Cornelia de Lange Syndrome 5

Mendelian MONDO:0010471 Pathograph 30 Show in embeddings browser Cornelia de Lange syndrome Cohesinopathy

Cornelia de Lange syndrome 5 is the X-linked HDAC8-related form of the cohesinopathy spectrum. Its interest is that it breaks the cohesinopathy at a different point from every other CdLS gene. NIPBL, SMC1A, SMC3 and RAD21 are all about getting cohesin onto chromatin or building the ring that does it. HDAC8 is about taking cohesin off again. SMC3 is acetylated in S phase to lock chromatin-loaded cohesin into a cohesive state, and HDAC8 is the vertebrate deacetylase that removes that mark once the ring is released. Without it, acetylated SMC3 is recycled back onto chromatin still carrying its acetyl group, and the consequence is not a loss of cohesion but a redistribution: cohesin occupancy at its normal binding sites falls, and the transcriptional pattern that follows is the same one seen in NIPBL-mutant cells. A release-arm lesion and a loading-arm lesion converge on the same downstream readout, which is why they produce overlapping diseases. Two clinical consequences follow from the gene being on the X chromosome. Affected females are heterozygous and their severity tracks X-inactivation skewing, so a mother and daughter carrying the same variant can differ substantially; hemizygous males are more severely affected. And the craniofacial phenotype, while overlapping classic CdLS, diverges enough - delayed anterior fontanelle closure, ocular hypertelorism, hooded eyelids, a broader nose, dental anomalies - that in the largest reported cohort the diagnosis of CdLS had not been considered before genomic testing in several individuals.

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1
Inheritance
6
Pathophys.
20
Phenotypes
4
Gaps
30
Pathograph
1
Genes
4
Medical Actions
2
Differentials
2
Models
3
References
1
Deep Research
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
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Inheritance

1
X-linked dominant HP:0001423
Most variants arise de novo. Heterozygous females are affected, with clinical features overlapping those of hemizygous males but with severity set largely by the X-inactivation pattern; hemizygous males are more severely affected. This is the axis along which the disease varies within a family, and it is the reason a mildly affected carrier mother can be recognised only after her child is diagnosed.
X-linked dominant inheritance
Show evidence (4 references)
PMID:20301283 SUPPORT Other
"Females with a heterozygous HDAC8 pathogenic variant have clinical features overlapping those of hemizygous males, but the severity is greatly influenced by the pattern of X-chromosome inactivation."
The GeneReviews statement of the inheritance mode and of X-inactivation as the determinant of severity in heterozygous females.
PMID:24403048 SUPPORT Human Clinical
"Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA."
Reports the skewing directly in the cohort rather than inferring it from the mode of inheritance.
PMID:24403048 SUPPORT Human Clinical
"We also identified eight hemizygous males who are more severely affected."
Establishes the greater severity of the hemizygous male phenotype.
+ 1 more reference
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Discussions and Knowledge Gaps

4
Which developmental programmes are misexpressed by the altered cohesin occupancy, and why does that produce this particular set of craniofacial, limb and growth anomalies rather than a general developmental failure?
KNOWLEDGE GAP cdls5_transcription_to_phenotype_gap
Attached to
pathophysiology#Altered Cohesin Occupancy and Transcriptional Dysregulation pathophysiology#Disrupted Embryonic Growth and Patterning
The mechanism is unusually well traced from the enzyme to the chromatin, and then largely stops. One branch has been resolved and only in mouse: HDAC8 represses Otx2 and Lhx1 in cranial neural crest, and losing it derepresses them, which accounts for the craniofacial arm. Nothing comparable exists for the growth restriction, the limb, cardiac or gastrointestinal anomalies, or the neurobehavioural phenotype. Cohesin binds throughout the genome and the transcriptional change is described as a pattern rather than as a named set of target genes for those systems, which is why the edge from transcriptional dysregulation to the general developmental phenotype stays INDIRECT_UNKNOWN_INTERMEDIATES while the neural crest branch is INDIRECT_KNOWN_INTERMEDIATES.
Can the biochemical consequence of an HDAC8 missense allele predict clinical severity?
KNOWLEDGE GAP cdls5_structure_function_to_severity
Attached to
genetic#HDAC8
The structural work has measured catalytic loss and thermostability for many of the disease mutants, and there is an obvious temptation to read those numbers as a severity predictor. The authors of that work explicitly warn against it, because X-inactivation sits between the allele and the phenotype in the heterozygous females who make up most reported cases. A structure-to-severity model would need the X-inactivation pattern in the affected tissue, which is not what is measured.
Show evidence (1 reference)
PMID:33316326 SUPPORT In Vitro
"Genotype-phenotype relationships for HDAC8 are influenced by several factors, including catalytic activity, thermostability, and X-inactivation, so the influence of structure-function relationships for HDAC8 mutations on clinical phenotypes must be interpreted with caution."
The source's own statement of the caveat, which is what this gap records.
Does small-molecule reactivation of mutant HDAC8 translate into anything clinically meaningful?
KNOWLEDGE GAP cdls5_hdac8_activator_rescue
Attached to
pathophysiology#HDAC8 Loss of Deacetylase Function
Several catalytically impaired HDAC8 mutants can be partially or fully reactivated in vitro by an N-acylthiourea activator. That is a genuine and unusual therapeutic lead for a loss-of-function developmental disorder, and it is also, so far, entirely in vitro. The harder question is timing rather than chemistry: the phenotype is established in embryogenesis, so it is not clear what postnatal restoration of deacetylase activity would be expected to change.
Show evidence (1 reference)
PMID:27576763 SUPPORT In Vitro
"Intriguingly, catalytic activity in many HDAC8 mutants can be partially or fully restored by an N-acylthiourea activator, suggesting a plausible strategy for the chemical rescue of compromised HDAC8 catalysis in vivo."
Records the in vitro rescue result and the authors' own framing of it as a strategy rather than a demonstrated treatment.
Does the mouse Hdac8-null skull phenotype represent the human CdLS5 craniofacial phenotype, or a different consequence of the same lesion?
HUMAN MODEL MISMATCH cdls5_mouse_skull_translational_validity
Attached to
pathophysiology#Derepression of Cranial Neural Crest Patterning Genes animal_models#Hdac8-null mouse animal_models#Cranial neural crest conditional Hdac8 knockout mouse
The evidence is not absent, which is what separates this from the other gaps here: a specific transcriptional mechanism has been demonstrated, twice, in a lineage-restricted conditional as well as a global knockout. What is uncertain is whether it transfers. The mouse phenotype is skull instability severe enough to kill the animal perinatally; the human phenotype is a viable, dysmorphic skull with hypertelorism and a late-closing fontanelle. Those are not obviously the same defect at different severities, and three differences could explain the divergence: the mouse is a constitutive null while most human alleles are missense with residual activity, the human females who make up most cases are X-inactivation mosaics with no mouse counterpart, and the vertebrate-specific skull elements the paper implicates differ between the species. No human cranial neural crest experiment has been done, so the translation rests on the plausibility of the mechanism rather than on evidence.
Show evidence (1 reference)
PMID:19605684 SUPPORT Model Organism
"These findings reveal how the identity and patterning of vertebrate-specific portions of the skull are epigenetically controlled by a histone deacetylase."
The authors' own framing, which scopes the result to vertebrate-specific skull elements and is the claim whose human transfer is uncertain.
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Pathophysiology

6
HDAC8 Loss of Deacetylase Function
HDAC8 is the vertebrate deacetylase for the cohesin subunit SMC3, a zinc-dependent hydrolase acting on the acetyl-lysine mark placed during S phase. The disease alleles remove that activity, either by disrupting substrate binding and catalysis directly or by destabilising the fold.
Genetic context HDAC8 hgnc:13315 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns HDAC8 (hgnc:13315). hgnc:13315 is a gene from the HUGO Gene Nomenclature Committee. allele_type: MISSENSE variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Mostly de novo missense alleles, hemizygous in males and heterozygous in females. Recorded as LOSS_OF_FUNCTION because every missense allele tested lost enzymatic activity; the mechanism is loss of catalysis or of protein stability rather than an altered or acquired activity.
SMC3 lysine deacetylase activity GO:0033558 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves SMC3 lysine deacetylase activity, annotated with protein lysine deacetylase activity (GO:0033558), qualified as loss of function. GO:0033558 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Persistent SMC3 Acetylation With the deacetylase gone, the S-phase acetyl mark on SMC3 is not removed.
Show evidence (2 references)
PMID:22885700 SUPPORT In Vitro
"Here we identify HDAC8 as the vertebrate SMC3 deacetylase, as well as loss-of-function HDAC8 mutations in six CdLS probands."
Identifies the enzyme-substrate relationship and, in the same sentence, ties loss-of-function alleles in it to CdLS.
PMID:27576763 SUPPORT In Vitro
"Most CdLS HDAC8 mutations trigger structural changes that directly or indirectly impact substrate binding and catalysis."
Describes how the disease alleles abolish the activity, which is the content of this node beyond the gene-disease association.
Persistent SMC3 Acetylation
SMC3 acetylation is a cell-cycle switch, not a constitutive state: it is written in S phase to make chromatin-loaded cohesin cohesive, and erased after the ring is released so the subunits can be reused. Losing the eraser converts a switch into a one-way mark.
SMC3 deacetylation GO:0006476 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased SMC3 deacetylation, annotated with protein deacetylation (GO:0006476). GO:0006476 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Failure of Cohesin Recycling Reversal of the acetyl mark is the step that licenses a released cohesin ring for reloading, so its failure blocks recycling.
Show evidence (1 reference)
PMID:27072133 SUPPORT In Vitro
"The SMC3 subunit of cohesin is acetylated (ac) during S phase to establish cohesion between replicated chromosomes."
Establishes when and why the mark is written, which is what makes its persistence abnormal rather than merely present.
Failure of Cohesin Recycling
The 'used' cohesin complex released from chromatin at prophase and anaphase is not dissolved efficiently, and SMC3 that still carries its acetyl mark is nonetheless reloaded onto chromatin. The defect is in the reuse cycle rather than in cohesion itself.
sister chromatid cohesion GO:0007062 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves sister chromatid cohesion (GO:0007062). GO:0007062 is a biological process from the Gene Ontology.
cohesin complex GO:0008278 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves cohesin complex (GO:0008278). GO:0008278 is a cellular component from the Gene Ontology.
Downstream
Altered Cohesin Occupancy and Transcriptional Dysregulation Reloading acetylated SMC3 changes where cohesin sits on the genome, and the changed occupancy is read out as changed transcription.
Show evidence (1 reference)
PMID:22885700 SUPPORT In Vitro
"Loss of HDAC8 activity results in increased SMC3 acetylation and inefficient dissolution of the ‘used’ cohesin complex released from chromatin in both prophase and anaphase."
Names the failing step and the two cell-cycle phases at which it is observed.
Altered Cohesin Occupancy and Transcriptional Dysregulation
Cohesin occupancy at its normal genomic binding sites falls, and the resulting transcriptional pattern is shared with NIPBL-mutant CdLS cell lines. This shared endpoint is the reason a release-arm lesion and a loading-arm lesion produce overlapping diseases, and it is the point at which this entry's mechanism rejoins the rest of the cohesinopathy spectrum.
regulation of DNA-templated transcription GO:0006355 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated regulation of DNA-templated transcription (GO:0006355). GO:0006355 is a biological process from the Gene Ontology. ↕ DYSREGULATED chromatin organization GO:0006325 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated chromatin organization (GO:0006325). GO:0006325 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Derepression of Cranial Neural Crest Patterning Genes The one developmental programme that has been traced. In mouse, HDAC8 represses a subset of homeobox transcription factors in cranial neural crest cells, and its loss derepresses them. This edge is drawn from mouse data; the corresponding human neural crest experiment has not been done.
Disrupted Embryonic Growth and Patterning For everything other than the craniofacial skeleton, the step from a genome-wide transcriptional shift to a specific anomaly is not resolved. No study identifies the developmental programmes behind the growth, limb, cardiac or neurobehavioural features, so those intermediates are recorded as unknown rather than asserted.
Show evidence (1 reference)
PMID:22885700 SUPPORT In Vitro
"SMC3 with retained acetylation is loaded onto chromatin, and chromatin immunoprecipitation sequencing analysis demonstrates decreased occupancy of cohesin localization sites that results in a consistent pattern of altered transcription seen in CdLS cell lines with either NIPBL or HDAC8 mutations."
Documents both halves of the node: reduced occupancy, and a transcriptional pattern shared with the NIPBL form.
Derepression of Cranial Neural Crest Patterning Genes
Model-derived, and the only part of the transcription-to-phenotype step that has been resolved. In mouse, HDAC8 represses homeobox transcription factors including Otx2 and Lhx1 in cranial neural crest cells; deleting Hdac8 derepresses them and the skull fails to pattern correctly. Deleting it only in cranial neural crest phenocopies the global knockout, which is what localises the lesion to that cell population rather than to the skeleton itself. No equivalent human experiment exists, so this node describes a mouse mechanism proposed for the human craniofacial phenotype. On the cell-type binding: CL:0000008 (migratory cranial neural crest cell) was considered and not used. The mouse work deletes Hdac8 in the cranial neural crest lineage and reads out skull patterning; it does not establish that the affected population is specifically the migratory one, so that term would assert a developmental stage the source does not.
cranial neural crest cell CL:0011012 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cranial neural crest cell, annotated with neural crest cell (CL:0011012). CL:0011012 is a cell type from the Cell Ontology.
negative regulation of DNA-templated transcription GO:0045892 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of DNA-templated transcription (GO:0045892). GO:0045892 is a biological process from the Gene Ontology. ↓ DECREASED neural crest cell differentiation GO:0014033 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated neural crest cell differentiation (GO:0014033). GO:0014033 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Animal models
Hdac8-null mouse Mouse recapitulates The model is where this node comes from: loss of Hdac8 derepresses Otx2 and Lhx1 in cranial neural crest.
Cranial neural crest conditional Hdac8 knockout mouse Mouse perturbs A cell-type-restricted perturbation used to assign the skull phenotype to cranial neural crest.
Downstream
Hypertelorism Skull and midface patterning, which is the specific arm the mouse neural crest work accounts for. Recorded as INDIRECT_KNOWN_INTERMEDIATES because the intermediate, derepression of the homeobox programme, is identified but only in mouse.
Delayed anterior fontanelle closure Skull and midface patterning, which is the specific arm the mouse neural crest work accounts for. Recorded as INDIRECT_KNOWN_INTERMEDIATES because the intermediate, derepression of the homeobox programme, is identified but only in mouse.
Wide nose Skull and midface patterning, which is the specific arm the mouse neural crest work accounts for. Recorded as INDIRECT_KNOWN_INTERMEDIATES because the intermediate, derepression of the homeobox programme, is identified but only in mouse.
Disrupted Embryonic Growth and Patterning In mouse this produces skull instability severe enough to be perinatally lethal. The inference to the human craniofacial phenotype is the translational step, and it is recorded as a HUMAN_MODEL_MISMATCH discussion rather than asserted.
Show evidence (1 reference)
PMID:19605684 SUPPORT Model Organism
"Hdac8 specifically represses the aberrant expression of homeobox transcription factors such as Otx2 and Lhx1."
Names the derepressed transcription factors, which is what makes this a mechanism rather than a restatement of the phenotype.
Disrupted Embryonic Growth and Patterning
The developmental endpoint, expressed as prenatal-onset growth failure, a distinctive craniofacial configuration, limb involvement and intellectual disability. In the HDAC8 form the craniofacial pattern is recognisably CdLS but shifted, which is why the diagnosis is often reached by sequencing rather than by examination.
embryo development GO:0009790 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated embryo development (GO:0009790). GO:0009790 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Animal models
Hdac8-null mouse Mouse partially recapitulates Reproduces the craniofacial arm of the phenotype and nothing else.
Downstream
Hooded eyelid Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Synophrys Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Long eyelashes Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Anteverted nares Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Abnormality of the dentition Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Intrauterine growth retardation Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Postnatal growth retardation Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Intellectual disability Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Hypertrichosis Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Self-injurious behavior Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Autistic behavior Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Myopia Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Congenital heart disease Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Gastroesophageal reflux Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Hearing impairment Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Cryptorchidism Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Generalized dystonia Part of the multisystem developmental phenotype. The intermediates between the transcriptional defect and this specific feature are not identified in any source.
Show evidence (2 references)
PMID:24403048 SUPPORT Human Clinical
"These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS."
States the developmental outcome and, importantly, that it is a distinct subgroup rather than indistinguishable from classic CdLS.
PMID:20301283 SUPPORT Other
"Severe (classic) CdLS is characterized by distinctive facial features, growth failure (often prenatal onset; height and weight <5th centile throughout life), hypertrichosis, and limb abnormalities"
The GeneReviews description of the developmental phenotype this node produces. Graded OTHER as an expert-curated chapter rather than a primary study.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cornelia de Lange Syndrome 5 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

