variant
  description: >-
    Hypotonia is one of the two neurological features the source enumerates
    within its aggregate neurological count, reported in 4 of the 25 phenotyped
    sequence-variant carriers.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  frequency: OCCASIONAL
  evidence:
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      variable neurological features (n = 14; including 4 with
    explanation: >-
      Opens the enumeration of the neurological aggregate; the count of 4 is
      attached to hypotonia in the continuation quoted below.
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypotonia, 2 with small head circumference).
    explanation: >-
      Completes the sentence and names hypotonia as the feature carrying the
      count of 4. 4 of 25 (16%) supports the OCCASIONAL band (5-29%), the same
      count and band used for clubfoot. The two quotes are given separately
      because the sentence spans a page-layout line break in the source.
- category: Craniofacial
  name: Decreased Head Circumference
  subtype: WAPL Variant
  description: >-
    Two of the 25 phenotyped sequence-variant carriers had a small head
    circumference. The bound term is the descriptive HP:0040195, not
    HP:0000252 Microcephaly, because the source reports the observation without
    stating that it meets a formal standard-deviation threshold.
  phenotype_term:
    preferred_term: Decreased head circumference
    term:
      id: HP:0040195
      label: Decreased head circumference
  frequency: OCCASIONAL
  evidence:
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypotonia, 2 with small head circumference).
    explanation: >-
      2 of 25 (8%) supports the OCCASIONAL band (5-29%).
  notes: >-
    Contrast with the 10q Deletion subtype, where macrocephaly - the opposite
    direction - is the reported head-size finding. The two are curated on
    different subtypes and are not reconciled by any current source.
- category: Neurologic
  name: Delayed Speech and Language Development
  subtype: 10q Deletion
  description: >-
    In the recurrent LCR3-4 deletion cohort the developmental delay was reported
    as mainly affecting speech, and reciprocal deletions were summarised as
    leading to speech and language delay.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:21248748
    reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most of the individuals with the LCR3-4 deletion had developmental delay,
      mainly affecting speech.
    explanation: >-
      Directly supports speech-predominant delay in the deletion subtype.
  notes: >-
    Attributed to the deletion subtype only. The abstract of the defining WAPL
    paper does not break the 27-individual sequence-variant cohort down by
    speech versus global delay.
- category: Behavioral
  name: Autism
  subtype: 10q Deletion
  description: >-
    Autism was among the behavioural abnormalities identified in the families
    that established 10q22-q23 deletion as a genomic disorder.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:17436248
    reference_title: "Recurrent 10q22-q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      rearrangements in this region are associated with behavioral and
      neurodevelopmental abnormalities, including cognitive impairment, autism,
      hyperactivity, and possibly psychiatric disease
    explanation: >-
      Names autism among the behavioural features of the deletion.
  notes: >-
    Deliberately unbanded. The rCNV deletion cohort codes behaviour only at the
    aggregate HPO level (atypical behavior, 5 of 41), and that count cannot be
    apportioned between autism and hyperactivity. The aggregate is banded on the
    separate Atypical Behavior phenotype below.
- category: Behavioral
  name: Hyperactivity
  subtype: 10q Deletion
  description: >-
    Hyperactivity was reported alongside autism and cognitive impairment in the
    original 10q22-q23 deletion families.
  phenotype_term:
    preferred_term: Hyperactivity
    term:
      id: HP:0000752
      label: Hyperactivity
  evidence:
  - reference: PMID:17436248
    reference_title: "Recurrent 10q22-q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      rearrangements in this region are associated with behavioral and
      neurodevelopmental abnormalities, including cognitive impairment, autism,
      hyperactivity, and possibly psychiatric disease
    explanation: >-
      Names hyperactivity among the behavioural features of the deletion. The
      bound term is HP:0000752 Hyperactivity, an exact match for the reported
      feature; a formal ADHD diagnosis (HP:0007018) is not asserted by the
      source and is deliberately not used.
  notes: >-
    Deliberately unbanded, for the same reason as Autism above: the rCNV cohort
    reports behaviour only as an aggregate.
- category: Behavioral
  name: Atypical Behavior (10q Deletion)
  subtype: 10q Deletion
  description: >-
    The aggregate behavioural phenotype of the deletion, as coded in the
    cross-disorder rCNV cohort. Autism and hyperactivity, curated separately
    above from the original deletion families, are named instances of it; this
    entry exists to carry the one frequency the source actually supports, at the
    level at which it was reported.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  frequency: OCCASIONAL
  evidence:
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and atypical behavior (n = 5)
    explanation: >-
      5 of the 41 rCNV deletion carriers (12%) supports the OCCASIONAL band
      (5-29%).
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our analysis identified 41 carriers of the canonical
    explanation: >-
      Establishes the 41-carrier denominator for the deletion-arm bands.
  notes: >-
    The comparable sequence-variant figure is 11 of 25 (44%, FREQUENT) on the
    Behavioral Abnormality phenotype. The two arms are not directly comparable -
    the deletion count comes from HPO-coded microarray-referral records and the
    sequence-variant count from direct clinical phenotyping - so the difference
    should not be read as a dosage effect.
- category: Musculoskeletal
  name: Talipes Equinovarus (10q Deletion)
  subtype: 10q Deletion
  description: >-
    Clubfoot recurs in the published deletion cases, as it does in the WAPL
    sequence-variant cohort. Musculoskeletal anomaly is one of the organ systems
    the delineating study calls out as being of equivalent prevalence in the two
    arms, which is part of the evidence nominating WAPL as the driver.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  frequency: OCCASIONAL
  evidence:
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      musculoskeletal abnormalities (including clubfoot in 6 individuals)
    explanation: >-
      6 of the 27 published deletion cases (22%) supports the OCCASIONAL band
      (5-29%).
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we performed a literature review and identified 27 published cases of the
    explanation: >-
      Establishes the denominator for this band - the 27 published deletion
      cases, a different cohort from the 41 rCNV carriers used for the other
      deletion-arm bands.
- category: Craniofacial
  name: Macrocephaly
  subtype: 10q Deletion
  description: >-
    Macrocephaly was observed in individuals with the recurrent LCR3-4 deletion.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:21248748
    reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, macrocephaly, mild facial dysmorphisms, cerebellar anomalies,
      cardiac defects and congenital breast aplasia were observed.
    explanation: >-
      Lists macrocephaly among the features of the LCR3-4 deletion cohort.
- category: Craniofacial
  name: Abnormality of the Face (10q Deletion)
  subtype: 10q Deletion
  description: >-
    Facial abnormalities occur in the deletion cohort; an earlier case series
    described them as mild dysmorphisms. The frequency source counts the broad
    HPO parent, so the assertion remains at that same level rather than deriving
    a frequency for a narrower facial-shape term.
  phenotype_term:
    preferred_term: Abnormality of the face
    term:
      id: HP:0000271
      label: Abnormality of the face
