CDK8-Related Disorder

Mendelian MONDO:0032897 Pathograph 68 Show in embeddings browser Autosomal dominant intellectual disability Neurodevelopmental disorder CDK8-kinase module-associated disorder

CDK8-related disorder is an autosomal dominant neurodevelopmental condition associated primarily with heterozygous kinase-domain missense variants. Most reported variants arose de novo, but transmission from an affected mother is documented. Developmental and speech delay, variable intellectual disability, hypotonia and behavioral difficulties occur with craniofacial differences and variable cardiac, ocular, auditory and gastrointestinal anomalies. Tested variants reduce kinase output while retaining protein stability and module interactions; residual activity differs between alleles. A dominant-negative mechanism has been proposed but not established, and simple haploinsufficiency should not be assumed. Management addresses the individual clinical findings; experimental CDK8/19 inhibition is a developmental perturbation model, not an established therapy for this disorder.

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9
Pathophys.
70
Phenotypes
5
Gaps
68
Pathograph
1
Genes
6
Variants
14
Medical Actions
3
Differentials
8
Models
6
References
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC
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Discussions and Knowledge Gaps

5
How do catalytically impaired CDK8 proteins cause dominant disease while retaining module association?
KNOWLEDGE GAP OPEN dominant_negative_mechanism
Attached to
pathophysiology#Nonproductive Mediator Kinase Module Occupancy pathophysiology#Reduced CDK8 Kinase Activity
Missense clustering, retained stability and reduced catalysis motivate a model in which nonproductive modules compete with active ones. The reference/Ser62Leu mixing experiment did not clearly depart from linearity. CDK19 interference, developmental substrate specificity and simple dosage reduction remain distinguishable possibilities rather than demonstrated equivalences.
Show evidence (2 references)
PMID:30905399 NO_EVIDENCE DIRECT PRIMARY RESULT In Vitro
"the observed reduction in phosphorylation in mixed samples did not obviously deviate from a linear response"
The mixing assay did not establish a dominant-negative interaction.
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT In Vitro
"none of the substitutions cause gross mis-folding of the protein, and most or all are still able to bind ATP"
Thermal stability and ATP-response experiments.
Why do viable heterozygous human missense alleles differ from mouse Cdk8 gene-trap loss?
HUMAN MODEL MISMATCH OPEN null_missense_mismatch
Attached to
genetic#CDK8
Homozygous mouse loss arrests preimplantation development, and heterozygotes lacked a reported overt phenotype. Neither outcome models the human missense syndrome directly. The heterozygote observation supports caution about simple haploinsufficiency but does not provide a complete neurobehavioral assessment or establish benignity of every human loss-of-function variant.
Show evidence (2 references)
PMID:17620419 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Cdk8-/- preimplantation embryos had fragmented blastomeres and did not proceed to compaction."
Early embryonic phenotype of complete mouse gene loss.
PMID:17620419 SUPPORT DIRECT PRIMARY RESULT Model Organism
"No phenotypes were noted in heterozygote Cdk8+/- mice"
No reported overt phenotype in the heterozygous gene-trap animals.
Does allele-specific kinase activity predict developmental severity or organ involvement?
KNOWLEDGE GAP OPEN activity_severity_relationship
Attached to
pathophysiology#Reduced CDK8 Kinase Activity
Residual STAT1 phosphorylation differs among the founding alleles, and Asn156Ser reduced autophosphorylation more than Gly28Ala despite the latter child having more severe clinical findings. Small numbers, age differences, distinct assays and additional variation preclude a validated activity–severity relationship.
Show evidence (2 references)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT In Vitro
"an intermediate level of phosphorylation (∼63% and ∼51% in comparison to the WT, respectively), was observed"
Residual activity in two alleles.
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Both the CDK8-G28A and CDK8-N156S mutations resulted in lower kinase activities compared with CDK8-WT"
Autophosphorylation assay of later variants.
Which uncommon findings are reproducible CDK8-associated features rather than individual or multilocus observations?
INTERPRETATION OPEN individual_feature_attribution
Attached to
genetic#CDK8 phenotypes#Metopic Synostosis phenotypes#Decreased CSF Homovanillic Acid
The Val27Leu case also carried a CACNA1A variant of uncertain significance and mosaic HDAC9 truncation, while the Gly30Ser case carried additional uncertain variation including COL3A1. The authors did not establish these as modifiers. Metopic synostosis and low CSF homovanillic acid remain isolated findings with uncertain mechanistic attribution; neither proves a uniform craniosynostosis or dopamine-synthesis mechanism.
Show evidence (2 references)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"An additional de novo missense variant was identified in the CACNA1A gene"
Potential multilocus complexity without demonstrated modifier action.
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"a low cerebrospinal fluid (CSF) homovanillic acid level, the significance of which is unclear"
Explicitly uncertain biochemical finding.
Which neural and cardiac transcriptional programs connect reduced CDK8 activity to human developmental phenotypes?
KNOWLEDGE GAP OPEN patient_developmental_programs
Attached to
pathophysiology#Altered Developmental Transcription
STAT1 phosphorylation is a measured cell-assay readout, while candidate WNT, TGFβ/BMP, SHH and NOTCH changes were not demonstrated in these patients. Fish chemical inhibition affects both CDK8 and CDK19. Patient-derived cell studies are needed before assigning a specific developmental signaling defect or generalizing paralog-specific mitochondrial results to CDK8 disease.
Show evidence (2 references)
PMID:30905399 SUPPORT DIRECT BACKGROUND Other
"Thus, a disruption of the proper activity of CDK8 could modify any of these developmental signaling networks."
Proposed developmental-signaling interpretation.
PMID:33067521 SUPPORT DIRECT BACKGROUND Other
"Senexin A inhibits both CDK19 and CDK8"
The pharmacological model cannot isolate CDK8.
⚙

Pathophysiology

9
CDK8 Coding Missense Substitutions
Mechanism confidence: Established
Heterozygous coding single-nucleotide substitutions alter conserved residues in or near the ATP-binding pocket. Their physical sequence changes are distinct from the resulting catalytic and developmental effects.
CDK8 hgnc:1779 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CDK8 (hgnc:1779). hgnc:1779 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context CDK8 hgnc:1779 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CDK8 (hgnc:1779). hgnc:1779 is a gene from the HUGO Gene Nomenclature Committee. Variant type: single nucleotide variant Genomic context: coding sequence variant_origin: GERMLINE
Downstream
Altered Substrate-Binding Geometry Ser62Leu and Arg178Gln change substrate-pocket dynamics in computational simulations.
Reduced CDK8 Kinase Activity Tested missense variants reduce catalytic readouts.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects"
Physical variant class in affected individuals.
Altered Substrate-Binding Geometry
Mechanism confidence: Provisional
Molecular-dynamics models of Ser62Leu and Arg178Gln predict a less open substrate-binding region. Gross protein misfolding and loss of ATP binding were not observed in biochemical studies; restricted substrate access remains a mechanistic interpretation.
Computational models
CDK8–Cyclin C Molecular Dynamics STRUCTURAL PREDICTION Predicts reduced access to the catalytic pocket.
Downstream
Reduced CDK8 Kinase Activity Restricted substrate access could reduce phosphoryl transfer despite retained ATP binding.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Computational
"the substrate-binding site of the WT CDK8 protein can adopt more open conformations than its mutated counterparts"
Structural-dynamics prediction.
Reduced CDK8 Kinase Activity
Mechanism confidence: Established
Tested alleles reduce kinase output. Most founding variants approach the kinase-dead control in the STAT1 assay, whereas Phe97Leu and Ile223Met retain intermediate activity. Gly28Ala and Asn156Ser also reduce autophosphorylation. Protein stability and cyclin-C binding are retained, so this is not equivalent to complete loss of the gene product.
CDK8 hgnc:1779 ⇓ LOSS OF FUNCTION HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CDK8 (hgnc:1779), qualified as loss of function. hgnc:1779 is a gene from the HUGO Gene Nomenclature Committee.
cyclin-dependent protein serine/threonine kinase activity GO:0004693 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased cyclin-dependent protein serine/threonine kinase activity (GO:0004693). GO:0004693 is a molecular function from the Gene Ontology.
Experimental models
SW620 CDK8/CDK19 Double-Knockout Complementation CELL LINE Measures variant-dependent substrate phosphorylation.
HEK293 Gly28Ala/Asn156Ser Autophosphorylation CELL LINE Measures catalytic output of the two later patient variants.
Animal models
Zebrafish Human CDK8 mRNA Overexpression Danio rerio perturbs Variant mRNAs perturb development less than reference CDK8 under overexpression.
Cdk8 Gene-Trap Mouse Mus musculus perturbs Complete Cdk8 loss reveals an early developmental requirement but does not reproduce the clinical missense syndrome.
Downstream
Reduced STAT1 Ser727 Phosphorylation Reduced phosphorylation of this experimentally tested substrate is a direct kinase readout.
Nonproductive Mediator Kinase Module Occupancy Catalytically impaired proteins that retain module association might compete with active modules; dominance is not established.
Altered Developmental Transcription Altered phosphorylation of transcription-associated substrates may change developmental expression programs.
Show evidence (2 references)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT In Vitro
"We observed that the cellular levels of pSTAT1 were reduced to a statistically significant extent, compared to WT, in all mutant-transfected cells"
Variant activity in a double-knockout cell background.
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Both the CDK8-G28A and CDK8-N156S mutations resulted in lower kinase activities compared with CDK8-WT"
Autophosphorylation assay of later variants.
Reduced STAT1 Ser727 Phosphorylation
Mechanism confidence: Established
Variant CDK8 produces less STAT1 Ser727 phosphorylation in SW620 cells lacking both endogenous CDK8 and CDK19. This is a measured biochemical readout, not evidence that STAT1 deficiency or immune dysfunction is the clinical disease mechanism.
Experimental models
SW620 CDK8/CDK19 Double-Knockout Complementation CELL LINE Measures variant-dependent substrate phosphorylation.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT In Vitro
"We observed that the cellular levels of pSTAT1 were reduced to a statistically significant extent, compared to WT, in all mutant-transfected cells"
Direct substrate readout.
Nonproductive Mediator Kinase Module Occupancy
Mechanism confidence: Hypothetical
Retained cyclin-C/module association despite impaired catalysis could reduce availability of productive kinase modules. This proposed dominant-negative route remains unconfirmed: mixing reference and Ser62Leu constructs did not show a clearly nonlinear reduction in STAT1 phosphorylation.
Experimental models
HEK293T Kinase-Module Assembly and Thermal Stability CELL LINE Assesses whether catalytically impaired proteins can remain in stable kinase modules.
Reference/Ser62Leu Mixing Assay CELL LINE Directly probes the proposed dominant-negative interpretation without establishing it.
Downstream
Altered Developmental Transcription Competition between productive and nonproductive modules could impair transcriptional regulation if the active module is limiting.
Show evidence (2 references)
PMID:30905399 SUPPORT DIRECT BACKGROUND Other
"we predict that up to 50% of CDK8 modules could be present in a kinase-inactive, non-productive state"
Authors explicitly frame this as a prediction.
PMID:30905399 NO_EVIDENCE DIRECT PRIMARY RESULT In Vitro
"the observed reduction in phosphorylation in mixed samples did not obviously deviate from a linear response"
The mixing assay did not establish a dominant-negative interaction.
Altered Developmental Transcription
Mechanism confidence: Provisional
CDK8 regulates transcription through Mediator and phosphorylation of multiple regulators. The relevant altered expression programs in patient neural and cardiac cells have not been identified. Candidate developmental pathways should not be treated as measured patient defects.
regulation of transcription by RNA polymerase II GO:0006357 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology.
Downstream
Impaired Neural Development Abnormal developmental gene regulation is a candidate link to the neurodevelopmental syndrome.
Impaired Cardiac Morphogenesis Developmental gene regulation may contribute to congenital cardiac anomalies.
Impaired Craniofacial Patterning Altered developmental regulation may affect craniofacial formation.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT BACKGROUND Other
"Thus, a disruption of the proper activity of CDK8 could modify any of these developmental signaling networks."
Proposed developmental-signaling interpretation.
Impaired Neural Development
Mechanism confidence: Provisional
Developmental delay, intellectual disability and callosal abnormalities indicate altered neural development. The specific transcriptional, cell-type and circuit intermediates downstream of CDK8 variants remain unresolved.
Downstream
Global Developmental Delay Altered brain development can impair acquisition of developmental skills.
Intellectual disability Disturbed neural development is a candidate substrate of cognitive impairment.
Delayed Speech and Language Development Abnormal circuit development may affect language acquisition.
Hypotonia Central developmental dysfunction may contribute to reduced muscle tone.
Autism Altered neural development may contribute to autistic features.
Attention Deficit Hyperactivity Disorder Developmental circuit dysfunction may contribute to attention and activity regulation.
Corpus callosum agenesis Disrupted commissural development provides a candidate route to callosal agenesis.
Thin Corpus Callosum Altered commissural development may contribute to callosal thinning.
Seizures Altered circuit development may contribute to seizure susceptibility; the precise epileptogenic pathway is unknown.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Mild to moderate developmental delay was universal, and older children had ID"
Clinical evidence for developmental impairment, not a direct neuronal transcription assay.
Impaired Cardiac Morphogenesis
Mechanism confidence: Provisional
Developmental kinase perturbation can disrupt heart formation: dual CDK8/19 inhibition produces cardiac anomalies in zebrafish, while affected humans have variable congenital lesions. The pharmacological model does not isolate CDK8 from CDK19 or reproduce each human defect.
Animal models
Zebrafish Dual CDK8/CDK19 Inhibition Danio rerio perturbs Dual kinase inhibition disrupts this developmental process.
Downstream
Congenital heart disease Abnormal cardiac development can produce the varied structural lesions observed clinically.
Ventricular Septal Defect Altered cardiac morphogenesis can produce this specific structural lesion; its variant-specific developmental pathway remains unknown.
Atrial Septal Defect Altered cardiac morphogenesis can produce this specific structural lesion; its variant-specific developmental pathway remains unknown.
Bicuspid Aortic Valve Altered cardiac morphogenesis can produce this specific structural lesion; its variant-specific developmental pathway remains unknown.
Tetralogy of Fallot Altered cardiac morphogenesis can produce this specific structural lesion; its variant-specific developmental pathway remains unknown.
Coarctation of Aorta Altered cardiac morphogenesis can produce this specific structural lesion; its variant-specific developmental pathway remains unknown.
Double Orifice Mitral Valve Altered cardiac morphogenesis can produce this specific structural lesion; its variant-specific developmental pathway remains unknown.
Double Outlet Right Ventricle Altered cardiac morphogenesis can produce this specific structural lesion; its variant-specific developmental pathway remains unknown.
Congenital Mitral Stenosis Altered cardiac morphogenesis can produce this specific structural lesion; its variant-specific developmental pathway remains unknown.
Hypoplastic Left Heart Syndrome Altered cardiac morphogenesis can produce this structural lesion; the exact variant-specific pathway is unknown.
Hypoplastic Aortic Arch Altered cardiac morphogenesis can produce this structural lesion; the exact variant-specific pathway is unknown.
Subvalvular Aortic Stenosis A specific congenital outflow lesion within the variable cardiac phenotype.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Model Organism
"the inhibition of Cdk8 kinase activity by Senexin A induced structural anomalies in the heart and craniofacial cartilage of the zebrafish"
Experimental developmental perturbation by a dual-kinase inhibitor.
Impaired Craniofacial Patterning
Mechanism confidence: Provisional
CDK8/19 inhibition perturbs zebrafish cranial cartilage formation, providing experimental support for a developmental craniofacial role. Variant-specific human craniofacial intermediates are not established.
Animal models
Zebrafish Dual CDK8/CDK19 Inhibition Danio rerio perturbs Dual kinase inhibition disrupts this developmental process.
Downstream
Facial dysmorphism Altered craniofacial development may account for variable facial differences.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Model Organism
"the inhibition of Cdk8 kinase activity by Senexin A induced structural anomalies in the heart and craniofacial cartilage of the zebrafish"
Craniofacial development in the inhibitor model.
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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 CDK8-Related Disorder 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