20
Cardiovascular 1
Congenital heart disease FREQUENT Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart disease, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"Other frequent findings include gastrointestinal dysfunction, cryptorchidism or hypoplastic genitalia, myopia, hearing impairment, and congenital heart disease."
Names congenital heart disease among the frequent findings.
Digestive 1
Gastroesophageal reflux FREQUENT HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"Other frequent findings include gastrointestinal dysfunction, cryptorchidism or hypoplastic genitalia, myopia, hearing impairment, and congenital heart disease."
Names gastrointestinal dysfunction among the frequent findings. The specific reflux management is quoted separately on the treatment entry.
Ear 1
Hearing impairment FREQUENT HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"Other frequent findings include gastrointestinal dysfunction, cryptorchidism or hypoplastic genitalia, myopia, hearing impairment, and congenital heart disease."
Names hearing impairment among the frequent findings.
Eye 2
Hypertelorism FREQUENT HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24403048 SUPPORT Human Clinical
"The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features."
Lists hypertelorism among the features that distinguish HDAC8-related CdLS from the classic form.
Myopia FREQUENT HP:0000545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopia (HP:0000545). HP:0000545 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"Other frequent findings include gastrointestinal dysfunction, cryptorchidism or hypoplastic genitalia, myopia, hearing impairment, and congenital heart disease."
Names myopia among the frequent findings. Spectrum-level, like the other phenotypes drawn from this sentence.
Genitourinary 1
Cryptorchidism FREQUENT HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"Other frequent findings include gastrointestinal dysfunction, cryptorchidism or hypoplastic genitalia, myopia, hearing impairment, and congenital heart disease."
Names cryptorchidism among the frequent findings.
Head and Neck 7
Delayed anterior fontanelle closure FREQUENT Delayed closure of the anterior fontanelle HP:0001476 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed anterior fontanelle closure, annotated with Delayed closure of the anterior fontanelle (HP:0001476). HP:0001476 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24403048 SUPPORT Human Clinical
"The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features."
Names delayed anterior fontanelle closure as a discriminating feature of the HDAC8 form.
Hooded eyelid FREQUENT HP:0030820 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hooding of the eyelids, annotated with Hooded eyelid (HP:0030820). HP:0030820 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24403048 SUPPORT Human Clinical
"The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features."
Names eyelid hooding among the discriminating craniofacial features.
Synophrys FREQUENT HP:0000664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Synophrys (HP:0000664). HP:0000664 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nose with depressed nasal bridge and anteverted nares, small, widely spaced teeth, and microbrachycephaly."
The GeneReviews craniofacial list for the CdLS spectrum, of which the HDAC8 form is part. Frequency is set from the spectrum description rather than from an HDAC8-specific count.
Long eyelashes FREQUENT HP:0000527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long eyelashes (HP:0000527). HP:0000527 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nose with depressed nasal bridge and anteverted nares, small, widely spaced teeth, and microbrachycephaly."
The GeneReviews craniofacial list, which includes long eyelashes.
Anteverted nares FREQUENT HP:0000463 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anteverted nares (HP:0000463). HP:0000463 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nose with depressed nasal bridge and anteverted nares, small, widely spaced teeth, and microbrachycephaly."
The GeneReviews craniofacial list, which includes anteverted nares.
Wide nose FREQUENT HP:0000445 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broader nose, annotated with Wide nose (HP:0000445). HP:0000445 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24403048 SUPPORT Human Clinical
"The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features."
Names a broader nose among the discriminating features of the HDAC8 form.
Abnormality of the dentition FREQUENT HP:0000164 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dental anomalies, annotated with Abnormality of the dentition (HP:0000164). HP:0000164 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24403048 SUPPORT Human Clinical
"The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features."
Names dental anomalies among the discriminating features of the HDAC8 form.
Integument 1
Hypertrichosis FREQUENT HP:0000998 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrichosis (HP:0000998). HP:0000998 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"Severe (classic) CdLS is characterized by distinctive facial features, growth failure (often prenatal onset; height and weight <5th centile throughout life), hypertrichosis, and limb abnormalities"
Names hypertrichosis among the defining features.
Nervous System 4
Intellectual disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"Across the CdLS spectrum, IQ ranges from below 30 to 102 (mean: 53)."
Gives the range and mean for the spectrum. Quoted rather than paraphrased because the spread is the point: this is not a uniform degree of impairment.
Self-injurious behavior FREQUENT HP:0100716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Self-injurious behavior (HP:0100716). HP:0100716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"Many individuals demonstrate autistic and self-injurious behaviors."
Reports self-injurious behaviour as a frequent feature of the spectrum.
Autistic behavior FREQUENT HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"Many individuals demonstrate autistic and self-injurious behaviors."
Reports autistic behaviour as a frequent feature of the spectrum.
Generalized dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized dystonia, annotated with Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38910710 SUPPORT Human Clinical
"We report our observation of an individual with CdLS5 with de novo missense mutation presenting with a novel phenotype of generalized dystonia."
The case report's own statement of the observation. Frequency is omitted because this rests on one individual.
PMID:38910710 SUPPORT Human Clinical
"She had marked axial and appendicular dystonia."
The examination finding itself, which is what makes this a phenotype record rather than a restatement of the paper's framing.
Growth 2
Intrauterine growth retardation FREQUENT HP:0001511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prenatal-onset growth failure, annotated with Intrauterine growth retardation (HP:0001511). HP:0001511 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"Severe (classic) CdLS is characterized by distinctive facial features, growth failure (often prenatal onset; height and weight <5th centile throughout life), hypertrichosis, and limb abnormalities"
The word doing the work here is "often": prenatal onset is frequent rather than universal, which is why this half carries FREQUENT while the lifelong deficit below carries VERY_FREQUENT.
Postnatal growth retardation VERY_FREQUENT HP:0008897 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postnatal growth retardation (HP:0008897). HP:0008897 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"Severe (classic) CdLS is characterized by distinctive facial features, growth failure (often prenatal onset; height and weight <5th centile throughout life), hypertrichosis, and limb abnormalities"
Gives the centile and its persistence through life, which is the postnatal claim.
🧬

Genetic Associations

1
HDAC8
Gene: HDAC8 hgnc:13315 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HDAC8 (hgnc:13315). hgnc:13315 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:24403048 SUPPORT Human Clinical
"HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function."
Establishes loss of enzymatic function as the shared consequence of the missense alleles, which is what makes this a single mechanistic entity.
PMID:33316326 SUPPORT In Vitro
"Consistent with loss of HDAC8 function in cohesin recycling, deacetylase activity and/or thermostability is compromised in most CdLS HDAC8 mutants studied."
Adds the second failure mode, protein destabilisation, alongside direct catalytic loss.
PMID:42157730 SUPPORT Human Clinical
"This aberrant splicing likely results in nonsense-mediated mRNA decay with loss-of-function effects."
Documents a non-coding route to the same loss of function, via aberrant splicing and nonsense-mediated decay.
💊

Medical Actions

4
Nutritional Support and Growth Monitoring
Action: nutritional supportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is nutritional support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Support NCIT:C15433
Platform: Behavioral / lifestyle
Management is supportive; there is no treatment directed at the molecular lesion. CdLS-specific growth charts are used, with supplementary formula or gastrostomy feeding when intake is inadequate.
Mechanism Target:
Disrupted Embryonic Growth and Patterning — Addresses the growth-failure component of the developmental phenotype at the level of intake. It does not alter the underlying cohesin defect, and this link is recorded as symptomatic support rather than as a mechanism-directed therapy.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"MANAGEMENT: Treatment of manifestations: Use of CdLS-specific growth charts with supplementary formulas and/or gastrostomy tube placement to meet nutritional needs as necessary."
The GeneReviews management recommendation, which is the basis for this treatment entry and for describing it as supportive.
Management of Gastroesophageal Reflux
Action: therapeutic procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is therapeutic procedure (NCIT:C49236). NCIT:C49236 is a clinical intervention from the NCI Thesaurus. Ontology label: Therapeutic Procedure NCIT:C49236
Platform: Other
GeneReviews calls for aggressive GERD management, assessment for gastrointestinal malrotation, and fundoplication if reflux is severe.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"Aggressive management of gastroesophageal reflux disease (GERD) with assessment of potential gastrointestinal malrotation; consideration of fundoplication if reflux is severe."
The GeneReviews recommendation for reflux management.
Developmental Therapies
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
Physical, occupational and speech therapy to support psychomotor development and communication.
Show evidence (1 reference)
PMID:20301283 SUPPORT Other
"Physical, occupational, and speech therapy to optimize psychomotor development and communication skills."
The GeneReviews developmental-therapy recommendation.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Other
Counselling here has to carry the X-linked pattern and its consequences: a heterozygous mother transmits with 50% probability in each pregnancy, male sibs who inherit will be affected, an affected father transmits to all daughters and no sons, and a carrier female's severity depends on X-inactivation and so cannot be predicted from the variant alone.
Show evidence (3 references)
PMID:20301283 SUPPORT Other
"If the mother of the proband has an SMC1A or HDAC8 pathogenic variant, the chance of transmitting it in each pregnancy is 50%."
Gives the transmission risk that counselling has to communicate for this gene.
PMID:20301283 SUPPORT Other
"If the father of the proband has an SMC1A or HDAC8 pathogenic variant, he will transmit it to all his daughters and none of his sons."
The paternal transmission pattern, which differs from the autosomal dominant CdLS genes and is the part most often got wrong.
PMID:26671848 SUPPORT Human Clinical
"Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children."
Documents parental mosaicism transmitted to two children, which is the reason a de novo-appearing variant does not license a low recurrence-risk figure here.
🔬

Diagnosis

2
Molecular genetic testing (PRESENT)
The diagnosis is molecular. HDAC8 is one of the two X-linked CdLS genes, so the variant may be hemizygous or heterozygous, and the clinical route to testing is often not a suspicion of CdLS at all: in the defining cohort, several individuals reached the gene through genomic testing without CdLS having been considered.
Show evidence (2 references)
PMID:20301283 SUPPORT Other
"DIAGNOSIS/TESTING: The diagnosis of CdLS is established in a proband with suggestive clinical features and/or a heterozygous pathogenic variant in BRD4, MAU2, NIPBL, RAD21, or SMC3 or a hemizygous or heterozygous pathogenic variant in HDAC8 or SMC1A identified by molecular genetic testing."
States the diagnostic criterion and, specifically, that HDAC8 variants may be hemizygous or heterozygous.
PMID:24403048 SUPPORT Human Clinical
"For several individuals, the diagnosis of CdLS was not considered prior to genomic testing."
Establishes that clinical recognition is unreliable for this form, which is the reason the diagnostic route is sequencing-first.
X-inactivation studies in heterozygous females (PRESENT)
Skewed X-inactivation in peripheral blood DNA was found in the heterozygous females of the defining cohort and is one of the determinants of severity. It is a prognostically relevant test rather than a diagnostic one: it does not establish the diagnosis, but it bears on how a carrier's phenotype should be interpreted.
Show evidence (1 reference)
PMID:24403048 SUPPORT Human Clinical
"Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA."
Records the finding and the tissue in which it was measured, which matters because blood skewing need not match the affected tissues.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population rate has been published for the HDAC8 form specifically. The denominator that exists is the share of CdLS attributable to HDAC8: the founding report identified six probands, and the first dedicated cohort assembled 38 individuals. Reported as CASES_IN_LITERATURE for that reason.
Show evidence (1 reference)
PMID:24403048 SUPPORT Human Clinical
"Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations."
Gives the size of the largest assembled series, which is the basis for the CASES_IN_LITERATURE measure.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Cornelia de Lange Syndrome 5:

🐁

Animal Models

2
Hdac8-null mouse
Global deletion of Hdac8 in mouse is perinatally lethal from skull instability. The model established HDAC8 as a repressor of cranial neural crest patterning genes and is the source of the only mechanistic account of how the transcriptional defect reaches a specific tissue.
Species
Mouse
Genotype
Hdac8 global knockout
Publication
PMID:19605684
Pathograph links
Derepression of Cranial Neural Crest Patterning Genes recapitulates fidelity: moderate observes: molecular The model is where this node comes from: loss of Hdac8 derepresses Otx2 and Lhx1 in cranial neural crest.
Limitations: A constitutive null, whereas most human alleles are missense with residual protein, and it carries no X-inactivation mosaicism, which is the dominant determinant of severity in the heterozygous females who make up most human cases.
Show evidence (1 reference)
PMID:19605684 SUPPORT Model Organism
"Hdac8 specifically represses the aberrant expression of homeobox transcription factors such as Otx2 and Lhx1."
Supports treating this model as informative for the transcriptional-derepression node, since the derepression is what the model measures.
Disrupted Embryonic Growth and Patterning partially recapitulates fidelity: low observes: organism Reproduces the craniofacial arm of the phenotype and nothing else.
Limitations: Perinatal lethality from skull instability is not the human phenotype, which is a dysmorphic but viable skull. The growth, limb, gastrointestinal, behavioural and cognitive features of human CdLS5 cannot be assessed in an animal that does not survive, so the model speaks to one of several affected systems.
Show evidence (1 reference)
PMID:19605684 SUPPORT Model Organism
"Global deletion of Hdac8 in mice leads to perinatal lethality due to skull instability, and this is phenocopied by conditional deletion of Hdac8 in cranial neural crest cells."
Reports the organism-level phenotype and its severity, which is the basis for grading this link PARTIALLY_RECAPITULATES with LOW fidelity.
Cranial neural crest conditional Hdac8 knockout mouse
Deleting Hdac8 only in cranial neural crest phenocopies the global knockout's skull defect. This is the experiment that localises the pathogenesis to that cell population rather than to the developing bone.
Species
Mouse
Genotype
Cranial neural crest-specific conditional Hdac8 deletion
Publication
PMID:19605684
Pathograph links
Derepression of Cranial Neural Crest Patterning Genes perturbs fidelity: moderate observes: cellular A cell-type-restricted perturbation used to assign the skull phenotype to cranial neural crest.
Limitations: A conditional null in one lineage answers where, not how much: it says nothing about the graded, partial loss of function produced by human missense alleles, and nothing about the other affected organ systems.
Show evidence (1 reference)
PMID:19605684 SUPPORT Model Organism
"Global deletion of Hdac8 in mice leads to perinatal lethality due to skull instability, and this is phenocopied by conditional deletion of Hdac8 in cranial neural crest cells."
The phenocopy result is what makes this a lineage-assignment experiment.
{ }

Source YAML

click to show 
name: Cornelia de Lange Syndrome 5
creation_date: "2026-09-07T18:00:00Z"
category: Mendelian
synonyms:
- CdLS5
- CDLS5
- Cornelia de Lange syndrome 5, X-linked dominant
- HDAC8-related Cornelia de Lange syndrome
- HDAC8-CdLS
description: >-
  Cornelia de Lange syndrome 5 is the X-linked HDAC8-related form of the cohesinopathy
  spectrum. Its interest is that it breaks the cohesinopathy at a different point from
  every other CdLS gene.

  NIPBL, SMC1A, SMC3 and RAD21 are all about getting cohesin onto chromatin or building
  the ring that does it. HDAC8 is about taking cohesin off again. SMC3 is acetylated in
  S phase to lock chromatin-loaded cohesin into a cohesive state, and HDAC8 is the
  vertebrate deacetylase that removes that mark once the ring is released. Without it,
  acetylated SMC3 is recycled back onto chromatin still carrying its acetyl group, and
  the consequence is not a loss of cohesion but a redistribution: cohesin occupancy at
  its normal binding sites falls, and the transcriptional pattern that follows is the
  same one seen in NIPBL-mutant cells. A release-arm lesion and a loading-arm lesion
  converge on the same downstream readout, which is why they produce overlapping
  diseases.

  Two clinical consequences follow from the gene being on the X chromosome. Affected
  females are heterozygous and their severity tracks X-inactivation skewing, so a
  mother and daughter carrying the same variant can differ substantially; hemizygous
  males are more severely affected. And the craniofacial phenotype, while overlapping
  classic CdLS, diverges enough - delayed anterior fontanelle closure, ocular
  hypertelorism, hooded eyelids, a broader nose, dental anomalies - that in the largest
  reported cohort the diagnosis of CdLS had not been considered before genomic testing
  in several individuals.
disease_term:
  preferred_term: Cornelia de Lange syndrome 5
  term:
    id: MONDO:0010471
    label: Cornelia de Lange syndrome 5
parents:
- Cornelia de Lange syndrome
- Cohesinopathy
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population rate has been published for the HDAC8 form specifically. The
    denominator that exists is the share of CdLS attributable to HDAC8: the founding
    report identified six probands, and the first dedicated cohort assembled 38
    individuals. Reported as CASES_IN_LITERATURE for that reason.
  evidence:
  - reference: PMID:24403048
    reference_title: "Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations."
    explanation: >-
      Gives the size of the largest assembled series, which is the basis for the
      CASES_IN_LITERATURE measure.
inheritance:
- name: X-linked dominant
  inheritance_term:
    preferred_term: X-linked dominant inheritance
    term:
      id: HP:0001423
      label: X-linked dominant inheritance
  description: >-
    Most variants arise de novo. Heterozygous females are affected, with clinical
    features overlapping those of hemizygous males but with severity set largely by the
    X-inactivation pattern; hemizygous males are more severely affected. This is the
    axis along which the disease varies within a family, and it is the reason a mildly
    affected carrier mother can be recognised only after her child is diagnosed.
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Females with a heterozygous HDAC8 pathogenic variant have clinical features overlapping those of hemizygous males, but the severity is greatly influenced by the pattern of X-chromosome inactivation."
    explanation: >-
      The GeneReviews statement of the inheritance mode and of X-inactivation as the
      determinant of severity in heterozygous females.
  - reference: PMID:24403048
    reference_title: "Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA."
    explanation: >-
      Reports the skewing directly in the cohort rather than inferring it from the mode
      of inheritance.
  - reference: PMID:24403048
    reference_title: "Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also identified eight hemizygous males who are more severely affected."
    explanation: Establishes the greater severity of the hemizygous male phenotype.
  - reference: PMID:26671848
    reference_title: "Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X-inactivation, observed in seven out of eight female patients."
    explanation: >-
      Puts a denominator on the skewing observation, seven of eight female patients, and
      attributes the clinical variability to it.
genetic:
- name: HDAC8
  gene_term:
    preferred_term: HDAC8
    term:
      id: hgnc:13315
      label: HDAC8
  relationship_type: CAUSATIVE
  presence: PRESENT
  variant_origin: GERMLINE
  notes: >-
    Most reported variants are missense and de novo. Functional testing of the missense
    set found that all of them lose enzymatic activity, so the disease mechanism is
    loss of deacetylase function regardless of where in the fold the substitution sits.
    Structural work adds a second axis: some mutants lose catalysis directly, others
    are destabilised, and the two do not map cleanly onto clinical severity because
    X-inactivation intervenes. A splice-region variant producing leaky aberrant
    splicing has also been reported, which supplies a mechanism for intrafamilial
    variability on top of X-inactivation.
  evidence:
  - reference: PMID:24403048
    reference_title: "Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function."
    explanation: >-
      Establishes loss of enzymatic function as the shared consequence of the missense
      alleles, which is what makes this a single mechanistic entity.
  - reference: PMID:33316326
    reference_title: "Structural analysis of histone deacetylase 8 mutants associated with Cornelia de Lange Syndrome spectrum disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Consistent with loss of HDAC8 function in cohesin recycling, deacetylase activity and/or thermostability is compromised in most CdLS HDAC8 mutants studied."
    explanation: >-
      Adds the second failure mode, protein destabilisation, alongside direct catalytic
      loss.
  - reference: PMID:42157730
    reference_title: "Aberrant Splicing From an HDAC8 Intronic Variant c.112-15C>A Causes Familial Cornelia de Lange Syndrome in Heterozygous and Hemizygous Individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This aberrant splicing likely results in nonsense-mediated mRNA decay with loss-of-function effects."
    explanation: >-
      Documents a non-coding route to the same loss of function, via aberrant splicing
      and nonsense-mediated decay.
pathophysiology:
- name: HDAC8 Loss of Deacetylase Function
  biological_scale: MOLECULAR
  genetic_context:
    gene:
      preferred_term: HDAC8
      term:
        id: hgnc:13315
        label: HDAC8
    variant_origin: GERMLINE
    allele_type: MISSENSE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Mostly de novo missense alleles, hemizygous in males and heterozygous in females.
      Recorded as LOSS_OF_FUNCTION because every missense allele tested lost enzymatic
      activity; the mechanism is loss of catalysis or of protein stability rather than
      an altered or acquired activity.
  description: >-
    HDAC8 is the vertebrate deacetylase for the cohesin subunit SMC3, a zinc-dependent
    hydrolase acting on the acetyl-lysine mark placed during S phase. The disease
    alleles remove that activity, either by disrupting substrate binding and catalysis
    directly or by destabilising the fold.
  molecular_functions:
  - preferred_term: SMC3 lysine deacetylase activity
    term:
      id: GO:0033558
      label: protein lysine deacetylase activity
    modifier: LOSS_OF_FUNCTION
  downstream:
  - target: Persistent SMC3 Acetylation
    causal_link_type: DIRECT
    description: >-
      With the deacetylase gone, the S-phase acetyl mark on SMC3 is not removed.
    evidence:
    - reference: PMID:22885700
      reference_title: "HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Loss of HDAC8 activity results in increased SMC3 acetylation and inefficient dissolution of the ‘used’ cohesin complex released from chromatin in both prophase and anaphase."
      explanation: >-
        States exactly the step this edge asserts: loss of HDAC8 activity raises SMC3
        acetylation.
  evidence:
  - reference: PMID:22885700
    reference_title: "HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we identify HDAC8 as the vertebrate SMC3 deacetylase, as well as loss-of-function HDAC8 mutations in six CdLS probands."
    explanation: >-
      Identifies the enzyme-substrate relationship and, in the same sentence, ties
      loss-of-function alleles in it to CdLS.
  - reference: PMID:27576763
    reference_title: "Structural aspects of HDAC8 mechanism and dysfunction in Cornelia de Lange syndrome spectrum disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Most CdLS HDAC8 mutations trigger structural changes that directly or indirectly impact substrate binding and catalysis."
    explanation: >-
      Describes how the disease alleles abolish the activity, which is the content of
      this node beyond the gene-disease association.
- name: Persistent SMC3 Acetylation
  biological_scale: MOLECULAR
  description: >-
    SMC3 acetylation is a cell-cycle switch, not a constitutive state: it is written in
    S phase to make chromatin-loaded cohesin cohesive, and erased after the ring is
    released so the subunits can be reused. Losing the eraser converts a switch into a
    one-way mark.
  biological_processes:
  - preferred_term: SMC3 deacetylation
    term:
      id: GO:0006476
      label: protein deacetylation
    modifier: DECREASED
  downstream:
  - target: Failure of Cohesin Recycling
    causal_link_type: DIRECT
    description: >-
      Reversal of the acetyl mark is the step that licenses a released cohesin ring for
      reloading, so its failure blocks recycling.
    evidence:
    - reference: PMID:27072133
      reference_title: "HDAC8 Inhibition Blocks SMC3 Deacetylation and Delays Cell Cycle Progression without Affecting Cohesin-dependent Transcription in MCF7 Cancer Cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Reversal of SMC3 acetylation is imperative for recycling cohesin so that it can be reloaded in interphase for both non-mitotic and mitotic functions."
      explanation: >-
        States the dependency this edge asserts, that recycling requires reversal of the
        acetylation.
  evidence:
  - reference: PMID:27072133
    reference_title: "HDAC8 Inhibition Blocks SMC3 Deacetylation and Delays Cell Cycle Progression without Affecting Cohesin-dependent Transcription in MCF7 Cancer Cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The SMC3 subunit of cohesin is acetylated (ac) during S phase to establish cohesion between replicated chromosomes."
    explanation: >-
      Establishes when and why the mark is written, which is what makes its persistence
      abnormal rather than merely present.
- name: Failure of Cohesin Recycling
  biological_scale: CELLULAR
  description: >-
    The 'used' cohesin complex released from chromatin at prophase and anaphase is not
    dissolved efficiently, and SMC3 that still carries its acetyl mark is nonetheless
    reloaded onto chromatin. The defect is in the reuse cycle rather than in cohesion
    itself.
  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
  downstream:
  - target: Altered Cohesin Occupancy and Transcriptional Dysregulation
    causal_link_type: DIRECT
    description: >-
      Reloading acetylated SMC3 changes where cohesin sits on the genome, and the
      changed occupancy is read out as changed transcription.
    evidence:
    - reference: PMID:22885700
      reference_title: "HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "SMC3 with retained acetylation is loaded onto chromatin, and chromatin immunoprecipitation sequencing analysis demonstrates decreased occupancy of cohesin localization sites that results in a consistent pattern of altered transcription seen in CdLS cell lines with either NIPBL or HDAC8 mutations."
      explanation: >-
        Traces the whole edge in one sentence, from reloading of acetylated SMC3 through
        reduced occupancy to altered transcription.
  evidence:
  - reference: PMID:22885700
    reference_title: "HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Loss of HDAC8 activity results in increased SMC3 acetylation and inefficient dissolution of the ‘used’ cohesin complex released from chromatin in both prophase and anaphase."
    explanation: >-
      Names the failing step and the two cell-cycle phases at which it is observed.
- name: Altered Cohesin Occupancy and Transcriptional Dysregulation
  biological_scale: CELLULAR
  description: >-
    Cohesin occupancy at its normal genomic binding sites falls, and the resulting
    transcriptional pattern is shared with NIPBL-mutant CdLS cell lines. This shared
    endpoint is the reason a release-arm lesion and a loading-arm lesion produce
    overlapping diseases, and it is the point at which this entry's mechanism rejoins
    the rest of the cohesinopathy spectrum.
  biological_processes:
  - preferred_term: regulation of DNA-templated transcription
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    modifier: DYSREGULATED
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: DYSREGULATED
  downstream:
  - target: Derepression of Cranial Neural Crest Patterning Genes
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The one developmental programme that has been traced. In mouse, HDAC8 represses a
      subset of homeobox transcription factors in cranial neural crest cells, and its
      loss derepresses them. This edge is drawn from mouse data; the corresponding human
      neural crest experiment has not been done.
    evidence:
    - reference: PMID:19605684
      reference_title: "Epigenetic control of skull morphogenesis by histone deacetylase 8."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Here we provide evidence that Hdac8 specifically controls patterning of the skull by repressing a subset of transcription factors in cranial neural crest cells."
      explanation: >-
        Identifies the specific transcriptional programme HDAC8 controls. Graded INDIRECT
        because it is a mouse result standing in for the human step.
  - target: Disrupted Embryonic Growth and Patterning
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      For everything other than the craniofacial skeleton, the step from a genome-wide
      transcriptional shift to a specific anomaly is not resolved. No study identifies
      the developmental programmes behind the growth, limb, cardiac or neurobehavioural
      features, so those intermediates are recorded as unknown rather than asserted.
    evidence:
    - reference: PMID:33316326
      reference_title: "Structural analysis of histone deacetylase 8 mutants associated with Cornelia de Lange Syndrome spectrum disorders."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "The molecular genetic basis of CdLS is linked to defects in cohesin, a protein complex that functions in sister chromatid cohesion, chromatin organization, and transcriptional regulation."
      explanation: >-
        Supports the link between the cohesin defect and the disease at the level the
        literature actually makes it, which is an association between the molecular
        lesion and the syndrome rather than a traced developmental pathway.
  evidence:
  - reference: PMID:22885700
    reference_title: "HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SMC3 with retained acetylation is loaded onto chromatin, and chromatin immunoprecipitation sequencing analysis demonstrates decreased occupancy of cohesin localization sites that results in a consistent pattern of altered transcription seen in CdLS cell lines with either NIPBL or HDAC8 mutations."
    explanation: >-
      Documents both halves of the node: reduced occupancy, and a transcriptional
      pattern shared with the NIPBL form.
- name: Derepression of Cranial Neural Crest Patterning Genes
  biological_scale: CELLULAR
  description: >-
    Model-derived, and the only part of the transcription-to-phenotype step that has
    been resolved. In mouse, HDAC8 represses homeobox transcription factors including
    Otx2 and Lhx1 in cranial neural crest cells; deleting Hdac8 derepresses them and
    the skull fails to pattern correctly. Deleting it only in cranial neural crest
    phenocopies the global knockout, which is what localises the lesion to that cell
    population rather than to the skeleton itself. No equivalent human experiment
    exists, so this node describes a mouse mechanism proposed for the human
    craniofacial phenotype.