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:21248748
    reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reciprocal deletions lead to speech and language delay, mild facial
      dysmorphisms and, in some individuals, to cerebellar, breast developmental
      and cardiac defects.
    explanation: >-
      Summarises the deletion phenotype including mild facial dysmorphism.
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormality of the face (n = 8; 20%)
    explanation: >-
      Frequency evidence. 8 of the 41 rCNV deletion carriers (20%) carried an
      HPO term for abnormality of the face, which places the identically bound
      phenotype in the OCCASIONAL band (5-29%).
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our analysis identified 41 carriers of the canonical
    explanation: >-
      Establishes the denominator (41 deletion carriers ascertained from the
      cross-disorder rCNV microarray dataset) against which the 20% is computed.
- category: Neurologic
  name: Cerebellar Anomalies
  subtype: 10q Deletion
  description: >-
    Structural cerebellar anomalies were reported in a subset of individuals
    with the recurrent deletion.
  phenotype_term:
    preferred_term: Abnormal cerebellum morphology
    term:
      id: HP:0001317
      label: Abnormal cerebellum morphology
  evidence:
  - reference: PMID:21248748
    reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, macrocephaly, mild facial dysmorphisms, cerebellar anomalies,
      cardiac defects and congenital breast aplasia were observed.
    explanation: >-
      Lists cerebellar anomalies among the deletion features.
- category: Cardiovascular
  name: Cardiovascular Abnormality (10q Deletion)
  subtype: 10q Deletion
  description: >-
    Cardiovascular abnormalities occur in a subset of deletion carriers. An
    earlier series reports cardiac defects and nominates BMPR1A and GRID1, but
    the frequency source counts the broader cardiovascular-system parent; the
    ontology assertion therefore stays at that broader level.
  phenotype_term:
    preferred_term: Abnormality of the cardiovascular system
    term:
      id: HP:0001626
      label: Abnormality of the cardiovascular system
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:21248748
    reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For cardiac defects, BMPR1A and GRID1 are putative candidate genes because
      of their association with cardiac structure and function.
    explanation: >-
      Supports both the occurrence of cardiac defects in this deletion and their
      attribution to genes other than WAPL.
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the cardiovascular system (n = 5; 12%)
    explanation: >-
      Frequency evidence. 5 of the 41 rCNV deletion carriers (12%) carried the
      identically bound cardiovascular-system parent, placing this feature in
      the OCCASIONAL band (5-29%).
- category: Other
  name: Congenital Breast Aplasia
  subtype: 10q Deletion
  description: >-
    Congenital absence of breast tissue is an unusual and relatively specific
    feature of the recurrent 10q22.3q23.3 deletion. The delineating study
    proposes NRG3, not WAPL, as the responsible gene, so this feature is not
    attributed to WAPL haploinsufficiency.
  phenotype_term:
    preferred_term: Breast aplasia
    term:
      id: HP:0100783
      label: Breast aplasia
  evidence:
  - reference: PMID:21248748
    reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For congenital breast aplasia, the NRG3 gene, known to be involved in
      early mammary gland development in mice, is a putative candidate gene.
    explanation: >-
      Supports the feature and records its attribution to NRG3 rather than WAPL.
- category: Gastrointestinal
  name: Hamartomatous Polyposis
  subtype: 10q Deletion
  description: >-
    The recurrent deletion removes one copy of BMPR1A, in which loss-of-function
    variants cause juvenile polyposis syndrome - a hamartomatous polyposis with
    a high risk of malignant transformation. This is the deletion's
    cancer-predisposition arm, and the most clinically actionable feature in the
    entry: the reported adult developed severe juvenile polyposis requiring
    preventive colectomy at 25 and died of gastric adenocarcinoma at 32. It is
    attributed to BMPR1A, not to WAPL, and so is curated on the deletion subtype
    only; WAPL sequence-variant carriers have no reported polyposis risk.
  phenotype_term:
    preferred_term: Hamartomatous polyposis
    term:
      id: HP:0004390
      label: Hamartomatous polyposis
    onset:
      onset_category: YOUNG_ADULT
  evidence:
  - reference: PMID:31561016
    reference_title: "Patients with 10q22.3q23.1 recurrent deletion syndrome are at risk for juvenile polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present the case of a young adult harboring this recurrent deletion, in
      a context of intellectual disability, ventricular septal defect and severe
      juvenile polyposis syndrome diagnosed at the age of 25 years, requiring a
      surgical preventive colectomy.
    explanation: >-
      The index observation linking the recurrent deletion to juvenile
      polyposis, alongside the intellectual disability and cardiac defect that
      are already curated on this subtype. Onset is recorded as YOUNG_ADULT
      because that is the age at diagnosis in the only reported case.
  - reference: PMID:31561016
    reference_title: "Patients with 10q22.3q23.1 recurrent deletion syndrome are at risk for juvenile polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This observation highlights the importance of an active digestive
      surveillance of patients with 10q22.3q23.1 deletion.
    explanation: >-
      The surveillance recommendation, which is the actionable consequence of
      this phenotype and the reason it is curated despite resting on a single
      reported case.
  notes: >-
    Frequency is deliberately omitted: the source reports a single case and
    explicitly argues that juvenile polyps have never previously been reported
    in this deletion because the deletion is now diagnosed by CNV array years
    before the digestive phenotype appears. That is an ascertainment argument
    for under-reporting, not a frequency estimate, so no band can be derived.
    The interval is labelled 10q22.3q23.1 (7 Mb) in this source and
    10q22.3q23.2 elsewhere in the entry - see the entry notes on
    source-inherited cytoband labelling.
genetic:
- name: WAPL
  gene_term:
    preferred_term: WAPL
    term:
      id: hgnc:23293
      label: WAPL
  presence: Present
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Heterozygous predicted damaging WAPL variants, and heterozygous deletion of
    WAPL within the recurrent 10q22.3q23.2 interval, cause a developmental
    disorder characterised by developmental delay and intellectual disability.
    WAPL encodes cohesin's DNA release factor; this is the first cohesin release
    factor to be associated with Mendelian disease.
  notes: >-
    No ClinGen Gene-Disease Validity assertion and no ClinGen dosage curation
    were available for WAPL as a disease gene at the time of curation, so the
    gene-disease relationship is supported by primary literature alone. Detailed
    allele-level curation awaits the full text of PMID:42431198.
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In summary, we delineated a genetic condition caused by cohesin release
      factor deficiency, nominated WAPL as a driver gene within a genomic
      disorder region, and further illuminated dosage sensitivity of human
      cohesin.
    explanation: >-
      The authors' own summary of the gene-disease claim.
- name: PDS5A
  gene_term:
    preferred_term: PDS5A
    term:
      id: hgnc:29088
      label: PDS5A
  presence: Uncertain
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  association: >-
    Eight individuals with heterozygous predicted damaging PDS5A variants were
    phenotyped in the same study. They exhibited features of developmental
    disorders, but neither cohort-based statistics nor subject phenotyping
    associated PDS5A with specific phenotypes. PDS5A is therefore recorded as
    investigated and unconfirmed, not as a disease gene.