70
Blood 1
Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"he had an anemia of unknown origin, which improved with iron supplements"
The report establishes anemia and an observed iron response while leaving the underlying cause uncertain.
Cardiovascular 12
Congenital heart disease Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Coarse binding: variable spectrum
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Congenital heart defects (CHDs) were present in six of the twelve subjects"
Six of twelve individuals had a cardiac defect; heterogeneous lesions justify the organ-level summary alongside specific phenotypes.
Context-specific annotations (1)
Founding 12-person 2019 cohort; assessed denominator is specified for each finding FREQUENT
6/12 in this selected clinical series, not population prevalence or penetrance.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Congenital heart defects (CHDs) were present in six of the twelve subjects"
Original cohort evidence; counts derive from its clinical narrative or Table 1.
Ventricular Septal Defect HP:0001629 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular septal defect (HP:0001629). HP:0001629 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He had been f ollowed by the cardiology team secondary to a VSD, which has not required any surgical repair."
The case history names a VSD and records surveillance without surgical repair.
Atrial Septal Defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"an atrial sep tal defect, ventricular septal defect (VSD), bicuspid aortic valve, and a hypoplastic aortic arch"
The supplementary cardiac-anatomy description explicitly names an atrial septal defect.
Bicuspid Aortic Valve HP:0001647 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bicuspid aortic valve (HP:0001647). HP:0001647 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"an atrial sep tal defect, ventricular septal defect (VSD), bicuspid aortic valve, and a hypoplastic aortic arch"
The supplementary cardiac-anatomy description explicitly names a bicuspid valve.
Tetralogy of Fallot HP:0001636 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tetralogy of Fallot (HP:0001636). HP:0001636 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"echocardiography showed tetralogy of Fallot"
Echocardiography directly established the cardiac diagnosis in the supplementary case.
Coarctation of Aorta HP:0001680 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coarctation of aorta (HP:0001680). HP:0001680 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"She underwent aortic coarctation repair aged 5 mo with a good result."
The documented repair establishes the presence of coarctation in this individual.
Double Orifice Mitral Valve HP:0011568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Double orifice mitral valve (HP:0011568). HP:0011568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"a perimembranous ventricular septal defect with a double orifice mitral valve"
The supplementary anatomy description specifies a double-orifice mitral valve.
Double Outlet Right Ventricle HP:0001719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Double outlet right ventricle (HP:0001719). HP:0001719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"diagnosed at birth with a double outlet right ventricle, mitral valve stenosis, and dysmorphic craniofacial features"
The birth diagnosis directly specifies double-outlet right ventricle in the Gly28Ala case.
Congenital Mitral Stenosis HP:0011570 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital mitral stenosis (HP:0011570). HP:0011570 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"diagnosed at birth with a double outlet right ventricle, mitral valve stenosis, and dysmorphic craniofacial features"
The same birth diagnosis separately specifies mitral valve stenosis.
Hypoplastic Left Heart Syndrome Hypoplastic left ventricle HP:0004383 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic left ventricle (HP:0004383). HP:0004383 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The prenatal ultrasound revealed a hypoplastic left heart and agenesis of the corpus callosum."
Specific congenital cardiac anatomy documented in the founding supplementary cases.
Hypoplastic Aortic Arch HP:0012304 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic aortic arch (HP:0012304). HP:0012304 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"bicuspid aortic valve, and a hypoplastic aortic arch"
Specific congenital cardiac anatomy documented in the founding supplementary cases.
Subvalvular Aortic Stenosis HP:0001682 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Subvalvular aortic stenosis (HP:0001682). HP:0001682 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"coarctation of the aorta, subaortic stenosis, mitral stenosis"
Subaortic stenosis accompanied coarctation and mitral stenosis in the Ser62Leu infant.
Digestive 8
Feeding Difficulties in Infancy HP:0008872 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties in infancy (HP:0008872). HP:0008872 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"two additional infants required feeding via gastrostomy tube"
Gastrostomy dependence documents clinically significant feeding difficulty in the reported infants.
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"She had dysphagia requiring a gastrostomy tube aged 7 mo, but now eats completely by mouth."
The narrative explicitly names dysphagia and distinguishes early tube dependence from later oral feeding.
Gastroesophageal Reflux HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Severe gastroesophageal reflux disease was treated by fundoplication and a gastrostomy."
Reflux can be severe and clinically consequential. Fundoplication and gastrostomy were required in the Gly28Ala child. The Asn156Ser narrative also reports reflux, despite its absence in that paper's summary table.
Vomiting HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"gastro-esophageal reflux or episodic vomiting were significant management issues in four individuals"
Episodic or cyclic vomiting contributes to management in some individuals; it may overlap with reflux but is not synonymous with it.
Anteriorly Placed Anus HP:0001545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anteriorly placed anus (HP:0001545). HP:0001545 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"anterior anus, recto-perianal fistula ... undescended testes ... rectal mucosal prolapse"
The case-level anatomical description explicitly identifies anterior placement of the anus.
Rectoperineal Fistula HP:0004792 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rectoperineal fistula (HP:0004792). HP:0004792 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"anterior anus, recto-perianal fistula ... undescended testes ... rectal mucosal prolapse"
The supplementary case description names a recto-perianal fistula, supporting the specific perineal fistula binding.
Rectal Prolapse HP:0002035 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rectal prolapse (HP:0002035). HP:0002035 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"recurrent loose stool and intermittent rectal mucosal prolapse"
The case narrative describes intermittent rectal mucosal prolapse rather than a congenital anorectal malformation.
Pyloric Stenosis HP:0002021 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pyloric stenosis (HP:0002021). HP:0002021 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Present congenital gastrointestinal problems were ano-rectal abnormalities (n = 2) and pyloric stenosis (n = 1)"
The founding cohort narrative counts one case of pyloric stenosis.
Ear 2
Sensorineural Hearing Impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Three individuals had moderate-severe sensorineural hearing loss"
The cohort narrative gives three moderate-severe sensorineural cases; supplemental details refine laterality.
Context-specific annotations (1)
Founding 12-person 2019 cohort; assessed denominator is specified for each finding OCCASIONAL
3/12 in this selected clinical series, not population prevalence or penetrance.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Three individuals had moderate-severe sensorineural hearing loss"
Original cohort evidence; counts derive from its clinical narrative or Table 1.
Low-Set Ears HP:0000369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-set ears (HP:0000369). HP:0000369 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"arched eyebrows, epicanthic folds, prominent eyes, a prominent nasal tip or long columella, a long philtrum, wide or open-mouth posture, prognathism, and low set and prominent ears"
One of the variable facial findings highlighted in at least two founding subjects; no precise component-specific frequency is assigned.
Eye 6
Myopia HP:0000545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopia (HP:0000545). HP:0000545 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"including myopia (n = 6), eyelid ptosis (n = 2), and/or strabismus (n = 4)"
The cohort narrative explicitly counts six cases; overlapping ocular findings are not independent individuals.
Context-specific annotations (1)
Founding 12-person 2019 cohort; assessed denominator is specified for each finding FREQUENT
6/12 in this selected clinical series, not population prevalence or penetrance.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"including myopia (n = 6), eyelid ptosis (n = 2), and/or strabismus (n = 4)"
Original cohort evidence; counts derive from its clinical narrative or Table 1.
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"including myopia (n = 6), eyelid ptosis (n = 2), and/or strabismus (n = 4)"
The cohort narrative explicitly counts two cases, avoiding the inconsistent later secondary tabulation.
Context-specific annotations (1)
Founding 12-person 2019 cohort; assessed denominator is specified for each finding OCCASIONAL
2/12 in this selected clinical series, not population prevalence or penetrance.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"including myopia (n = 6), eyelid ptosis (n = 2), and/or strabismus (n = 4)"
Original cohort evidence; counts derive from its clinical narrative or Table 1.
Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"including myopia (n = 6), eyelid ptosis (n = 2), and/or strabismus (n = 4)"
The cohort narrative explicitly counts four cases; this does not establish a population frequency.
Context-specific annotations (1)
Founding 12-person 2019 cohort; assessed denominator is specified for each finding FREQUENT
4/12 in this selected clinical series, not population prevalence or penetrance.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"including myopia (n = 6), eyelid ptosis (n = 2), and/or strabismus (n = 4)"
Original cohort evidence; counts derive from its clinical narrative or Table 1.
Visual Impairment HP:0000505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visual impairment (HP:0000505). HP:0000505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"these were associated with marked visual impairment in two children"
The narrative identifies marked visual impairment in two children without specifying a cerebral cause.
Context-specific annotations (1)
Founding 12-person 2019 cohort; assessed denominator is specified for each finding OCCASIONAL
2/12 in this selected clinical series, not population prevalence or penetrance.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"these were associated with marked visual impairment in two children"
Original cohort evidence; counts derive from its clinical narrative or Table 1.
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"ophthalmology for nystagmus, high myopia, and optic nerve cupping of both eyes"
Nystagmus was reported in the Arg29Gly case alongside high myopia and optic-disc cupping.
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"hypertelorism, epicanthal folds, low-set ears, prominent antihelix, short philtrum, flat nasal bridge, high arched palate, down-turned corners of the mouth, micrognathia"
Reported among the facial findings in the later Gly28Ala/Asn156Ser cases.
Genitourinary 2
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He also had an undescended left testis and left multicystic dysplastic kidney."
An undescended testis was described in the Gly28Ala child and the Ser62Leu boy with tetralogy of Fallot.
Multicystic Kidney Dysplasia HP:0000003 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multicystic kidney dysplasia (HP:0000003). HP:0000003 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He also had an undescended left testis and left multicystic dysplastic kidney."
Left multicystic dysplastic kidney was reported in the Gly28Ala child; this is a case observation, not an obligatory renal phenotype.
Head and Neck 12
Macrocephaly HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"one subject, who had mild macrocephaly (+2.21 standard deviations [SD])"
Mild macrocephaly was reported in a Ser62Leu infant with callosal agenesis.
Acquired Microcephaly Secondary microcephaly HP:0005484 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Secondary microcephaly (HP:0005484). HP:0005484 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"he had global developmental delay and acquired microcephaly"
The supplementary case explicitly reports acquired microcephaly; serial head measurements support the secondary-microcephaly binding.
Metopic Synostosis HP:0011330 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metopic synostosis (HP:0011330). HP:0011330 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Apart from the metopic synostosis present in the index individual, no other individuals had craniosynostosis."
The source confines metopic synostosis to the index subject; it does not establish a recurrent syndrome feature.
Facial dysmorphism Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Coarse binding: variable spectrum
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Facial dysmorphism was identified in 11 subjects; this was not characteristic"
The narrative gives 11/12 affected subjects and explicitly rejects a characteristic facial gestalt.
Context-specific annotations (1)
Founding 12-person 2019 cohort; assessed denominator is specified for each finding VERY_FREQUENT
11/12 in this selected clinical series, not population prevalence or penetrance.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Facial dysmorphism was identified in 11 subjects; this was not characteristic"
Original cohort evidence; counts derive from its clinical narrative or Table 1.
Epicanthus HP:0000286 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epicanthus (HP:0000286). HP:0000286 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"arched eyebrows, epicanthic folds, prominent eyes, a prominent nasal tip or long columella, a long philtrum, wide or open-mouth posture, prognathism, and low set and prominent ears"
One of the variable facial findings highlighted in at least two founding subjects; no precise component-specific frequency is assigned.
Long Philtrum HP:0000343 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long philtrum (HP:0000343). HP:0000343 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"arched eyebrows, epicanthic folds, prominent eyes, a prominent nasal tip or long columella, a long philtrum, wide or open-mouth posture, prognathism, and low set and prominent ears"
One of the variable facial findings highlighted in at least two founding subjects; no precise component-specific frequency is assigned.
Wide Mouth HP:0000154 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide mouth (HP:0000154). HP:0000154 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"arched eyebrows, epicanthic folds, prominent eyes, a prominent nasal tip or long columella, a long philtrum, wide or open-mouth posture, prognathism, and low set and prominent ears"
One of the variable facial findings highlighted in at least two founding subjects; no precise component-specific frequency is assigned.
Mandibular Prognathia HP:0000303 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mandibular prognathia (HP:0000303). HP:0000303 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"arched eyebrows, epicanthic folds, prominent eyes, a prominent nasal tip or long columella, a long philtrum, wide or open-mouth posture, prognathism, and low set and prominent ears"
One of the variable facial findings highlighted in at least two founding subjects; no precise component-specific frequency is assigned.
High Palate HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"hypertelorism, epicanthal folds, low-set ears, prominent antihelix, short philtrum, flat nasal bridge, high arched palate, down-turned corners of the mouth, micrognathia"
Reported among the facial findings in the later Gly28Ala/Asn156Ser cases.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"hypertelorism, epicanthal folds, low-set ears, prominent antihelix, short philtrum, flat nasal bridge, high arched palate, down-turned corners of the mouth, micrognathia"
Reported among the facial findings in the later Gly28Ala/Asn156Ser cases.
Bifid Uvula HP:0000193 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bifid uvula (HP:0000193). HP:0000193 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"protruding ears, bifid uvula, and micrognathia"
A bifid uvula was documented in the Asn156Ser girl.
Highly Arched Eyebrow HP:0002553 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Highly arched eyebrow (HP:0002553). HP:0002553 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"arched eyebrows, epicanthic folds, prominent eyes, a prominent nasal tip or long columella"
One of the variable facial components observed in at least two founding individuals.
Limbs 4
Hip Contracture HP:0003273 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hip contracture (HP:0003273). HP:0003273 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38193604 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"undocumented progressive contractures of the hips and knees as well as scoliosis were also observed in the child"
The inherited-variant report explicitly identifies progressive hip contractures in the child, without this finding in the mother.
Knee Contracture HP:0034671 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Knee contracture (HP:0034671). HP:0034671 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38193604 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"undocumented progressive contractures of the hips and knees as well as scoliosis were also observed in the child"
The inherited-variant report explicitly identifies progressive knee contractures in the child, without this finding in the mother.
Pes Planus HP:0001763 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes planus (HP:0001763). HP:0001763 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"as well as intermittent esotropia and pes planovalgus"
Flat or planovalgus feet occur in several individuals, with orthopedic procedures or orthoses used in some.
Overlapping Toe HP:0001845 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Overlapping toe (HP:0001845). HP:0001845 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"overlapping toes were noted on the left foot"
Overlapping toes on the left foot were described in the Gly28Ala child.
Metabolism 1
Decreased CSF Homovanillic Acid Decreased CSF homovanillic acid concentration HP:0003785 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased CSF homovanillic acid concentration (HP:0003785). HP:0003785 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"a low cerebrospinal fluid (CSF) homovanillic acid level, the significance of which is unclear"
The report explicitly qualifies this isolated CSF measurement as of uncertain significance.
Musculoskeletal 3
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"hypotonia (noted in 11/12 subjects) was frequently evident"
The explicit narrative count is 11/12; the combined motor/hypotonia table row is less specific.
Context-specific annotations (1)
Founding 12-person 2019 cohort; assessed denominator is specified for each finding VERY_FREQUENT
11/12 in this selected clinical series, not population prevalence or penetrance.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"hypotonia (noted in 11/12 subjects) was frequently evident"
Original cohort evidence; counts derive from its clinical narrative or Table 1.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38193604 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"undocumented progressive contractures of the hips and knees as well as scoliosis were also observed in the child"
The inherited-variant report names scoliosis in the child and notes that this presentation was absent in the mother.
Joint Hypermobility HP:0001382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint hypermobility (HP:0001382). HP:0001382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Hypotonia was improving; he had significant generalized joint laxity."
Joint laxity was documented in some supplementary cases.
Nervous System 16
Global Developmental Delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Mild to moderate developmental delay was universal, and older children had ID"
The cohort narrative identifies developmental delay in every founding subject; cognitive assessment was age-dependent.
Context-specific annotations (1)
Founding 12-person 2019 cohort; assessed denominator is specified for each finding OBLIGATE
12/12 in this selected clinical series, not population prevalence or penetrance.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Mild to moderate developmental delay was universal, and older children had ID"
Original cohort evidence; counts derive from its clinical narrative or Table 1.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"older children had ID which ranged from mild (two cases) to moderate–severe (two cases); most were in the moderate range (five cases)"
The narrative gives nine assessable older subjects: two mild, five moderate and two moderate-severe cases.
Context-specific annotations (1)
Founding 12-person 2019 cohort; assessed denominator is specified for each finding OBLIGATE
9/9 in this selected clinical series, not population prevalence or penetrance.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"older children had ID which ranged from mild (two cases) to moderate–severe (two cases); most were in the moderate range (five cases)"
Original cohort evidence; counts derive from its clinical narrative or Table 1.
Delayed Speech and Language Development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"said her first word at 4 yr, and spoke in sentences at 6 yr"
Reported milestone ages directly document delayed first words and sentence formation in one child.
Gait Disturbance HP:0001288 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gait disturbance (HP:0001288). HP:0001288 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"On examination he was well-proportioned with an unsteady broad-based gait."
The examination describes an abnormal broad-based gait rather than inferring gait impairment from hypotonia.
Autism HP:0000717 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism (HP:0000717). HP:0000717 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"seven of ten of the older individuals had formal diagnoses of autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD)"
Table 1 separates five formal autism diagnoses among ten older subjects; the quoted combined count also includes ADHD.
Context-specific annotations (1)
Founding 12-person 2019 cohort; assessed denominator is specified for each finding FREQUENT
5/10 in this selected clinical series, not population prevalence or penetrance.
Show evidence (2 references)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"seven of ten of the older individuals had formal diagnoses of autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD)"
Original cohort evidence; counts derive from its clinical narrative or Table 1.
PMID:33067521 SUPPORT DIRECT BACKGROUND Human Clinical
"ADHD: 4/10, autism spectrum disorder: 5/10"
Secondary tabulation of the founding cohort, checked against the original case-level Table 1; the two diagnoses overlap.
Attention Deficit Hyperactivity Disorder HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"seven of ten of the older individuals had formal diagnoses of autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD)"
Table 1 separates four formal ADHD diagnoses among ten older subjects; the quoted combined count also includes autism.
Context-specific annotations (1)
Founding 12-person 2019 cohort; assessed denominator is specified for each finding FREQUENT
4/10 in this selected clinical series, not population prevalence or penetrance.
Show evidence (2 references)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"seven of ten of the older individuals had formal diagnoses of autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD)"
Original cohort evidence; counts derive from its clinical narrative or Table 1.
PMID:33067521 SUPPORT DIRECT BACKGROUND Human Clinical
"ADHD: 4/10, autism spectrum disorder: 5/10"
Secondary tabulation of the founding cohort, checked against the original case-level Table 1; the two diagnoses overlap.
Sleep Disturbance HP:0002360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"She has ADHD, with a sweet personality, but is sometimes aggressive, and has a severe sleep disorder."
Sleep-onset or severe sleep disturbance was reported in individual cases and contributed to management needs.
Anxiety HP:0000739 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anxiety (HP:0000739). HP:0000739 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Behavioral problems include ADHD, tantrums and anxiety."
Anxiety and tantrums were described in some supplementary case reports; no population frequency is established.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Two individuals had seizures, but brain imaging was either normal or was not available."
The narrative gives two affected individuals; the supplementary case history distinguishes epileptic from nonepileptic events.
Context-specific annotations (1)
Founding 12-person 2019 cohort; assessed denominator is specified for each finding OCCASIONAL
2/12 in this selected clinical series, not population prevalence or penetrance.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Two individuals had seizures, but brain imaging was either normal or was not available."
Original cohort evidence; counts derive from its clinical narrative or Table 1.
Corpus callosum agenesis Agenesis of corpus callosum HP:0001274 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agenesis of corpus callosum (HP:0001274). HP:0001274 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"magnetic resonance imaging (MRI) of the brain showed agenesis or thinning of the corpus callosum in four subjects"
Table 1 separates three agenesis cases from one thinning case in the combined four-person callosal-abnormality count.
Thin Corpus Callosum HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"a thin corpus callosum with bilateral posterior supratentorial and perihippocampal white matte r volume loss"
The supplementary MRI report explicitly describes thinning, supporting a separate phenotype from agenesis.
Ventriculomegaly HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"confirmed agenesis of the corpus callosum and mild ventriculomegaly."
Mild ventriculomegaly accompanied callosal agenesis in the Ser62Leu girl with hypoplastic left heart.
Delayed CNS Myelination HP:0002188 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed CNS myelination (HP:0002188). HP:0002188 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"A repeat MRI scan showed no progression of the previously observed changes but no ted incomplete myelination."
The follow-up MRI describes incomplete myelination without progression of the previously observed abnormalities.
Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"An additional diagnosis of a movement disorder consisting of tremor and dystonia was made by 4 yr."
Dystonia accompanied tremor in the Phe97Leu case. The contribution of low CSF homovanillic acid remains unresolved.
Tremor HP:0001337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tremor (HP:0001337). HP:0001337 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"An additional diagnosis of a movement disorder consisting of tremor and dystonia was made by 4 yr."
Tremor was documented with dystonia in the Phe97Leu case.
Obstructive Sleep Apnea HP:0002870 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obstructive sleep apnea (HP:0002870). HP:0002870 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"severe obstructive sleep apnea requiring supplemental oxygen"
Severe obstructive sleep apnea in the Arg29Gly case required supplemental oxygen temporarily; oxygen was no longer needed at later follow-up.
Respiratory 1
Laryngomalacia HP:0001601 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Laryngomalacia (HP:0001601). HP:0001601 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He was found to have laryngomalacia and a sleep stud y demonstrated severe obstructive sleep apnea"
Laryngomalacia was diagnosed in the Arg29Gly case with feeding and respiratory difficulties.
Growth 2
Failure to Thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The patient had difficulty feeding and failed to thrive."
Poor weight gain occurred in some children with feeding problems or congenital anomalies.
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"one individual, who had mild short stature (−2.53 SD)"
Short stature was present in one founding individual and both later Japanese cases; available measurements vary with age.
🧬