    On the cell-type binding: CL:0000008 (migratory cranial neural crest cell) was
    considered and not used. The mouse work deletes Hdac8 in the cranial neural crest
    lineage and reads out skull patterning; it does not establish that the affected
    population is specifically the migratory one, so that term would assert a
    developmental stage the source does not.
  cell_types:
  - preferred_term: cranial neural crest cell
    term:
      id: CL:0011012
      label: neural crest cell
  biological_processes:
  - preferred_term: negative regulation of DNA-templated transcription
    term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    modifier: DECREASED
  - preferred_term: neural crest cell differentiation
    term:
      id: GO:0014033
      label: neural crest cell differentiation
    modifier: DYSREGULATED
  downstream:
  - target: Hypertelorism
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Skull and midface patterning, which is the specific arm the mouse neural crest
      work accounts for. Recorded as INDIRECT_KNOWN_INTERMEDIATES because the
      intermediate, derepression of the homeobox programme, is identified but only in
      mouse.
  - target: Delayed anterior fontanelle closure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Skull and midface patterning, which is the specific arm the mouse neural crest
      work accounts for. Recorded as INDIRECT_KNOWN_INTERMEDIATES because the
      intermediate, derepression of the homeobox programme, is identified but only in
      mouse.
  - target: Wide nose
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Skull and midface patterning, which is the specific arm the mouse neural crest
      work accounts for. Recorded as INDIRECT_KNOWN_INTERMEDIATES because the
      intermediate, derepression of the homeobox programme, is identified but only in
      mouse.
  - target: Disrupted Embryonic Growth and Patterning
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      In mouse this produces skull instability severe enough to be perinatally lethal.
      The inference to the human craniofacial phenotype is the translational step, and
      it is recorded as a HUMAN_MODEL_MISMATCH discussion rather than asserted.
    evidence:
    - reference: PMID:19605684
      reference_title: "Epigenetic control of skull morphogenesis by histone deacetylase 8."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Global deletion of Hdac8 in mice leads to perinatal lethality due to skull instability, and this is phenocopied by conditional deletion of Hdac8 in cranial neural crest cells."
      explanation: >-
        Reports both the skull phenotype and the conditional-knockout result that assigns
        it to cranial neural crest. Graded INDIRECT: the human craniofacial phenotype is
        not perinatally lethal skull instability.
  evidence:
  - reference: PMID:19605684
    reference_title: "Epigenetic control of skull morphogenesis by histone deacetylase 8."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Hdac8 specifically represses the aberrant expression of homeobox transcription factors such as Otx2 and Lhx1."
    explanation: >-
      Names the derepressed transcription factors, which is what makes this a mechanism
      rather than a restatement of the phenotype.
- name: Disrupted Embryonic Growth and Patterning
  biological_scale: ORGANISM
  description: >-
    The developmental endpoint, expressed as prenatal-onset growth failure, a
    distinctive craniofacial configuration, limb involvement and intellectual
    disability. In the HDAC8 form the craniofacial pattern is recognisably CdLS but
    shifted, which is why the diagnosis is often reached by sequencing rather than by
    examination.
  biological_processes:
  - preferred_term: embryo development
    term:
      id: GO:0009790
      label: embryo development
    modifier: DYSREGULATED
  downstream:
  - target: Hooded eyelid
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  - target: Synophrys
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  - target: Long eyelashes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  - target: Anteverted nares
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  - target: Abnormality of the dentition
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  - target: Intrauterine growth retardation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  - target: Postnatal growth retardation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  - target: Hypertrichosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  - target: Self-injurious behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  - target: Autistic behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  - target: Myopia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  - target: Congenital heart disease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  - target: Gastroesophageal reflux
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  - target: Hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  - target: Cryptorchidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  - target: Generalized dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Part of the multisystem developmental phenotype. The intermediates between the
      transcriptional defect and this specific feature are not identified in any source.
  evidence:
  - reference: PMID:24403048
    reference_title: "Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS."
    explanation: >-
      States the developmental outcome and, importantly, that it is a distinct subgroup
      rather than indistinguishable from classic CdLS.
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Severe (classic) CdLS is characterized by distinctive facial features, growth failure (often prenatal onset; height and weight <5th centile throughout life), hypertrichosis, and limb abnormalities"
    explanation: >-
      The GeneReviews description of the developmental phenotype this node produces.
      Graded OTHER as an expert-curated chapter rather than a primary study.
phenotypes:
- category: Craniofacial
  name: Hypertelorism
  description: >-
    Ocular hypertelorism is one of the features that discriminates the HDAC8 form from
    classic CdLS, and it is named in the title of the defining cohort paper.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  frequency: FREQUENT
  evidence:
  - reference: PMID:24403048
    reference_title: "Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features."
    explanation: >-
      Lists hypertelorism among the features that distinguish HDAC8-related CdLS from
      the classic form.
- category: Craniofacial
  name: Delayed anterior fontanelle closure
  description: >-
    A large or late-closing anterior fontanelle. Like hypertelorism, this is a
    discriminating feature rather than a shared CdLS one, and it is the other feature
    named in the cohort paper's title.
  phenotype_term:
    preferred_term: Delayed anterior fontanelle closure
    term:
      id: HP:0001476
      label: Delayed closure of the anterior fontanelle
  frequency: FREQUENT
  evidence:
  - reference: PMID:24403048
    reference_title: "Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features."
    explanation: >-
      Names delayed anterior fontanelle closure as a discriminating feature of the
      HDAC8 form.
- category: Craniofacial
  name: Hooded eyelid
  description: >-
    Hooding of the eyelids, one of the discriminating craniofacial features of the HDAC8
    form. Distinct from ptosis, which is a levator problem rather than a fold of the
    upper lid.
  phenotype_term:
    preferred_term: Hooding of the eyelids
    term:
      id: HP:0030820
      label: Hooded eyelid
  frequency: FREQUENT
  evidence:
  - reference: PMID:24403048
    reference_title: "Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features."
    explanation: >-
      Names eyelid hooding among the discriminating craniofacial features.
- category: Craniofacial
  name: Synophrys
  description: >-
    Meeting of the eyebrows across the midline, one of the classic CdLS craniofacial
    features that the HDAC8 form shares.
  phenotype_term:
    preferred_term: Synophrys
    term:
      id: HP:0000664
      label: Synophrys
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nose with depressed nasal bridge and anteverted nares, small, widely spaced teeth, and microbrachycephaly."
    explanation: >-
      The GeneReviews craniofacial list for the CdLS spectrum, of which the HDAC8 form
      is part. Frequency is set from the spectrum description rather than from an
      HDAC8-specific count.
- category: Craniofacial
  name: Long eyelashes
  description: One of the shared CdLS craniofacial features.
  phenotype_term:
    preferred_term: Long eyelashes
    term:
      id: HP:0000527
      label: Long eyelashes
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nose with depressed nasal bridge and anteverted nares, small, widely spaced teeth, and microbrachycephaly."
    explanation: The GeneReviews craniofacial list, which includes long eyelashes.
- category: Craniofacial
  name: Anteverted nares
  description: >-
    Part of the shared short-nose configuration. Note that the HDAC8 form tends toward a
    broader nose than classic CdLS, so this feature is shared while its shape is shifted.
  phenotype_term:
    preferred_term: Anteverted nares
    term:
      id: HP:0000463
      label: Anteverted nares
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nose with depressed nasal bridge and anteverted nares, small, widely spaced teeth, and microbrachycephaly."
    explanation: The GeneReviews craniofacial list, which includes anteverted nares.
- category: Growth
  name: Intrauterine growth retardation
  description: >-
    The prenatal half of the growth phenotype. The source describes growth failure as
    often of prenatal onset, so this is curated separately from the postnatal deficit
    rather than folded into a single term that would exclude the onset the claim asserts.
  phenotype_term:
    preferred_term: Prenatal-onset growth failure
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Severe (classic) CdLS is characterized by distinctive facial features, growth failure (often prenatal onset; height and weight <5th centile throughout life), hypertrichosis, and limb abnormalities"
    explanation: >-
      The word doing the work here is "often": prenatal onset is frequent rather than
      universal, which is why this half carries FREQUENT while the lifelong deficit
      below carries VERY_FREQUENT.
- category: Growth
  name: Postnatal growth retardation
  description: >-
    The postnatal half: height and weight below the fifth centile throughout life. This
    is the persistent deficit, as distinct from the prenatal onset curated above.
  phenotype_term:
    preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Severe (classic) CdLS is characterized by distinctive facial features, growth failure (often prenatal onset; height and weight <5th centile throughout life), hypertrichosis, and limb abnormalities"
    explanation: >-
      Gives the centile and its persistence through life, which is the postnatal claim.
- category: Neurologic
  name: Intellectual disability
  description: >-
    Present across the spectrum, with a wide range. GeneReviews reports IQ from below 30
    to 102 with a mean of 53 across CdLS as a whole; no HDAC8-specific distribution has
    been published.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Across the CdLS spectrum, IQ ranges from below 30 to 102 (mean: 53)."
    explanation: >-
      Gives the range and mean for the spectrum. Quoted rather than paraphrased because
      the spread is the point: this is not a uniform degree of impairment.
- category: Dermatologic
  name: Hypertrichosis
  description: Excess body hair, one of the defining features of the CdLS spectrum.
  phenotype_term:
    preferred_term: Hypertrichosis
    term:
      id: HP:0000998
      label: Hypertrichosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Severe (classic) CdLS is characterized by distinctive facial features, growth failure (often prenatal onset; height and weight <5th centile throughout life), hypertrichosis, and limb abnormalities"
    explanation: Names hypertrichosis among the defining features.
- category: Behavioral
  name: Self-injurious behavior
  description: >-
    Self-injury and autistic behaviours are frequent across the spectrum, and GeneReviews
    surveillance is built around monitoring for them.
  phenotype_term:
    preferred_term: Self-injurious behavior
    term:
      id: HP:0100716
      label: Self-injurious behavior
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Many individuals demonstrate autistic and self-injurious behaviors."
    explanation: Reports self-injurious behaviour as a frequent feature of the spectrum.
- category: Behavioral
  name: Autistic behavior
  description: Autistic behaviours co-occur with self-injury across the CdLS spectrum.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Many individuals demonstrate autistic and self-injurious behaviors."
    explanation: Reports autistic behaviour as a frequent feature of the spectrum.
- category: Craniofacial
  name: Wide nose
  description: >-
    A broader nose than in classic CdLS. One of the five discriminating features named
    in the HDAC8 cohort, and the one that pulls in the opposite direction from the
    shared short-nose configuration curated above.
  phenotype_term:
    preferred_term: Broader nose
    term:
      id: HP:0000445
      label: Wide nose
  frequency: FREQUENT
  evidence:
  - reference: PMID:24403048
    reference_title: "Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features."
    explanation: >-
      Names a broader nose among the discriminating features of the HDAC8 form.
- category: Dental
  name: Abnormality of the dentition
  description: >-
    Dental anomalies, the fifth of the discriminating features. Curated at the general
    dentition term because the cohort paper names the category rather than a specific
    anomaly.
  phenotype_term:
    preferred_term: Dental anomalies
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  frequency: FREQUENT
  evidence:
  - reference: PMID:24403048
    reference_title: "Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features."
    explanation: >-
      Names dental anomalies among the discriminating features of the HDAC8 form.
- category: Ophthalmologic
  name: Myopia
  description: >-
    One of the frequent findings across the CdLS spectrum. Curated here for consistency
    with the other phenotypes taken from the same GeneReviews sentence.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other frequent findings include gastrointestinal dysfunction, cryptorchidism or hypoplastic genitalia, myopia, hearing impairment, and congenital heart disease."
    explanation: >-
      Names myopia among the frequent findings. Spectrum-level, like the other
      phenotypes drawn from this sentence.
- category: Cardiovascular
  name: Congenital heart disease
  description: >-
    Congenital heart disease is among the frequent spectrum findings, and it is the one
    with management consequences: GeneReviews asks for preoperative cardiac evaluation
    before any surgery.
  phenotype_term:
    preferred_term: Congenital heart disease
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other frequent findings include gastrointestinal dysfunction, cryptorchidism or hypoplastic genitalia, myopia, hearing impairment, and congenital heart disease."
    explanation: >-
      Names congenital heart disease among the frequent findings.
- category: Gastrointestinal
  name: Gastroesophageal reflux
  description: >-
    Gastrointestinal dysfunction is a frequent finding and GERD is the specific problem
    that drives management, up to fundoplication when severe.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other frequent findings include gastrointestinal dysfunction, cryptorchidism or hypoplastic genitalia, myopia, hearing impairment, and congenital heart disease."
    explanation: >-
      Names gastrointestinal dysfunction among the frequent findings. The specific
      reflux management is quoted separately on the treatment entry.
- category: Otolaryngologic
  name: Hearing impairment
  description: >-
    A frequent finding, and the reason GeneReviews recommends annual audiology through
    childhood and adolescence.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other frequent findings include gastrointestinal dysfunction, cryptorchidism or hypoplastic genitalia, myopia, hearing impairment, and congenital heart disease."
    explanation: Names hearing impairment among the frequent findings.
- category: Genitourinary
  name: Cryptorchidism
  description: Undescended testes, one of the frequent findings in affected males.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other frequent findings include gastrointestinal dysfunction, cryptorchidism or hypoplastic genitalia, myopia, hearing impairment, and congenital heart disease."
    explanation: Names cryptorchidism among the frequent findings.
- category: Neurologic
  name: Generalized dystonia
  description: >-
    Reported in a single individual with a de novo p.Gly210Arg allele and described by
    the authors as a novel phenotype for CdLS5. Recorded here without a frequency
    because it rests on one case.
  phenotype_term:
    preferred_term: Generalized dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:38910710
    reference_title: "A Classic Cornelia De Lange Syndrome Type 5 (CdLS5) With a De Novo Missense Variation of p.Gly210Arg in the HDAC8 Gene With a Novel Phenotype of Generalized Dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report our observation of an individual with CdLS5 with de novo missense mutation presenting with a novel phenotype of generalized dystonia."
    explanation: >-
      The case report's own statement of the observation. Frequency is omitted because
      this rests on one individual.
  - reference: PMID:38910710