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While individuals with PDS5A or PDS5B variants exhibited features of
      developmental disorders, neither cohort-based statistics nor subject
      phenotyping associated these genes with specific phenotypes.
    explanation: >-
      Explicitly declines to establish a gene-disease association for PDS5A,
      which is why the relationship type is UNKNOWN.
- name: PDS5B
  gene_term:
    preferred_term: PDS5B
    term:
      id: hgnc:20418
      label: PDS5B
  presence: Uncertain
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  association: >-
    As for PDS5A, eight individuals with heterozygous predicted damaging PDS5B
    variants were phenotyped without a specific phenotype association emerging.
    PDS5B is a WAPL binding partner and, with PDS5A, controls loop length
    together with WAPL, so it remains a strong biological candidate awaiting
    additional cases.
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While individuals with PDS5A or PDS5B variants exhibited features of
      developmental disorders, neither cohort-based statistics nor subject
      phenotyping associated these genes with specific phenotypes.
    explanation: >-
      Same negative-association statement as for PDS5A.
  - reference: PMID:29217591
    reference_title: "Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the cohesin unloading factor WAPL and its PDS5 binding partners control
      the length of loops
    explanation: >-
      Biological rationale for treating PDS5A/PDS5B as candidate genes in the
      same mechanism, independent of the currently unestablished clinical
      association.
animal_models:
- name: Wapl hypomorphic mouse dosage series
  species: Mus musculus
  genotype: Wapl hypomorphic allelic series (approximately 50% and 25% residual Wapl expression)
  description: >-
    A graded Wapl-dosage mouse series is the in vivo arm of the defining study
    and is the source of the dosage-liability-threshold claim. Mice retaining
    about half of normal Wapl expression show mild growth and learning/memory
    deficits. Mice retaining only a quarter show birth defects and die after
    birth. Translation of that mouse dose-response to humans remains explicitly
    unresolved in the HUMAN_MODEL_MISMATCH discussion.
  genes:
  - preferred_term: WAPL
    term:
      id: hgnc:23293
      label: WAPL
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice with 50% Wapl expression exhibited mild deficits of growth and
      learning/memory, whereas those with 25% residual Wapl displayed birth
      defects and postnatal lethality, revealing a dosage liability threshold
      below the level of heterozygosity.
    explanation: >-
      Describes the model, both dosage arms, and the threshold inference.
experimental_models:
- name: Isogenic WAPL-truncating and 10q-deletion human iPSC and induced-neuron model
  description: >-
    CRISPR-engineered human induced pluripotent stem cells and induced neurons
    carrying either WAPL truncating variants or an engineered 10q22.3q23.2
    deletion (or the reciprocal duplication) in an otherwise isogenic
    background. Transcriptomic comparison of the two genotypes is the experiment
    that links the monogenic lesion to the genomic disorder: their
    differentially expressed gene sets overlap significantly.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: induced pluripotent stem cell
    term:
      id: CL:0002248
      label: pluripotent stem cell
  - preferred_term: induced neuron
    term:
      id: CL:0000540
      label: neuron
  conditions:
  - CRISPR-engineered WAPL truncating variant
  - CRISPR-engineered 10q22.3q23.2 deletion
  - CRISPR-engineered 10q22.3q23.2 duplication
  culture_system: Isogenic iPSC lines differentiated to induced neurons, profiled by transcriptomics
  publication: PMID:42431198
  modeled_mechanisms:
  - target: Transcriptional Dysregulation
    description: >-
      The model provides the transcriptional read-out that WAPL
      haploinsufficiency and 10q deletion converge on shared gene-expression
      changes in a human neural lineage.
    evidence:
    - reference: PMID:42431198
      reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Transcriptomics identified significant overlap between WAPL
        haploinsufficiency and 10q deletion differentially expressed genes.
      explanation: >-
        Links this model system to the Transcriptional Dysregulation node it
        supports.
  findings:
  - statement: >-
      WAPL haploinsufficiency and 10q22.3q23.2 deletion produce significantly
      overlapping differentially expressed gene sets in isogenic human iPSCs and
      induced neurons.
    supporting_text: >-
      Transcriptomics identified significant overlap between WAPL
      haploinsufficiency and 10q deletion differentially expressed genes.
    evidence:
    - reference: PMID:42431198
      reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Transcriptomics identified significant overlap between WAPL
        haploinsufficiency and 10q deletion differentially expressed genes.
      explanation: >-
        The sentence reporting this finding.
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We used CRISPR to generate truncating variants in WAPL and 10q deletion or
      duplication in human induced pluripotent stem cells (iPSCs) and induced
      neurons.
    explanation: >-
      Describes the engineered genotypes and cell systems of the model.
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Transcriptomics identified significant overlap between WAPL
      haploinsufficiency and 10q deletion differentially expressed genes.
    explanation: >-
      The model's key finding.
- name: WAPL-knockout human HAP1 Hi-C model
  description: >-
    CRISPR WAPL-knockout HAP1 cells profiled by Hi-C, the system in which the
    chromosome-folding consequences of losing cohesin release were first
    resolved genome-wide. Not a disease model in itself, but the source of the
    mechanistic node linking WAPL loss to extended chromatin loops and degraded
    TAD insulation.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  conditions:
  - CRISPR WAPL knockout
  cell_source: HAP1 near-haploid human cell line
  culture_system: Genome-wide chromosome conformation capture (Hi-C) and CTCF/SMC1 ChIP-seq
  publication: PMID:28475897
  modeled_mechanisms:
  - target: Extended Chromatin Loops and Altered Genome Folding
    description: >-
      Provides the direct experimental demonstration that loss of WAPL lengthens
      chromatin loops and increases inter-TAD contact.
    evidence:
    - reference: PMID:28475897
      reference_title: "The Cohesin Release Factor WAPL Restricts Chromatin Loop Extension."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        WAPL deficiency led to the extension of chromatin loops and strongly
        increased interaction frequencies between nearby TADs
      explanation: >-
        The Hi-C result from this model that the pathophysiology node rests on.
  evidence:
  - reference: PMID:28475897
    reference_title: "The Cohesin Release Factor WAPL Restricts Chromatin Loop Extension."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we generated WAPL knockout HAP1 cells using CRISPR technology
    explanation: >-
      Describes the model system.
diagnosis:
- name: Molecular identification of a damaging WAPL sequence variant
  description: >-
    The sequence-variant subtype is defined by a heterozygous predicted damaging
    WAPL variant. The cited cohort does not establish a preferred clinical assay
    or validated variant-classification algorithm, so no specific sequencing
    platform is asserted here.
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      phenotyping individuals with heterozygous predicted damaging variants in
      WAPL (n = 27)
    explanation: >-
      Establishes that the diagnostic finding is a heterozygous predicted
      damaging WAPL sequence variant.
- name: Chromosomal microarray for the recurrent 10q22.3q23.2 deletion
  description: >-
    The contiguous-gene subtype is detected by chromosomal microarray as a
    recurrent copy-number loss between the low-copy repeats LCR3 and LCR4.
    Because the breakpoints are LCR-mediated, the deletion is recurrent and of