Genetic Associations

1
CDK8 (Heterozygous kinase-domain missense variants cause a variable developmental disorder. De novo occurrence predominates in the founding series, but maternal transmission of Arg200Gln to an affected child establishes that inheritance is possible.)
Gene: CDK8 hgnc:1779 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CDK8 (hgnc:1779). hgnc:1779 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal Dominant
Show evidence (2 references)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects"
Case-level genetic evidence.
PMID:38193604 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The clinical presentation of the child and mother is within the described clinical spectrum for IDDHBA"
Both generations were clinically affected.
Variants (6)
c.185C>T (p.Ser62Leu)
Recurrent alpha-C-helix allele in five founding subjects; de novo status was confirmed in three, while paternal samples were unavailable in two. STAT1 phosphorylation was markedly reduced.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"a recurrent mutation, c.185C>T (p.Ser62Leu), was present in five individuals"
Recurrence in the original cohort.
p.Val27Leu, p.Arg29Gly and p.Gly30Ser
Founding glycine-rich-loop substitutions c.79G>C, c.85C>G and c.88G>A. Kinase output was reduced without evidence of gross misfolding.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Computational
"are clustered in the Gly-rich loop (amino acids 27–35), a highly conserved protein-kinase motif"
Variant positions.
c.291T>G (p.Phe97Leu) and c.669A>G (p.Ile223Met)
These founding alleles retained approximately 63% and 51% of reference STAT1 phosphorylation in the cell assay, respectively. Relative assay activity does not establish a clinical severity ranking.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT In Vitro
"an intermediate level of phosphorylation (∼63% and ∼51% in comparison to the WT, respectively), was observed"
Residual activity in two alleles.
c.533G>A (p.Arg178Gln) and c.578T>G (p.Val193Gly)
Activation-segment alleles from the founding series, with reduced kinase output. Arg178Gln was also investigated by molecular-dynamics simulation.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Computational
"Two substitutions, c.533G>A (p.Arg178Gln) and c.578T>G (p.Val193Gly), affect amino acids located in the activation segment"
Structural localization.
c.83G>C (p.Gly28Ala) and c.467A>G (p.Asn156Ser)
De novo alleles in two additional patients with lower autophosphorylation activity. Asn156Ser reduced the assay readout more strongly than Gly28Ala; developmental severity in two differently aged patients cannot validate an activity-severity correlation.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Both the CDK8-G28A and CDK8-N156S mutations resulted in lower kinase activities compared with CDK8-WT"
Functional analysis of the later alleles.
c.599G>A (p.Arg200Gln) Likely Pathogenic
Likely pathogenic variant transmitted from an affected mother to her child. Progressive hip and knee contractures and scoliosis were reported in the child but not the mother.
Show evidence (1 reference)
PMID:38193604 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"a likely pathogenic heterozygous CDK8 variant c.599G>A, p.(Arg200Gln) inherited from the biological mother"
Inherited allele and reported classification.
💊

Medical Actions

14
Cardiac Surgery
Action: Cardiac SurgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Cardiac Surgery (NCIT:C157806). NCIT:C157806 is a clinical intervention from the NCI Thesaurus. NCIT:C157806
Platform: Surgery
Cardiac procedures depend on the structural lesion. The hypoplastic-left-heart child underwent staged Norwood, Glenn and Fontan operations, and a different infant had a good result after coarctation repair. These case reports do not compare surgical strategies.
Target Phenotypes: Hypoplastic left ventricle HP:0004383 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypoplastic left ventricle (HP:0004383). HP:0004383 is a phenotype from the Human Phenotype Ontology. Coarctation of aorta HP:0001680 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Coarctation of aorta (HP:0001680). HP:0001680 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"underwent cardiac surgery at 4 days of age via a Norwood procedure."
First stage of the documented palliation.
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"a Fontan procedure aged 4 yr."
Later stage in the same child.
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"She underwent aortic coarctation repair aged 5 mo with a good result."
Reported outcome in another child.
Tube Feeding and Gastrostomy
Action: Gastrostomy Tube ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Gastrostomy Tube Procedure (NCIT:C157864). NCIT:C157864 is a clinical intervention from the NCI Thesaurus. NCIT:C157864
Platform: Surgery
Nasogastric or gastrostomy feeding supports children with inefficient feeding, dysphagia or poor growth. The Ser62Leu girl later achieved complete oral feeding; gastrostomy dependence is not universal or necessarily permanent.
Target Phenotypes: Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology. Feeding difficulties in infancy HP:0008872 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Feeding difficulties in infancy (HP:0008872). HP:0008872 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"A nasogastric tube was also placed for supplemental nutrition."
Early nutritional support in the Arg29Gly child.
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"She had dysphagia requiring a gastrostomy tube aged 7 mo, but now eats completely by mouth."
Gastrostomy followed by later oral feeding in the Ser62Leu child.
Fundoplication for Severe Reflux
Action: FundoplicationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Fundoplication (NCIT:C91834). NCIT:C91834 is a clinical intervention from the NCI Thesaurus. NCIT:C91834
Platform: Surgery
Fundoplication and gastrostomy were performed in the Gly28Ala child with severe reflux. The report documents treatment without a quantified reflux outcome.
Target Phenotypes: Gastroesophageal reflux HP:0002020 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Severe gastroesophageal reflux disease was treated by fundoplication and a gastrostomy."
Individual surgical treatment.
Developmental Therapies
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Behavioral / lifestyle
Physical, speech and occupational therapies and special education are documented in affected children. These reports describe service use without controlled estimates of developmental benefit.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology. Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"receives physical therapy, speech therapy, and occupational therapy."
Documented developmental support in the Ile223Met child.
Orthoses and Orthopedic Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
Ankle-foot orthoses helped ambulation in the Ile223Met child. Another boy underwent bilateral lateral column lengthening and serial casting for pes planus. Progressive contractures in the later inherited case warrant individual orthopedic assessment, but a CDK8-specific protocol has not been studied.
Target Phenotypes: Gait disturbance HP:0001288 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Gait disturbance (HP:0001288). HP:0001288 is a phenotype from the Human Phenotype Ontology. Pes planus HP:0001763 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Pes planus (HP:0001763). HP:0001763 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"He wears ankle -foot orthoses, which help with ambulation."
Reported orthotic benefit.
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"serial plaster casting for pes planus and can walk for approximately 2 miles."
Orthopedic care and functional status in another individual.
Antiseizure Pharmacotherapy
Action: Anticonvulsant TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Anticonvulsant Therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. NCIT:C64172
Agent: valproic acid CHEBI:39867 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses valproic acid (CHEBI:39867). CHEBI:39867 is a therapeutic agent from Chemical Entities of Biological Interest. lamotrigine CHEBI:6367 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses lamotrigine (CHEBI:6367). CHEBI:6367 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Valproic acid improved complex partial seizures and migraines in one Ser62Leu boy. Lamotrigine was started in a Phe97Leu girl who later continued to have epileptic and nonepileptic events; complete seizure control was not demonstrated. These observations do not establish an allele-specific drug choice.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"complex partial seizures and migraines, both improved with valproic acid."
Positive response in one patient.
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf NO_EVIDENCE DIRECT PRIMARY RESULT Human Clinical
"A diagnosis of a seizure disorder was made by one year of age and Lamotrigine treatment started."
Documented use; subsequent ongoing events limit efficacy inference.
Melatonin for Sleep-Onset Difficulty
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: melatonin CHEBI:16796 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses melatonin (CHEBI:16796). CHEBI:16796 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Melatonin was used for difficulty falling asleep in the Gly30Ser boy. The report does not state the treatment response.
Target Phenotypes: Sleep disturbance HP:0002360 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf NO_EVIDENCE DIRECT PRIMARY RESULT Human Clinical
"He had trouble going to sleep for which melatonin was used."
Documented use without a stated efficacy outcome.
Methylphenidate (Unsuccessful Individual Trial)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: methylphenidate CHEBI:6887 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses methylphenidate (CHEBI:6887). CHEBI:6887 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Ritalin worsened ADHD in the Gly30Ser child and was discontinued. This is a negative individual response, not evidence of efficacy or a universal contraindication for all affected patients.
Target Phenotypes: Attention deficit hyperactivity disorder HP:0007018 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf REFUTE DIRECT PRIMARY RESULT Human Clinical
"the ADHD worsened in response to Ritalin and was thus stopped."
Negative individual treatment outcome.
Pyridostigmine (Temporary Individual Response)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Pyridostigmine CHEBI:8665 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses Pyridostigmine (CHEBI:8665). CHEBI:8665 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
A trial for suspected congenital myasthenic syndrome in the Val27Leu girl produced mild, temporary improvement. Neuromuscular-junction disease was not established, and other candidate variants complicate attribution. This is not a validated disease-directed CDK8 treatment.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"A pyridostigmine treatment trial resulted in a mild, temporary improvement."
Limited temporary response in one individual.
Flunarizine for Cyclic Vomiting
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: flunarizine CHEBI:135652 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses flunarizine (CHEBI:135652). CHEBI:135652 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
The Val193Gly girl continued treatment at age twelve for cyclic vomiting that had persisted since age three. The supplement spells the drug flunarazine; no quantified response is reported.
Target Phenotypes: Vomiting HP:0002013 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf NO_EVIDENCE DIRECT PRIMARY RESULT Human Clinical
"This problem has persisted, and aged 12 yr she continues to be treated with flunarazine."
Ongoing treatment with persistent symptoms; benefit cannot be determined.
Iron Supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Iron supplementation, formulation unspecified Relation: this treatment uses this therapeutic agent This treatment uses Iron supplementation, formulation unspecified.
Anemia of uncertain origin improved with iron supplements in one Ser62Leu child. The observation does not establish iron deficiency as the cause of anemia or indicate supplementation for all patients.
Target Phenotypes: Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"he had an anemia of unknown origin, which improved with iron supplements."
Case-specific improvement; iron formulation and cause of anemia were not established.
Supplemental Oxygen
Action: Oxygen TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Oxygen Therapy (NCIT:C94624). NCIT:C94624 is a clinical intervention from the NCI Thesaurus. NCIT:C94624
The Arg29Gly child required oxygen for severe obstructive sleep apnea early in life and later no longer needed it. The report does not identify a disease-specific respiratory treatment protocol.
Target Phenotypes: Obstructive sleep apnea HP:0002870 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Obstructive sleep apnea (HP:0002870). HP:0002870 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"severe obstructive sleep apnea requiring supplemental oxygen"
Individual respiratory support.
Visual Correction
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
Glasses were used for myopia in affected children. Refractive correction addresses the documented ocular finding rather than the underlying developmental disorder.
Target Phenotypes: Myopia HP:0000545 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Myopia (HP:0000545). HP:0000545 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"She wears glasses for myopia and has normal hearin g."
Documented refractive correction.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling incorporates variant-specific evidence and parental testing. Most confirmed pathogenic missense variants are de novo, but affected-parent transmission is documented. A negative parental blood result cannot eliminate germline mosaicism, and these case series do not quantify penetrance or recurrence risk.
Show evidence (1 reference)
PMID:38193604 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"a likely pathogenic heterozygous CDK8 variant c.599G>A, p.(Arg200Gln) inherited from the biological mother"
Documented maternal transmission of an allele classified as likely pathogenic.
🔬

Diagnosis

5
Molecular Diagnosis and Parental Testing
Trio exome or genome sequencing identified heterozygous kinase-domain missense variants. Interpretation integrates phenotype, inheritance, population frequency and allele-specific functional evidence. The published signature does not justify classifying every rare CDK8 variant or truncating allele as pathogenic.
Whole Exome Sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Using whole-exome or whole-genome sequencing, and by international collaboration, we identified eight different heterozygous missense CDK8 substitutions"
Molecular ascertainment in the original cohort.
Cardiac Assessment
Echocardiography characterizes variable congenital lesions and informs lesion-specific management; not every patient has heart disease.
Echocardiography NCIT:C16525 NCI Thesaurus (NCIT)
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"echocardiography showed tetralogy of Fallot."
Diagnostic cardiac imaging in a reported case.
Brain MRI
Imaging may show callosal agenesis or thinning, ventriculomegaly or white-matter abnormalities. A normal scan does not exclude CDK8-related disorder.
Magnetic Resonance Imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"magnetic resonance imaging (MRI) of the brain showed agenesis or thinning of the corpus callosum in four subjects"
Variable structural imaging findings.
EEG for Paroxysmal Events
EEG helps distinguish epileptic from nonepileptic spells. The Phe97Leu girl had both types over time, so observation of jerking alone does not establish seizures.
Electroencephalography NCIT:C38054 NCI Thesaurus (NCIT)
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"These events were captured during an electro encephalogram (EEG) recording and were not felt to be epileptic."
Nonepileptic early events preceded later diagnosed epilepsy.
Hearing and Ophthalmologic Assessment
Hearing and eye evaluation identify sensorineural hearing loss, refractive errors, strabismus and other visual difficulties that may affect communication and development.
Show evidence (2 references)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Three individuals had moderate-severe sensorineural hearing loss"
Cohort hearing findings.
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"including myopia (n = 6), eyelid ptosis (n = 2), and/or strabismus (n = 4)"
Cohort ocular findings.
📊

Prevalence

3
Founding 2019 international clinical cohort
Cases In Literature
Twelve unrelated individuals carried eight distinct missense substitutions; ten had confirmed de novo variants, while paternal samples were unavailable in two recurrent-allele cases. This selected cohort and subsequent reports do not establish population prevalence.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects"
Founding cohort size and confirmed inheritance.
Additional 2020 clinical report
Cases In Literature
Two additional patients carried Gly28Ala or Asn156Ser, bringing the cases tabulated in that report to fourteen. This is a literature count, not population prevalence.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We presented the cases of two patients with CDK8-associated disorder"
The 2020 report adds two individuals to the founding twelve.
Mother and child reported online in 2023 and published in 2024
Cases In Literature
An affected mother and child shared a likely pathogenic Arg200Gln variant. They represent two related individuals, rather than two independent de novo occurrences.
Show evidence (1 reference)
PMID:38193604 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The clinical presentation of the child and mother is within the described clinical spectrum for IDDHBA"
The case report describes affected members of two generations.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from CDK8-Related Disorder:

Noonan Syndrome
Overlapping Features Tetralogy of Fallot, neonatal lymphedema, cryptorchidism and neck/ear findings initially suggested Noonan syndrome in the Ser62Leu boy. The resemblance is case-specific.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"An initial diagnosis of Noonan Syndrome was proposed."
Documented differential before CDK8 diagnosis.
Congenital Myasthenic Syndrome
Overlapping Features Ptosis, facial weakness and hypotonia prompted this differential in the Val27Leu girl. A transient pyridostigmine response did not establish a neuromuscular-junction defect, and additional candidate variants limit attribution of every feature to CDK8.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Pediatric neurological examination also showed facial weakness and a congenital myasthenic syndrome was suspected."
Clinical suspicion rather than a confirmed coexisting diagnosis.
Prader-Willi or Angelman Syndrome
Overlapping Features Methylation studies for both conditions were unrevealing in the hypotonic Arg29Gly child with feeding and developmental difficulties. These are reported differential investigations, not diagnostic criteria for CDK8 disease.
Show evidence (1 reference)
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical
"methylation studies for Prader-Willi and Angelman syndromes."
Negative workup is stated in the surrounding sentence; this excerpt identifies the tested conditions.
🧫

