CDK19-Related Disorder

🏷

Classifications

Harrison's Part

?

Discussions and Knowledge Gaps

4

How do kinase activity, substrate choice and cellular context determine the clinical effects of distinct CDK19 missense alleles?

KNOWLEDGE GAP OPEN allele_assay_dependence

Attached to

pathophysiology#Reduced CDK19 Kinase Activity pathophysiology#Increased CDK19 Kinase Activity pathophysiology#Impaired CDK19 Functional Complementation

Tyr32His increases catalytic output in biochemical assays while its rescue varies across fly tissues, temperatures and residual ortholog expression. Failed complementation, overexpression toxicity and reduced catalytic activity are distinct observations. Dominant-negative interaction with the normal human allele remains unproven.

Show evidence (2 references)

PMID:33495529 SUPPORT DIRECT PRIMARY RESULT In Vitro

"kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein."

Variant catalytic assay.

PMID:41251503 SUPPORT DIRECT PRIMARY RESULT Model Organism

"both variants are unable to rescue the cdk8 depletion muscle myofibril thickening as the wild-type CDK19 can"

Readout-specific persistent defect.

Do CDK19 patient neurons share the mitochondrial and Drp1 abnormalities found in sensitized fly models?

HUMAN MODEL MISMATCH OPEN human_mitochondrial_translation

Attached to

pathophysiology#Impaired Mitochondrial Fission pathophysiology#Reduced Drp1 Phosphorylation pathophysiology#Elevated Cellular Oxidative Stress

Cytoplasmic rescue and patient-variant fly experiments support a route beyond transcription. Patient-neuron mitochondrial morphology, phosphorylation and energy defects have not been established in these studies. NACA effects in flies provide a hypothesis for further testing, not a validated human therapy.

Show evidence (1 reference)

PMID:38637532 SUPPORT DIRECT PRIMARY RESULT Model Organism

"These results show that cytoplasmic CDK19 is sufficient to regulate mitochondrial morphology."

Model evidence underlying the translational gap.

Are CSF protein and glycine abnormalities reproducible CDK19-associated findings, and do they contribute to seizures?

KNOWLEDGE GAP OPEN glycine_biomarker_mechanism

Attached to

phenotypes#Increased CSF Protein phenotypes#Increased CSF Glycine

These biochemical findings come from one Tyr32His case. A normal CSF/plasma ratio, negative GLDC/AMT testing and unsuccessful dextromethorphan treatment limit an NKH-like mechanistic interpretation. Replication and direct metabolic studies are needed before these values can be used as diagnostic or treatment biomarkers.

Show evidence (1 reference)

PMID:33134521 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The mechanism through which the CDK19 variant leads to the CSF abnormalities remains unknown."

Explicit uncertainty in the primary report.

How does the historical CDK19-disrupting inversion relate to the later kinase-domain missense syndrome?

INTERPRETATION OPEN structural_allele_scope

Attached to

genetic#CDK19

The pericentric inversion was mapped to CDK19 intron 1 and reduced transcript levels in transformed lymphoblasts, supporting a dosage effect. Retinal folds, microcephaly and milder intellectual disability without reported epilepsy differ from many missense cases. Breakpoint mapping did not establish a nucleotide-resolved junction, and the isolated structural case does not establish pathogenicity of all CDK19 deletions or truncations.

Show evidence (1 reference)

PMID:20563892 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The transcript level for CDK19 in the patient was found to be 54% (p = 0.022) when compared with the control mean"

Inversion-associated RNA decrease.

⚙

Pathophysiology

14

CDK19 Coding Missense Substitutions

Mechanism confidence: Established

Heterozygous coding single-nucleotide substitutions alter conserved residues of the kinase domain, particularly the glycine-rich loop and activation segment. This physical variant class is distinct from its allele-dependent functional consequences.

CDK19 hgnc:19338

Genetic context CDK19 hgnc:19338 Variant type: single nucleotide variant Genomic context: coding sequence variant_origin: GERMLINE

Heterozygous de novo variants in the primary series.

Animal models

Zebrafish CDK19 mRNA Overexpression Danio rerio perturbs Tests developmental effects of coding-variant overexpression.

Downstream

Reduced CDK19 Kinase Activity Gly28Arg reduces catalytic output in biochemical assays.

Increased CDK19 Kinase Activity Tyr32His increases catalytic output in biochemical assays.

Impaired CDK19 Functional Complementation Several variants fail to replace endogenous fly Cdk8 under defined experimental conditions; this does not by itself identify a dominant-negative mechanism.

Show evidence (1 reference)

PMID:33495529 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We describe 11 unrelated individuals (age range: 9 months to 14 years) with de novo missense variants mapped to the kinase domain of CDK19"

Physical missense variants in the clinical series.

Reduced CDK19 Kinase Activity

Mechanism confidence: Established

Gly28Arg reduces autophosphorylation and phosphorylation of recombinant RNA-polymerase-II CTD and STAT1. The mutant can still assemble with cyclin C, MED12 and MED13 in the purified module; defective catalysis does not require wholesale loss of the complex.

CDK19 hgnc:19338 ⇓ LOSS OF FUNCTION

cyclin-dependent protein serine/threonine kinase activity GO:0004693 ↓ DECREASED

Experimental models

HEK293 CDK19 Autophosphorylation Assay CELL LINE Measures allele-dependent catalytic output.

Reconstituted CDK19 Kinase Module OTHER Purified-complex substrate phosphorylation provides a biochemical readout.

Computational models

Thr31Asn CDK19–Cyclin C Structural Prediction STRUCTURAL PREDICTION Predicts an impaired ATP-binding/catalytic consequence for Thr31Asn.

Downstream

Altered Transcriptional Regulation Altered phosphorylation of transcription-associated substrates provides a plausible route to dysregulated gene expression; patient neuronal transcriptional consequences remain unresolved.

Show evidence (1 reference)

PMID:33495529 SUPPORT DIRECT PRIMARY RESULT In Vitro

"kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein."

Direct comparison of variant kinase activities.

Increased CDK19 Kinase Activity

Mechanism confidence: Established

Tyr32His increases autophosphorylation and substrate phosphorylation in the reported biochemical assays. This increase does not guarantee preserved function in every developmental or cellular readout.

CDK19 hgnc:19338 ⇑ GAIN OF FUNCTION

cyclin-dependent protein serine/threonine kinase activity GO:0004693 ↑ INCREASED

Experimental models

HEK293 CDK19 Autophosphorylation Assay CELL LINE Measures allele-dependent catalytic output.

Reconstituted CDK19 Kinase Module OTHER Purified-complex substrate phosphorylation provides a biochemical readout.

Downstream

Altered Transcriptional Regulation Altered phosphorylation of transcription-associated substrates provides a plausible route to dysregulated gene expression; patient neuronal transcriptional consequences remain unresolved.

Show evidence (1 reference)

PMID:33495529 SUPPORT DIRECT PRIMARY RESULT In Vitro

"kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein."

Direct comparison of variant kinase activities.

Impaired CDK19 Functional Complementation

Mechanism confidence: Provisional

Tyr32His and Thr196Ala fail to rescue severe fly Cdk8 depletion or null phenotypes. In milder knockdown conditions, Tyr32His rescues climbing and mitochondrial morphology while failing to normalize lifespan and myofibril width; Thr196Ala remains broadly impaired. A dominant-negative mechanism is a hypothesis rather than proof of interaction with the human wild-type allele.

CDK19 hgnc:19338

Animal models

Fly Cdk8 Null and Strong Neuronal Depletion with Human Rescue Drosophila melanogaster partially recapitulates Reference but not variant CDK19 restores the severe depletion/null phenotype.

Fly Sensitized Cdk8 Depletion with Tyr32His or Thr196Ala Drosophila melanogaster partially recapitulates Complementation varies by variant, residual ortholog expression and measured trait.