    reproducible size, which is what makes it a classical genomic disorder.
  evidence:
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We screened our cross-disorder rare copy number variant (rCNV) microarray
      dataset ... Our analysis identified 41 carriers of the canonical ...
      10q22.3q23.2 deletion
    explanation: >-
      Directly documents detection of the canonical deletion in a microarray dataset.
- name: Investigational DNA methylation episignature analysis
  description: >-
    EpiSign analysis of peripheral blood DNA identified a cohesin release factor
    deficiency-associated methylation episignature, and a second signature
    combining WAPL sequence-variant and 10q deletion samples. Both classifiers
    showed high specificity against other episignature disorders, including
    Cornelia de Lange syndrome, whose overall methylation pattern these profiles
    do NOT mimic - so the episignature is not simply a cohesinopathy readout.
    The small research analyses do not establish a clinically validated
    diagnostic assay. The important bound is that the study did not find a
    methylation signature for WAPL sequence variants alone (the
    left-out sample clustered with cases in 0 of 8 leave-one-out iterations of
    that analysis). This assay therefore cannot currently be used to
    reclassify an isolated WAPL variant of uncertain significance; the reported
    profiles apply only to the combined and release-factor-wide research
    groupings.
  evidence:
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified an overall cohesin release factor deficiency -associated DNA
    explanation: >-
      Establishes that a methylation episignature exists for cohesin release
      factor deficiency as a group. The sentence is split across a page-layout
      line break in the source, so its continuation is quoted as the next
      evidence item rather than joined here.
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      methylation signature and a DNA methylation signature combining WAPL SNV
      and 10q del
    explanation: >-
      Completes the preceding quote and establishes the second, combined
      sequence-variant-plus-deletion signature.
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We did not identify a DNA methylation signature for WAPL SNVs alone.
    explanation: >-
      The explicit negative result that bounds the assay's diagnostic use.
      Recorded as PARTIAL because it supports the existence of the episignature
      workup while refuting its applicability to isolated WAPL sequence
      variants.
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      methylation patterns do not mimic the overall CdLS methylation pattern
    explanation: >-
      Distinguishes the release-factor episignature from the Cornelia de Lange
      syndrome signature, which is the principal differential diagnosis.
treatments:
- name: Digestive surveillance for 10q deletion carriers
  action_category: MONITORING
  description: >-
    Active digestive surveillance is recommended for carriers of the recurrent
    10q22.3q23.1/10q22.3q23.2 deletion because the interval includes BMPR1A and
    a reported adult developed severe juvenile polyposis. The manifestation
    being surveilled for is the hamartomatous polyposis curated in the
    `phenotypes` section (HP:0004390); this is detection, not treatment, so the
    action carries no `target_phenotypes` link. This recommendation applies to
    the contiguous-deletion subtype, not to isolated WAPL variants; the source
    does not specify a surveillance modality or interval.
  treatment_term:
    preferred_term: clinical evaluation
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:31561016
    reference_title: "Patients with 10q22.3q23.1 recurrent deletion syndrome are at risk for juvenile polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This observation highlights the importance of an active digestive
      surveillance of patients with 10q22.3q23.1 deletion.
    explanation: Directly supports surveillance limited to deletion carriers.
differential_diagnoses:
- name: Cornelia de Lange Syndrome
  description: >-
    The archetypal cohesinopathy, caused mainly by NIPBL (the cohesin loader)
    and by cohesin subunit genes. It sits on the opposite side of the same
    cohesin cycle from WAPL: loading versus release. The methylation results and
    opposing mouse dosage effects support keeping the entities distinct rather
    than treating WAPL deficiency as an untyped Cornelia de Lange syndrome.
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genes encoding cohesin and cohesin loaders have been associated with
      Mendelian disorders, whereas genes encoding cohesin release factors,
      including WAPL and its binding partners PDS5A and PDS5B, have not.
    explanation: >-
      Places WAPL-related disorder beside the already-known cohesin and
      cohesin-loader disorders, of which Cornelia de Lange syndrome is the
      prototype.
  - reference: PMID:36449618
    reference_title: "Decreasing Wapl dosage partially corrects embryonic growth and brain transcriptome phenotypes in Nipbl(+/-) embryos."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Since WAPL and NIPBL have opposite effects on cohesin's association with
      DNA, we asked whether decreasing Wapl dosage could correct phenotypes seen
      in Nipbl+/- mice. Gene expression and embryonic growth are partially
      corrected, but perinatal lethality is not.
    explanation: >-
      Establishes the relationship between the two disorders as genuinely
      antagonistic rather than merely adjacent: lowering Wapl partially rescues
      the CdLS model. That the rescue is only partial - perinatal lethality
      persists - is why the two remain distinct entities and why this is a
      differential rather than a shared mechanism. Note the counterintuitive
      direction: reduced WAPL is the lesion in this disorder but a partial
      corrective in the loader disorder.
  notes: >-
    The methylation episignature is the practical discriminator: the
    cohesin-release-factor profiles do not mimic the overall CdLS methylation
    pattern, so an EpiSign result cannot be read as simply "a cohesinopathy".
- name: 10q22.3q23.3 microduplication syndrome
  description: >-
    The reciprocal duplication of the same LCR3-4 interval. It has its own MONDO
    identity (MONDO:0017180) and a distinct, more variably penetrant
    presentation - speech and motor delay with a broad forehead, deep-set eyes,
    upslanting palpebral fissures, a smooth philtrum and a thin upper lip - and
    duplications have also been found in healthy family members. It is a
    different dosage direction and is deliberately not modelled as a subtype
    here.
  evidence:
  - reference: PMID:21248748
    reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Duplications between LCRs3 and 4 are associated with variable phenotypic
      penetrance.
    explanation: >-
      Distinguishes the reciprocal duplication by its variable penetrance.
  - reference: PMID:21248748
    reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Probands had speech and/or motor delays and dysmorphisms including a broad
      forehead, deep-set eyes, upslanting palpebral fissures, a smooth philtrum
      and a thin upper lip.
    explanation: Supports the detailed reciprocal-duplication phenotype used in the differential.
discussions:
- discussion_id: wapl_full_text_curation
  prompt: >-
    What is the organ-system-level phenotypic spectrum, allelic spectrum, and
    frequency breakdown of the 27-individual WAPL cohort?
  kind: CURATION_TODO
  status: OPEN
  rationale: >-
    PMID:42431198 was published online ahead of print on 2026-07-10 and is
    cached as abstract only. The original framing of this discussion - that the
    detail had to wait for the PMC deposit - was wrong: the same study is openly
    available as a medRxiv preprint, DOI:10.64898/2026.02.23.26346364, which is
    now fetched and cited here. From that full text the entry has since gained
    per-feature frequency bands for the sequence-variant cohort (n = 25
    phenotyped), the clubfoot and cardiac malformation phenotypes, and the DNA
    methylation episignature diagnostic entry.