Experimental Models

4
SW620 CDK8/CDK19 Double-Knockout Complementation CELL_LINE
STAT1 Ser727 phosphorylation was reduced by all eight founding variants. Phe97Leu and Ile223Met retained approximately 63% and 51% of reference output, while most variants approached the engineered Asp173Ala kinase-dead control. Asp173Ala is an assay control, not a patient allele.
Organism
Homo sapiens NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
CRISPR-edited SW620 colorectal carcinoma cells lacking CDK8 and CDK19; transient reference or variant human CDK8 expression
Publication
PMID:30905399
Pathograph links
Reduced CDK8 Kinase Activity measures fidelity: moderate observes: molecular Measures variant-dependent substrate phosphorylation.
Limitations: A cancer cell line with both endogenous paralogs deleted is not a heterozygous patient neural cell. The substrate assay does not identify the disease-relevant transcriptional program.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT In Vitro
"We observed that the cellular levels of pSTAT1 were reduced to a statistically significant extent, compared to WT, in all mutant-transfected cells"
Variant activity in a double-knockout cell background.
Reduced STAT1 Ser727 Phosphorylation measures fidelity: moderate observes: molecular Measures variant-dependent substrate phosphorylation.
Limitations: A cancer cell line with both endogenous paralogs deleted is not a heterozygous patient neural cell. The substrate assay does not identify the disease-relevant transcriptional program.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT In Vitro
"We observed that the cellular levels of pSTAT1 were reduced to a statistically significant extent, compared to WT, in all mutant-transfected cells"
Variant activity in a double-knockout cell background.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT In Vitro
"We observed that the cellular levels of pSTAT1 were reduced to a statistically significant extent, compared to WT, in all mutant-transfected cells"
Variant activity in a double-knockout cell background.
HEK293T Kinase-Module Assembly and Thermal Stability CELL_LINE
Variant proteins retained cyclin-C association and showed no gross loss of thermal stability. Most or all retained ATP-responsive stabilization; the supplemental co-immunoprecipitation also recovered MED12 and MED13. These findings constrain a simple protein-destabilization explanation without proving dominant-negative competition.
Organism
Homo sapiens NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Transiently transfected HEK293T cells; immunoprecipitated tagged CDK8 modules
Publication
PMID:30905399
Pathograph links
Nonproductive Mediator Kinase Module Occupancy measures fidelity: low observes: molecular Assesses whether catalytically impaired proteins can remain in stable kinase modules.
Limitations: Retained association is compatible with the proposed occupancy model but does not demonstrate competition with the normal allele in patient cells.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT In Vitro
"none of the substitutions cause gross mis-folding of the protein, and most or all are still able to bind ATP"
Thermal stability and ATP-response experiments.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT In Vitro
"none of the substitutions cause gross mis-folding of the protein, and most or all are still able to bind ATP"
Thermal stability and ATP-response experiments.
Reference/Ser62Leu Mixing Assay CELL_LINE
Equal reference and Ser62Leu constructs did not produce an obviously nonlinear fall in STAT1 phosphorylation. The authors reported this result without showing the data and stated that further experiments were needed.
Organism
Homo sapiens NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Mixed reference and Ser62Leu CDK8 constructs in the STAT1-phosphorylation assay
Publication
PMID:30905399
Pathograph links
Nonproductive Mediator Kinase Module Occupancy measures fidelity: low observes: molecular Directly probes the proposed dominant-negative interpretation without establishing it.
Limitations: One variant, one substrate, transient expression and data not shown; lack of nonlinear inhibition does not exclude a different context-dependent mechanism.
Show evidence (1 reference)
PMID:30905399 NO_EVIDENCE DIRECT PRIMARY RESULT In Vitro
"the observed reduction in phosphorylation in mixed samples did not obviously deviate from a linear response"
The mixing assay did not establish a dominant-negative interaction.
Show evidence (1 reference)
PMID:30905399 NO_EVIDENCE DIRECT PRIMARY RESULT In Vitro
"the observed reduction in phosphorylation in mixed samples did not obviously deviate from a linear response"
The mixing assay did not establish a dominant-negative interaction.
HEK293 Gly28Ala/Asn156Ser Autophosphorylation CELL_LINE
Gly28Ala and Asn156Ser reduced autophosphorylation activity, with the stronger reduction for Asn156Ser. This biochemical ordering does not establish a human severity ordering.
Organism
Homo sapiens NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
HEK293 cells expressing tagged human CDK8 with cyclin C; immunoprecipitate ADP-GLO assay
Publication
PMID:33067521
Pathograph links
Reduced CDK8 Kinase Activity measures fidelity: moderate observes: molecular Measures catalytic output of the two later patient variants.
Limitations: Overexpressed immunoprecipitates and autophosphorylation differ from developmental substrate selection in patient cells.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Both the CDK8-G28A and CDK8-N156S mutations resulted in lower kinase activities compared with CDK8-WT"
Autophosphorylation assay of later variants.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Both the CDK8-G28A and CDK8-N156S mutations resulted in lower kinase activities compared with CDK8-WT"
Autophosphorylation assay of later variants.
🐁

Animal Models

3
Zebrafish Human CDK8 mRNA Overexpression
At one day postfertilization, reference CDK8 overexpression caused the largest fraction of embryos with shortened body axis, small anterior structures and abnormal tails. Both variants had less defect-inducing activity, especially Asn156Ser. This comparison supports reduced activity, not greater variant toxicity.
Species
Danio rerio
Genotype
One-cell injection of reference, Gly28Ala or Asn156Ser human CDK8 mRNA
Publication
PMID:33067521
Pathograph links
Reduced CDK8 Kinase Activity perturbs fidelity: low observes: organism Variant mRNAs perturb development less than reference CDK8 under overexpression.
Limitations: Overexpression toxicity is an indirect activity readout. This is not an endogenous heterozygous knock-in or a genomic knockdown, and human intellectual disability is not measured.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Model Organism
"The relative fraction of embryos with defects was largest when mRNA encoding the human wild-type CDK8 protein was injected"
Reference overexpression perturbed development more than either tested variant.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Model Organism
"The relative fraction of embryos with defects was largest when mRNA encoding the human wild-type CDK8 protein was injected"
Reference overexpression perturbed development more than either tested variant.
Zebrafish Dual CDK8/CDK19 Inhibition
Senexin A exposure produced craniofacial cartilage and cardiac abnormalities with disturbed circulation in all 46 reported exposed embryos. The compound inhibits both paralogs. Exposure models developmental loss of kinase activity and is not a therapeutic rescue.
Species
Danio rerio
Genotype
Unmodified embryos exposed to 2 micromolar Senexin A
Publication
PMID:33067521
Pathograph links
Impaired Cardiac Morphogenesis perturbs fidelity: low observes: tissue Dual kinase inhibition disrupts this developmental process.
Limitations: Chemical inhibition does not isolate CDK8 from CDK19 and does not reproduce a specific patient allele. The methods contain an internally inconsistent exposure-start time, so no start time is assigned here.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Model Organism
"the inhibition of Cdk8 kinase activity by Senexin A induced structural anomalies in the heart and craniofacial cartilage of the zebrafish"
Experimental developmental perturbation by a dual-kinase inhibitor.
Impaired Craniofacial Patterning perturbs fidelity: low observes: tissue Dual kinase inhibition disrupts this developmental process.
Limitations: Chemical inhibition does not isolate CDK8 from CDK19 and does not reproduce a specific patient allele. The methods contain an internally inconsistent exposure-start time, so no start time is assigned here.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Model Organism
"the inhibition of Cdk8 kinase activity by Senexin A induced structural anomalies in the heart and craniofacial cartilage of the zebrafish"
Experimental developmental perturbation by a dual-kinase inhibitor.
Show evidence (1 reference)
PMID:33067521 SUPPORT DIRECT PRIMARY RESULT Model Organism
"the inhibition of Cdk8 kinase activity by Senexin A induced structural anomalies in the heart and craniofacial cartilage of the zebrafish"
Experimental developmental perturbation by a dual-kinase inhibitor.
Cdk8 Gene-Trap Mouse
Heterozygotes had no reported overt phenotype, while homozygous embryos failed before implantation at approximately embryonic days 2.5–3.0 with fragmented blastomeres and absent compaction. Complete gene loss differs substantially from the viable human missense disorder.
Species
Mus musculus
Genotype
Heterozygous or homozygous gene-trap inactivation of Cdk8
Publication
PMID:17620419
Pathograph links
Reduced CDK8 Kinase Activity perturbs fidelity: low observes: organism Complete Cdk8 loss reveals an early developmental requirement but does not reproduce the clinical missense syndrome.
Limitations: Gene trapping removes gene function rather than retaining an altered kinase module. The abstract does not establish comprehensive neurobehavioral testing of heterozygotes; normal appearance is not proof of complete haplosufficiency.
Show evidence (2 references)
PMID:17620419 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Cdk8-/- preimplantation embryos had fragmented blastomeres and did not proceed to compaction."
Early embryonic phenotype of complete mouse gene loss.
+ 1 more reference
Show evidence (2 references)
PMID:17620419 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Cdk8-/- preimplantation embryos had fragmented blastomeres and did not proceed to compaction."
Early embryonic phenotype of complete mouse gene loss.
PMID:17620419 SUPPORT DIRECT PRIMARY RESULT Model Organism
"No phenotypes were noted in heterozygote Cdk8+/- mice"
No reported overt phenotype in the heterozygous gene-trap animals.
🧮

Computational Models

1
CDK8–Cyclin C Molecular Dynamics STRUCTURAL_PREDICTION
Reference, Ser62Leu and Arg178Gln CDK8–cyclin C structures with ATP were compared by molecular dynamics. The modeling used CDK8 structure 4F7S and an aligned CDK9 ATP template, with unresolved regions modeled in MOE and replicate simulations in GROMACS. The variants were predicted to restrict substrate-pocket opening without grossly changing the overall fold.
PMID:30905399
Pathograph links
Altered Substrate-Binding Geometry measures fidelity: low observes: molecular Predicts reduced access to the catalytic pocket.
Limitations: Predicted conformations do not directly measure substrate binding, phosphorylation kinetics or patient-cell transcription.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Computational
"the substrate-binding site of the WT CDK8 protein can adopt more open conformations than its mutated counterparts"
Structural-dynamics prediction.
Show evidence (1 reference)
PMID:30905399 SUPPORT DIRECT PRIMARY RESULT Computational
"the substrate-binding site of the WT CDK8 protein can adopt more open conformations than its mutated counterparts"
Structural-dynamics prediction.
{ }