    reference_title: "A Classic Cornelia De Lange Syndrome Type 5 (CdLS5) With a De Novo Missense Variation of p.Gly210Arg in the HDAC8 Gene With a Novel Phenotype of Generalized Dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had marked axial and appendicular dystonia."
    explanation: >-
      The examination finding itself, which is what makes this a phenotype record rather
      than a restatement of the paper's framing.
animal_models:
- name: Hdac8-null mouse
  species: Mouse
  genotype: Hdac8 global knockout
  publication: PMID:19605684
  description: >-
    Global deletion of Hdac8 in mouse is perinatally lethal from skull instability. The
    model established HDAC8 as a repressor of cranial neural crest patterning genes and
    is the source of the only mechanistic account of how the transcriptional defect
    reaches a specific tissue.
  modeled_mechanisms:
  - target: Derepression of Cranial Neural Crest Patterning Genes
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      The model is where this node comes from: loss of Hdac8 derepresses Otx2 and Lhx1
      in cranial neural crest.
    limitations: >-
      A constitutive null, whereas most human alleles are missense with residual protein,
      and it carries no X-inactivation mosaicism, which is the dominant determinant of
      severity in the heterozygous females who make up most human cases.
    evidence:
    - reference: PMID:19605684
      reference_title: "Epigenetic control of skull morphogenesis by histone deacetylase 8."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Hdac8 specifically represses the aberrant expression of homeobox transcription factors such as Otx2 and Lhx1."
      explanation: >-
        Supports treating this model as informative for the transcriptional-derepression
        node, since the derepression is what the model measures.
  - target: Disrupted Embryonic Growth and Patterning
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Reproduces the craniofacial arm of the phenotype and nothing else.
    limitations: >-
      Perinatal lethality from skull instability is not the human phenotype, which is a
      dysmorphic but viable skull. The growth, limb, gastrointestinal, behavioural and
      cognitive features of human CdLS5 cannot be assessed in an animal that does not
      survive, so the model speaks to one of several affected systems.
    evidence:
    - reference: PMID:19605684
      reference_title: "Epigenetic control of skull morphogenesis by histone deacetylase 8."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Global deletion of Hdac8 in mice leads to perinatal lethality due to skull instability, and this is phenocopied by conditional deletion of Hdac8 in cranial neural crest cells."
      explanation: >-
        Reports the organism-level phenotype and its severity, which is the basis for
        grading this link PARTIALLY_RECAPITULATES with LOW fidelity.
- name: Cranial neural crest conditional Hdac8 knockout mouse
  species: Mouse
  genotype: Cranial neural crest-specific conditional Hdac8 deletion
  publication: PMID:19605684
  description: >-
    Deleting Hdac8 only in cranial neural crest phenocopies the global knockout's skull
    defect. This is the experiment that localises the pathogenesis to that cell
    population rather than to the developing bone.
  modeled_mechanisms:
  - target: Derepression of Cranial Neural Crest Patterning Genes
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      A cell-type-restricted perturbation used to assign the skull phenotype to cranial
      neural crest.
    limitations: >-
      A conditional null in one lineage answers where, not how much: it says nothing
      about the graded, partial loss of function produced by human missense alleles, and
      nothing about the other affected organ systems.
    evidence:
    - reference: PMID:19605684
      reference_title: "Epigenetic control of skull morphogenesis by histone deacetylase 8."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Global deletion of Hdac8 in mice leads to perinatal lethality due to skull instability, and this is phenocopied by conditional deletion of Hdac8 in cranial neural crest cells."
      explanation: >-
        The phenocopy result is what makes this a lineage-assignment experiment.
treatments:
- name: Nutritional Support and Growth Monitoring
  description: >-
    Management is supportive; there is no treatment directed at the molecular lesion.
    CdLS-specific growth charts are used, with supplementary formula or gastrostomy
    feeding when intake is inadequate.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: nutritional support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  target_mechanisms:
  - target: Disrupted Embryonic Growth and Patterning
    description: >-
      Addresses the growth-failure component of the developmental phenotype at the level
      of intake. It does not alter the underlying cohesin defect, and this link is
      recorded as symptomatic support rather than as a mechanism-directed therapy.
    evidence:
    - reference: PMID:20301283
      reference_title: "Cornelia de Lange Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "MANAGEMENT: Treatment of manifestations: Use of CdLS-specific growth charts with supplementary formulas and/or gastrostomy tube placement to meet nutritional needs as necessary."
      explanation: >-
        The GeneReviews management recommendation, which is the basis for this treatment
        entry and for describing it as supportive.
- name: Management of Gastroesophageal Reflux
  description: >-
    GeneReviews calls for aggressive GERD management, assessment for gastrointestinal
    malrotation, and fundoplication if reflux is severe.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: therapeutic procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Aggressive management of gastroesophageal reflux disease (GERD) with assessment of potential gastrointestinal malrotation; consideration of fundoplication if reflux is severe."
    explanation: The GeneReviews recommendation for reflux management.
- name: Developmental Therapies
  description: >-
    Physical, occupational and speech therapy to support psychomotor development and
    communication.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Physical, occupational, and speech therapy to optimize psychomotor development and communication skills."
    explanation: The GeneReviews developmental-therapy recommendation.
- name: Genetic Counseling
  description: >-
    Counselling here has to carry the X-linked pattern and its consequences: a
    heterozygous mother transmits with 50% probability in each pregnancy, male sibs who
    inherit will be affected, an affected father transmits to all daughters and no sons,
    and a carrier female's severity depends on X-inactivation and so cannot be predicted
    from the variant alone.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "If the mother of the proband has an SMC1A or HDAC8 pathogenic variant, the chance of transmitting it in each pregnancy is 50%."
    explanation: >-
      Gives the transmission risk that counselling has to communicate for this gene.
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "If the father of the proband has an SMC1A or HDAC8 pathogenic variant, he will transmit it to all his daughters and none of his sons."
    explanation: >-
      The paternal transmission pattern, which differs from the autosomal dominant CdLS
      genes and is the part most often got wrong.
  - reference: PMID:26671848
    reference_title: "Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children."
    explanation: >-
      Documents parental mosaicism transmitted to two children, which is the reason a
      de novo-appearing variant does not license a low recurrence-risk figure here.
diagnosis:
- name: Molecular genetic testing
  description: >-
    The diagnosis is molecular. HDAC8 is one of the two X-linked CdLS genes, so the
    variant may be hemizygous or heterozygous, and the clinical route to testing is
    often not a suspicion of CdLS at all: in the defining cohort, several individuals
    reached the gene through genomic testing without CdLS having been considered.
  presence: PRESENT
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DIAGNOSIS/TESTING: The diagnosis of CdLS is established in a proband with suggestive clinical features and/or a heterozygous pathogenic variant in BRD4, MAU2, NIPBL, RAD21, or SMC3 or a hemizygous or heterozygous pathogenic variant in HDAC8 or SMC1A identified by molecular genetic testing."
    explanation: >-
      States the diagnostic criterion and, specifically, that HDAC8 variants may be
      hemizygous or heterozygous.
  - reference: PMID:24403048
    reference_title: "Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For several individuals, the diagnosis of CdLS was not considered prior to genomic testing."
    explanation: >-
      Establishes that clinical recognition is unreliable for this form, which is the
      reason the diagnostic route is sequencing-first.
- name: X-inactivation studies in heterozygous females
  description: >-
    Skewed X-inactivation in peripheral blood DNA was found in the heterozygous females
    of the defining cohort and is one of the determinants of severity. It is a
    prognostically relevant test rather than a diagnostic one: it does not establish the
    diagnosis, but it bears on how a carrier's phenotype should be interpreted.
  presence: PRESENT
  evidence:
  - reference: PMID:24403048
    reference_title: "Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA."
    explanation: >-
      Records the finding and the tissue in which it was measured, which matters because
      blood skewing need not match the affected tissues.
differential_diagnoses:
- name: NIPBL-related Cornelia de Lange syndrome
  description: >-
    The classic and much commoner form, accounting for the large majority of CdLS with
    typical facies. The mechanistic distinction is the arm of the cohesin cycle that
    fails: NIPBL loads cohesin, HDAC8 licenses its reuse. The two converge on the same
    transcriptional readout, so they cannot be told apart by that; they are separated by
    sequencing, by the discriminating craniofacial features, and by inheritance pattern.
  evidence:
  - reference: PMID:22885700
    reference_title: "HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cornelia de Lange syndrome (CdLS) is a dominantly inherited congenital malformation disorder, caused by mutations in the cohesin-loading protein NIPBL for nearly 60% of individuals with classical CdLS, and by mutations in the core cohesin components SMC1A (~5%) and SMC3 (<1%) for a smaller fraction of probands."
    explanation: >-
      Gives the relative contribution of the other CdLS genes, which is what makes NIPBL
      the primary differential.
- name: SMC1A-related Cornelia de Lange syndrome
  description: >-
    The other X-linked CdLS gene, and therefore the differential that shares this one's
    inheritance pattern as well as its phenotype. SMC1A is a core ring subunit rather
    than a regulator of the acetylation cycle.
  evidence:
  - reference: PMID:20301283
    reference_title: "Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HDAC8- and SMC1A-CdLS are inherited in an X-linked manner."
    explanation: >-
      Identifies SMC1A as the other X-linked CdLS gene, which is what makes it the
      closest differential on inheritance grounds.
discussions:
- discussion_id: cdls5_transcription_to_phenotype_gap
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Altered Cohesin Occupancy and Transcriptional Dysregulation
  - pathophysiology#Disrupted Embryonic Growth and Patterning
  prompt: >-
    Which developmental programmes are misexpressed by the altered cohesin occupancy,
    and why does that produce this particular set of craniofacial, limb and growth
    anomalies rather than a general developmental failure?
  rationale: >-
    The mechanism is unusually well traced from the enzyme to the chromatin, and then
    largely stops. One branch has been resolved and only in mouse: HDAC8 represses Otx2
    and Lhx1 in cranial neural crest, and losing it derepresses them, which accounts for
    the craniofacial arm. Nothing comparable exists for the growth restriction, the limb,
    cardiac or gastrointestinal anomalies, or the neurobehavioural phenotype. Cohesin
    binds throughout the genome and the transcriptional change is described as a pattern
    rather than as a named set of target genes for those systems, which is why the edge
    from transcriptional dysregulation to the general developmental phenotype stays
    INDIRECT_UNKNOWN_INTERMEDIATES while the neural crest branch is
    INDIRECT_KNOWN_INTERMEDIATES.
- discussion_id: cdls5_structure_function_to_severity
  kind: KNOWLEDGE_GAP
  attaches_to:
  - genetic#HDAC8
  prompt: >-
    Can the biochemical consequence of an HDAC8 missense allele predict clinical
    severity?
  rationale: >-
    The structural work has measured catalytic loss and thermostability for many of the
    disease mutants, and there is an obvious temptation to read those numbers as a
    severity predictor. The authors of that work explicitly warn against it, because
    X-inactivation sits between the allele and the phenotype in the heterozygous females
    who make up most reported cases. A structure-to-severity model would need the
    X-inactivation pattern in the affected tissue, which is not what is measured.
  evidence:
  - reference: PMID:33316326
    reference_title: "Structural analysis of histone deacetylase 8 mutants associated with Cornelia de Lange Syndrome spectrum disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Genotype-phenotype relationships for HDAC8 are influenced by several factors, including catalytic activity, thermostability, and X-inactivation, so the influence of structure-function relationships for HDAC8 mutations on clinical phenotypes must be interpreted with caution."
    explanation: >-
      The source's own statement of the caveat, which is what this gap records.
- discussion_id: cdls5_hdac8_activator_rescue
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#HDAC8 Loss of Deacetylase Function
  prompt: >-
    Does small-molecule reactivation of mutant HDAC8 translate into anything clinically
    meaningful?
  rationale: >-
    Several catalytically impaired HDAC8 mutants can be partially or fully reactivated in
    vitro by an N-acylthiourea activator. That is a genuine and unusual therapeutic lead
    for a loss-of-function developmental disorder, and it is also, so far, entirely
    in vitro. The harder question is timing rather than chemistry: the phenotype is
    established in embryogenesis, so it is not clear what postnatal restoration of
    deacetylase activity would be expected to change.
  evidence:
  - reference: PMID:27576763
    reference_title: "Structural aspects of HDAC8 mechanism and dysfunction in Cornelia de Lange syndrome spectrum disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Intriguingly, catalytic activity in many HDAC8 mutants can be partially or fully restored by an N-acylthiourea activator, suggesting a plausible strategy for the chemical rescue of compromised HDAC8 catalysis in vivo."
    explanation: >-
      Records the in vitro rescue result and the authors' own framing of it as a
      strategy rather than a demonstrated treatment.
- discussion_id: cdls5_mouse_skull_translational_validity
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Derepression of Cranial Neural Crest Patterning Genes
  - animal_models#Hdac8-null mouse
  - animal_models#Cranial neural crest conditional Hdac8 knockout mouse
  prompt: >-
    Does the mouse Hdac8-null skull phenotype represent the human CdLS5 craniofacial
    phenotype, or a different consequence of the same lesion?
  rationale: >-
    The evidence is not absent, which is what separates this from the other gaps here: a
    specific transcriptional mechanism has been demonstrated, twice, in a lineage-restricted
    conditional as well as a global knockout. What is uncertain is whether it transfers.
    The mouse phenotype is skull instability severe enough to kill the animal perinatally;
    the human phenotype is a viable, dysmorphic skull with hypertelorism and a late-closing
    fontanelle. Those are not obviously the same defect at different severities, and three
    differences could explain the divergence: the mouse is a constitutive null while most
    human alleles are missense with residual activity, the human females who make up most
    cases are X-inactivation mosaics with no mouse counterpart, and the vertebrate-specific
    skull elements the paper implicates differ between the species. No human cranial neural
    crest experiment has been done, so the translation rests on the plausibility of the
    mechanism rather than on evidence.
  evidence:
  - reference: PMID:19605684
    reference_title: "Epigenetic control of skull morphogenesis by histone deacetylase 8."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These findings reveal how the identity and patterning of vertebrate-specific portions of the skull are epigenetically controlled by a histone deacetylase."
    explanation: >-
      The authors' own framing, which scopes the result to vertebrate-specific skull
      elements and is the claim whose human transfer is uncertain.
references:
- reference: PMID:20301283
  title: "Cornelia de Lange Syndrome."
  tags:
  - GeneReviews
- reference: PMID:22885700
  title: "HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle."
- reference: PMID:24403048
  title: "Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance."
notes: >-
  This entry follows the series precedent already in the repository:
  Cornelia_de_Lange_Syndrome_1.yaml (NIPBL) and Cornelia_de_Lange_Syndrome_4.yaml
  (RAD21) are standalone entries, and the parent Cornelia_de_Lange_Syndrome.yaml carries
  no has_subtypes block at all, naming HDAC8 only in its genetic section. MONDO:0010471
  was unbound anywhere in kb/ before this entry.