    What genuinely remains blocked is case-level detail. The preprint states
    that Table 1, Table S4, Fig. 2 and Fig. S12 have had case-level data -
    including age, sex, phenotype and photographs - removed per medRxiv
    guidelines. So a per-individual `variants:` block and the facial-gestalt
    description still cannot be curated from any currently available source,
    and the peer-reviewed full text remains the route to them.
  notes: >-
    Concretely, what is still outstanding: (1) a `variants:` block, blocked on
    the redacted case-level tables; (2) facial-gestalt detail, blocked the same
    way - note the preprint explicitly reports that no typical set of facial
    features is shared across individuals, so a gestalt may not exist to curate;
    (3) a re-check of whether the subtype split used here matches the published
    nosology. Re-run `just fetch-reference PMID:42431198` after the PMC deposit
    for (1) and (2).
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a WAPL-related disorder featuring developmental delay,
      intellectual disability, and risk of other developmental anomalies.
    explanation: >-
      The abstract-level statement that is currently the whole of the available
      clinical description, which is what makes full-text re-curation necessary.
- discussion_id: wapl_10q_deletion_orphanet_phenotypes
  prompt: >-
    What additional phenotypes and frequency bands does ORPHA:276413 record for
    the recurrent 10q22.3q23.3 deletion subtype?
  kind: CURATION_TODO
  status: OPEN
  rationale: >-
    The deletion subtype here is grounded on MONDO:0012830, whose Orphanet
    source record (ORPHA:276413) enumerates features this entry does not
    capture - among them hypertelorism/hypotelorism, low-set ears, flat nasal
    bridge, cleft palate, arachnodactyly, joint hyperlaxity, feeding
    difficulties and failure to thrive - together with HPO-coded frequency
    bands. None of those features is quotable from any reference currently
    cached for this entry, so they are omitted rather than asserted without
    evidence.