Zebrafish cdk8 and cdk19 Morpholino Knockdown Danio rerio perturbs Perturbs partially redundant kinase functions during development.

Downstream

Reduced Drp1 Phosphorylation Thr196Ala lowers the Drp1 phospho-readout in the sensitized fly background; competition with endogenous Cdk8 is proposed, not directly demonstrated.

Impaired Dendritic Arborization Fly depletion and rescue studies link deficient CDK19/Cdk8 function to neuronal arbor and synapse defects.

Reduced Synaptic Bouton Formation Fly neuronal depletion reduces the number of synaptic boutons.

Show evidence (2 references)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Model Organism

"expression of either CDK19 p.Tyr32His or p.Thr196Ala failed to rescue the lethality."

Failure of stringent complementation.

PMID:41251503 SUPPORT DIRECT PRIMARY RESULT Model Organism

"both variants are unable to rescue the cdk8 depletion muscle myofibril thickening as the wild-type CDK19 can"

Persistent phenotype despite selective Tyr32His rescue elsewhere.

Altered Transcriptional Regulation

Mechanism confidence: Provisional

CDK19 is a Mediator-associated transcriptional kinase. Variant-dependent phosphorylation changes can alter transcription, but an abnormal neuronal expression program has not been directly delineated in these patients. The cytoplasmic rescue experiments indicate that transcription alone need not account for every phenotype.

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

Downstream

Impaired Dendritic Arborization Transcriptional dysregulation may disturb neuronal development; the specific intervening gene program has not been established.

Show evidence (1 reference)

PMID:33568421 SUPPORT DIRECT BACKGROUND Other

"We assumed that the disruption of CDK19 kinase activity by pathogenic variants impaired the total transcriptional activity for the CDK module"

Explicitly proposed transcriptional mechanism.

Reduced Drp1 Phosphorylation

Mechanism confidence: Provisional

Fly Cdk8 depletion can reduce Drp1 Ser616 phosphorylation. Thr196Ala expression reduces this readout in a milder knockdown background where depletion alone does not. Tyr32His shows only a nonsignificant upward trend in that experiment. Direct phosphorylation by an isolated human CDK19 protein was not demonstrated.

Experimental models

S2R+ Cdk8–Drp1 Interaction and Kinase Assay CELL LINE Measures the Cdk8-associated Drp1 phosphorylation reaction relevant to the proposed route.

Animal models

Fly Sensitized Cdk8 Depletion with Tyr32His or Thr196Ala Drosophila melanogaster partially recapitulates Thr196Ala lowers the Drp1 phospho-readout in this sensitized background.

Downstream

Impaired Mitochondrial Fission Reduced activation of the fission regulator can shift mitochondrial morphology toward fused or elongated networks.

Show evidence (2 references)

PMID:38637532 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the data show that Cdk8 interacts with Drp1 and promotes phosphorylation of Drp1 at S616"

Fly protein interaction and phosphorylation support the route.

PMID:41251503 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the pDrp1:Drp1 ratio is significantly lower in the T196A background"

Variant-specific fly result.

Impaired Mitochondrial Fission

Mechanism confidence: Provisional

Cdk8 depletion produces elongated muscle mitochondria and abnormal neuronal mitochondrial organization. Wild-type and cytoplasmically targeted human CDK19 rescue these defects. Thr196Ala fails to rescue muscle mitochondrial morphology, while Tyr32His can rescue it under milder conditions. A mitochondrial lesion in human patient neurons remains unconfirmed.

mitochondrial fission GO:0000266 ↓ DECREASED

Animal models

Fly Tissue-Specific Cdk8 Depletion and Cytoplasmic CDK19 Rescue Drosophila melanogaster rescues Cytoplasmic human CDK19 rescues the knockdown mitochondrial morphology.

Downstream

Reduced Synaptic Mitochondrial Availability Altered mitochondrial organization can impair transport or retention at neuronal terminals.

Mitochondrial Energetic Stress Abnormal mitochondrial dynamics accompanies impaired energy production in the neuronal depletion model.

Elevated Cellular Oxidative Stress Mitochondrial defects can contribute to elevated ROS; their causal contribution has not been isolated in the human variant model.

Show evidence (2 references)

PMID:38637532 SUPPORT DIRECT PRIMARY RESULT Model Organism

"These results show that cytoplasmic CDK19 is sufficient to regulate mitochondrial morphology."

Cytoplasmic rescue supports a mechanism beyond nuclear transcription.

PMID:41251503 SUPPORT DIRECT PRIMARY RESULT Model Organism

"expression of T196A fails to rescue the mitochondrial dysmorphology"

Variant-specific complementation outcome.

Reduced Synaptic Mitochondrial Availability

Mechanism confidence: Provisional

Fly neuronal Cdk8 depletion redistributes mitochondria toward cell bodies and reduces their presence at photoreceptor terminals. The retinal readout is experimental and does not establish a matching patient retinal lesion.

Downstream

Impaired Synaptic Transmission Insufficient local mitochondrial support may limit energy-dependent synaptic function.

Show evidence (1 reference)

PMID:38637532 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the number of mitochondria is reduced in photoreceptor terminals"

Subcellular distribution in the fly model.

Mitochondrial Energetic Stress

Mechanism confidence: Provisional

Neuronal Cdk8 depletion increases mitochondrial Hsp60 and reduces ATP in fly heads. Patient biochemical evidence for this route is lacking.

Downstream

Impaired Synaptic Transmission Reduced energy availability can compromise neurotransmission.

Show evidence (1 reference)

PMID:38637532 SUPPORT DIRECT PRIMARY RESULT Model Organism

"we quantified mitochondrial stress by measuring the level of the mitochondrial stress protein Hsp60 ... mitochondrial stress is significantly increased in adult brains. Furthermore, the function of mitochondria is also affected as the ATP synthesis level is significantly reduced upon depletion of Cdk8"

Neuronal Cdk8 depletion raises the Hsp60 stress marker and reduces ATP synthesis in the fly model.

Elevated Cellular Oxidative Stress

Mechanism confidence: Provisional

ROS is elevated in strong tissue-specific Cdk8 depletion and in the Thr196Ala sensitized fly model. It is not elevated in every knockdown or variant condition. Patient tissue ROS has not been measured in these studies.

Animal models

Fly Sensitized Cdk8 Depletion with Tyr32His or Thr196Ala Drosophila melanogaster rescues NACA suppresses the elevated muscle ROS of Thr196Ala flies.

Downstream

Impaired Neuromuscular Function Oxidative stress may contribute to dysfunction; antioxidant rescue is partial and assay dependent.

Show evidence (1 reference)

PMID:41251503 SUPPORT DIRECT PRIMARY RESULT Model Organism

"a significant increase in the mean DHE fluorescent intensity for the escaper T196A flies"

Increased oxidative-stress readout in the variant model.

Impaired Dendritic Arborization

Mechanism confidence: Provisional

Two fly Cdk8 RNA-interference constructs reduce sensory-neuron dendritic branching. This supports a conserved developmental function but is not patient-neuron histology or a missense-specific assay.

neuron CL:0000540

dendrite development GO:0016358 ↓ DECREASED

Animal models

Fly Sensory-Neuron Cdk8 Knockdown Drosophila melanogaster partially recapitulates Reduced dendritic branching after endogenous Cdk8 depletion.

Downstream

Global developmental delay Defective neuronal development provides a candidate explanation for developmental impairment.

Delayed Speech and Language Development Altered neural circuit development may contribute to language impairment.

Intellectual Disability Neuronal developmental dysfunction is a candidate substrate of intellectual disability.

Absent Speech Abnormal neural circuit development may contribute to profound language impairment.

Show evidence (1 reference)

PMID:20563892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Quantification of dendritic branching revealed a 35% reduction (p < 0.001) in dendrite ends upon Cdk8 knockdown"

Larval sensory-neuron readout.