Source YAML

click to show 
name: CDK8-Related Disorder
creation_date: '2026-07-31T00:00:00Z'
category: Mendelian
synonyms:
- Intellectual developmental disorder with hypotonia and behavioral abnormalities
- IDDHBA
- CDK8-associated neurodevelopmental disorder
- CDK8-related syndromic developmental disorder
description: >-
  CDK8-related disorder is an autosomal dominant neurodevelopmental condition associated primarily with heterozygous kinase-domain missense variants. Most reported variants arose de novo, but transmission from an affected mother is documented. Developmental and speech delay, variable intellectual disability, hypotonia and behavioral difficulties occur with craniofacial differences and variable cardiac, ocular, auditory and gastrointestinal anomalies. Tested variants reduce kinase output while retaining protein stability and module interactions; residual activity differs between alleles. A dominant-negative mechanism has been proposed but not established, and simple haploinsufficiency should not be assumed. Management addresses the individual clinical findings; experimental CDK8/19 inhibition is a developmental perturbation model, not an established therapy for this disorder.
disease_term:
  preferred_term: Intellectual developmental disorder with hypotonia and behavioral abnormalities
  term:
    id: MONDO:0032897
    label: intellectual developmental disorder with hypotonia and behavioral abnormalities
parents:
- Autosomal dominant intellectual disability
- Neurodevelopmental disorder
- CDK8-kinase module-associated disorder
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:30905399
      reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we report CDK8 mutations (located at 13q12.13) that cause a phenotypically related disorder."
      explanation: Supports classification as a heritable genetic disorder caused by CDK8 variants.
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:30905399
      reference_title: "De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism."
      explanation: Supports classification as a neurodevelopmental / neurologic disorder.
prevalence:
- population: Founding 2019 international clinical cohort
  measure_type: CASES_IN_LITERATURE
  notes: Twelve unrelated individuals carried eight distinct missense substitutions; ten had confirmed de novo variants, while paternal samples were unavailable in two recurrent-allele cases. This selected cohort and subsequent reports do not establish population prevalence.
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects
    explanation: Founding cohort size and confirmed inheritance.
- population: Additional 2020 clinical report
  measure_type: CASES_IN_LITERATURE
  notes: Two additional patients carried Gly28Ala or Asn156Ser, bringing the cases tabulated in that report to fourteen. This is a literature count, not population prevalence.
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We presented the cases of two patients with CDK8-associated disorder
    explanation: The 2020 report adds two individuals to the founding twelve.
- population: Mother and child reported online in 2023 and published in 2024
  measure_type: CASES_IN_LITERATURE
  notes: An affected mother and child shared a likely pathogenic Arg200Gln variant. They represent two related individuals, rather than two independent de novo occurrences.
  evidence:
  - reference: PMID:38193604
    reference_title: 'Expanding the phenotypic spectrum for CDK8-related disease: A case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The clinical presentation of the child and mother is within the described clinical spectrum for IDDHBA
    explanation: The case report describes affected members of two generations.
pathophysiology:
- name: CDK8 Coding Missense Substitutions
  description: Heterozygous coding single-nucleotide substitutions alter conserved residues in or near the ATP-binding pocket. Their physical sequence changes are distinct from the resulting catalytic and developmental effects.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects
    explanation: Physical variant class in affected individuals.
  role: trigger
  gene:
    preferred_term: CDK8
    term:
      id: hgnc:1779
      label: CDK8
  genetic_context:
    gene:
      preferred_term: CDK8
      term:
        id: hgnc:1779
        label: CDK8
    variant_type: single nucleotide variant
    variant_origin: GERMLINE
    genomic_contexts:
    - coding sequence
  downstream:
  - target: Altered Substrate-Binding Geometry
    description: Ser62Leu and Arg178Gln change substrate-pocket dynamics in computational simulations.
    causal_link_type: DIRECT
  - target: Reduced CDK8 Kinase Activity
    description: Tested missense variants reduce catalytic readouts.
    causal_link_type: DIRECT
- name: Altered Substrate-Binding Geometry
  description: Molecular-dynamics models of Ser62Leu and Arg178Gln predict a less open substrate-binding region. Gross protein misfolding and loss of ATP binding were not observed in biochemical studies; restricted substrate access remains a mechanistic interpretation.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the substrate-binding site of the WT CDK8 protein can adopt more open conformations than its mutated counterparts
    explanation: Structural-dynamics prediction.
  downstream:
  - target: Reduced CDK8 Kinase Activity
    description: Restricted substrate access could reduce phosphoryl transfer despite retained ATP binding.
    causal_link_type: DIRECT
- name: Reduced CDK8 Kinase Activity
  description: Tested alleles reduce kinase output. Most founding variants approach the kinase-dead control in the STAT1 assay, whereas Phe97Leu and Ile223Met retain intermediate activity. Gly28Ala and Asn156Ser also reduce autophosphorylation. Protein stability and cyclin-C binding are retained, so this is not equivalent to complete loss of the gene product.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We observed that the cellular levels of pSTAT1 were reduced to a statistically significant extent, compared to WT, in all mutant-transfected cells
    explanation: Variant activity in a double-knockout cell background.
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Both the CDK8-G28A and CDK8-N156S mutations resulted in lower kinase activities compared with CDK8-WT
    explanation: Autophosphorylation assay of later variants.
  role: central_effector
  gene:
    preferred_term: CDK8
    term:
      id: hgnc:1779
      label: CDK8
    modifier: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: cyclin-dependent protein serine/threonine kinase activity
    term:
      id: GO:0004693
      label: cyclin-dependent protein serine/threonine kinase activity
    modifier: DECREASED
  downstream:
  - target: Reduced STAT1 Ser727 Phosphorylation
    description: Reduced phosphorylation of this experimentally tested substrate is a direct kinase readout.
    causal_link_type: DIRECT
  - target: Nonproductive Mediator Kinase Module Occupancy
    description: Catalytically impaired proteins that retain module association might compete with active modules; dominance is not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Altered Developmental Transcription
    description: Altered phosphorylation of transcription-associated substrates may change developmental expression programs.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced STAT1 Ser727 Phosphorylation
  description: Variant CDK8 produces less STAT1 Ser727 phosphorylation in SW620 cells lacking both endogenous CDK8 and CDK19. This is a measured biochemical readout, not evidence that STAT1 deficiency or immune dysfunction is the clinical disease mechanism.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We observed that the cellular levels of pSTAT1 were reduced to a statistically significant extent, compared to WT, in all mutant-transfected cells
    explanation: Direct substrate readout.
- name: Nonproductive Mediator Kinase Module Occupancy
  description: 'Retained cyclin-C/module association despite impaired catalysis could reduce availability of productive kinase modules. This proposed dominant-negative route remains unconfirmed: mixing reference and Ser62Leu constructs did not show a clearly nonlinear reduction in STAT1 phosphorylation.'
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: we predict that up to 50% of CDK8 modules could be present in a kinase-inactive, non-productive state
    explanation: Authors explicitly frame this as a prediction.
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: NO_EVIDENCE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the observed reduction in phosphorylation in mixed samples did not obviously deviate from a linear response
    explanation: The mixing assay did not establish a dominant-negative interaction.
  downstream:
  - target: Altered Developmental Transcription
    description: Competition between productive and nonproductive modules could impair transcriptional regulation if the active module is limiting.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Altered Developmental Transcription
  description: CDK8 regulates transcription through Mediator and phosphorylation of multiple regulators. The relevant altered expression programs in patient neural and cardiac cells have not been identified. Candidate developmental pathways should not be treated as measured patient defects.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Thus, a disruption of the proper activity of CDK8 could modify any of these developmental signaling networks.
    explanation: Proposed developmental-signaling interpretation.
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DYSREGULATED
  downstream:
  - target: Impaired Neural Development
    description: Abnormal developmental gene regulation is a candidate link to the neurodevelopmental syndrome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired Cardiac Morphogenesis
    description: Developmental gene regulation may contribute to congenital cardiac anomalies.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired Craniofacial Patterning
    description: Altered developmental regulation may affect craniofacial formation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Neural Development
  description: Developmental delay, intellectual disability and callosal abnormalities indicate altered neural development. The specific transcriptional, cell-type and circuit intermediates downstream of CDK8 variants remain unresolved.
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Mild to moderate developmental delay was universal, and older children had ID
    explanation: Clinical evidence for developmental impairment, not a direct neuronal transcription assay.
  downstream:
  - target: Global Developmental Delay
    description: Altered brain development can impair acquisition of developmental skills.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intellectual disability
    description: Disturbed neural development is a candidate substrate of cognitive impairment.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Delayed Speech and Language Development
    description: Abnormal circuit development may affect language acquisition.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypotonia
    description: Central developmental dysfunction may contribute to reduced muscle tone.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Autism
    description: Altered neural development may contribute to autistic features.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Attention Deficit Hyperactivity Disorder
    description: Developmental circuit dysfunction may contribute to attention and activity regulation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Corpus callosum agenesis
    description: Disrupted commissural development provides a candidate route to callosal agenesis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Thin Corpus Callosum
    description: Altered commissural development may contribute to callosal thinning.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Seizures
    description: Altered circuit development may contribute to seizure susceptibility; the precise epileptogenic pathway is unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Cardiac Morphogenesis
  description: 'Developmental kinase perturbation can disrupt heart formation: dual CDK8/19 inhibition produces cardiac anomalies in zebrafish, while affected humans have variable congenital lesions. The pharmacological model does not isolate CDK8 from CDK19 or reproduce each human defect.'
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the inhibition of Cdk8 kinase activity by Senexin A induced structural anomalies in the heart and craniofacial cartilage of the zebrafish
    explanation: Experimental developmental perturbation by a dual-kinase inhibitor.
  downstream:
  - target: Congenital heart disease
    description: Abnormal cardiac development can produce the varied structural lesions observed clinically.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ventricular Septal Defect
    description: Altered cardiac morphogenesis can produce this specific structural lesion; its variant-specific developmental pathway remains unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Atrial Septal Defect
    description: Altered cardiac morphogenesis can produce this specific structural lesion; its variant-specific developmental pathway remains unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Bicuspid Aortic Valve
    description: Altered cardiac morphogenesis can produce this specific structural lesion; its variant-specific developmental pathway remains unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Tetralogy of Fallot
    description: Altered cardiac morphogenesis can produce this specific structural lesion; its variant-specific developmental pathway remains unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Coarctation of Aorta
    description: Altered cardiac morphogenesis can produce this specific structural lesion; its variant-specific developmental pathway remains unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Double Orifice Mitral Valve
    description: Altered cardiac morphogenesis can produce this specific structural lesion; its variant-specific developmental pathway remains unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Double Outlet Right Ventricle
    description: Altered cardiac morphogenesis can produce this specific structural lesion; its variant-specific developmental pathway remains unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Congenital Mitral Stenosis
    description: Altered cardiac morphogenesis can produce this specific structural lesion; its variant-specific developmental pathway remains unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypoplastic Left Heart Syndrome
    description: Altered cardiac morphogenesis can produce this structural lesion; the exact variant-specific pathway is unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypoplastic Aortic Arch
    description: Altered cardiac morphogenesis can produce this structural lesion; the exact variant-specific pathway is unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Subvalvular Aortic Stenosis
    description: A specific congenital outflow lesion within the variable cardiac phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Craniofacial Patterning
  description: CDK8/19 inhibition perturbs zebrafish cranial cartilage formation, providing experimental support for a developmental craniofacial role. Variant-specific human craniofacial intermediates are not established.
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the inhibition of Cdk8 kinase activity by Senexin A induced structural anomalies in the heart and craniofacial cartilage of the zebrafish
    explanation: Craniofacial development in the inhibitor model.
  downstream:
  - target: Facial dysmorphism
    description: Altered craniofacial development may account for variable facial differences.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
# frequency: bands omitted where the source gives only undifferentiated
# narrative support (per docs/frequency-evidence-guidelines.md); retained only
# where a count or all-patients statement in the cited snippet backs a band.
- name: Global Developmental Delay
  category: Neurologic
  description: Developmental delay is the central presenting feature, with broad variation in severity and age of assessment.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Mild to moderate developmental delay was universal, and older children had ID
    explanation: The cohort narrative identifies developmental delay in every founding subject; cognitive assessment was age-dependent.
  phenotype_contexts:
  - population: Founding 12-person 2019 cohort; assessed denominator is specified for each finding
    frequency: OBLIGATE
    notes: 12/12 in this selected clinical series, not population prevalence or penetrance.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Mild to moderate developmental delay was universal, and older children had ID
      explanation: Original cohort evidence; counts derive from its clinical narrative or Table 1.
- name: Intellectual disability
  category: Neurologic
  description: Intellectual disability ranges from mild to moderate-severe in the founding series; severe disability was described in the later Gly28Ala child. Children too young for cognitive assessment should not be counted as unaffected.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: older children had ID which ranged from mild (two cases) to moderate–severe (two cases); most were in the moderate range (five cases)
    explanation: 'The narrative gives nine assessable older subjects: two mild, five moderate and two moderate-severe cases.'
  phenotype_contexts:
  - population: Founding 12-person 2019 cohort; assessed denominator is specified for each finding
    frequency: OBLIGATE
    notes: 9/9 in this selected clinical series, not population prevalence or penetrance.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: older children had ID which ranged from mild (two cases) to moderate–severe (two cases); most were in the moderate range (five cases)
      explanation: Original cohort evidence; counts derive from its clinical narrative or Table 1.
- name: Hypotonia
  category: Neurologic
  description: The original narrative reports hypotonia in 11/12 individuals, often evident in infancy. Its table combines hypotonia, motor delay and walking difficulty and marks one individual unavailable; the narrative denominator is retained explicitly.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: hypotonia (noted in 11/12 subjects) was frequently evident
    explanation: The explicit narrative count is 11/12; the combined motor/hypotonia table row is less specific.
  phenotype_contexts:
  - population: Founding 12-person 2019 cohort; assessed denominator is specified for each finding
    frequency: VERY_FREQUENT
    notes: 11/12 in this selected clinical series, not population prevalence or penetrance.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: hypotonia (noted in 11/12 subjects) was frequently evident
      explanation: Original cohort evidence; counts derive from its clinical narrative or Table 1.
- name: Delayed Speech and Language Development
  category: Neurologic
  description: Speech and language milestones can be substantially delayed. The founding Ser62Leu girl spoke her first word at four years and sentences at six.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: said her first word at 4 yr, and spoke in sentences at 6 yr
    explanation: Reported milestone ages directly document delayed first words and sentence formation in one child.
- name: Gait Disturbance
  category: Neurologic
  description: Walking may be delayed or unsteady. Orthoses and other mobility support are used in some cases.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: On examination he was well-proportioned with an unsteady broad-based gait.
    explanation: The examination describes an abnormal broad-based gait rather than inferring gait impairment from hypotonia.
- name: Autism
  category: Behavioral
  description: Five of ten older individuals in the founding cohort had a formal autism diagnosis. Other behavioral observations without a formal diagnosis are not added to this numerator.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: seven of ten of the older individuals had formal diagnoses of autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD)
    explanation: Table 1 separates five formal autism diagnoses among ten older subjects; the quoted combined count also includes ADHD.
  phenotype_contexts:
  - population: Founding 12-person 2019 cohort; assessed denominator is specified for each finding
    frequency: FREQUENT
    notes: 5/10 in this selected clinical series, not population prevalence or penetrance.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: seven of ten of the older individuals had formal diagnoses of autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD)
      explanation: Original cohort evidence; counts derive from its clinical narrative or Table 1.
    - reference: PMID:33067521
      reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: DIRECT
      snippet: 'ADHD: 4/10, autism spectrum disorder: 5/10'
      explanation: Secondary tabulation of the founding cohort, checked against the original case-level Table 1; the two diagnoses overlap.
- name: Attention Deficit Hyperactivity Disorder
  category: Behavioral
  description: Four of ten older individuals had formal ADHD in the founding series; diagnoses overlap with autism. Attention-related traits in other cases do not imply formal ADHD.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: seven of ten of the older individuals had formal diagnoses of autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD)
    explanation: Table 1 separates four formal ADHD diagnoses among ten older subjects; the quoted combined count also includes autism.
  phenotype_contexts:
  - population: Founding 12-person 2019 cohort; assessed denominator is specified for each finding
    frequency: FREQUENT
    notes: 4/10 in this selected clinical series, not population prevalence or penetrance.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: seven of ten of the older individuals had formal diagnoses of autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD)
      explanation: Original cohort evidence; counts derive from its clinical narrative or Table 1.
    - reference: PMID:33067521
      reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: DIRECT
      snippet: 'ADHD: 4/10, autism spectrum disorder: 5/10'
      explanation: Secondary tabulation of the founding cohort, checked against the original case-level Table 1; the two diagnoses overlap.
- name: Sleep Disturbance
  category: Behavioral
  description: Sleep-onset or severe sleep disturbance was reported in individual cases and contributed to management needs.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She has ADHD, with a sweet personality, but is sometimes aggressive, and has a severe sleep disorder.
    explanation: Sleep-onset or severe sleep disturbance was reported in individual cases and contributed to management needs.
- name: Anxiety
  category: Behavioral
  description: Anxiety and tantrums were described in some supplementary case reports; no population frequency is established.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Behavioral problems include ADHD, tantrums and anxiety.
    explanation: Anxiety and tantrums were described in some supplementary case reports; no population frequency is established.
- name: Seizures
  category: Neurologic
  description: Two individuals had epilepsy in the founding series. Some paroxysmal events in one patient were nonepileptic on EEG; all spells should not be counted as seizures.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Two individuals had seizures, but brain imaging was either normal or was not available.
    explanation: The narrative gives two affected individuals; the supplementary case history distinguishes epileptic from nonepileptic events.
  phenotype_contexts:
  - population: Founding 12-person 2019 cohort; assessed denominator is specified for each finding
    frequency: OCCASIONAL
    notes: 2/12 in this selected clinical series, not population prevalence or penetrance.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Two individuals had seizures, but brain imaging was either normal or was not available.
      explanation: Original cohort evidence; counts derive from its clinical narrative or Table 1.
- name: Corpus callosum agenesis
  category: Neurologic
  description: Agenesis was recorded in three founding subjects; the fourth callosal abnormality was thinning rather than agenesis. A later Gly28Ala child also had agenesis.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: magnetic resonance imaging (MRI) of the brain showed agenesis or thinning of the corpus callosum in four subjects
    explanation: Table 1 separates three agenesis cases from one thinning case in the combined four-person callosal-abnormality count.
- name: Thin Corpus Callosum