    Scope note: this is now a gap in the *feature list*, not in frequency data
    as such. The deletion arm does carry frequency bands, derived from the
    delineating study's own 41-carrier rCNV cohort and its 27-case literature
    review rather than from Orphanet - facial dysmorphism 20%, cardiovascular
    12%, atypical behaviour 12%, clubfoot 22%. Those are preferable here anyway,
    because they are same-source and same-analysis as the sequence-variant
    bands and so support the equivalent-prevalence comparison the driver-gene
    argument rests on. What ORPHA:276413 would still add is the long tail of
    dysmorphic and growth features listed above, which no cached source
    supports.
  notes: >-
    Blocked, not merely undone. `just refresh-orphadata` currently fails with a
    checksum mismatch on `en_product1.xml` against the pin in
    `data/orphadata/MANIFEST.yaml`, so `just structured-rebuild-orphanet --id
    276413` cannot produce `references_cache/ORPHA_276413.md`. Re-pinning the
    Orphadata snapshot is a repo-wide operation (it would rebuild all committed
    `ORPHA_*.md` files) and belongs in its own change, not in a single disorder
    curation. Once the snapshot is re-pinned, rebuild ORPHA:276413 and mine its
    `## Phenotypes` table for the deletion subtype.
- discussion_id: wapl_pds5a_pds5b_validity
  prompt: >-
    Are PDS5A and PDS5B Mendelian disease genes, and if so what phenotypes do
    they cause?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Cohesin Release from Chromatin
  rationale: >-
    PDS5A and PDS5B are WAPL's binding partners and, with WAPL, control chromatin
    loop length, so they are strong biological candidates for a parallel
    disorder. Eight individuals with damaging variants in each were phenotyped
    and did show features of developmental disorders, yet neither cohort
    statistics nor phenotyping produced a specific association. It is therefore
    unresolved whether these are genuine but low-penetrance or heterogeneous
    disease genes, whether the cohorts were simply too small, or whether the
    variants are tolerated.