Reduced Synaptic Bouton Formation

Mechanism confidence: Provisional

Neuronal fly Cdk8 depletion reduces neuromuscular-junction boutons by approximately 30% without reducing branch number. This is a distinct synaptic-development readout, not a human histological finding.

synapse organization GO:0050808 ↕ DYSREGULATED

Animal models

Fly Cdk8 Null and Strong Neuronal Depletion with Human Rescue Drosophila melanogaster partially recapitulates Neuronal Cdk8 depletion reduces bouton number.

Downstream

Impaired Synaptic Transmission Reduced synaptic connectivity may compromise circuit communication.

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Model Organism

"we observed a significant decrease (~30%) in the total number of boutons"

Larval neuromuscular-junction readout.

Impaired Synaptic Transmission

Mechanism confidence: Provisional

Neuronal Cdk8 depletion nearly abolishes fly electroretinogram on/off transients while preserving response amplitudes, supporting deficient synaptic communication rather than loss of phototransduction. Translation to human seizure networks remains provisional.

Animal models

Fly Tissue-Specific Cdk8 Depletion and Cytoplasmic CDK19 Rescue Drosophila melanogaster partially recapitulates Photoreceptor synaptic transients are severely reduced while response amplitudes are retained.

Downstream

Seizures Abnormal neuronal communication may promote network dysfunction, but epileptogenesis has not been directly mapped in patient neurons.

Hypotonia Neuronal signaling abnormalities may contribute to reduced tone.

Epileptic Encephalopathy Abnormal network activity may add an epileptic component to developmental impairment; the patient-specific circuit mechanism remains unresolved.

Developmental Regression Seizure-associated network dysfunction may contribute to acquired skill loss in the reported case.

Show evidence (1 reference)

PMID:38637532 SUPPORT DIRECT PRIMARY RESULT Model Organism

"synaptic transmission is nearly abolished"

Fly electroretinogram result.

Impaired Neuromuscular Function

Mechanism confidence: Provisional

Fly depletion models show reduced climbing and altered muscle organization. The contribution of a direct muscle defect versus central neuronal dysfunction to patient hypotonia and gait problems is uncertain.

Downstream

Hypotonia Experimental neuromuscular dysfunction offers a candidate route to patient reduced tone.

Gait Disturbance Altered neuronal and muscle function may contribute to gait and balance abnormalities.

Ataxia Disordered neuronal control of movement may contribute to impaired coordination; the anatomical substrate has not been identified.

Show evidence (2 references)

PMID:41251503 SUPPORT DIRECT PRIMARY RESULT Model Organism

"flies with depleted cdk8 present with significant climbing defects compared to control flies"

Model neuromuscular phenotype.

PMID:41251503 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Under these experimental conditions, ubiquitous depletion of cdk8 yields reduced lifespan, climbing defects, and muscle and mitochondrial dysmorphology."

Supports the altered muscle organization clause alongside the climbing defect.

⬡

Pathograph

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

●

Phenotypes

45

Digestive 1

Constipation HP:0002019

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Her clinical features, including hypotonia, ataxia, mouthing behaviors, constipation, seizures, hand flapping, and absent speech"

Reported in the adult Thr196Ala founding case; population frequency and mechanistic specificity remain uncertain.

Eye 7

Ophthalmologic anomalies Abnormality of the eye HP:0000478

Coarse binding: variable spectrum

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Ophthalmological abnormalities were frequent (64%) including strabismus"

The clinical spectrum includes strabismus, refractive error, optic atrophy and cortical blindness; individual components are curated separately.

Context-specific annotations (1)

Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals FREQUENT

9/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Ophthalmological abnormalities were frequent (64%) including strabismus"

Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.

Strabismus HP:0000486

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)"

Reported in the selected 14-person 2021 series; not an obligatory finding.

Context-specific annotations (1)

Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals FREQUENT

7/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)"

Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.

Refractive Error Abnormality of refraction HP:0000539

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)"

Reported in the selected 14-person 2021 series; not an obligatory finding.

Context-specific annotations (1)

Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals OCCASIONAL

3/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)"

Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.

Optic Atrophy HP:0000648

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)"

Reported in the selected 14-person 2021 series; not an obligatory finding.

Context-specific annotations (1)

Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals OCCASIONAL

1/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)"

Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.

Cortical Blindness Cerebral visual impairment HP:0100704

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)"

Reported in the selected 14-person 2021 series; not an obligatory finding.

Context-specific annotations (1)

Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals OCCASIONAL

1/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)"

Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.

Hypertelorism HP:0000316

Show evidence (1 reference)

PMID:33134521 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She had distinct facial dysmorphism characterized by hypertelorism, a prominent nose with a bulbous tip, and a large mouth with widely spaced teeth."

Reported in the Tyr32His case and other affected individuals; facial configuration is variable.

Hypotelorism HP:0000601

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Dysmorphic facial features, including hypotelorism and a prominent nose with a bulbous tip, were observed in proband 2."

Hypotelorism was present in two founding Thr196Ala cases, whereas hypertelorism occurs in others.

Head and Neck 10

Microcephaly HP:0000252

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The head circumference was normal except in one subject, who had signi ﬁcant microcephaly"

Microcephaly occurs in some cases, including acquired microcephaly in the adult Thr196Ala case and marked microcephaly in one newly described 2021 individual. Most in the broader series had normal head circumference.

Dysmorphic features Abnormal facial shape HP:0001999

Coarse binding: variable spectrum

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Dysmorphic features Yes Yes Yes Yes Yes Yes Yes 14/14 (100%)"

Variable facial differences were recorded in all 14 individuals in the 2021 series; individual facial components and their variability are represented below.

Context-specific annotations (1)

Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals OBLIGATE

14/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Dysmorphic features Yes Yes Yes Yes Yes Yes Yes 14/14 (100%)"

Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.

Coarse Facial Features HP:0000280

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Common features included full lips, coarsening of face, thick alea nasi, hypertelorism, low nasal bridge"

One of the variably expressed facial findings illustrated in the 2021 cohort.

Thick Vermilion Border HP:0012471

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Common features included full lips, coarsening of face, thick alea nasi, hypertelorism, low nasal bridge"

One of the variably expressed facial findings illustrated in the 2021 cohort.

Thick Nasal Alae HP:0009928

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Common features included full lips, coarsening of face, thick alea nasi, hypertelorism, low nasal bridge"

One of the variably expressed facial findings illustrated in the 2021 cohort.

Depressed Nasal Bridge HP:0005280

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Common features included full lips, coarsening of face, thick alea nasi, hypertelorism, low nasal bridge"

One of the variably expressed facial findings illustrated in the 2021 cohort.

Bulbous Nose HP:0000414

Show evidence (1 reference)

PMID:33134521 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She had distinct facial dysmorphism characterized by hypertelorism, a prominent nose with a bulbous tip, and a large mouth with widely spaced teeth."

Reported in the Tyr32His case and other affected individuals; facial configuration is variable.

Wide Mouth HP:0000154

Show evidence (1 reference)

PMID:33134521 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She had distinct facial dysmorphism characterized by hypertelorism, a prominent nose with a bulbous tip, and a large mouth with widely spaced teeth."

Reported in the Tyr32His case and other affected individuals; facial configuration is variable.

Widely Spaced Teeth HP:0000687

Show evidence (1 reference)

PMID:33134521 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She had distinct facial dysmorphism characterized by hypertelorism, a prominent nose with a bulbous tip, and a large mouth with widely spaced teeth."

Reported in the Tyr32His case and other affected individuals; facial configuration is variable.

High Palate HP:0000218

Show evidence (1 reference)

PMID:33568421 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"hypertelorism, a prominent nose with a bulbous tip and low nasal bridge, and high-arched palate"

Palatal finding in the Thr31Asn case.