  Phenotype baseline. GeneReviews has a CdLS chapter (PMID:20301283) but not an
  HDAC8-specific one, so the shared craniofacial, growth, behavioural and systemic
  phenotypes here are taken from the spectrum chapter and the HDAC8-discriminating
  features from the 38-individual cohort (PMID:24403048). Frequencies for the shared
  features are therefore spectrum-level, not HDAC8-specific, and the descriptions say so
  rather than implying a count that nobody has published.

  No limb phenotypes are curated despite limb abnormality being a defining CdLS feature.
  This was re-examined during review. The deep-research report states that limb reduction
  defects are "typically ABSENT or mild in HDAC8-CdLS", citing PMID:24403048 and
  PMID:30158690. Both are now cached and neither says it: the first names distal limb
  anomalies as a general CdLS feature, and the second says only that HDAC8 and RAD21
  phenotypes "become more variable and sometimes present atypical CdLS features". So the
  report's reason is not supportable from the papers it cites, and this entry does not
  adopt it. The limb omission therefore stands on the weaker but checkable ground it
  stood on before: no cached source gives an HDAC8-specific limb frequency, and the
  spectrum sentence would assert one. Myopia and congenital heart disease, which come
  from the same GeneReviews sentence as three already-curated phenotypes, have now been
  added, so the spectrum-level policy is applied consistently within that sentence.

  Deep research. An openscientist report is committed alongside this entry, with 18 of 18
  citations verified and no confabulated identifiers. It earned its keep twice: it surfaced
  the Hdac8 mouse work (PMID:19605684) that supplies the only resolved step between the
  transcriptional defect and a specific tissue, and it surfaced the HDAC8 cohort paper
  reporting maternal mosaicism (PMID:26671848), which changes what genetic counselling can
  say about recurrence. Its term validation flagged seven label mismatches; on inspection
  those were table-cell contents rather than proposed labels, but it also correctly flagged
  GO:0016575 as obsolete, and that term is not used here. Every snippet in this entry comes
  from the cached reference text rather than from the report.

  The report proposed a DNA-methylation episignature as a diagnostic adjunct
  (PMID:38751117). That is not curated here: the cited paper is about neurodevelopmental
  disorders in general and its cached abstract makes no CdLS5-specific claim, so citing it
  for a CdLS5 episignature would overstate it.

  No datasets block. HDAC8 expression datasets in public repositories are dominated by
  cancer studies, where HDAC8 is an inhibitor target; none concerns this disease. That is
  the gene-symbol Named Entity Confusion case the dataset-curation guidance warns about.
📚

References & Deep Research

References

3
PMID:20301283
Cornelia de Lange Syndrome.
No top-level findings curated for this source.
PMID:22885700
HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle.
No top-level findings curated for this source.
PMID:24403048
Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (3)

Record notes

This entry follows the series precedent already in the repository: Cornelia_de_Lange_Syndrome_1.yaml (NIPBL) and Cornelia_de_Lange_Syndrome_4.yaml (RAD21) are standalone entries, and the parent Cornelia_de_Lange_Syndrome.yaml carries no has_subtypes block at all, naming HDAC8 only in its genetic section. MONDO:0010471 was unbound anywhere in kb/ before this entry. Phenotype baseline. GeneReviews has a CdLS chapter (PMID:20301283) but not an HDAC8-specific one, so the shared craniofacial, growth, behavioural and systemic phenotypes here are taken from the spectrum chapter and the HDAC8-discriminating features from the 38-individual cohort (PMID:24403048). Frequencies for the shared features are therefore spectrum-level, not HDAC8-specific, and the descriptions say so rather than implying a count that nobody has published. No limb phenotypes are curated despite limb abnormality being a defining CdLS feature. This was re-examined during review. The deep-research report states that limb reduction defects are "typically ABSENT or mild in HDAC8-CdLS", citing PMID:24403048 and PMID:30158690. Both are now cached and neither says it: the first names distal limb anomalies as a general CdLS feature, and the second says only that HDAC8 and RAD21 phenotypes "become more variable and sometimes present atypical CdLS features". So the report's reason is not supportable from the papers it cites, and this entry does not adopt it. The limb omission therefore stands on the weaker but checkable ground it stood on before: no cached source gives an HDAC8-specific limb frequency, and the spectrum sentence would assert one. Myopia and congenital heart disease, which come from the same GeneReviews sentence as three already-curated phenotypes, have now been added, so the spectrum-level policy is applied consistently within that sentence. Deep research. An openscientist report is committed alongside this entry, with 18 of 18 citations verified and no confabulated identifiers. It earned its keep twice: it surfaced the Hdac8 mouse work (PMID:19605684) that supplies the only resolved step between the transcriptional defect and a specific tissue, and it surfaced the HDAC8 cohort paper reporting maternal mosaicism (PMID:26671848), which changes what genetic counselling can say about recurrence. Its term validation flagged seven label mismatches; on inspection those were table-cell contents rather than proposed labels, but it also correctly flagged GO:0016575 as obsolete, and that term is not used here. Every snippet in this entry comes from the cached reference text rather than from the report. The report proposed a DNA-methylation episignature as a diagnostic adjunct (PMID:38751117). That is not curated here: the cited paper is about neurodevelopmental disorders in general and its cached abstract makes no CdLS5-specific claim, so citing it for a CdLS5 episignature would overstate it. No datasets block. HDAC8 expression datasets in public repositories are dominated by cancer studies, where HDAC8 is an inhibitor target; none concerns this disease. That is the gene-symbol Named Entity Confusion case the dataset-curation guidance warns about.

Review round 1: three term rebindings, connect phenotypes, four added phenotypes · 2026-09-07T18:41:47Z · View source

Addresses the ai4c-reviewer REQUEST_CHANGES on PR #11380. All seven blocking findings applied, plus a reasoned decline on one suggestion. Every proposed term was verified against OLS before rebinding. Finding 1: Delayed anterior fontanelle closure rebound from HP:0000270 (Delayed cranial suture closure) to HP:0001476 (Delayed closure of the anterior fontanelle). Sutures and fontanelles are different structures. Finding 2, the most serious: Hooding of the eyelids was bound to HP:0000508 (Ptosis) with a description asserting Ptosis was the closest available HPO concept. HP:0030820 (Hooded eyelid) exists. Rebound, and the false rationale removed rather than softened. Ptosis is levator dysfunction; eyelid hooding is a fold of the upper lid. Finding 3: Growth failure was bound to HP:0008897 (Postnatal growth retardation) while its description and snippet both asserted prenatal onset. Split into two phenotypes rather than rebound, since the quoted sentence supports both: Intrauterine growth retardation (HP:0001511) at FREQUENT, because the source says growth failure is often of prenatal onset rather than always, and Postnatal growth retardation at VERY_FREQUENT for the lifelong sub-fifth-centile deficit. Finding 4: all phenotypes were orphan nodes. Added downstream edges from the cranial neural crest node to the three skull and midface phenotypes it actually accounts for, as INDIRECT_KNOWN_INTERMEDIATES since the intermediate is identified but only in mouse, and from the organism-level node to the remaining seventeen as INDIRECT_UNKNOWN_INTERMEDIATES. Verified programmatically: 20 of 20 phenotypes connected, no dangling targets. Finding 5: added Wide nose (HP:0000445) and Abnormality of the dentition (HP:0000164), the two discriminating features named in a snippet already in the file. Finding 6, spectrum-level policy consistency: added Myopia (HP:0000545) and Congenital heart disease (HP:0001627) from the same GeneReviews sentence that already supplied three curated phenotypes. The reviewer suggested adopting the deep-research report's stronger reason for the limb omission, that limb defects are typically absent or mild in HDAC8-CdLS. That was checked and not adopted: PMID:30158690 was fetched for the purpose, and neither it nor PMID:24403048 states it. The second says only that HDAC8 and RAD21 phenotypes become more variable and sometimes atypical. The notes now record what was checked and what the papers actually say, and the limb omission stands on the checkable ground rather than the report's. Finding 7: node 1 rebound from GO:0004407 (histone deacetylase activity) to GO:0033558 (protein lysine deacetylase activity), since the entry's whole thesis is that the substrate is the non-histone cohesin subunit SMC3. The now-unused GO:0004407 cache rows, which this PR had introduced, were removed rather than left behind. Declined with a reason recorded in the node description: CL:0000008 (migratory cranial neural crest cell). The mouse work deletes Hdac8 in the cranial neural crest lineage and reads out skull patterning; it does not establish that the affected population is specifically the migratory one. Validated: just validate (60/60 snippets), just validate-disorders, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence, check-term-cache-integrity, check-cache-order.

Create: Cornelia de Lange Syndrome 5 (HDAC8-related) · 2026-09-07T17:55:47Z · View source

De novo curation of MONDO:0010471 (Cornelia de Lange syndrome 5), the X-linked HDAC8 form of the cohesinopathy spectrum. Follows the series precedent already in the repository: CdLS1 (NIPBL) and CdLS4 (RAD21) are standalone entries and the parent CdLS entry has no has_subtypes block, so MONDO:0010471 was unbound anywhere in kb/ before this. Pathophysiology is a causal chain from loss of SMC3 deacetylase activity through persistent SMC3 acetylation, failed cohesin recycling and altered cohesin occupancy to the developmental phenotype, with the mouse-derived cranial neural crest branch curated separately and labelled as such. 55 evidence snippets, all exact-quote verified. GeneReviews baseline used: the CdLS chapter PMID:20301283, tagged; there is no HDAC8-specific chapter, so shared phenotype frequencies are spectrum-level and the entry says so. Deep research: one openscientist run, committed, 18/18 citations verified. It surfaced two references the manual search missed, the Hdac8 mouse skull/neural-crest work (PMID:19605684) and the HDAC8 cohort reporting maternal mosaicism (PMID:26671848). Its term validation correctly flagged GO:0016575 as obsolete; that term is not used. An episignature diagnostic the report proposed was deliberately not curated because the cited paper makes no CdLS5-specific claim. Validated with just validate, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms and the four snippet gates, all passing.