    The preprint full text has since been read, and it does not resolve the
    question - but it does sharpen it in two ways, so this gap is no longer
    "waiting on the full text". First, the negative result is not that the
    carriers were unaffected: every PDS5A/PDS5B subject had neurodevelopmental
    and/or neurological features, and what failed was the coalescence of those
    features into a defined syndrome. Second, PDS5A and PDS5B truncating
    variants were pooled with WAPL in Analysis 1 of the methylation work, and
    that combined analysis did yield a cohesin-release-factor-deficiency
    episignature - which is suggestive of a shared molecular consequence, but
    cannot be attributed to PDS5A/PDS5B individually from a pooled classifier.
    Neither observation changes relationship_type: UNKNOWN, which remains the
    correct call.
  proposed_experiments:
  - experiment_id: exp_pds5_matchmaking_cohort
    name: Powered PDS5A and PDS5B variant cohort with repeated association statistics
    description: >-
      Assemble larger international PDS5A and PDS5B variant cohorts through
      matchmaking platforms and repeat the phenotype-association statistics with
      adequate power.
  - experiment_id: exp_pds5_isogenic_ipsc_transcriptomics
    name: Isogenic PDS5A/PDS5B iPSC and induced-neuron transcriptomic comparison
    description: >-
      Apply the same isogenic iPSC and induced-neuron CRISPR and transcriptomic
      pipeline used for WAPL to PDS5A and PDS5B knockouts, and test whether
      their differentially expressed gene sets overlap the WAPL signature.
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While individuals with PDS5A or PDS5B variants exhibited features of
      developmental disorders, neither cohort-based statistics nor subject
      phenotyping associated these genes with specific phenotypes.
    explanation: >-
      States the unresolved association directly.
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      every subject had neurodevelopmental and/or neurological features
    explanation: >-
      Shows the carriers were not unaffected, which is what makes this a genuine
      open question rather than a negative result. PARTIAL because it supports
      the existence of a phenotype while leaving the gene-disease association
      unresolved.
  - reference: DOI:10.64898/2026.02.23.26346364
    reference_title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis 1 combined truncating variants
    explanation: >-
      Records that PDS5A and PDS5B were pooled with WAPL in the episignature
      analysis that succeeded, so the positive methylation result cannot be
      apportioned to them individually.
  - reference: PMID:34070827
    reference_title: "PDS5A and PDS5B in Cohesin Function and Human Disease."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      PDS5 deficiency did not affect mice’s brains, showing that their role in
      the cohesin complex does not affect the development of the CNS
    explanation: >-
      The strongest evidence against PDS5A/PDS5B being neurodevelopmental
      disease genes, and a genuine counterweight to the biological-candidacy
      argument: unlike Wapl heterozygotes, Pds5 knockout mice have no reported
      brain phenotype, though they do have cardiac, palatal and skeletal
      defects. Fenced as MODEL_ORGANISM, and note the review also records that
      the two published Pds5 mouse models disagree with each other on
      redundancy and embryonic lethality, so this is not a settled negative.
- discussion_id: wapl_mouse_dosage_threshold_translation
  prompt: >-
    Does the mouse Wapl dosage-liability threshold, which lies below
    heterozygosity, actually describe the human dose-response, and does it
    predict that severely hypomorphic or biallelic human WAPL genotypes are
    non-viable?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  rationale: >-
    The dosage-series evidence is retained in the animal model rather than as a
    human causal-graph node because it exists only in mouse. Every reported human
    is heterozygous, so the 25%-residual arm - birth defects and postnatal
    lethality - has no human counterpart and its translational validity is
    untested. The mismatch is mechanistically meaningful in two directions: if
    the human curve is shifted, apparently mild human heterozygotes could still
    harbour subclinical cohesin-folding defects; and if it holds, human
    sub-heterozygous WAPL genotypes would be expected to present as pregnancy
    loss or lethal congenital anomaly rather than as this neurodevelopmental
    disorder, which would systematically hide them from neurodevelopmental
    cohorts.
  proposed_experiments:
  - experiment_id: exp_wapl_perinatal_loss_cohort_search
    name: Search perinatal-loss and lethal-anomaly cohorts for sub-heterozygous WAPL genotypes
    description: >-
      Search prenatal and perinatal-loss and lethal-congenital-anomaly
      sequencing cohorts for biallelic or severely hypomorphic WAPL genotypes,
      which the mouse data predict should exist there and nowhere else.
  - experiment_id: exp_wapl_human_residual_dosage_assay
    name: Residual WAPL protein and cohesin residence time in human heterozygote cells
    description: >-
      Quantify residual WAPL protein and cohesin residence time in cells from
      human heterozygotes and relate them to phenotype severity, to place human
      carriers on the mouse dose-response curve directly.
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice with 50% Wapl expression exhibited mild deficits of growth and
      learning/memory, whereas those with 25% residual Wapl displayed birth
      defects and postnatal lethality, revealing a dosage liability threshold
      below the level of heterozygosity.
    explanation: >-
      The model-organism result whose human translation is the open question.
- discussion_id: wapl_mondo_term_request
  prompt: >-
    Should a MONDO term be requested for the monogenic WAPL-related
    developmental disorder, distinct from MONDO:0012830 (the contiguous-gene 10q
    deletion)?
  kind: CURATION_TODO
  status: OPEN
  rationale: >-
    `disease_term` is currently omitted because no MONDO class exists for the
    monogenic entity. MONDO:0012830 is deliberately not reused, since conflating
    a single-gene disorder with the deletion syndrome that contains it is
    exactly the named-entity-confusion failure mode the curation SOP warns
    about. Once the full text and additional cases are published, a MONDO
    new-term request would let this entry carry a proper `disease_term` and
    would let the deletion/sequence-variant distinction be represented in the
    ontology rather than only in dismech.
  evidence:
  - reference: PMID:42431198
    reference_title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In summary, we delineated a genetic condition caused by cohesin release
      factor deficiency, nominated WAPL as a driver gene within a genomic
      disorder region, and further illuminated dosage sensitivity of human
      cohesin.
    explanation: >-
      The publication delineating a distinct genetic condition, which is the
      basis on which a new MONDO class would be requested.
references:
- reference: PMID:42431198
  title: "Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder."
  findings:
  - statement: >-
      Defining publication. Phenotypes 27 individuals with heterozygous damaging
      WAPL variants (plus 8 each with PDS5A and PDS5B variants), delineates a
      WAPL-related disorder of developmental delay and intellectual disability,
      nominates WAPL as the driver gene of the recurrent 10q22.3q23.2 deletion
      via overlapping iPSC and induced-neuron transcriptomes, and defines a
      mouse Wapl dosage-liability threshold below heterozygosity.
- reference: DOI:10.64898/2026.02.23.26346364
  title: "Clinical, <i>in vitro,</i> and <i>in vivo</i> evidence of <i>WAPL</i> as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder"
  findings:
  - statement: >-
      medRxiv preprint of the defining publication (PMID:42431198), posted
      2026-02-28 and openly available in full text. Supplies the per-feature
      counts the ahead-of-print abstract omits - of 25 phenotyped individuals,
      21 have mild-moderate developmental delay/intellectual disability, 15
      craniofacial dysmorphism, 14 neurological features, 11 behavioral
      features, 7 cardiac findings and 4 clubfoot - and reports the EpiSign
      DNA methylation analysis, which found a cohesin-release-factor-deficiency
      episignature and a combined WAPL-SNV-plus-10q-deletion signature but no
      signature for WAPL sequence variants alone. Case-level data in Table 1,
      Table S4, Fig. 2 and Fig. S12 are redacted per medRxiv guidelines, so
      variant-level and facial-gestalt curation is still blocked.
- reference: PMID:17113138
  title: "Wapl controls the dynamic association of cohesin with chromatin."
  findings:
  - statement: >-
      Identifies WAPL as the factor required to unlock cohesin from its stably
      chromatin-bound state; WAPL depletion increases cohesin residence time on
      chromatin in interphase.
- reference: PMID:28475897
  title: "The Cohesin Release Factor WAPL Restricts Chromatin Loop Extension."
  findings:
  - statement: >-
      WAPL-knockout human cells show extended chromatin loops, increased contact
      between neighbouring TADs, and looping between incorrectly oriented CTCF
      sites, establishing WAPL as the brake on cohesin loop extrusion.
- reference: PMID:29217591
  title: "Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins."
  findings:
  - statement: >-
      Independent demonstration that WAPL and its PDS5 binding partners set loop
      length, with vermicelli-like axial cohesin accumulation on their loss;
      supplies the mechanistic rationale for treating PDS5A and PDS5B as
      candidate genes.
- reference: PMID:17436248
  title: "Recurrent 10q22-q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities."
  findings:
  - statement: >-
      Original delineation of the recurrent LCR-mediated 10q22-q23 deletion as a
      genomic disorder associated with cognitive impairment, autism,
      hyperactivity and possible psychiatric disease.
- reference: PMID:21248748
  title: "The phenotype of recurrent 10q22q23 deletions and duplications."
  findings:
  - statement: >-
      Clinical and molecular characterisation of eight deletions and six
      duplications of 10q22.3q23.3; LCR3-4 deletion carriers had
      speech-predominant developmental delay, macrocephaly, mild facial
      dysmorphism, cerebellar anomalies, cardiac defects and congenital breast
      aplasia, with NRG3 proposed for breast aplasia and BMPR1A/GRID1 for
      cardiac defects.
review_notes: >-
  The 2026 REVIEW retained the deliberate distinction between the monogenic
  WAPL sequence-variant entity and the WAPL-containing recurrent deletion while
  auditing every subtype-specific count against its actual denominator. Broad
  rCNV counts are now bound to the same broad HPO terms rather than used as
  frequency evidence for narrower structural phenotypes. All DOI-preprint
  snippets skipped by the standard prefix-aware validator were independently
  checked against the cached full text. The causal graph now gives every edge
  claim-level evidence, treats the folding-to-transcription and
  transcription-to-neurodevelopment routes as emerging hypotheses, and does not
  generalize engineered frameshift haploinsufficiency to every clinical missense
  allele. The mouse dosage threshold remains an animal-model result and a
  HUMAN_MODEL_MISMATCH question, not a human lethality prediction. Active
  digestive surveillance is included only for the BMPR1A-containing deletion
  subtype. Case-level variants, a monogenic MONDO term, and the uncached
  Orphanet phenotype tail remain explicit open curation items rather than
  unsupported assertions.