Metabolism 4

Peripheral Edema HP:0012398

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"edema of hands and feet was present in three individuals"

Edema of the hands and feet was described in three individuals. A lymphatic mechanism was not established in the missense cohort.

Context-specific annotations (1)

Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals OCCASIONAL

3/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"edema of hands and feet was present in three individuals"

Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.

Increased CSF Protein Increased CSF protein concentration HP:0002922

Show evidence (1 reference)

PMID:33134521 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The CSF examinations performed at 3 years 8 months and at 3 years 11 months reproduced hyperproteinorrachia."

Observed in one Tyr32His patient. The CSF/plasma glycine ratio was normal and GLDC/AMT testing was negative. This is not a validated diagnostic biomarker or proof of nonketotic hyperglycinemia.

Increased CSF Glycine Increased CSF glycine concentration HP:0500230

Show evidence (1 reference)

PMID:33134521 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"moderate elevation of glycine concentration in the CSF and plasma were identified"

Observed in one Tyr32His patient. The CSF/plasma glycine ratio was normal and GLDC/AMT testing was negative. This is not a validated diagnostic biomarker or proof of nonketotic hyperglycinemia.

Hyperglycinemia HP:0002154

Show evidence (1 reference)

PMID:33134521 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"moderate elevation of glycine concentration in the CSF and plasma were identified"

Observed in one Tyr32His patient. The CSF/plasma glycine ratio was normal and GLDC/AMT testing was negative. This is not a validated diagnostic biomarker or proof of nonketotic hyperglycinemia.

Musculoskeletal 4

Hypotonia HP:0001252

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hypotonia Yes Yes No Yes Yes Yes Yes 11/14 (79%)"

Hypotonia often begins in infancy and can be profound. It was present in 11 of 14 individuals in the combined 2021 series.

Context-specific annotations (1)

Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals FREQUENT

11/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hypotonia Yes Yes No Yes Yes Yes Yes 11/14 (79%)"

Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.

Joint Hypermobility HP:0001382

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"she has significant joint laxity resulting in many joint dislocations and a history of severe pica"

Reported in the adult Thr196Ala founding case; population frequency and mechanistic specificity remain uncertain.

Joint Dislocation HP:0001373

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"she has significant joint laxity resulting in many joint dislocations and a history of severe pica"

Reported in the adult Thr196Ala founding case; population frequency and mechanistic specificity remain uncertain.

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She has mild scoliosis. Her neurological exam was notable for acquired microcephaly"

Reported in the adult Thr196Ala founding case; population frequency and mechanistic specificity remain uncertain.

Nervous System 18

Global developmental delay HP:0001263

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Development delay Yes Yes Yes Yes Yes Yes Yes 14/14 (100%)"

Developmental delay was reported in all 14 individuals in the 2021 series, with variable severity; this selected cohort does not establish complete penetrance.

Context-specific annotations (1)

Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals OBLIGATE

14/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Development delay Yes Yes Yes Yes Yes Yes Yes 14/14 (100%)"

Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.

Delayed Speech and Language Development HP:0000750

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Speech Delay Nonverbal Nonverbal Nonverbal Minimal delay Nonverbal Nonverbal Delayed 13/13 (100%)"

Speech delay ranged from minimal delay to profound language impairment. All 13 assessed individuals in Table 1 were affected.

Context-specific annotations (1)

Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals OBLIGATE

13/13 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Speech Delay Nonverbal Nonverbal Nonverbal Minimal delay Nonverbal Nonverbal Delayed 13/13 (100%)"

Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.

Absent Speech HP:0001344

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"8/11 individuals 3 years or older were nonverbal"

Eight of 11 individuals aged at least three years were nonverbal in the 2021 series; the age-restricted denominator is important.

Context-specific annotations (1)

Individuals aged at least three years in the 2021 clinical series FREQUENT

8/11 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"8/11 individuals 3 years or older were nonverbal"

Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.

Intellectual Disability HP:0001249

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Proband 1 is currently a 25-year-old female with a long-standing history of severe developmental delay and intellectual disability."

Intellectual disability, including severe disability in the adult founding case, accompanies the developmental disorder. Young children were not all assessable for intellectual disability.

Seizures HP:0001250

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Seizures were present in 64% including four individuals with infantile spasms"

Epilepsy was reported in nine of 14 individuals in the 2021 cohort; this 64% figure is for seizures, not specifically epileptic encephalopathy. Seizure types and treatment response vary.

Context-specific annotations (1)

Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals FREQUENT

9/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Seizures were present in 64% including four individuals with infantile spasms"

Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.

Epileptic Encephalopathy HP:0200134

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features."

Severe developmental and epileptic encephalopathy occurs in a subset, including the founding cases. It is not an obligatory presentation of all CDK19 missense variants.

Infantile Spasms HP:0012469

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Seizures were present in 64% including four individuals with infantile spasms"

Infantile spasms were reported in four of the 14 individuals assessed in 2021; onset at four to nine months is described in individual reports.

Context-specific annotations (1)

Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals OCCASIONAL

4/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Seizures were present in 64% including four individuals with infantile spasms"

Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.

Hypsarrhythmia HP:0002521

Show evidence (1 reference)

PMID:33134521 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The diagnosis of IS was confirmed by hypsarrhythmia on interictal EEG."

Hypsarrhythmia is documented in children with infantile spasms, including the Tyr32His CSF case.

Developmental Regression HP:0002376

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"At 15 months of age, she developed generalized tonic-clonic seizures that were refractory to multiple anti-epileptic medications and led to neurologic regression with loss of speech."

The adult Thr196Ala case lost previously acquired speech after seizure onset at 15 months. This individual course does not establish progressive degeneration throughout the disorder.

Autistic behavior HP:0000729

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Autistic behavior Autistic traits No No No Autism N/A N/A Autism 5/9 (56%)"

Autism or autistic traits were reported in five of nine assessed individuals, rather than five of all 14; formal diagnostic status and assessment varied.

Context-specific annotations (1)

Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals FREQUENT

5/9 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Autistic behavior Autistic traits No No No Autism N/A N/A Autism 5/9 (56%)"

Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.

Gait Disturbance HP:0001288

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Abnormal gait/balance No Yes No No Yes No No 6/14 (43%)"

Gait or balance abnormalities were present in six of 14 individuals. Some affected children had not yet attained independent walking.

Context-specific annotations (1)

Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals FREQUENT

6/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Abnormal gait/balance No Yes No No Yes No No 6/14 (43%)"

Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.

Ataxia HP:0001251

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Her clinical features, including hypotonia, ataxia, mouthing behaviors, constipation, seizures, hand flapping, and absent speech"

Ataxia and a wide-based gait were described in the adult Thr196Ala case.

Hyporeflexia HP:0001265

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Her neurological exam was notable for acquired microcephaly, absent speech, diffuse hypotonia, symmetrically reduced reflexes"

Symmetrically reduced reflexes occurred in the adult founding case.

Brain Atrophy HP:0012444

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"brain atrophy being the most common in three individuals"

Brain atrophy occurred in three of 14 individuals in the 2021 aggregate. Serial imaging in a separate Tyr32His case showed nonprogressive atrophy and white-matter abnormalities; atrophy alone does not establish ongoing neurodegeneration.

Context-specific annotations (1)

Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals OCCASIONAL

3/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"brain atrophy being the most common in three individuals"

Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.

Thin Corpus Callosum HP:0033725

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Other ﬁndings included thinning of the corpus callosum, delayed myelination, and ventriculomegaly"

A variably reported MRI finding; no reliable feature-specific frequency is available.

Delayed CNS Myelination HP:0002188

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Other ﬁndings included thinning of the corpus callosum, delayed myelination, and ventriculomegaly"

A variably reported MRI finding; no reliable feature-specific frequency is available.

Ventriculomegaly HP:0002119

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Other ﬁndings included thinning of the corpus callosum, delayed myelination, and ventriculomegaly"

A variably reported MRI finding; no reliable feature-specific frequency is available.