  category: Neurologic
  description: The Arg29Gly founding case had a thin corpus callosum with regional white-matter volume loss; this differs from complete agenesis.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a thin corpus callosum with bilateral posterior supratentorial and perihippocampal white matte r volume loss
    explanation: The supplementary MRI report explicitly describes thinning, supporting a separate phenotype from agenesis.
- name: Ventriculomegaly
  category: Neurologic
  description: Mild ventriculomegaly accompanied callosal agenesis in the Ser62Leu girl with hypoplastic left heart.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: confirmed agenesis of the corpus callosum and mild ventriculomegaly.
    explanation: Mild ventriculomegaly accompanied callosal agenesis in the Ser62Leu girl with hypoplastic left heart.
- name: Delayed CNS Myelination
  category: Neurologic
  description: Incomplete myelination was noted in the Phe97Leu case without progression of earlier MRI changes; it is not proof of a progressive degenerative process.
  phenotype_term:
    preferred_term: Delayed CNS myelination
    term:
      id: HP:0002188
      label: Delayed CNS myelination
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: A repeat MRI scan showed no progression of the previously observed changes but no ted incomplete myelination.
    explanation: The follow-up MRI describes incomplete myelination without progression of the previously observed abnormalities.
- name: Dystonia
  category: Neurologic
  description: Dystonia accompanied tremor in the Phe97Leu case. The contribution of low CSF homovanillic acid remains unresolved.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: An additional diagnosis of a movement disorder consisting of tremor and dystonia was made by 4 yr.
    explanation: Dystonia accompanied tremor in the Phe97Leu case. The contribution of low CSF homovanillic acid remains unresolved.
- name: Tremor
  category: Neurologic
  description: Tremor was documented with dystonia in the Phe97Leu case.
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: An additional diagnosis of a movement disorder consisting of tremor and dystonia was made by 4 yr.
    explanation: Tremor was documented with dystonia in the Phe97Leu case.
- name: Decreased CSF Homovanillic Acid
  category: Laboratory
  description: A low CSF homovanillic acid level was reported in one child with movement abnormalities. Its significance was explicitly uncertain; it is not a validated CDK8 biomarker or a confirmed dopamine-synthesis disorder.
  phenotype_term:
    preferred_term: Decreased CSF homovanillic acid concentration
    term:
      id: HP:0003785
      label: Decreased CSF homovanillic acid concentration
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a low cerebrospinal fluid (CSF) homovanillic acid level, the significance of which is unclear
    explanation: The report explicitly qualifies this isolated CSF measurement as of uncertain significance.
- name: Sensorineural Hearing Impairment
  category: Auditory
  description: Moderate to severe sensorineural hearing loss occurred in three founding individuals. Laterality and severity varied; the supplementary Phe97Leu report describes bilateral loss despite a less detailed table entry.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Three individuals had moderate-severe sensorineural hearing loss
    explanation: The cohort narrative gives three moderate-severe sensorineural cases; supplemental details refine laterality.
  phenotype_contexts:
  - population: Founding 12-person 2019 cohort; assessed denominator is specified for each finding
    frequency: OCCASIONAL
    notes: 3/12 in this selected clinical series, not population prevalence or penetrance.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Three individuals had moderate-severe sensorineural hearing loss
      explanation: Original cohort evidence; counts derive from its clinical narrative or Table 1.
- name: Myopia
  category: Ophthalmologic
  description: Reported in the original clinical cohort; eye findings can overlap in the same individual.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: including myopia (n = 6), eyelid ptosis (n = 2), and/or strabismus (n = 4)
    explanation: The cohort narrative explicitly counts six cases; overlapping ocular findings are not independent individuals.
  phenotype_contexts:
  - population: Founding 12-person 2019 cohort; assessed denominator is specified for each finding
    frequency: FREQUENT
    notes: 6/12 in this selected clinical series, not population prevalence or penetrance.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: including myopia (n = 6), eyelid ptosis (n = 2), and/or strabismus (n = 4)
      explanation: Original cohort evidence; counts derive from its clinical narrative or Table 1.
- name: Ptosis
  category: Ophthalmologic
  description: Reported in the original clinical cohort; eye findings can overlap in the same individual.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: including myopia (n = 6), eyelid ptosis (n = 2), and/or strabismus (n = 4)
    explanation: The cohort narrative explicitly counts two cases, avoiding the inconsistent later secondary tabulation.
  phenotype_contexts:
  - population: Founding 12-person 2019 cohort; assessed denominator is specified for each finding
    frequency: OCCASIONAL
    notes: 2/12 in this selected clinical series, not population prevalence or penetrance.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: including myopia (n = 6), eyelid ptosis (n = 2), and/or strabismus (n = 4)
      explanation: Original cohort evidence; counts derive from its clinical narrative or Table 1.
- name: Strabismus
  category: Ophthalmologic
  description: Reported in the original clinical cohort; eye findings can overlap in the same individual.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: including myopia (n = 6), eyelid ptosis (n = 2), and/or strabismus (n = 4)
    explanation: The cohort narrative explicitly counts four cases; this does not establish a population frequency.
  phenotype_contexts:
  - population: Founding 12-person 2019 cohort; assessed denominator is specified for each finding
    frequency: FREQUENT
    notes: 4/12 in this selected clinical series, not population prevalence or penetrance.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: including myopia (n = 6), eyelid ptosis (n = 2), and/or strabismus (n = 4)
      explanation: Original cohort evidence; counts derive from its clinical narrative or Table 1.
- name: Visual Impairment
  category: Ophthalmologic
  description: Reported in the original clinical cohort; eye findings can overlap in the same individual.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: these were associated with marked visual impairment in two children
    explanation: The narrative identifies marked visual impairment in two children without specifying a cerebral cause.
  phenotype_contexts:
  - population: Founding 12-person 2019 cohort; assessed denominator is specified for each finding
    frequency: OCCASIONAL
    notes: 2/12 in this selected clinical series, not population prevalence or penetrance.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: these were associated with marked visual impairment in two children
      explanation: Original cohort evidence; counts derive from its clinical narrative or Table 1.
- name: Nystagmus
  category: Ophthalmologic
  description: Nystagmus was reported in the Arg29Gly case alongside high myopia and optic-disc cupping.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: ophthalmology for nystagmus, high myopia, and optic nerve cupping of both eyes
    explanation: Nystagmus was reported in the Arg29Gly case alongside high myopia and optic-disc cupping.
- name: Congenital heart disease
  category: Cardiovascular
  description: Six of twelve founding individuals had heterogeneous structural cardiac defects. Specific lesions are represented separately; this percentage is not a population risk estimate.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Congenital heart defects (CHDs) were present in six of the twelve subjects
    explanation: Six of twelve individuals had a cardiac defect; heterogeneous lesions justify the organ-level summary alongside specific phenotypes.
  phenotype_contexts:
  - population: Founding 12-person 2019 cohort; assessed denominator is specified for each finding
    frequency: FREQUENT
    notes: 6/12 in this selected clinical series, not population prevalence or penetrance.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Congenital heart defects (CHDs) were present in six of the twelve subjects
      explanation: Original cohort evidence; counts derive from its clinical narrative or Table 1.
- name: Ventricular Septal Defect
  category: Cardiovascular
  description: A specific congenital lesion reported in the founding cohort; cardiac anatomy differs between individuals.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: He had been f ollowed by the cardiology team secondary to a VSD, which has not required any surgical repair.
    explanation: The case history names a VSD and records surveillance without surgical repair.
- name: Atrial Septal Defect
  category: Cardiovascular
  description: A specific congenital lesion reported in the founding cohort; cardiac anatomy differs between individuals.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: an atrial sep tal defect, ventricular septal defect (VSD), bicuspid aortic valve, and a hypoplastic aortic arch
    explanation: The supplementary cardiac-anatomy description explicitly names an atrial septal defect.
- name: Bicuspid Aortic Valve
  category: Cardiovascular
  description: A specific congenital lesion reported in the founding cohort; cardiac anatomy differs between individuals.
  phenotype_term:
    preferred_term: Bicuspid aortic valve
    term:
      id: HP:0001647
      label: Bicuspid aortic valve
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: an atrial sep tal defect, ventricular septal defect (VSD), bicuspid aortic valve, and a hypoplastic aortic arch
    explanation: The supplementary cardiac-anatomy description explicitly names a bicuspid valve.
- name: Tetralogy of Fallot
  category: Cardiovascular
  description: A specific congenital lesion reported in the founding cohort; cardiac anatomy differs between individuals.
  phenotype_term:
    preferred_term: Tetralogy of Fallot
    term:
      id: HP:0001636
      label: Tetralogy of Fallot
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: echocardiography showed tetralogy of Fallot
    explanation: Echocardiography directly established the cardiac diagnosis in the supplementary case.
- name: Coarctation of Aorta
  category: Cardiovascular
  description: A specific congenital lesion reported in the founding cohort; cardiac anatomy differs between individuals.
  phenotype_term:
    preferred_term: Coarctation of aorta
    term:
      id: HP:0001680
      label: Coarctation of aorta
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She underwent aortic coarctation repair aged 5 mo with a good result.
    explanation: The documented repair establishes the presence of coarctation in this individual.
- name: Double Orifice Mitral Valve
  category: Cardiovascular
  description: A specific congenital lesion reported in the founding cohort; cardiac anatomy differs between individuals.
  phenotype_term:
    preferred_term: Double orifice mitral valve
    term:
      id: HP:0011568
      label: Double orifice mitral valve
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a perimembranous ventricular septal defect with a double orifice mitral valve
    explanation: The supplementary anatomy description specifies a double-orifice mitral valve.
- name: Double Outlet Right Ventricle
  category: Cardiovascular
  description: Diagnosed at birth in the later Gly28Ala child, who underwent a Glenn procedure.
  phenotype_term:
    preferred_term: Double outlet right ventricle
    term:
      id: HP:0001719
      label: Double outlet right ventricle
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: diagnosed at birth with a double outlet right ventricle, mitral valve stenosis, and dysmorphic craniofacial features
    explanation: The birth diagnosis directly specifies double-outlet right ventricle in the Gly28Ala case.
- name: Congenital Mitral Stenosis
  category: Cardiovascular
  description: Diagnosed at birth in the later Gly28Ala child, who underwent a Glenn procedure.
  phenotype_term:
    preferred_term: Congenital mitral stenosis
    term:
      id: HP:0011570
      label: Congenital mitral stenosis
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: diagnosed at birth with a double outlet right ventricle, mitral valve stenosis, and dysmorphic craniofacial features
    explanation: The same birth diagnosis separately specifies mitral valve stenosis.
- name: Feeding Difficulties in Infancy
  category: Gastrointestinal
  description: Early feeding difficulties can require tube feeding. Severity varies, and some children later achieve complete oral feeding.
  phenotype_term:
    preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: two additional infants required feeding via gastrostomy tube
    explanation: Gastrostomy dependence documents clinically significant feeding difficulty in the reported infants.
- name: Dysphagia
  category: Gastrointestinal
  description: Swallowing impairment prompted gastrostomy in a Ser62Leu child, who later ate fully by mouth.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She had dysphagia requiring a gastrostomy tube aged 7 mo, but now eats completely by mouth.
    explanation: The narrative explicitly names dysphagia and distinguishes early tube dependence from later oral feeding.
- name: Failure to Thrive
  category: Growth
  description: Poor weight gain occurred in some children with feeding problems or congenital anomalies.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The patient had difficulty feeding and failed to thrive.
    explanation: Poor weight gain occurred in some children with feeding problems or congenital anomalies.
- name: Gastroesophageal Reflux
  category: Gastrointestinal
  description: Reflux can be severe and clinically consequential. Fundoplication and gastrostomy were required in the Gly28Ala child. The Asn156Ser narrative also reports reflux, despite its absence in that paper's summary table.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Severe gastroesophageal reflux disease was treated by fundoplication and a gastrostomy.
    explanation: Reflux can be severe and clinically consequential. Fundoplication and gastrostomy were required in the Gly28Ala child. The Asn156Ser narrative also reports reflux, despite its absence in that paper's summary table.
- name: Vomiting
  category: Gastrointestinal
  description: Episodic or cyclic vomiting contributes to management in some individuals; it may overlap with reflux but is not synonymous with it.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: gastro-esophageal reflux or episodic vomiting were significant management issues in four individuals
    explanation: Episodic or cyclic vomiting contributes to management in some individuals; it may overlap with reflux but is not synonymous with it.
- name: Anteriorly Placed Anus
  category: Gastrointestinal
  description: An individual gastrointestinal finding; rectal mucosal prolapse is distinguished from a congenital anorectal malformation.
  phenotype_term:
    preferred_term: Anteriorly placed anus
    term:
      id: HP:0001545
      label: Anteriorly placed anus
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: anterior anus, recto-perianal fistula ... undescended testes ... rectal mucosal prolapse
    explanation: The case-level anatomical description explicitly identifies anterior placement of the anus.
- name: Rectoperineal Fistula
  category: Gastrointestinal
  description: An individual gastrointestinal finding; rectal mucosal prolapse is distinguished from a congenital anorectal malformation.
  phenotype_term:
    preferred_term: Rectoperineal fistula
    term:
      id: HP:0004792
      label: Rectoperineal fistula
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: anterior anus, recto-perianal fistula ... undescended testes ... rectal mucosal prolapse
    explanation: The supplementary case description names a recto-perianal fistula, supporting the specific perineal fistula binding.
- name: Rectal Prolapse
  category: Gastrointestinal
  description: An individual gastrointestinal finding; rectal mucosal prolapse is distinguished from a congenital anorectal malformation.
  phenotype_term:
    preferred_term: Rectal prolapse
    term:
      id: HP:0002035
      label: Rectal prolapse
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: recurrent loose stool and intermittent rectal mucosal prolapse
    explanation: The case narrative describes intermittent rectal mucosal prolapse rather than a congenital anorectal malformation.
- name: Pyloric Stenosis
  category: Gastrointestinal
  description: An individual gastrointestinal finding; rectal mucosal prolapse is distinguished from a congenital anorectal malformation.
  phenotype_term:
    preferred_term: Pyloric stenosis
    term:
      id: HP:0002021
      label: Pyloric stenosis
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Present congenital gastrointestinal problems were ano-rectal abnormalities (n = 2) and pyloric stenosis (n = 1)
    explanation: The founding cohort narrative counts one case of pyloric stenosis.
- name: Cryptorchidism
  category: Genitourinary
  description: An undescended testis was described in the Gly28Ala child and the Ser62Leu boy with tetralogy of Fallot.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: He also had an undescended left testis and left multicystic dysplastic kidney.
    explanation: An undescended testis was described in the Gly28Ala child and the Ser62Leu boy with tetralogy of Fallot.
- name: Multicystic Kidney Dysplasia
  category: Renal
  description: Left multicystic dysplastic kidney was reported in the Gly28Ala child; this is a case observation, not an obligatory renal phenotype.
  phenotype_term:
    preferred_term: Multicystic kidney dysplasia
    term:
      id: HP:0000003
      label: Multicystic kidney dysplasia
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: He also had an undescended left testis and left multicystic dysplastic kidney.
    explanation: Left multicystic dysplastic kidney was reported in the Gly28Ala child; this is a case observation, not an obligatory renal phenotype.
- name: Short Stature
  category: Growth
  description: Short stature was present in one founding individual and both later Japanese cases; available measurements vary with age.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: one individual, who had mild short stature (−2.53 SD)
    explanation: Short stature was present in one founding individual and both later Japanese cases; available measurements vary with age.
- name: Macrocephaly
  category: Growth
  description: Mild macrocephaly was reported in a Ser62Leu infant with callosal agenesis.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: one subject, who had mild macrocephaly (+2.21 standard deviations [SD])
    explanation: Mild macrocephaly was reported in a Ser62Leu infant with callosal agenesis.
- name: Acquired Microcephaly
  category: Growth
  description: The Arg178Gln supplementary case describes declining head-circumference percentiles to the second percentile at five years. This individual finding is more detailed than the cohort narrative's generally normal head-size statement.
  phenotype_term:
    preferred_term: Secondary microcephaly
    term:
      id: HP:0005484
      label: Secondary microcephaly
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: he had global developmental delay and acquired microcephaly
    explanation: The supplementary case explicitly reports acquired microcephaly; serial head measurements support the secondary-microcephaly binding.
- name: Metopic Synostosis
  category: Craniofacial
  description: Metopic synostosis occurred in the index Gly30Ser case. The authors explicitly considered whether its association with CDK8 was causal or coincidental.
  phenotype_term:
    preferred_term: Metopic synostosis
    term:
      id: HP:0011330
      label: Metopic synostosis
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Apart from the metopic synostosis present in the index individual, no other individuals had craniosynostosis.
    explanation: The source confines metopic synostosis to the index subject; it does not establish a recurrent syndrome feature.
- name: Hip Contracture
  category: Musculoskeletal
  description: Progressive contractures and scoliosis were reported in the child with maternally inherited Arg200Gln but not the affected mother, demonstrating variable expression.
  phenotype_term:
    preferred_term: Hip contracture
    term:
      id: HP:0003273
      label: Hip contracture
  evidence:
  - reference: PMID:38193604
    reference_title: 'Expanding the phenotypic spectrum for CDK8-related disease: A case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: undocumented progressive contractures of the hips and knees as well as scoliosis were also observed in the child
    explanation: The inherited-variant report explicitly identifies progressive hip contractures in the child, without this finding in the mother.
- name: Knee Contracture
  category: Musculoskeletal
  description: Progressive contractures and scoliosis were reported in the child with maternally inherited Arg200Gln but not the affected mother, demonstrating variable expression.
  phenotype_term:
    preferred_term: Knee contracture
    term:
      id: HP:0034671
      label: Knee contracture
  evidence:
  - reference: PMID:38193604
    reference_title: 'Expanding the phenotypic spectrum for CDK8-related disease: A case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: undocumented progressive contractures of the hips and knees as well as scoliosis were also observed in the child
    explanation: The inherited-variant report explicitly identifies progressive knee contractures in the child, without this finding in the mother.
- name: Scoliosis
  category: Musculoskeletal
  description: Progressive contractures and scoliosis were reported in the child with maternally inherited Arg200Gln but not the affected mother, demonstrating variable expression.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:38193604
    reference_title: 'Expanding the phenotypic spectrum for CDK8-related disease: A case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: undocumented progressive contractures of the hips and knees as well as scoliosis were also observed in the child
    explanation: The inherited-variant report names scoliosis in the child and notes that this presentation was absent in the mother.
- name: Pes Planus
  category: Musculoskeletal
  description: Flat or planovalgus feet occur in several individuals, with orthopedic procedures or orthoses used in some.
  phenotype_term:
    preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: as well as intermittent esotropia and pes planovalgus
    explanation: Flat or planovalgus feet occur in several individuals, with orthopedic procedures or orthoses used in some.
- name: Joint Hypermobility
  category: Musculoskeletal
  description: Joint laxity was documented in some supplementary cases.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hypotonia was improving; he had significant generalized joint laxity.
    explanation: Joint laxity was documented in some supplementary cases.
- name: Laryngomalacia
  category: Respiratory
  description: Laryngomalacia was diagnosed in the Arg29Gly case with feeding and respiratory difficulties.
  phenotype_term:
    preferred_term: Laryngomalacia
    term:
      id: HP:0001601
      label: Laryngomalacia
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: He was found to have laryngomalacia and a sleep stud y demonstrated severe obstructive sleep apnea
    explanation: Laryngomalacia was diagnosed in the Arg29Gly case with feeding and respiratory difficulties.
- name: Obstructive Sleep Apnea
  category: Respiratory
  description: Severe obstructive sleep apnea in the Arg29Gly case required supplemental oxygen temporarily; oxygen was no longer needed at later follow-up.
  phenotype_term:
    preferred_term: Obstructive sleep apnea
    term:
      id: HP:0002870
      label: Obstructive sleep apnea
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: severe obstructive sleep apnea requiring supplemental oxygen
    explanation: Severe obstructive sleep apnea in the Arg29Gly case required supplemental oxygen temporarily; oxygen was no longer needed at later follow-up.
- name: Anemia
  category: Hematologic
  description: Anemia of uncertain cause improved with iron supplementation in one Ser62Leu child. Iron deficiency itself was not established by the report.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: he had an anemia of unknown origin, which improved with iron supplements
    explanation: The report establishes anemia and an observed iron response while leaving the underlying cause uncertain.