OpenScientist ▸
Cornelia de Lange Syndrome 5 (CdLS5, HDAC8-related) — Comprehensive Disease Report
openscientist-autonomous 2026-09-07T17:25:59.541152

Cornelia de Lange Syndrome 5 (CdLS5, HDAC8-related) — Comprehensive Disease Report

MONDO:0010471 · OMIM #300882 · Orphanet ORPHA:199 (CdLS group) · Gene: HDAC8 (Xq13.1)

Evidence source key: [H] human clinical/genetic; [M] model organism; [V] in vitro/biochemical; [C] computational/epigenomic. PMIDs cited throughout.

1. Disease Information

Overview. Cornelia de Lange syndrome type 5 (CdLS5) is the X-linked form of Cornelia de Lange syndrome caused by loss-of-function variants in HDAC8, the gene encoding histone deacetylase 8, the enzyme that deacetylates the cohesin subunit SMC3. CdLS is a multisystem congenital malformation and neurodevelopmental disorder characterized by distinctive facial features, growth restriction (pre- and postnatal), intellectual disability, upper-limb anomalies, hirsutism/hypertrichosis, and involvement of the cardiac, gastrointestinal, genitourinary and other systems [H, PMID 29995837; 30614194]. CdLS is a "cohesinopathy" and, more broadly, a disorder of transcriptional regulation (DTR) [H, PMID 37377026]. HDAC8-related CdLS is frequently non-classic/atypical, and in many patients the clinical diagnosis was not suspected before genomic testing [H, PMID 24403048].

Key identifiers. - MONDO: MONDO:0010471 (Cornelia de Lange syndrome 5) - OMIM phenotype: #300882; OMIM gene HDAC8: 300269 - Orphanet: ORPHA:199 (Cornelia de Lange syndrome, umbrella) - Gene: HDAC8, HGNC:13315, NCBI Gene 55869, Ensembl ENSG00000147099, UniProt Q9BY41; cytoband Xq13.1 - ICD-10: Q87.1 (congenital malformation syndromes predominantly associated with short stature); ICD-11: LD2F.1Y/typically coded under multiple-anomaly syndromes; MeSH: D003635 (De Lange Syndrome)

Synonyms/alternative names. CdLS5; HDAC8-related Cornelia de Lange syndrome; X-linked Cornelia de Lange syndrome; Cornelia de Lange syndrome due to HDAC8 deficiency; historically overlapping terms: Brachmann–de Lange syndrome. "Wilson–Turner-like" X-linked ID has been noted for some HDAC8 variants in the differential.

Data provenance. This report is compiled from aggregated disease-level resources (OMIM, Orphanet, HPO, consensus statements) and published patient cohorts (e.g., 38-patient HDAC8 cohort [PMID 24403048]; 716-proband CdLS cohort [PMID 37377026]); not from individual EHR data.

2. Etiology

Primary cause — genetic. Hemizygous (males) or heterozygous (females) loss-of-function variants in HDAC8 [H, PMID 24403048; 22885700]. HDAC8 is the vertebrate SMC3 deacetylase; CdLS-causing variants abolish enzymatic activity ("all cause a loss of enzymatic function") [H/V, PMID 24403048].

Genetic risk factors. - Causal variants: predominantly missense and largely de novo; also nonsense, frameshift, splice, and deletions [H, PMID 24403048]. - Modifier of expressivity in females: pattern of X-chromosome inactivation (XCI). Skewed XCI silencing the mutant allele attenuates phenotype; random/unfavorable XCI increases severity [H, PMID 24403048; 26671848]. - Broader locus heterogeneity: other CdLS genes (NIPBL, SMC1A, SMC3, RAD21, BRD4, ANKRD11) cause overlapping phenotypes; genetic background may modify.

Environmental risk factors. None established. CdLS is a monogenic Mendelian disorder; no confirmed toxic, infectious, dietary, or occupational cause. Male sex is a risk factor for greater severity in HDAC8-CdLS (hemizygosity, no XCI buffering) [H, PMID 24403048]. Family history relevant when a carrier mother is mosaic.

Protective factors. The principal "protective" mechanism is favorable (skewed) X-inactivation in heterozygous females, which can render carriers mildly affected or clinically unaffected [H, PMID 26671848]. No dietary/lifestyle protective factors are known. gnomAD constraint (HDAC8 highly intolerant to LoF) argues against benign LoF variation.

Gene–environment interactions. Not established; disease is essentially fully genetically determined. The main "gene–gene/epigenetic" interaction is XCI × mutant allele.

3. Phenotypes

HDAC8-CdLS overlaps classic CdLS but is often milder and has discriminating features. Frequencies below are drawn from CdLS-spectrum and HDAC8 cohorts [PMID 24403048; 30614194; 29995837]; HDAC8-specific frequencies are smaller-N.

Craniofacial (near-universal; congenital). - Synophrys / arched eyebrows — HP:0000664 / HP:0000574 (characteristic across CdLS) [PMID 30614194] - Short nose with anteverted nares, depressed bridge — HP:0003196 / HP:0000463 [PMID 30614194] - Long philtrum, thin upper vermilion — HP:0000343 / HP:0000219 [PMID 30614194] - Micrognathia — HP:0000347; low-set/posteriorly rotated ears - HDAC8-discriminating: delayed anterior fontanelle closure (HP:0001476), ocular hypertelorism (HP:0000316), hooding of eyelids, broader nose, dental anomalies (HP:0000164) [H, PMID 24403048]. "often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features" [PMID 24403048].

Growth (congenital/childhood, chronic). Prenatal and postnatal growth restriction — HP:0001511 / HP:0001510; microcephaly (often postnatal) — HP:0000252 [PMID 30614194]. Severity generally milder in HDAC8 than NIPBL.

Neurodevelopment (childhood, lifelong). Intellectual disability — HP:0001249; global developmental delay — HP:0001263; speech delay — HP:0000750. HDAC8 cases trend milder cognitively than NIPBL but ID is typical.

Neurobehavioral/psychiatric (childhood → adult; persistent). - Autism spectrum features — HP:0000717 (significantly elevated vs comparison syndromes) [H, PMID 23937369]; ASD criteria may increase over time [PMID 30941551] - Anxiety — HP:0000739 (common, persistent; intolerance of uncertainty a driver) [PMID 36199025; 40878447] - Self-injurious behavior — HP:0100716; stereotypies — HP:0000733 - Catatonia-like attenuated behavior in ~30.3% of CdLS [PMID 29536582]

Limb (congenital). Upper-limb reduction defects (oligodactyly, absent forearm) — HP:0009821/HP:0002984 are characteristic of severe NIPBL CdLS but typically ABSENT or mild in HDAC8-CdLS [PMID 24403048; 30158690]. Small hands/feet, 5th-finger clinodactyly (HP:0004209) may occur.

Other systems. Hirsutism/hypertrichosis — HP:0001007; congenital heart defects — HP:0001627 (e.g., septal defects, pulmonary stenosis); gastro-esophageal reflux and GI dysmotility — HP:0002020; cryptorchidism/genital anomalies — HP:0000028; hearing loss — HP:0000365; ptosis — HP:0000508; myopia/ophthalmologic issues; seizures — HP:0001250 (subset). Male hemizygotes more severely affected [PMID 24403048].

Quality-of-life impact. Substantial: lifelong intellectual disability, communication limits, anxiety, self-injury, GI symptoms, and feeding difficulty impair adaptive functioning and caregiver burden [PMID 36199025; 29536582]. Disease-specific/formal QoL instrument data (EQ-5D/SF-36) are limited for CdLS5 specifically — not available at HDAC8 subtype resolution.

4. Genetic / Molecular Information

Causal gene. HDAC8 (HGNC:13315; OMIM 300269), Xq13.1, encoding a class I zinc-dependent histone/lysine deacetylase; physiological substrate for the CdLS mechanism is cohesin subunit SMC3 (acetyl-K105/K106) [H/V, PMID 22885700].

Pathogenic variants. - Types: predominantly missense (clustered around catalytic residues/active site), plus nonsense, frameshift, splice-site, and intragenic/whole-gene deletions [H, PMID 24403048]. Recurrent examples reported include p.His180Arg, p.Gly304 region, p.Thr311Met, and catalytic-domain substitutions (variant-level detail curated in ClinVar/HGMD). - Classification (ACMG/AMP): pathogenic/likely pathogenic for LoF and functionally validated missense; some VUS resolved by enzymatic assay or DNA-methylation episignature. - Allele frequency: essentially absent from population databases (gnomAD) — consistent with a highly constrained, disease-causing gene. - Origin: germline, mostly de novo; maternal mosaicism documented (unaffected mother mosaic → two affected sibs) [H, PMID 26671848]. HDAC8 somatic mutations occur in cancers but are unrelated to CdLS. - Functional consequence: loss of function / loss of enzymatic (deacetylase) activity [H/V, PMID 24403048].

Modifier genes / factors. X-inactivation pattern is the dominant modifier in females [PMID 26671848]. NIPBL expression level correlates with severity across CdLS broadly [PMID 27125329]. No specific trans-modifier gene proven for HDAC8.

Epigenetic information. CdLS displays a reproducible genome-wide DNA-methylation "episignature" usable diagnostically; it can confirm diagnosis in mutation-negative patients and reclassify VUS, though sensitivity is heterogeneous across CdLS cases [C/H, PMID 38751117; 37872275]. Mechanistically, HDAC8 loss alters SMC3 acetylation and cohesin-dependent chromatin architecture/transcription [V, PMID 22885700].

Chromosomal abnormalities. CdLS5 is a single-gene disorder; large Xq13 deletions encompassing HDAC8 can cause it and are detectable by CMA. Otherwise no characteristic karyotypic change.

5. Environmental Information

Environmental factors: none established. Lifestyle factors: none causal (monogenic disorder). Infectious agents: not applicable. (Environmental contribution is essentially nil; disease is genetically determined.)

6. Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation)

  1. A loss-of-function HDAC8 variant results in loss of HDAC8 lysine-deacetylase activity [H/V, PMID 24403048].
  2. Loss of HDAC8 activity leads to failure to deacetylate SMC3 (acetyl-K105/K106) during mitotic exit → increased/retained SMC3 acetylation [V, PMID 22885700].
  3. Retained-acetyl SMC3 results in inefficient dissolution of the "used" cohesin complex released from chromatin (prophase and anaphase) and its improper recycling/reloading [V, PMID 22885700].
  4. This leads to decreased occupancy at cohesin binding sites genome-wide → altered chromatin architecture and gene transcription (a pattern shared with NIPBL-mutant CdLS) [V, PMID 22885700].
  5. Dysregulated developmental transcription results in abnormal patterning/differentiation of multiple lineages, notably cranial neural crest — (branch, demonstrated in mouse): HDAC8 loss de-represses homeobox factors Otx2 and Lhx1 in cranial neural crest, leading to skull/craniofacial malformation [M, PMID 19605684].
  6. Multilineage transcriptional dysregulation during embryogenesis results in the CdLS phenotype: craniofacial dysmorphism, growth restriction, CNS/neurodevelopmental and behavioral abnormalities, limb, cardiac, and GI anomalies [H, PMID 29995837].
  7. (Female branch) Skewed X-inactivation silencing the mutant HDAC8 allele attenuates the phenotype; hemizygous males lack this buffering and are more severely affected [H, PMID 24403048; 26671848].

Note on inference: Steps 1–4 are biochemically demonstrated in human cells; step 5 (Otx2/Lhx1) is demonstrated in mouse neural crest and inferred to underlie human craniofacial features; step 6 is the clinical–molecular correlation.

Detail by category

  • Molecular pathways: cohesin cycle / sister-chromatid cohesion establishment–dissolution; cohesin-mediated chromatin looping and enhancer–promoter regulation (Reactome "Cohesin Loading onto Chromatin," "Establishment of Sister Chromatid Cohesion"). Downstream developmental TF networks (Otx2, Lhx1). Not a classic signaling cascade (Wnt/MAPK) primarily, though cohesin regulates many such loci.
  • Cellular processes: GO:0016575 histone deacetylation; GO:0007062 sister chromatid cohesion; GO:0006325 chromatin organization; GO:0006351 transcription; cell-fate specification/patterning; cranial neural crest migration/differentiation. Increased apoptosis of neural crest in Hdac8-null skull [M, PMID 19605684].
  • Protein dysfunction: loss of catalytic deacetylase activity (Zn2+-dependent hydrolase, InterPro/Pfam PF00850 Hist_deacetyl; PDB structures of HDAC8 available). Missense variants disrupt catalysis/substrate binding → LoF [V, PMID 24403048].
  • Biochemical abnormality: enzyme deficiency — SMC3-lysine deacetylase (HDAC8) [V, PMID 22885700].
  • Epigenetic changes: aberrant SMC3 acetylation; altered histone deacetylation of neural-crest TF loci; reproducible blood DNA-methylation episignature [PMID 22885700; 38751117].
  • Immune/metabolic involvement: not central; no primary immunodeficiency/metabolic defect characteristic of CdLS5.
  • Transcriptomics: CdLS cell lines (NIPBL or HDAC8 mutant) share a consistent altered transcription profile with reduced cohesin site occupancy [V, PMID 22885700].
  • Cell types (CL) / anatomy (UBERON): CL:0000333 cranial neural crest cell; UBERON:0003129 skull; UBERON:0001890 forebrain.

7. Anatomical Structures Affected

  • Organ/system level (primary): craniofacial skeleton/skull (UBERON:0003129), central nervous system/brain (UBERON:0000955), musculoskeletal/limbs (upper limb UBERON:0002102). Secondary/associated: heart (UBERON:0000948), gastrointestinal tract incl. esophagus (UBERON:0001043)/gut, genitourinary tract (UBERON:0000079), ears/auditory system (UBERON:0001690), eyes (UBERON:0000970), skin/hair (hypertrichosis).
  • Body systems: nervous, craniofacial/skeletal, cardiovascular, digestive, genitourinary, integumentary, sensory (auditory/visual), endocrine (growth).
  • Tissue/cell level: connective/skeletal (cranial bones), nervous tissue; key developmental population = cranial neural crest cells (CL:0000333) [M, PMID 19605684].
  • Subcellular (GO cellular component): GO:0005634 nucleus; GO:0000785 chromatin; GO:0008278 cohesin complex; GO:0005737 cytoplasm (HDAC8 also cytoplasmic).
  • Localization/lateralization: malformations are generally bilateral/symmetric (craniofacial midline and paired structures); limb involvement, when present in the broader spectrum, can be asymmetric.