Pica HP:0011856

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"she has significant joint laxity resulting in many joint dislocations and a history of severe pica"

Reported in the adult Thr196Ala founding case; population frequency and mechanistic specificity remain uncertain.

Growth 1

Tall Stature HP:0000098

Show evidence (1 reference)

PMID:33134521 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Tall stature was also identified as another physical feature encountered in our case and 1 of the 3 patients in the previous report."

Accelerated linear growth was noted in two Tyr32His cases, suggesting a possible allele-associated feature; the small case count does not establish a genotype-phenotype correlation.

🧬

Genetic Associations

1

CDK19 (Heterozygous de novo kinase-domain missense variants cause a variable neurodevelopmental disorder. Recurrent alleles cluster in the glycine-rich ATP-binding loop and activation segment. The direction of biochemical activity and the ability to substitute for fly Cdk8 depend on allele and assay. Neither a universal loss-of-function mechanism nor simple haploinsufficiency explains all reported variants.)

Gene: CDK19 hgnc:19338 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal Dominant

Show evidence (2 references)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We identified three unrelated individuals with de novo missense variants in CDK19"

Human case-level evidence for the de novo disorder.

PMID:33495529 SUPPORT DIRECT PRIMARY RESULT In Vitro

"kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein."

Opposite biochemical effects do not support a uniformly decreased activity annotation.

Variants (6)

p.Gly28Arg

Recurrent ATP-loop substitution encoded by c.82G>C or c.82G>A in the 2021 cohort. Autophosphorylation and substrate phosphorylation are reduced.

Show evidence (1 reference)

PMID:33495529 SUPPORT DIRECT PRIMARY RESULT In Vitro

"kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein."

Measured biochemical effects.

c.94T>C (p.Tyr32His)

Recurrent ATP-loop allele with increased activity in biochemical assays. It fails stringent fly rescue assays but restores selected functions under milder knockdown conditions; lifespan and myofibril defects can remain.

Show evidence (4 references)

PMID:41251503 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Y32H can functionally compensate for Cdk8 depletion in a manner similar to wild-type CDK19."

Supports restoration of selected functions under the milder knockdown conditions of this study.

PMID:41251503 SUPPORT DIRECT BACKGROUND Model Organism

"Y32H and T196A were unable to rescue lethality caused by cdk8 deficiency or aberrant phenotypes caused by severe cdk8 depletion in the way that wild-type CDK19 could"

Restates the earlier stringent rescue result (lethality and severe depletion) that Tyr32His failed.

PMID:41251503 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Expression of wild-type CDK19 in the cdk8 depleted background rescued lifespan with 50% viability climbing to around day 46, while the Y32H and T196A backgrounds reached 50% viability around day 27 and day 12 respectively"

Lifespan is not restored by Tyr32His.

+ 1 more reference

c.586A>G (p.Thr196Ala)

Activation-segment substitution in two founding patients. It fails functional rescue and decreases Drp1 phosphorylation in the sensitized fly model; a dominant-negative mechanism is proposed but not directly established in human cells.

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"p.Thr196Ala identified in probands 1 and 2"

Recurrent founding allele.

c.92C>A (p.Thr31Asn) Likely Pathogenic

De novo variant classified as likely pathogenic in the infantile-spasm case. ATP-pocket effects were modeled computationally; kinase activity was not directly measured in that report.

Show evidence (1 reference)

PMID:33568421 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We identified a novel de novo missense variant c.92C > A (p.Thr31Asn) in CDK19 that was classified as a likely pathogenic disease-causing variant."

Case-level classification and variant identity.

Additional kinase-domain substitutions

The 2021 series also reports p.Gly28Ala, p.Tyr32Cys, p.Phe197Leu, p.Trp198Cys and p.Arg200Trp. Direct biochemical results for Gly28Arg or Tyr32His should not be assigned to each untested allele.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The additional substitutions reported here, p.Phe197Leu, p.Trp198Cys, and p.Arg200Trp"

Activation-segment variants in the primary cohort.

Historical CDK19-disrupting pericentric inversion

A de novo inversion with a breakpoint mapped within intron 1 was associated with reduced CDK19 RNA in EBV-transformed lymphoblasts. Its retinal/microcephaly phenotype and dosage mechanism should be considered separately from the better-supported kinase-domain missense series.

Show evidence (1 reference)

PMID:20563892 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The transcript level for CDK19 in the patient was found to be 54% (p = 0.022) when compared with the control mean"

Measured transcript decrease in the inversion case; not a direct kinase assay.

💊

Medical Actions

7

Antiseizure Pharmacotherapy

Action: Anticonvulsant Therapy NCIT:C64172

Agent: valproic acid CHEBI:39867 clonazepam CHEBI:3756 topiramate CHEBI:63631 levetiracetam CHEBI:6437 lamotrigine CHEBI:6367

Platform: Small molecule

Antiseizure regimens are individualized. Reported agents include valproate, clonazepam, topiramate, levetiracetam and lamotrigine, often in combination. Some patients remain drug resistant; a transient partial response to topiramate in the Thr31Asn case does not establish sustained or allele-specific efficacy.

Target Phenotypes: Seizure HP:0001250

Show evidence (4 references)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Current antiepileptic medications include daily valproic acid and clonazepam as needed."

Documented regimen; seizure control remained incomplete.

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Currently, a combination of sodium valproate, topiramate, and lamotrigine are being used."

Combination use does not isolate efficacy of any one agent.

PMID:32330417 REFUTE DIRECT PRIMARY RESULT Human Clinical

"At 16 months of age, levetiracetam was added but was ineffective."

Negative evidence for successful seizure control in the reported individual; it does not establish lack of benefit in every patient.

+ 1 more reference

ACTH for Infantile Spasms

Action: Pharmacotherapy NCIT:C15986

Agent: corticotropin CHEBI:3892

Platform: Peptide

ACTH was tried for infantile spasms or severe early epilepsy. It failed to control seizures in one Thr196Ala child and was stopped after one week in a Tyr32His child because of an intercurrent infection and immunosuppression concerns. The latter is a tolerability/interruption observation, not proof of inefficacy.

Target Phenotypes: Infantile spasms HP:0012469

Show evidence (2 references)

PMID:32330417 REFUTE DIRECT PRIMARY RESULT Human Clinical

"Parenteral adrenocorticotropic hormone (ACTH) injections and oral antiepileptic drugs, including sodium valproate and topiramate, failed to control the seizures."

Negative evidence for successful seizure control in the reported individual; it does not establish lack of benefit in every patient.

PMID:32330417 NO_EVIDENCE DIRECT PRIMARY RESULT Human Clinical

"After he was given ACTH for 1 week, the drug was stopped because of a concomitant infection and immunosuppression concerns."

Treatment was interrupted for infection and immunosuppression concerns, so this observation does not establish efficacy or inefficacy.

Ketogenic Diet

Action: Ketogenic Diet NCIT:C173168

Platform: Behavioral / lifestyle

Responses differ between reported cases. The adult Thr196Ala patient previously responded well, whereas another Thr196Ala child and the Tyr32His CSF case had no adequate seizure response. These uncontrolled observations do not identify a uniformly effective or ineffective diet.

Target Phenotypes: Seizure HP:0001250

Show evidence (3 references)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Her seizures had previously responded well to a ketogenic diet."

Reported benefit in one patient.

PMID:32330417 REFUTE DIRECT PRIMARY RESULT Human Clinical

"A ketogenic diet was tried but did not help to control seizures."

Negative evidence for successful seizure control in the reported individual; it does not establish lack of benefit in every patient.

PMID:33134521 REFUTE DIRECT PRIMARY RESULT Human Clinical

"Her epilepsy was refractory to conventional antiepileptic drugs and ketogenic diet."