📚

References & Deep Research

References

7

PMID:42431198

Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder.

1 finding

Defining publication. Phenotypes 27 individuals with heterozygous damaging WAPL variants (plus 8 each with PDS5A and PDS5B variants), delineates a WAPL-related disorder of developmental delay and intellectual disability, nominates WAPL as the driver gene of the recurrent 10q22.3q23.2 deletion via overlapping iPSC and induced-neuron transcriptomes, and defines a mouse Wapl dosage-liability threshold below heterozygosity.

DOI:10.64898/2026.02.23.26346364

Clinical, in vitro, and in vivo evidence of WAPL as a novel cohesinopathy gene and phenotypic driver of 10q22.3q23.2 genomic disorder

1 finding

medRxiv preprint of the defining publication (PMID:42431198), posted 2026-02-28 and openly available in full text. Supplies the per-feature counts the ahead-of-print abstract omits - of 25 phenotyped individuals, 21 have mild-moderate developmental delay/intellectual disability, 15 craniofacial dysmorphism, 14 neurological features, 11 behavioral features, 7 cardiac findings and 4 clubfoot - and reports the EpiSign DNA methylation analysis, which found a cohesin-release-factor-deficiency episignature and a combined WAPL-SNV-plus-10q-deletion signature but no signature for WAPL sequence variants alone. Case-level data in Table 1, Table S4, Fig. 2 and Fig. S12 are redacted per medRxiv guidelines, so variant-level and facial-gestalt curation is still blocked.

PMID:17113138

Wapl controls the dynamic association of cohesin with chromatin.

1 finding

Identifies WAPL as the factor required to unlock cohesin from its stably chromatin-bound state; WAPL depletion increases cohesin residence time on chromatin in interphase.

PMID:28475897

The Cohesin Release Factor WAPL Restricts Chromatin Loop Extension.

1 finding

WAPL-knockout human cells show extended chromatin loops, increased contact between neighbouring TADs, and looping between incorrectly oriented CTCF sites, establishing WAPL as the brake on cohesin loop extrusion.

PMID:29217591

Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins.

1 finding

Independent demonstration that WAPL and its PDS5 binding partners set loop length, with vermicelli-like axial cohesin accumulation on their loss; supplies the mechanistic rationale for treating PDS5A and PDS5B as candidate genes.

PMID:17436248

Recurrent 10q22-q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities.

1 finding

Original delineation of the recurrent LCR-mediated 10q22-q23 deletion as a genomic disorder associated with cognitive impairment, autism, hyperactivity and possible psychiatric disease.

PMID:21248748

The phenotype of recurrent 10q22q23 deletions and duplications.

1 finding

Clinical and molecular characterisation of eight deletions and six duplications of 10q22.3q23.3; LCR3-4 deletion carriers had speech-predominant developmental delay, macrocephaly, mild facial dysmorphism, cerebellar anomalies, cardiac defects and congenital breast aplasia, with NRG3 proposed for breast aplasia and BMPR1A/GRID1 for cardiac defects.

WAPL-Related Developmental Disorder

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