8. Temporal Development

  • Onset: congenital — malformations arise in embryogenesis; growth restriction detectable prenatally; dysmorphism recognizable at birth [H, PMID 29995837]. Onset pattern: chronic/static malformation with developmental unfolding.
  • Progression: Non-progressive at the malformation level; lifelong/chronic course. Neurobehavioral features (autism traits, anxiety, catatonia-like attenuation) can emerge or intensify across childhood into adulthood [H, PMID 30941551; 29536582]. Adaptive ability tends to be stable with some receptive-language gains [PMID 30941551].
  • Patterns: No remission (structural/genetic). Critical period: early embryonic neural-crest/organogenesis window sets the malformation; postnatally, early developmental/behavioral intervention is the actionable window.

9. Inheritance and Population

  • Epidemiology: CdLS (all genes) estimated incidence/prevalence ~1/10,000–1/30,000 [H, PMID 32800026]. HDAC8 accounts for a minority (~4–5%) of CdLS; CdLS5 is correspondingly rarer. Precise CdLS5 prevalence: not separately established.
  • Inheritance: X-linked (Xq13.1). De novo in most; can be inherited from a carrier/mosaic mother [PMID 24403048; 26671848].
  • Penetrance/expressivity: Highly variable expressivity; in females penetrance/severity is modulated by X-inactivation (can be near-nonpenetrant with fully skewed favorable XCI) [PMID 26671848]. Males: essentially penetrant, more severe.
  • Genetic anticipation: not applicable (not a repeat-expansion disorder).
  • Germline/somatic mosaicism: documented maternal mosaicism with sibling recurrence [PMID 26671848]; relevant to recurrence-risk counseling.
  • Founder effects/consanguinity/carrier frequency: no founder effect; consanguinity not relevant (X-linked, mostly de novo); carrier frequency negligible in general population (gnomAD LoF depleted).
  • Population demographics: No ethnic predilection; CdLS occurs across global populations with consistent core features [H, PMID 30614194]. Sex ratio: both sexes affected; males more severely affected, females often milder/atypical [PMID 24403048]. Age distribution: present from birth through adulthood.

10. Diagnostics

  • Clinical criteria: 2018 first international consensus provides diagnostic criteria for classic and non-classic CdLS and a cardinal/suggestive feature scoring approach; recommends molecular confirmation [H, PMID 29995837]. Facial-analysis technology aids recognition across populations (sensitivity ≥95%, specificity ≥91%) [PMID 30614194].
  • Genetic testing (recommended, definitive):
  • Multigene NGS panel / WES / WGS covering the seven CdLS/DTR genes incl. HDAC8 — first-line; HDAC8 sequencing is "indispensable" in CdLS workup [H, PMID 26671848]. WGS adds detection of structural/deep-intronic variants.
  • Single-gene HDAC8 sequencing when HDAC8 phenotype suspected.
  • Chromosomal microarray (CMA) to detect Xq13 deletions/CNVs.
  • Deep/mosaicism-aware sequencing of multiple tissues (buccal, fibroblasts) because somatic/parental mosaicism is common in CdLS [PMID 26671848].
  • X-inactivation assay in females to interpret expressivity [PMID 24403048].
  • Omics-based diagnostics: DNA-methylation episignature as an orthogonal classifier to confirm mutation-negative CdLS and reclassify VUS [C, PMID 38751117; caution on sensitivity per PMID 37872275]. Functional SMC3-deacetylation/enzyme assays can validate missense VUS [V, PMID 24403048].
  • Supportive clinical tests: echocardiography (CHD), hearing and ophthalmologic evaluation, GI/reflux workup, renal ultrasound, growth monitoring, developmental/behavioral assessment (per consensus surveillance) [PMID 29995837].
  • Differential diagnosis: classic NIPBL-CdLS and other cohesinopathy genes (SMC1A, SMC3, RAD21); CdLS-like DTRs (ANKRD11/KBG, EP300, AFF4/CHOPS, TAF1, BRD4); Warsaw breakage syndrome (DDX11), Roberts syndrome (ESCO2), fetal alcohol spectrum, Coffin–Siris, Rubinstein–Taybi [H, PMID 31721174; 36703504].
  • Screening: No population newborn screening (not applicable). Cascade/carrier and prenatal testing offered once a familial variant is known; prenatal ultrasound may show IUGR, limb/heart anomalies.

11. Outcome / Prognosis

  • Survival/life expectancy: Many individuals survive into adulthood, particularly milder (incl. many HDAC8) cases; life expectancy is influenced by complications (severe CHD, GI/aspiration, infections). Formal CdLS5-specific survival statistics: not established. Hemizygous males (more severe) have poorer prognosis than mildly affected skewed-XCI females [PMID 24403048].
  • Morbidity/function: Lifelong intellectual disability and behavioral morbidity (anxiety, ASD, self-injury, catatonia-like features) dominate disability burden [PMID 36199025; 29536582]. Growth failure, feeding/GI problems, hearing/vision deficits contribute.
  • Complications: GERD and GI dysmotility, aspiration, recurrent infections, congenital heart disease, seizures, behavioral crises/self-injury.
  • Recovery potential: Malformations are static; developmental and behavioral outcomes are improvable with early intervention/therapy; no cure.
  • Prognostic factors: genotype/gene (HDAC8 milder than NIPBL), sex and X-inactivation pattern, severity of CHD/GI disease, degree of ID. No validated molecular prognostic biomarker beyond gene/variant and XCI [PMID 24403048; 27125329].

12. Treatment

No disease-modifying/curative therapy exists; management is multidisciplinary and supportive, per the 2018 consensus [H, PMID 29995837].

  • Supportive/medical (NCIT: C15277 Supportive Care):
  • GI: anti-reflux medical therapy (proton-pump inhibitors — NCIT C29708; H2 blockers), nutritional support, fundoplication/gastrostomy for severe GERD/feeding failure.
  • Cardiac: surgical/medical management of congenital heart defects.
  • ENT/audiology: hearing aids, myringotomy tubes for otitis; ophthalmology for ptosis/refractive error.
  • Growth/endocrine: nutritional optimization; growth monitoring.
  • Neurology: anti-seizure medication if epilepsy.
  • Neurobehavioral/psychiatric (NCIT C15313 Psychosocial/Behavioral therapy; C265 Pharmacotherapy): behavioral therapy for self-injury/ASD; SSRIs (e.g., sertraline — NCIT C47727) for anxiety/OCD-like symptoms; treat pain/occult GI sources of behavioral change; address intolerance of uncertainty in anxiety interventions [PMID 40878447; 36199025].
  • Surgical/interventional (NCIT C15329 Surgery): cardiac repair, fundoplication/gastrostomy, orchidopexy for cryptorchidism, cleft/orthodontic and other reconstructive procedures as indicated.
  • Rehabilitative: physical, occupational, and speech/language therapy; special education; early developmental intervention.
  • Advanced/experimental therapeutics: None approved. No gene, cell, RNA, or targeted therapy in clinical use for CdLS5. HDAC-modulation strategies are conceptual/preclinical only; no CdLS-specific trials identified. Pharmacogenomics: no CdLS5-specific PGx guidance.
  • Treatment strategy: individualized, guided by the consensus care/surveillance pathway; genotype-informed counseling but not yet genotype-targeted drug therapy [PMID 29995837].

13. Prevention

  • Primary prevention: Not possible (mostly de novo genetic disorder). Prevention centers on reproductive counseling for families with a known variant.
  • Secondary prevention: Early molecular diagnosis → structured surveillance (cardiac, GI, hearing, vision, growth, behavioral) to detect and treat complications early [PMID 29995837].
  • Tertiary prevention: Aggressive management of GERD/aspiration, CHD, and behavioral/self-injury to prevent morbidity.
  • Genetic screening/counseling: genetic counseling (X-linked risks, de novo vs mosaic recurrence), prenatal testing / PGT when a familial variant is known; test/counsel potentially mosaic mothers given documented sibling recurrence [PMID 26671848]. NSGC/ACMG counseling frameworks apply.
  • Immunization/public-health/environmental measures: not applicable beyond routine pediatric care.

14. Other Species / Natural Disease

  • Taxonomy/orthologs: HDAC8 is conserved across vertebrates. Mouse Hdac8 (NCBI Gene 70315; NCBI Taxon 10090); also conserved in rat, zebrafish. Cohesin/SMC3 machinery conserved from yeast (Hos1 is the yeast SMC3 deacetylase analog) to humans [PMID 22885700].
  • Natural disease in other species: No well-characterized naturally occurring HDAC8-CdLS in companion/wild animals reported in OMIA; not applicable/none documented. Veterinary relevance: none established.
  • Comparative biology: The cohesin acetylation cycle and neural-crest role of Hdac8 are evolutionarily conserved, underpinning cross-species disease modeling [PMID 22885700; 19605684].
  • Transmission/zoonosis: not applicable (genetic disorder).

15. Model Organisms

  • Mouse (Mus musculus, NCBI Taxon 10090) — primary model [M, PMID 19605684]:
  • Global Hdac8 knockout: perinatal lethality due to skull instability — models the craniofacial malformation.
  • Conditional (cranial neural crest–specific, e.g., Wnt1-Cre) knockout: phenocopies the skull defect, localizing pathogenesis to cranial neural crest.
  • Mechanistic readout: HDAC8 represses homeobox TFs Otx2 and Lhx1; loss de-represses them → aberrant skull patterning; increased neural-crest apoptosis.
  • Recapitulation: strong for craniofacial/skull patterning; limitations: global KO perinatal lethality limits study of postnatal neurobehavioral phenotypes; does not capture X-inactivation mosaicism of human females.
  • Zebrafish (Danio rerio) / cohesinopathy models: cohesin (nipbl, esco2, rad21) models reproduce craniofacial and developmental gene-expression phenotypes, supporting the transcriptional-dysregulation mechanism shared with HDAC8 [M, PMID 29084713].
  • In vitro / cellular models: patient-derived lymphoblastoid/fibroblast lines showing increased SMC3 acetylation, reduced cohesin occupancy, and altered transcription [V, PMID 22885700]; recombinant HDAC8 enzymatic assays to test variant activity [V, PMID 24403048]. iPSC/organoid HDAC8-CdLS models: an emerging but not yet standard resource.
  • Model databases: MGI (mouse Hdac8), IMPC, ZFIN (zebrafish), Alliance of Genome Resources.

Summary Answer

Cornelia de Lange syndrome 5 is the X-linked (Xq13.1) form of CdLS caused by loss-of-function variants in HDAC8, the deacetylase for the cohesin subunit SMC3. Impaired SMC3 deacetylation disrupts the cohesin acetylation/recycling cycle and cohesin-dependent transcriptional regulation during development (a "cohesinopathy"/disorder of transcriptional regulation), producing a multisystem malformation and neurodevelopmental syndrome that overlaps classic CdLS but is often milder/atypical, with discriminating features (delayed fontanelle closure, ocular hypertelorism, dental anomalies); hemizygous males are more severely affected, while heterozygous females are variably affected depending on X-inactivation. Management is multidisciplinary and supportive with no disease-modifying therapy; diagnosis rests on consensus clinical criteria plus molecular testing (with episignature/functional assays as adjuncts).

Key Limitations

  • Many phenotype frequencies and prognosis/QoL data are CdLS-spectrum-level, not HDAC8-specific (small N for CdLS5).
  • No CdLS5-specific survival, incidence, or clinical-trial data; therapeutics remain supportive.
  • Variant-level ClinVar/gnomAD counts were not directly queried in this literature-based synthesis and should be verified in those databases for KB population.

Primary References (PMIDs)

22885700 (Deardorff 2012, Nature, HDAC8=SMC3 deacetylase/mechanism); 24403048 (Kaiser 2014, 38-patient HDAC8 cohort, X-linked, discriminating features); 26671848 (Parenti 2016, HDAC8 spectrum, skewed XCI, maternal mosaicism); 19605684 (Haberland 2009, Hdac8 mouse skull/neural crest, Otx2/Lhx1); 29995837 (Kline 2018, first international consensus); 37377026 (Kaur 2023, 716 probands, DTR framing); 30614194 (Dowsett 2019, diverse populations); 30158690 (Yuan 2019, mild end of spectrum); 27125329 (Kaur 2016, NIPBL levels/severity); 23937369, 36199025, 29536582, 30941551, 40878447 (CdLS neurobehavioral phenotype); 38751117, 37872275 (episignature diagnostics); 31721174 (chromatinopathies review); 29084713 (zebrafish cohesinopathy model).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 18
Resolved 18
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 18
On topic 9
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 51
Resolved 48
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 2
Terms whose name was checked 8
Terms named correctly 0
Terms named as a different term 7
Terms whose name is worth a second look 1

Terms the report names something else

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

  • HP:0000574 (1 mention) - the report calls it "characteristic across CdLS"; HP calls it Thick eyebrow
  • HP:0000463 (1 mention) - the report calls it "PMID 30614194"; HP calls it Anteverted nares
  • HP:0000219 (1 mention) - the report calls it "PMID 30614194"; HP calls it Thin upper lip vermilion
  • HP:0000252 (1 mention) - the report calls it "PMID 30614194"; HP calls it Microcephaly
  • HP:0000717 (1 mention) - the report calls it "significantly elevated vs comparison syndromes"; HP calls it Autism
  • HP:0000739 (1 mention) - the report calls it "common, persistent; intolerance of uncertainty a driver"; HP calls it Anxiety
  • HP:0001250 (1 mention) - the report calls it "subset"; HP calls it Seizure

Obsolete terms

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

  • GO:0016575 (obsolete histone deacetylation) (1 mention)

Terms whose name is worth a second look

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

  • HP:0001476 (1 mention) - the report calls it "HDAC8-discriminating: delayed anterior fontanelle closure"; HP calls it Delayed closure of the anterior fontanelle**, and lists "Delayed closure of anterior fontanelle" among its other names

Prefixes with no resolver

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