Negative evidence for successful seizure control in the reported individual; it does not establish lack of benefit in every patient.

Dextromethorphan (Unsuccessful Case Trial)

Action: Pharmacotherapy NCIT:C15986

Agent: dextromethorphan CHEBI:4470

Platform: Small molecule

An NMDA-receptor antagonist was used at age four years in the Tyr32His patient with elevated CSF and plasma glycine, without clinical success. This is not an established treatment for CDK19-related disorder, and a glycine-driven mechanism remains unconfirmed.

Target Phenotypes: Seizure HP:0001250

Show evidence (1 reference)

PMID:33134521 REFUTE DIRECT PRIMARY RESULT Human Clinical

"Oral dextromethorphan administration was initiated at 4 years of age but was unsuccessful."

Negative evidence for successful seizure control in the reported individual; it does not establish lack of benefit in every patient.

N-Acetylcysteine Amide (Experimental Fly Intervention)

Action: Pharmacotherapy NCIT:C15986

Agent: N-Acetylcysteine amide CHEBI:231847

Platform: Small molecule

Dietary N-acetylcysteine amide (NACA), distinct from N-acetylcysteine, reduced muscle ROS in Thr196Ala-expressing flies and shortened mitochondria across all tested genotypes. Myofibril width was not rescued. The proportion reaching the climbing endpoint did not significantly improve, although per-assay climbing distributions showed mild improvement. No human efficacy or seizure benefit was tested.

Mechanism Target:

INHIBITS Elevated Cellular Oxidative Stress — Reduced DHE fluorescence in the sensitized Thr196Ala fly background; human translation is untested.

Show evidence (1 reference)

PMID:41251503 SUPPORT DIRECT PRIMARY RESULT Model Organism

"expression of T196A is contributing to elevated muscular ROS that NACA can suppress"

Model-specific antioxidant effect.

Show evidence (2 references)

PMID:41251503 SUPPORT DIRECT PRIMARY RESULT Model Organism

"NACA can indiscriminately induce mitochondrial fission in all backgrounds regardless of the mitochondrial morphology and counteract the T196A failure to rescue the cdk8 depletion mitochondrial morphology"

Supports the shortened mitochondria across all tested fly genotypes; an experimental fly exposure, not a human dose recommendation.

PMID:41251503 REFUTE DIRECT PRIMARY RESULT Model Organism

"there is no significant difference in the adult IFM myofibril width from adults raised with or without NACA supplementation"

Refutes structural myofibril rescue by NACA. The ROS and mitochondrial effects are separate readouts supported by their own evidence.

Supportive Developmental and Mobility Care

Action: Supportive Care NCIT:C15747

Platform: Other

Care addresses developmental, communication and mobility needs. Orthotics helped the adult founding patient attain walking at age five; that observation does not establish the efficacy of a specific rehabilitation protocol.

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She walked at 5 years of age with the help of orthotics."

Individual mobility-support observation.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Variant interpretation and parental testing inform counseling. Most reported missense cases are de novo, but a negative parental blood result does not exclude germline mosaicism. A quantitative recurrence or penetrance estimate is not established by these reports.

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We identified three unrelated individuals with de novo missense variants in CDK19"

De novo case evidence informs counseling; this is not a measured recurrence-risk estimate.

🔬

Diagnosis

5

Molecular Diagnosis and Parental Testing

Trio exome or genome sequencing identified heterozygous de novo kinase-domain missense variants. Earlier nondiagnostic testing does not exclude CDK19 disease. Variant assessment should integrate phenotype, inheritance and allele-specific evidence rather than treating any rare CDK19 variant as causal.

Whole Exome Sequencing NCIT:C101295

Show evidence (2 references)

PMID:33134521 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"identified using trio-based whole-exome sequencing"

Trio sequencing confirmed the recurrent Tyr32His allele.

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"a de novo coding variant was identified in CDK19"

Genome-based diagnosis in the founding adult.

Electroencephalography

EEG characterizes seizure type and epileptic encephalopathy. Hypsarrhythmia, sometimes with burst suppression, occurs in affected infants; an EEG abnormality is not required in individuals without epilepsy.

Electroencephalography NCIT:C38054

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Electroencephalogram (EEG) showed hypsarrhythmia with burst suppression."

Documented infant EEG finding.

Brain MRI

Imaging may demonstrate atrophy, thin corpus callosum, delayed myelination or ventriculomegaly. Findings are variable and nonspecific; a normal scan does not exclude the disorder. Atrophy was stable on repeat imaging in one Tyr32His patient.

Magnetic Resonance Imaging NCIT:C16809

Show evidence (1 reference)

PMID:33134521 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Nonprogressive brain atrophy was concomitant with white matter abnormalities that were suggestive of delayed myelination."

Serial imaging in one case.

Ophthalmologic Assessment

Eye evaluation characterizes strabismus, refractive errors, optic atrophy and cortical visual impairment. These are overlapping clinical findings rather than a unique diagnostic signature.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)"

Multiple ocular findings in the clinical cohort.

Biochemical Assessment of Atypical Cases

One Tyr32His case had persistently elevated CSF protein and later elevated CSF/plasma glycine, prompting evaluation for nonketotic hyperglycinemia. These case-specific results do not establish a screening biomarker or justify routine invasive CSF testing for every CDK19 diagnosis.

Show evidence (1 reference)

PMID:33134521 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The CSF/plasma glycine ratio was normal, and genetic testing for GLDC and AMT, the responsible genes for nonketotic hyperglycinemia (NKH), was negative."

The reported case was not confirmed to have NKH.

📊

Prevalence

1

Published missense-variant cases assessed in the 2021 study

Cases In Literature

The study assembled 11 new individuals and three previously reported individuals. This is a dated, selected clinical series, not population prevalence; later case reports should not be counted as independent without checking overlap.

Show evidence (1 reference)

PMID:33495529 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We describe 11 unrelated individuals (age range: 9 months to 14 years) with de novo missense variants mapped to the kinase domain of CDK19"

Defines the newly reported series; the 14-person aggregate includes the three founding cases.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from CDK19-Related Disorder:

Angelman Syndrome

Overlapping Features Severe speech impairment, ataxia, mouthing and hand-flapping behaviors in the adult Thr196Ala case resembled Angelman syndrome. Appropriate Angelman molecular testing was negative before CDK19 diagnosis.

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"were considered to be similar to those of Angelman syndrome (MIM: 105830), but genetic testing for that syndrome was negative."

Documented diagnostic overlap, not a proposed alternative in molecularly confirmed CDK19 disease.

Nonketotic Hyperglycinemia

Overlapping Features Elevated glycine prompted this differential in a Tyr32His case, but normal CSF/plasma ratio and negative GLDC/AMT testing did not support that diagnosis. The source does not establish glycine-cleavage deficiency as a CDK19 mechanism.

Show evidence (1 reference)

PMID:33134521 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The CSF/plasma glycine ratio was normal, and genetic testing for GLDC and AMT, the responsible genes for nonketotic hyperglycinemia (NKH), was negative."

Case-specific differential workup.

🧫

Experimental Models

3

HEK293 CDK19 Autophosphorylation Assay CELL_LINE

Immunoprecipitated kinase was assayed for autophosphorylation. Gly28Arg had lower and Tyr32His higher activity than reference CDK19; the Tyr32His increase was statistically significant in this assay.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Transfected HEK293 cells expressing reference or variant CDK19 with cyclin C

Publication

PMID:33495529

Pathograph links

Reduced CDK19 Kinase Activity measures fidelity: moderate observes: molecular Measures allele-dependent catalytic output.

Limitations: Overexpression in a nonneuronal line and autophosphorylation do not define the complete neuronal phenotype.

Show evidence (1 reference)

PMID:33495529 SUPPORT DIRECT PRIMARY RESULT In Vitro

"kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein."

Variant catalytic assay.