- name: Facial dysmorphism
  category: Craniofacial
  description: Facial differences were reported in 11 of 12 cohort subjects but were not a consistent diagnostic gestalt. Components vary and occasional supplementary descriptions differ from the table.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Facial dysmorphism was identified in 11 subjects; this was not characteristic
    explanation: The narrative gives 11/12 affected subjects and explicitly rejects a characteristic facial gestalt.
  phenotype_contexts:
  - population: Founding 12-person 2019 cohort; assessed denominator is specified for each finding
    frequency: VERY_FREQUENT
    notes: 11/12 in this selected clinical series, not population prevalence or penetrance.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Facial dysmorphism was identified in 11 subjects; this was not characteristic
      explanation: Original cohort evidence; counts derive from its clinical narrative or Table 1.
- name: Epicanthus
  category: Craniofacial
  description: One of the variable facial findings highlighted in at least two founding subjects; no precise component-specific frequency is assigned.
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: arched eyebrows, epicanthic folds, prominent eyes, a prominent nasal tip or long columella, a long philtrum, wide or open-mouth posture, prognathism, and low set and prominent ears
    explanation: One of the variable facial findings highlighted in at least two founding subjects; no precise component-specific frequency is assigned.
- name: Long Philtrum
  category: Craniofacial
  description: One of the variable facial findings highlighted in at least two founding subjects; no precise component-specific frequency is assigned.
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: arched eyebrows, epicanthic folds, prominent eyes, a prominent nasal tip or long columella, a long philtrum, wide or open-mouth posture, prognathism, and low set and prominent ears
    explanation: One of the variable facial findings highlighted in at least two founding subjects; no precise component-specific frequency is assigned.
- name: Wide Mouth
  category: Craniofacial
  description: One of the variable facial findings highlighted in at least two founding subjects; no precise component-specific frequency is assigned.
  phenotype_term:
    preferred_term: Wide mouth
    term:
      id: HP:0000154
      label: Wide mouth
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: arched eyebrows, epicanthic folds, prominent eyes, a prominent nasal tip or long columella, a long philtrum, wide or open-mouth posture, prognathism, and low set and prominent ears
    explanation: One of the variable facial findings highlighted in at least two founding subjects; no precise component-specific frequency is assigned.
- name: Mandibular Prognathia
  category: Craniofacial
  description: One of the variable facial findings highlighted in at least two founding subjects; no precise component-specific frequency is assigned.
  phenotype_term:
    preferred_term: Mandibular prognathia
    term:
      id: HP:0000303
      label: Mandibular prognathia
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: arched eyebrows, epicanthic folds, prominent eyes, a prominent nasal tip or long columella, a long philtrum, wide or open-mouth posture, prognathism, and low set and prominent ears
    explanation: One of the variable facial findings highlighted in at least two founding subjects; no precise component-specific frequency is assigned.
- name: Low-Set Ears
  category: Craniofacial
  description: One of the variable facial findings highlighted in at least two founding subjects; no precise component-specific frequency is assigned.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: arched eyebrows, epicanthic folds, prominent eyes, a prominent nasal tip or long columella, a long philtrum, wide or open-mouth posture, prognathism, and low set and prominent ears
    explanation: One of the variable facial findings highlighted in at least two founding subjects; no precise component-specific frequency is assigned.
- name: Hypertelorism
  category: Craniofacial
  description: Reported among the facial findings in the later Gly28Ala/Asn156Ser cases.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: hypertelorism, epicanthal folds, low-set ears, prominent antihelix, short philtrum, flat nasal bridge, high arched palate, down-turned corners of the mouth, micrognathia
    explanation: Reported among the facial findings in the later Gly28Ala/Asn156Ser cases.
- name: High Palate
  category: Craniofacial
  description: Reported among the facial findings in the later Gly28Ala/Asn156Ser cases.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: hypertelorism, epicanthal folds, low-set ears, prominent antihelix, short philtrum, flat nasal bridge, high arched palate, down-turned corners of the mouth, micrognathia
    explanation: Reported among the facial findings in the later Gly28Ala/Asn156Ser cases.
- name: Micrognathia
  category: Craniofacial
  description: Reported among the facial findings in the later Gly28Ala/Asn156Ser cases.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: hypertelorism, epicanthal folds, low-set ears, prominent antihelix, short philtrum, flat nasal bridge, high arched palate, down-turned corners of the mouth, micrognathia
    explanation: Reported among the facial findings in the later Gly28Ala/Asn156Ser cases.
- name: Bifid Uvula
  category: Craniofacial
  description: A bifid uvula was documented in the Asn156Ser girl.
  phenotype_term:
    preferred_term: Bifid uvula
    term:
      id: HP:0000193
      label: Bifid uvula
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: protruding ears, bifid uvula, and micrognathia
    explanation: A bifid uvula was documented in the Asn156Ser girl.
- name: Hypoplastic Left Heart Syndrome
  category: Cardiovascular
  description: Specific congenital cardiac anatomy documented in the founding supplementary cases.
  phenotype_term:
    preferred_term: Hypoplastic left ventricle
    term:
      id: HP:0004383
      label: Hypoplastic left ventricle
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The prenatal ultrasound revealed a hypoplastic left heart and agenesis of the corpus callosum.
    explanation: Specific congenital cardiac anatomy documented in the founding supplementary cases.
- name: Hypoplastic Aortic Arch
  category: Cardiovascular
  description: Specific congenital cardiac anatomy documented in the founding supplementary cases.
  phenotype_term:
    preferred_term: Hypoplastic aortic arch
    term:
      id: HP:0012304
      label: Hypoplastic aortic arch
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: bicuspid aortic valve, and a hypoplastic aortic arch
    explanation: Specific congenital cardiac anatomy documented in the founding supplementary cases.
- name: Subvalvular Aortic Stenosis
  category: Cardiovascular
  description: Subaortic stenosis accompanied coarctation and mitral stenosis in the Ser62Leu infant.
  phenotype_term:
    preferred_term: Subvalvular aortic stenosis
    term:
      id: HP:0001682
      label: Subvalvular aortic stenosis
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: coarctation of the aorta, subaortic stenosis, mitral stenosis
    explanation: Subaortic stenosis accompanied coarctation and mitral stenosis in the Ser62Leu infant.
- name: Highly Arched Eyebrow
  category: Craniofacial
  description: One of the variable facial components observed in at least two founding individuals.
  phenotype_term:
    preferred_term: Highly arched eyebrow
    term:
      id: HP:0002553
      label: Highly arched eyebrow
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: arched eyebrows, epicanthic folds, prominent eyes, a prominent nasal tip or long columella
    explanation: One of the variable facial components observed in at least two founding individuals.
- name: Overlapping Toe
  category: Musculoskeletal
  description: Overlapping toes on the left foot were described in the Gly28Ala child.
  phenotype_term:
    preferred_term: Overlapping toe
    term:
      id: HP:0001845
      label: Overlapping toe
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: overlapping toes were noted on the left foot
    explanation: Overlapping toes on the left foot were described in the Gly28Ala child.
genetic:
- name: CDK8
  association: Heterozygous kinase-domain missense variants cause a variable developmental disorder. De novo occurrence predominates in the founding series, but maternal transmission of Arg200Gln to an affected child establishes that inheritance is possible.
  gene_term:
    preferred_term: CDK8
    term:
      id: hgnc:1779
      label: CDK8
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects
      explanation: Ten confirmed de novo heterozygous variants support autosomal dominant inheritance; paternal samples were unavailable in the other two cases.
    - reference: PMID:38193604
      reference_title: 'Expanding the phenotypic spectrum for CDK8-related disease: A case report.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: a likely pathogenic heterozygous CDK8 variant c.599G>A, p.(Arg200Gln) inherited from the biological mother
      explanation: Documented maternal transmission.
    description: Autosomal dominant inheritance includes both de novo and inherited variants. In the founding cohort, ten of twelve variants were confirmed de novo; two fathers were unavailable. A later mother-child pair shared a likely pathogenic Arg200Gln variant. Penetrance and recurrence rates have not been quantified.
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects
    explanation: Case-level genetic evidence.
  - reference: PMID:38193604
    reference_title: 'Expanding the phenotypic spectrum for CDK8-related disease: A case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The clinical presentation of the child and mother is within the described clinical spectrum for IDDHBA
    explanation: Both generations were clinically affected.
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: G2P
    external_id: G2P02783
    notes: G2P assertion SGC-124667.1 in GenCC, evaluated September 18, 2019. The attribution is to G2P rather than an independent ClinGen assertion.
    evidence:
    - reference: url:https://thegencc.org/submissions/SGC-124667.1
      reference_title: CDK8 | intellectual developmental disorder with hypotonia and behavioral abnormalities | Autosomal dominant by G2P submission information facts
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: 'Classification: ... Definitive ... Gene: ... CDK8 ... Disease: ... intellectual developmental disorder with hypotonia and behavioral abnormalities'
      explanation: External G2P classification.
  notes: The initial molecularly studied alleles are missense substitutions concentrated around the kinase active site. These data do not establish pathogenicity of all CDK8 truncating alleles or multigene deletions. Some founding subjects had additional uncertain variants; their individual findings should not automatically be attributed exclusively to CDK8.
  variants:
  - name: c.185C>T (p.Ser62Leu)
    description: Recurrent alpha-C-helix allele in five founding subjects; de novo status was confirmed in three, while paternal samples were unavailable in two. STAT1 phosphorylation was markedly reduced.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: a recurrent mutation, c.185C>T (p.Ser62Leu), was present in five individuals
      explanation: Recurrence in the original cohort.
  - name: p.Val27Leu, p.Arg29Gly and p.Gly30Ser
    description: Founding glycine-rich-loop substitutions c.79G>C, c.85C>G and c.88G>A. Kinase output was reduced without evidence of gross misfolding.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: are clustered in the Gly-rich loop (amino acids 27–35), a highly conserved protein-kinase motif
      explanation: Variant positions.
  - name: c.291T>G (p.Phe97Leu) and c.669A>G (p.Ile223Met)
    description: These founding alleles retained approximately 63% and 51% of reference STAT1 phosphorylation in the cell assay, respectively. Relative assay activity does not establish a clinical severity ranking.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: an intermediate level of phosphorylation (∼63% and ∼51% in comparison to the WT, respectively), was observed
      explanation: Residual activity in two alleles.
  - name: c.533G>A (p.Arg178Gln) and c.578T>G (p.Val193Gly)
    description: Activation-segment alleles from the founding series, with reduced kinase output. Arg178Gln was also investigated by molecular-dynamics simulation.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Two substitutions, c.533G>A (p.Arg178Gln) and c.578T>G (p.Val193Gly), affect amino acids located in the activation segment
      explanation: Structural localization.
  - name: c.83G>C (p.Gly28Ala) and c.467A>G (p.Asn156Ser)
    description: De novo alleles in two additional patients with lower autophosphorylation activity. Asn156Ser reduced the assay readout more strongly than Gly28Ala; developmental severity in two differently aged patients cannot validate an activity-severity correlation.
    evidence:
    - reference: PMID:33067521
      reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Both the CDK8-G28A and CDK8-N156S mutations resulted in lower kinase activities compared with CDK8-WT
      explanation: Functional analysis of the later alleles.
  - name: c.599G>A (p.Arg200Gln)
    description: Likely pathogenic variant transmitted from an affected mother to her child. Progressive hip and knee contractures and scoliosis were reported in the child but not the mother.
    evidence:
    - reference: PMID:38193604
      reference_title: 'Expanding the phenotypic spectrum for CDK8-related disease: A case report.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: a likely pathogenic heterozygous CDK8 variant c.599G>A, p.(Arg200Gln) inherited from the biological mother
      explanation: Inherited allele and reported classification.
    clinical_significance: LIKELY_PATHOGENIC
treatments:
- name: Cardiac Surgery
  description: Cardiac procedures depend on the structural lesion. The hypoplastic-left-heart child underwent staged Norwood, Glenn and Fontan operations, and a different infant had a good result after coarctation repair. These case reports do not compare surgical strategies.
  treatment_term:
    preferred_term: Cardiac Surgery
    term:
      id: NCIT:C157806
      label: Cardiac Surgery
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: underwent cardiac surgery at 4 days of age via a Norwood procedure.
    explanation: First stage of the documented palliation.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a Fontan procedure aged 4 yr.
    explanation: Later stage in the same child.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She underwent aortic coarctation repair aged 5 mo with a good result.
    explanation: Reported outcome in another child.
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Hypoplastic left ventricle
    term:
      id: HP:0004383
      label: Hypoplastic left ventricle
  - preferred_term: Coarctation of aorta
    term:
      id: HP:0001680
      label: Coarctation of aorta
- name: Tube Feeding and Gastrostomy
  description: Nasogastric or gastrostomy feeding supports children with inefficient feeding, dysphagia or poor growth. The Ser62Leu girl later achieved complete oral feeding; gastrostomy dependence is not universal or necessarily permanent.
  treatment_term:
    preferred_term: Gastrostomy Tube Procedure
    term:
      id: NCIT:C157864
      label: Gastrostomy Tube Procedure
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: A nasogastric tube was also placed for supplemental nutrition.
    explanation: Early nutritional support in the Arg29Gly child.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She had dysphagia requiring a gastrostomy tube aged 7 mo, but now eats completely by mouth.
    explanation: Gastrostomy followed by later oral feeding in the Ser62Leu child.
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  - preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
- name: Fundoplication for Severe Reflux
  description: Fundoplication and gastrostomy were performed in the Gly28Ala child with severe reflux. The report documents treatment without a quantified reflux outcome.
  treatment_term:
    preferred_term: Fundoplication
    term:
      id: NCIT:C91834
      label: Fundoplication
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Severe gastroesophageal reflux disease was treated by fundoplication and a gastrostomy.
    explanation: Individual surgical treatment.
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
- name: Developmental Therapies
  description: Physical, speech and occupational therapies and special education are documented in affected children. These reports describe service use without controlled estimates of developmental benefit.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: receives physical therapy, speech therapy, and occupational therapy.
    explanation: Documented developmental support in the Ile223Met child.
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
- name: Orthoses and Orthopedic Care
  description: Ankle-foot orthoses helped ambulation in the Ile223Met child. Another boy underwent bilateral lateral column lengthening and serial casting for pes planus. Progressive contractures in the later inherited case warrant individual orthopedic assessment, but a CDK8-specific protocol has not been studied.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: He wears ankle -foot orthoses, which help with ambulation.
    explanation: Reported orthotic benefit.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: serial plaster casting for pes planus and can walk for approximately 2 miles.
    explanation: Orthopedic care and functional status in another individual.
  therapeutic_modality: OTHER
  target_phenotypes:
  - preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  - preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
- name: Antiseizure Pharmacotherapy
  description: Valproic acid improved complex partial seizures and migraines in one Ser62Leu boy. Lamotrigine was started in a Phe97Leu girl who later continued to have epileptic and nonepileptic events; complete seizure control was not demonstrated. These observations do not establish an allele-specific drug choice.
  treatment_term:
    preferred_term: Anticonvulsant Therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
    therapeutic_agent:
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
    - preferred_term: lamotrigine
      term:
        id: CHEBI:6367
        label: lamotrigine
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: complex partial seizures and migraines, both improved with valproic acid.
    explanation: Positive response in one patient.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: A diagnosis of a seizure disorder was made by one year of age and Lamotrigine treatment started.
    explanation: Documented use; subsequent ongoing events limit efficacy inference.
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
- name: Melatonin for Sleep-Onset Difficulty
  description: Melatonin was used for difficulty falling asleep in the Gly30Ser boy. The report does not state the treatment response.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: melatonin
      term:
        id: CHEBI:16796
        label: melatonin
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: He had trouble going to sleep for which melatonin was used.
    explanation: Documented use without a stated efficacy outcome.
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
- name: Methylphenidate (Unsuccessful Individual Trial)
  description: Ritalin worsened ADHD in the Gly30Ser child and was discontinued. This is a negative individual response, not evidence of efficacy or a universal contraindication for all affected patients.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: methylphenidate
      term:
        id: CHEBI:6887
        label: methylphenidate
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the ADHD worsened in response to Ritalin and was thus stopped.
    explanation: Negative individual treatment outcome.
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
- name: Pyridostigmine (Temporary Individual Response)
  description: A trial for suspected congenital myasthenic syndrome in the Val27Leu girl produced mild, temporary improvement. Neuromuscular-junction disease was not established, and other candidate variants complicate attribution. This is not a validated disease-directed CDK8 treatment.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Pyridostigmine
      term:
        id: CHEBI:8665
        label: Pyridostigmine
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: A pyridostigmine treatment trial resulted in a mild, temporary improvement.
    explanation: Limited temporary response in one individual.
  therapeutic_modality: SMALL_MOLECULE
- name: Flunarizine for Cyclic Vomiting
  description: The Val193Gly girl continued treatment at age twelve for cyclic vomiting that had persisted since age three. The supplement spells the drug flunarazine; no quantified response is reported.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: flunarizine
      term:
        id: CHEBI:135652
        label: flunarizine
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: This problem has persisted, and aged 12 yr she continues to be treated with flunarazine.
    explanation: Ongoing treatment with persistent symptoms; benefit cannot be determined.
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
- name: Iron Supplementation
  description: Anemia of uncertain origin improved with iron supplements in one Ser62Leu child. The observation does not establish iron deficiency as the cause of anemia or indicate supplementation for all patients.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Iron supplementation, formulation unspecified
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: he had an anemia of unknown origin, which improved with iron supplements.
    explanation: Case-specific improvement; iron formulation and cause of anemia were not established.
  target_phenotypes:
  - preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
- name: Supplemental Oxygen
  description: The Arg29Gly child required oxygen for severe obstructive sleep apnea early in life and later no longer needed it. The report does not identify a disease-specific respiratory treatment protocol.
  treatment_term:
    preferred_term: Oxygen Therapy
    term:
      id: NCIT:C94624
      label: Oxygen Therapy
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: severe obstructive sleep apnea requiring supplemental oxygen
    explanation: Individual respiratory support.
  target_phenotypes:
  - preferred_term: Obstructive sleep apnea
    term:
      id: HP:0002870
      label: Obstructive sleep apnea
- name: Visual Correction
  description: Glasses were used for myopia in affected children. Refractive correction addresses the documented ocular finding rather than the underlying developmental disorder.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She wears glasses for myopia and has normal hearin g.
    explanation: Documented refractive correction.
  therapeutic_modality: OTHER
  target_phenotypes:
  - preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
- name: Genetic Counseling
  description: Counseling incorporates variant-specific evidence and parental testing. Most confirmed pathogenic missense variants are de novo, but affected-parent transmission is documented. A negative parental blood result cannot eliminate germline mosaicism, and these case series do not quantify penetrance or recurrence risk.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38193604
    reference_title: 'Expanding the phenotypic spectrum for CDK8-related disease: A case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a likely pathogenic heterozygous CDK8 variant c.599G>A, p.(Arg200Gln) inherited from the biological mother
    explanation: Documented maternal transmission of an allele classified as likely pathogenic.
diagnosis:
- name: Molecular Diagnosis and Parental Testing
  description: Trio exome or genome sequencing identified heterozygous kinase-domain missense variants. Interpretation integrates phenotype, inheritance, population frequency and allele-specific functional evidence. The published signature does not justify classifying every rare CDK8 variant or truncating allele as pathogenic.
  diagnosis_term:
    preferred_term: Whole Exome Sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Using whole-exome or whole-genome sequencing, and by international collaboration, we identified eight different heterozygous missense CDK8 substitutions
    explanation: Molecular ascertainment in the original cohort.
- name: Cardiac Assessment
  description: Echocardiography characterizes variable congenital lesions and informs lesion-specific management; not every patient has heart disease.
  diagnosis_term:
    preferred_term: Echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: echocardiography showed tetralogy of Fallot.
    explanation: Diagnostic cardiac imaging in a reported case.
- name: Brain MRI
  description: Imaging may show callosal agenesis or thinning, ventriculomegaly or white-matter abnormalities. A normal scan does not exclude CDK8-related disorder.
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: magnetic resonance imaging (MRI) of the brain showed agenesis or thinning of the corpus callosum in four subjects
    explanation: Variable structural imaging findings.
- name: EEG for Paroxysmal Events
  description: EEG helps distinguish epileptic from nonepileptic spells. The Phe97Leu girl had both types over time, so observation of jerking alone does not establish seizures.
  diagnosis_term:
    preferred_term: Electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These events were captured during an electro encephalogram (EEG) recording and were not felt to be epileptic.
    explanation: Nonepileptic early events preceded later diagnosed epilepsy.
- name: Hearing and Ophthalmologic Assessment
  description: Hearing and eye evaluation identify sensorineural hearing loss, refractive errors, strabismus and other visual difficulties that may affect communication and development.
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Three individuals had moderate-severe sensorineural hearing loss
    explanation: Cohort hearing findings.
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: including myopia (n = 6), eyelid ptosis (n = 2), and/or strabismus (n = 4)
    explanation: Cohort ocular findings.
differential_diagnoses:
- name: Noonan Syndrome
  description: Tetralogy of Fallot, neonatal lymphedema, cryptorchidism and neck/ear findings initially suggested Noonan syndrome in the Ser62Leu boy. The resemblance is case-specific.
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: An initial diagnosis of Noonan Syndrome was proposed.
    explanation: Documented differential before CDK8 diagnosis.
- name: Congenital Myasthenic Syndrome
  description: Ptosis, facial weakness and hypotonia prompted this differential in the Val27Leu girl. A transient pyridostigmine response did not establish a neuromuscular-junction defect, and additional candidate variants limit attribution of every feature to CDK8.
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Pediatric neurological examination also showed facial weakness and a congenital myasthenic syndrome was suspected.
    explanation: Clinical suspicion rather than a confirmed coexisting diagnosis.
- name: Prader-Willi or Angelman Syndrome
  description: Methylation studies for both conditions were unrevealing in the hypotonic Arg29Gly child with feeding and developmental difficulties. These are reported differential investigations, not diagnostic criteria for CDK8 disease.
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: methylation studies for Prader-Willi and Angelman syndromes.
    explanation: Negative workup is stated in the surrounding sentence; this excerpt identifies the tested conditions.
experimental_models:
- name: SW620 CDK8/CDK19 Double-Knockout Complementation
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: CRISPR-edited SW620 colorectal carcinoma cells lacking CDK8 and CDK19; transient reference or variant human CDK8 expression
  publication: PMID:30905399
  description: STAT1 Ser727 phosphorylation was reduced by all eight founding variants. Phe97Leu and Ile223Met retained approximately 63% and 51% of reference output, while most variants approached the engineered Asp173Ala kinase-dead control. Asp173Ala is an assay control, not a patient allele.
  modeled_mechanisms:
  - target: Reduced CDK8 Kinase Activity
    description: Measures variant-dependent substrate phosphorylation.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: We observed that the cellular levels of pSTAT1 were reduced to a statistically significant extent, compared to WT, in all mutant-transfected cells
      explanation: Variant activity in a double-knockout cell background.
    relationship: MEASURES
    model_scale: MOLECULAR
    limitations: A cancer cell line with both endogenous paralogs deleted is not a heterozygous patient neural cell. The substrate assay does not identify the disease-relevant transcriptional program.
    fidelity: MODERATE
  - target: Reduced STAT1 Ser727 Phosphorylation
    description: Measures variant-dependent substrate phosphorylation.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: We observed that the cellular levels of pSTAT1 were reduced to a statistically significant extent, compared to WT, in all mutant-transfected cells
      explanation: Variant activity in a double-knockout cell background.
    relationship: MEASURES
    model_scale: MOLECULAR
    limitations: A cancer cell line with both endogenous paralogs deleted is not a heterozygous patient neural cell. The substrate assay does not identify the disease-relevant transcriptional program.
    fidelity: MODERATE
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We observed that the cellular levels of pSTAT1 were reduced to a statistically significant extent, compared to WT, in all mutant-transfected cells
    explanation: Variant activity in a double-knockout cell background.
- name: HEK293T Kinase-Module Assembly and Thermal Stability
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Transiently transfected HEK293T cells; immunoprecipitated tagged CDK8 modules
  publication: PMID:30905399
  description: Variant proteins retained cyclin-C association and showed no gross loss of thermal stability. Most or all retained ATP-responsive stabilization; the supplemental co-immunoprecipitation also recovered MED12 and MED13. These findings constrain a simple protein-destabilization explanation without proving dominant-negative competition.
  modeled_mechanisms:
  - target: Nonproductive Mediator Kinase Module Occupancy
    description: Assesses whether catalytically impaired proteins can remain in stable kinase modules.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: none of the substitutions cause gross mis-folding of the protein, and most or all are still able to bind ATP
      explanation: Thermal stability and ATP-response experiments.
    relationship: MEASURES
    model_scale: MOLECULAR
    limitations: Retained association is compatible with the proposed occupancy model but does not demonstrate competition with the normal allele in patient cells.
    fidelity: LOW
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: none of the substitutions cause gross mis-folding of the protein, and most or all are still able to bind ATP
    explanation: Thermal stability and ATP-response experiments.
- name: Reference/Ser62Leu Mixing Assay
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Mixed reference and Ser62Leu CDK8 constructs in the STAT1-phosphorylation assay
  publication: PMID:30905399
  description: Equal reference and Ser62Leu constructs did not produce an obviously nonlinear fall in STAT1 phosphorylation. The authors reported this result without showing the data and stated that further experiments were needed.
  modeled_mechanisms:
  - target: Nonproductive Mediator Kinase Module Occupancy
    description: Directly probes the proposed dominant-negative interpretation without establishing it.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: NO_EVIDENCE
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: the observed reduction in phosphorylation in mixed samples did not obviously deviate from a linear response
      explanation: The mixing assay did not establish a dominant-negative interaction.
    relationship: MEASURES
    model_scale: MOLECULAR
    limitations: One variant, one substrate, transient expression and data not shown; lack of nonlinear inhibition does not exclude a different context-dependent mechanism.
    fidelity: LOW
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: NO_EVIDENCE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the observed reduction in phosphorylation in mixed samples did not obviously deviate from a linear response
    explanation: The mixing assay did not establish a dominant-negative interaction.
- name: HEK293 Gly28Ala/Asn156Ser Autophosphorylation
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: HEK293 cells expressing tagged human CDK8 with cyclin C; immunoprecipitate ADP-GLO assay
  publication: PMID:33067521
  description: Gly28Ala and Asn156Ser reduced autophosphorylation activity, with the stronger reduction for Asn156Ser. This biochemical ordering does not establish a human severity ordering.
  modeled_mechanisms:
  - target: Reduced CDK8 Kinase Activity
    description: Measures catalytic output of the two later patient variants.
    evidence:
    - reference: PMID:33067521
      reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Both the CDK8-G28A and CDK8-N156S mutations resulted in lower kinase activities compared with CDK8-WT
      explanation: Autophosphorylation assay of later variants.
    relationship: MEASURES
    model_scale: MOLECULAR
    limitations: Overexpressed immunoprecipitates and autophosphorylation differ from developmental substrate selection in patient cells.
    fidelity: MODERATE
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Both the CDK8-G28A and CDK8-N156S mutations resulted in lower kinase activities compared with CDK8-WT
    explanation: Autophosphorylation assay of later variants.
animal_models:
- name: Zebrafish Human CDK8 mRNA Overexpression
  species: Danio rerio
  genotype: One-cell injection of reference, Gly28Ala or Asn156Ser human CDK8 mRNA
  publication: PMID:33067521
  description: At one day postfertilization, reference CDK8 overexpression caused the largest fraction of embryos with shortened body axis, small anterior structures and abnormal tails. Both variants had less defect-inducing activity, especially Asn156Ser. This comparison supports reduced activity, not greater variant toxicity.
  modeled_mechanisms:
  - target: Reduced CDK8 Kinase Activity
    description: Variant mRNAs perturb development less than reference CDK8 under overexpression.
    evidence:
    - reference: PMID:33067521
      reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The relative fraction of embryos with defects was largest when mRNA encoding the human wild-type CDK8 protein was injected
      explanation: Reference overexpression perturbed development more than either tested variant.
    relationship: PERTURBS
    model_scale: ORGANISM
    limitations: Overexpression toxicity is an indirect activity readout. This is not an endogenous heterozygous knock-in or a genomic knockdown, and human intellectual disability is not measured.
    fidelity: LOW
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The relative fraction of embryos with defects was largest when mRNA encoding the human wild-type CDK8 protein was injected
    explanation: Reference overexpression perturbed development more than either tested variant.
- name: Zebrafish Dual CDK8/CDK19 Inhibition
  species: Danio rerio
  genotype: Unmodified embryos exposed to 2 micromolar Senexin A
  publication: PMID:33067521
  description: Senexin A exposure produced craniofacial cartilage and cardiac abnormalities with disturbed circulation in all 46 reported exposed embryos. The compound inhibits both paralogs. Exposure models developmental loss of kinase activity and is not a therapeutic rescue.
  modeled_mechanisms:
  - target: Impaired Cardiac Morphogenesis
    description: Dual kinase inhibition disrupts this developmental process.
    evidence:
    - reference: PMID:33067521
      reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: the inhibition of Cdk8 kinase activity by Senexin A induced structural anomalies in the heart and craniofacial cartilage of the zebrafish
      explanation: Experimental developmental perturbation by a dual-kinase inhibitor.
    relationship: PERTURBS
    model_scale: TISSUE
    limitations: Chemical inhibition does not isolate CDK8 from CDK19 and does not reproduce a specific patient allele. The methods contain an internally inconsistent exposure-start time, so no start time is assigned here.
    fidelity: LOW
  - target: Impaired Craniofacial Patterning
    description: Dual kinase inhibition disrupts this developmental process.
    evidence:
    - reference: PMID:33067521
      reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: the inhibition of Cdk8 kinase activity by Senexin A induced structural anomalies in the heart and craniofacial cartilage of the zebrafish
      explanation: Experimental developmental perturbation by a dual-kinase inhibitor.
    relationship: PERTURBS
    model_scale: TISSUE
    limitations: Chemical inhibition does not isolate CDK8 from CDK19 and does not reproduce a specific patient allele. The methods contain an internally inconsistent exposure-start time, so no start time is assigned here.
    fidelity: LOW
  evidence:
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the inhibition of Cdk8 kinase activity by Senexin A induced structural anomalies in the heart and craniofacial cartilage of the zebrafish
    explanation: Experimental developmental perturbation by a dual-kinase inhibitor.
- name: Cdk8 Gene-Trap Mouse
  species: Mus musculus
  genotype: Heterozygous or homozygous gene-trap inactivation of Cdk8
  publication: PMID:17620419
  description: Heterozygotes had no reported overt phenotype, while homozygous embryos failed before implantation at approximately embryonic days 2.5–3.0 with fragmented blastomeres and absent compaction. Complete gene loss differs substantially from the viable human missense disorder.
  modeled_mechanisms:
  - target: Reduced CDK8 Kinase Activity
    description: Complete Cdk8 loss reveals an early developmental requirement but does not reproduce the clinical missense syndrome.
    evidence:
    - reference: PMID:17620419
      reference_title: Cdk8 is essential for preimplantation mouse development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Cdk8-/- preimplantation embryos had fragmented blastomeres and did not proceed to compaction.
      explanation: Early embryonic phenotype of complete mouse gene loss.
    - reference: PMID:17620419
      reference_title: Cdk8 is essential for preimplantation mouse development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: No phenotypes were noted in heterozygote Cdk8+/- mice
      explanation: No reported overt phenotype in the heterozygous gene-trap animals.
    relationship: PERTURBS
    model_scale: ORGANISM
    limitations: Gene trapping removes gene function rather than retaining an altered kinase module. The abstract does not establish comprehensive neurobehavioral testing of heterozygotes; normal appearance is not proof of complete haplosufficiency.
    fidelity: LOW
  evidence:
  - reference: PMID:17620419
    reference_title: Cdk8 is essential for preimplantation mouse development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Cdk8-/- preimplantation embryos had fragmented blastomeres and did not proceed to compaction.
    explanation: Early embryonic phenotype of complete mouse gene loss.
  - reference: PMID:17620419
    reference_title: Cdk8 is essential for preimplantation mouse development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: No phenotypes were noted in heterozygote Cdk8+/- mice
    explanation: No reported overt phenotype in the heterozygous gene-trap animals.
computational_models:
- name: CDK8–Cyclin C Molecular Dynamics
  model_type: STRUCTURAL_PREDICTION
  publication: PMID:30905399
  description: Reference, Ser62Leu and Arg178Gln CDK8–cyclin C structures with ATP were compared by molecular dynamics. The modeling used CDK8 structure 4F7S and an aligned CDK9 ATP template, with unresolved regions modeled in MOE and replicate simulations in GROMACS. The variants were predicted to restrict substrate-pocket opening without grossly changing the overall fold.
  modeled_mechanisms:
  - target: Altered Substrate-Binding Geometry
    description: Predicts reduced access to the catalytic pocket.
    evidence:
    - reference: PMID:30905399
      reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: the substrate-binding site of the WT CDK8 protein can adopt more open conformations than its mutated counterparts
      explanation: Structural-dynamics prediction.
    relationship: MEASURES
    model_scale: MOLECULAR
    limitations: Predicted conformations do not directly measure substrate binding, phosphorylation kinetics or patient-cell transcription.
    fidelity: LOW
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the substrate-binding site of the WT CDK8 protein can adopt more open conformations than its mutated counterparts
    explanation: Structural-dynamics prediction.
discussions:
- discussion_id: dominant_negative_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: How do catalytically impaired CDK8 proteins cause dominant disease while retaining module association?
  attaches_to:
  - pathophysiology#Nonproductive Mediator Kinase Module Occupancy
  - pathophysiology#Reduced CDK8 Kinase Activity
  rationale: Missense clustering, retained stability and reduced catalysis motivate a model in which nonproductive modules compete with active ones. The reference/Ser62Leu mixing experiment did not clearly depart from linearity. CDK19 interference, developmental substrate specificity and simple dosage reduction remain distinguishable possibilities rather than demonstrated equivalences.
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: NO_EVIDENCE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the observed reduction in phosphorylation in mixed samples did not obviously deviate from a linear response
    explanation: The mixing assay did not establish a dominant-negative interaction.
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: none of the substitutions cause gross mis-folding of the protein, and most or all are still able to bind ATP
    explanation: Thermal stability and ATP-response experiments.
- discussion_id: null_missense_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Why do viable heterozygous human missense alleles differ from mouse Cdk8 gene-trap loss?
  attaches_to:
  - genetic#CDK8
  rationale: Homozygous mouse loss arrests preimplantation development, and heterozygotes lacked a reported overt phenotype. Neither outcome models the human missense syndrome directly. The heterozygote observation supports caution about simple haploinsufficiency but does not provide a complete neurobehavioral assessment or establish benignity of every human loss-of-function variant.
  evidence:
  - reference: PMID:17620419
    reference_title: Cdk8 is essential for preimplantation mouse development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Cdk8-/- preimplantation embryos had fragmented blastomeres and did not proceed to compaction.
    explanation: Early embryonic phenotype of complete mouse gene loss.
  - reference: PMID:17620419
    reference_title: Cdk8 is essential for preimplantation mouse development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: No phenotypes were noted in heterozygote Cdk8+/- mice
    explanation: No reported overt phenotype in the heterozygous gene-trap animals.
- discussion_id: activity_severity_relationship
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Does allele-specific kinase activity predict developmental severity or organ involvement?
  attaches_to:
  - pathophysiology#Reduced CDK8 Kinase Activity
  rationale: Residual STAT1 phosphorylation differs among the founding alleles, and Asn156Ser reduced autophosphorylation more than Gly28Ala despite the latter child having more severe clinical findings. Small numbers, age differences, distinct assays and additional variation preclude a validated activity–severity relationship.
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: an intermediate level of phosphorylation (∼63% and ∼51% in comparison to the WT, respectively), was observed
    explanation: Residual activity in two alleles.
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Both the CDK8-G28A and CDK8-N156S mutations resulted in lower kinase activities compared with CDK8-WT
    explanation: Autophosphorylation assay of later variants.
- discussion_id: individual_feature_attribution
  kind: INTERPRETATION
  status: OPEN
  prompt: Which uncommon findings are reproducible CDK8-associated features rather than individual or multilocus observations?
  attaches_to:
  - genetic#CDK8
  - phenotypes#Metopic Synostosis
  - phenotypes#Decreased CSF Homovanillic Acid
  rationale: The Val27Leu case also carried a CACNA1A variant of uncertain significance and mosaic HDAC9 truncation, while the Gly30Ser case carried additional uncertain variation including COL3A1. The authors did not establish these as modifiers. Metopic synostosis and low CSF homovanillic acid remain isolated findings with uncertain mechanistic attribution; neither proves a uniform craniosynostosis or dopamine-synthesis mechanism.
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: An additional de novo missense variant was identified in the CACNA1A gene
    explanation: Potential multilocus complexity without demonstrated modifier action.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a low cerebrospinal fluid (CSF) homovanillic acid level, the significance of which is unclear
    explanation: Explicitly uncertain biochemical finding.
- discussion_id: patient_developmental_programs
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which neural and cardiac transcriptional programs connect reduced CDK8 activity to human developmental phenotypes?
  attaches_to:
  - pathophysiology#Altered Developmental Transcription
  rationale: STAT1 phosphorylation is a measured cell-assay readout, while candidate WNT, TGFβ/BMP, SHH and NOTCH changes were not demonstrated in these patients. Fish chemical inhibition affects both CDK8 and CDK19. Patient-derived cell studies are needed before assigning a specific developmental signaling defect or generalizing paralog-specific mitochondrial results to CDK8 disease.
  evidence:
  - reference: PMID:30905399
    reference_title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Thus, a disruption of the proper activity of CDK8 could modify any of these developmental signaling networks.
    explanation: Proposed developmental-signaling interpretation.
  - reference: PMID:33067521
    reference_title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Senexin A inhibits both CDK19 and CDK8
    explanation: The pharmacological model cannot isolate CDK8.
notes: Clinical frequencies refer to selected cohorts and their assessed denominators, not population prevalence or penetrance. Original 2019 case-level data are retained where the 2020 secondary table recounted them inconsistently; later cases are described separately. No established clinical subtypes or validated allele-specific prognostic categories follow from these small series. The publisher-hosted mmc1 PDF is the complete supplemental material for PMID:30905399 and supplies detailed clinical courses and treatments; its generated reference title remains the PDF URL. Progressive contractures and scoliosis in the maternally inherited Arg200Gln case broaden the observed range without establishing uniform progression. Treatment observations are individual reports, not controlled efficacy studies. No disorder-specific GeneReviews chapter or congenital-disease intervention trial was identified; cancer trials of kinase inhibitors do not establish treatment of this developmental condition.
references:
- reference: PMID:17620419
  title: Cdk8 is essential for preimplantation mouse development.
- reference: PMID:30905399
  title: De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
- reference: PMID:33067521
  title: 'Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.'
- reference: PMID:38193604
  title: 'Expanding the phenotypic spectrum for CDK8-related disease: A case report.'
- reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
  title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
- reference: url:https://thegencc.org/submissions/SGC-124667.1
  title: CDK8 | intellectual developmental disorder with hypotonia and behavioral abnormalities | Autosomal dominant by G2P submission information facts
📚

References & Deep Research

References

6
PMID:17620419
Cdk8 is essential for preimplantation mouse development.
No top-level findings curated for this source.
PMID:30905399
De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.
No top-level findings curated for this source.
PMID:33067521
Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.
No top-level findings curated for this source.
PMID:38193604
Expanding the phenotypic spectrum for CDK8-related disease: A case report.
No top-level findings curated for this source.
url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
https://ars.els-cdn.com/content/image/1-s2.0-S0002929719300515-mmc1.pdf
No top-level findings curated for this source.
url:https://thegencc.org/submissions/SGC-124667.1
CDK8 | intellectual developmental disorder with hypotonia and behavioral abnormalities | Autosomal dominant by G2P submission information facts
No top-level findings curated for this source.