Increased CDK19 Kinase Activity measures fidelity: moderate observes: molecular Measures allele-dependent catalytic output.

Limitations: Overexpression in a nonneuronal line and autophosphorylation do not define the complete neuronal phenotype.

Show evidence (1 reference)

PMID:33495529 SUPPORT DIRECT PRIMARY RESULT In Vitro

"kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein."

Variant catalytic assay.

Show evidence (1 reference)

PMID:33495529 SUPPORT DIRECT PRIMARY RESULT In Vitro

"kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein."

Variant catalytic assay.

Reconstituted CDK19 Kinase Module OTHER

Purified modules phosphorylated recombinant RNA-polymerase-II CTD and STAT1 substrates. Gly28Arg reduced substrate phosphorylation despite retained module assembly; Tyr32His increased catalytic output.

Cell source

Baculovirus-produced recombinant human CDK19, cyclin C, MED12 and MED13 complex

Publication

PMID:33495529

Pathograph links

Reduced CDK19 Kinase Activity measures fidelity: moderate observes: molecular Purified-complex substrate phosphorylation provides a biochemical readout.

Limitations: Artificial substrate concentrations and reconstituted complexes do not establish a patient transcriptional signature.

Show evidence (1 reference)

PMID:33495529 SUPPORT DIRECT PRIMARY RESULT In Vitro

"kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein."

Variant catalytic assay.

Increased CDK19 Kinase Activity measures fidelity: moderate observes: molecular Purified-complex substrate phosphorylation provides a biochemical readout.

Limitations: Artificial substrate concentrations and reconstituted complexes do not establish a patient transcriptional signature.

Show evidence (1 reference)

PMID:33495529 SUPPORT DIRECT PRIMARY RESULT In Vitro

"kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein."

Variant catalytic assay.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT In Vitro

"this mutant still can form the complex with other subunits (cyclin C, MED12, and MED13)"

Gly28Arg complex assembly remains possible.

S2R+ Cdk8–Drp1 Interaction and Kinase Assay CELL_LINE

Cytoplasmic Cdk8/Drp1 immunoprecipitates show protein association and ATP-dependent Drp1 Ser616 phosphorylation. An associated kinase cannot be excluded by an immunoprecipitate experiment alone.

Organism

Drosophila melanogaster NCBITaxon:7227

Cell source

Transfected Drosophila S2R+ insect cells

Publication

PMID:38637532

Pathograph links

Reduced Drp1 Phosphorylation measures fidelity: low observes: molecular Measures the Cdk8-associated Drp1 phosphorylation reaction relevant to the proposed route.

Limitations: Uses fly Cdk8 rather than isolated human CDK19, and neither patient variant is tested.

Show evidence (1 reference)

PMID:38637532 SUPPORT DIRECT PRIMARY RESULT In Vitro

"phosphorylation of co-immunoprecipitated cytoplasmic Drp1 is significantly elevated in the presence of ATP"

ATP-dependent in-vitro phosphorylation.

Show evidence (1 reference)

PMID:38637532 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Drp1 was pulled down with Cdk8 in the Myc-tagged Cdk8 immunoprecipitation (IP), while Drp1 was absent from the control IgG IP. Cdk8 was also pulled down in the reciprocal pulldown using HA-tagged Drp1"

Reciprocal co-immunoprecipitation in transfected S2R+ cells shows the Cdk8-Drp1 association.

🐁

Animal Models

6

Fly Sensory-Neuron Cdk8 Knockdown

Larval type-IV multidendritic sensory neurons have fewer branches and reduced dendritic fields after Cdk8 knockdown. One fly ortholog represents functions divided between mammalian CDK8 and CDK19.

Species

Drosophila melanogaster

Genotype

477-Gal4-directed Cdk8 RNA interference, two independent constructs

Publication

PMID:20563892

Pathograph links

Impaired Dendritic Arborization partially recapitulates fidelity: moderate observes: cellular Reduced dendritic branching after endogenous Cdk8 depletion.

Limitations: Knockdown is not a patient missense allele, and fly sensory neurons do not model all human cortical cell types.

Show evidence (1 reference)

PMID:20563892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Quantification of dendritic branching revealed a 35% reduction (p < 0.001) in dendrite ends upon Cdk8 knockdown"

Sensory-neuron branching assay.

Show evidence (1 reference)

PMID:20563892 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Quantification of dendritic branching revealed a 35% reduction (p < 0.001) in dendrite ends upon Cdk8 knockdown"

Sensory-neuron branching assay.

Fly Cdk8 Null and Strong Neuronal Depletion with Human Rescue

Reference human CDK19 rescues stringent complementation, neuronal bang sensitivity and shortened lifespan; the two patient variants fail these readouts. Neuronal depletion reduces NMJ boutons. Glial depletion did not reproduce neuronal lethality or locomotor/lifespan defects.

Species

Drosophila melanogaster

Genotype

Cdk8-null or neuronal Cdk8 RNA interference; reference, Tyr32His or Thr196Ala human CDK19 transgenes

Publication

PMID:32330417

Pathograph links

Impaired CDK19 Functional Complementation partially recapitulates fidelity: moderate observes: cellular Reference but not variant CDK19 restores the severe depletion/null phenotype.

Limitations: A sensitized ortholog-loss/transgene assay is not an endogenous human heterozygous allele and does not prove dominant-negative interaction.

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Model Organism

"expression of either CDK19 p.Tyr32His or p.Thr196Ala failed to rescue the lethality."

Variant complementation failure.

Reduced Synaptic Bouton Formation partially recapitulates fidelity: moderate observes: cellular Neuronal Cdk8 depletion reduces bouton number.

Limitations: Larval motor synapses differ from human cortical networks; branch number was unchanged.

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Model Organism

"we observed a significant decrease (~30%) in the total number of boutons"

Synapse-development readout.

Show evidence (1 reference)

PMID:32330417 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Flies that lost Cdk8 in neurons exhibit strong bang sensitivity"

Seizure-like fly stress response.

Fly Tissue-Specific Cdk8 Depletion and Cytoplasmic CDK19 Rescue

Tissue-specific depletion perturbs mitochondrial morphology, neuronal energy state and synaptic transmission. Cytoplasmically targeted human CDK19 rescues several phenotypes, supporting a nonnuclear function. These experiments precede the direct comparison of patient variants.

Species

Drosophila melanogaster

Genotype

Neuronal or muscle Cdk8 RNA interference; human CDK19WT or CDK19ΔNLS transgenes

Publication

PMID:38637532

Pathograph links

Impaired Mitochondrial Fission rescues fidelity: moderate observes: cellular Cytoplasmic human CDK19 rescues the knockdown mitochondrial morphology.

Limitations: Fly ortholog depletion and transgenic rescue do not establish mitochondrial abnormalities in patient neurons.

Show evidence (1 reference)

PMID:38637532 SUPPORT DIRECT PRIMARY RESULT Model Organism

"These results show that cytoplasmic CDK19 is sufficient to regulate mitochondrial morphology."

Nonnuclear rescue.

Impaired Synaptic Transmission partially recapitulates fidelity: moderate observes: cellular Photoreceptor synaptic transients are severely reduced while response amplitudes are retained.

Limitations: A visual synapse assay does not directly measure epileptic network activity.

Show evidence (1 reference)

PMID:38637532 SUPPORT DIRECT PRIMARY RESULT Model Organism

"synaptic transmission is nearly abolished"

Electroretinographic readout.

Show evidence (1 reference)

PMID:38637532 SUPPORT DIRECT PRIMARY RESULT Model Organism

"These results show that cytoplasmic CDK19 is sufficient to regulate mitochondrial morphology."

Nonnuclear rescue.

Fly Sensitized Cdk8 Depletion with Tyr32His or Thr196Ala

The milder 25°C background preserves approximately 30% endogenous cdk8 expression. Tyr32His rescues climbing and mitochondrial length but not lifespan or myofibril width; Thr196Ala has broader defects and increased muscle ROS. More severe 29°C eclosion experiments impair both variants. Antioxidant NACA lowers Thr196Ala ROS with partial, readout-dependent benefits.

Species

Drosophila melanogaster

Genotype

da-Gal4-driven ubiquitous Cdk8 RNA interference plus human reference, Tyr32His or Thr196Ala CDK19

Publication

PMID:41251503

Pathograph links

Impaired CDK19 Functional Complementation partially recapitulates fidelity: moderate observes: cellular Complementation varies by variant, residual ortholog expression and measured trait.

Limitations: Driver, temperature and RNAi strength change the phenotype. Neither construct recreates a patient heterozygous genomic state.

Show evidence (1 reference)

PMID:41251503 SUPPORT DIRECT PRIMARY RESULT Model Organism

"both variants are unable to rescue the cdk8 depletion muscle myofibril thickening as the wild-type CDK19 can"

Persistent muscle-width defect despite selective rescue of other readouts.

Reduced Drp1 Phosphorylation partially recapitulates fidelity: moderate observes: cellular Thr196Ala lowers the Drp1 phospho-readout in this sensitized background.

Limitations: Tyr32His upward trend was nonsignificant; mild depletion alone did not lower this readout.

Show evidence (1 reference)

PMID:41251503 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the pDrp1:Drp1 ratio is significantly lower in the T196A background"

Variant-dependent phospho-readout.

Elevated Cellular Oxidative Stress rescues fidelity: moderate observes: cellular NACA suppresses the elevated muscle ROS of Thr196Ala flies.

Limitations: Biochemical rescue is not clinical efficacy or evidence that every motor phenotype is ROS dependent.

Show evidence (1 reference)

PMID:41251503 SUPPORT DIRECT PRIMARY RESULT Model Organism

"expression of T196A is contributing to elevated muscular ROS that NACA can suppress"

Experimental rescue.

Show evidence (1 reference)

PMID:41251503 SUPPORT DIRECT PRIMARY RESULT Model Organism

"both variants are unable to rescue the cdk8 depletion muscle myofibril thickening as the wild-type CDK19 can"

Persistent muscle-width defect despite selective rescue of other readouts.

Zebrafish CDK19 mRNA Overexpression

At five days postfertilization, approximately 35% of Gly28Arg-injected and 45% of Tyr32His-injected embryos had abnormalities, versus 17% after reference CDK19 mRNA. Short body axis, hypoplastic anterior structures, abnormal tails and increased lethality support developmental perturbation but do not reproduce human epilepsy.

Species

Danio rerio

Genotype

One-cell injection of human wild-type, Gly28Arg or Tyr32His CDK19 mRNA

Publication

PMID:33495529

Pathograph links

CDK19 Coding Missense Substitutions perturbs fidelity: low observes: organism Tests developmental effects of coding-variant overexpression.

Limitations: Wild-type overexpression itself is abnormal in a subset. Dosage and injection toxicity limit mechanistic inference; endogenous heterozygous alleles were not tested.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Model Organism

"injection of CDK19 mRNA with the Tyr32His variant and the Gly28Arg variant markedly ... increased the fraction of embryos with these morphological changes to 45%"

Developmental perturbation from mRNA overexpression.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Model Organism

"injection of CDK19 mRNA with the Tyr32His variant and the Gly28Arg variant markedly ... increased the fraction of embryos with these morphological changes to 45%"

Developmental perturbation from mRNA overexpression.

Zebrafish cdk8 and cdk19 Morpholino Knockdown

Combined morpholino knockdown produced more head abnormalities than either single knockdown, suggesting partially overlapping developmental functions. This is transient knockdown, not a genomic knockout or a patient-variant model.

Species

Danio rerio

Genotype

cdk8 and/or cdk19 morpholino-mediated knockdown

Publication

PMID:33495529

Pathograph links

Impaired CDK19 Functional Complementation perturbs fidelity: low observes: organism Perturbs partially redundant kinase functions during development.

Limitations: No patient allele or epileptic phenotype was tested; morpholino effects and paralog depletion differ from human de novo missense variation.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Model Organism

"Double knockdown of cdk8 and cdk19 (cdk8/19) showed anatomical defects, especially in the head region"

Combined ortholog depletion.

Show evidence (1 reference)

url:https://www.nature.com/articles/s41436-020-01091-9.pdf SUPPORT DIRECT PRIMARY RESULT Model Organism

"Double knockdown of cdk8 and cdk19 (cdk8/19) showed anatomical defects, especially in the head region"

Combined ortholog depletion.

🧮

Computational Models

1

Thr31Asn CDK19–Cyclin C Structural Prediction STRUCTURAL_PREDICTION

PyMOL-based structural analysis places Thr31 near ATP-positioning residues in the glycine-rich loop. Reduced ATP affinity and kinase activity were proposed, not measured. The paper also speculated that Tyr32His would reduce activity, which is not supported by the separate biochemical assays showing increased catalytic output.

PMID:33568421

Pathograph links

Reduced CDK19 Kinase Activity measures fidelity: low observes: molecular Predicts an impaired ATP-binding/catalytic consequence for Thr31Asn.

Limitations: Computational localization and structural speculation do not demonstrate catalytic loss or prove a dominant-negative effect.

Show evidence (1 reference)

PMID:33568421 SUPPORT DIRECT PRIMARY RESULT Computational

"We built a CDK19 protein model in complex with cyclin C with the presence of ATP using the program PyMOL"

Protein structural model.

Show evidence (1 reference)

PMID:33568421 SUPPORT DIRECT PRIMARY RESULT Computational

"We built a CDK19 protein model in complex with cyclin C with the presence of ATP using the program PyMOL"

Protein structural model.

{ }

Source YAML

click to show

name: CDK19-Related Disorder
creation_date: '2026-07-31T00:00:00Z'
category: Mendelian
synonyms:
- Developmental and epileptic encephalopathy 87
- DEE87
- CDK19-related developmental and epileptic encephalopathy
- CDK19-associated neurodevelopmental disorder
description: >-
  CDK19-related disorder is an autosomal dominant neurodevelopmental condition associated primarily with de novo missense variants in the kinase domain of CDK19. Developmental and speech impairment, hypotonia, variable craniofacial differences, ophthalmologic abnormalities and behavioral features occur with or without epilepsy. Some patients have severe developmental and epileptic encephalopathy with infantile spasms; seizures are not obligatory. Functional effects depend on allele and assay: Gly28Arg reduces and Tyr32His increases kinase activity in biochemical assays, while fly complementation varies with the tissue and degree of endogenous Cdk8 depletion. Altered transcriptional regulation and cytoplasmic mitochondrial/synaptic dysfunction are candidate contributors, but neither is fully established in patient neurons. Management is individualized and supportive. Antioxidant findings remain confined to experimental flies.
disease_term:
  preferred_term: Developmental and epileptic encephalopathy 87
  term:
    id: MONDO:0030059
    label: developmental and epileptic encephalopathy, 87
parents:
- Autosomal dominant intellectual disability
- Neurodevelopmental disorder
- CDK8-kinase module-associated disorder
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:32330417
      reference_title: "De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified three unrelated individuals with de novo missense variants in CDK19"
      explanation: Supports classification as a heritable genetic disorder caused by de novo CDK19 variants.
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:32330417
      reference_title: "De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features."
      explanation: Supports classification as a neurodevelopmental / neurologic disorder with epileptic encephalopathy.
prevalence:
- population: Published missense-variant cases assessed in the 2021 study
  measure_type: CASES_IN_LITERATURE
  notes: The study assembled 11 new individuals and three previously reported individuals. This is a dated, selected clinical series, not population prevalence; later case reports should not be counted as independent without checking overlap.
  evidence:
  - reference: PMID:33495529
    reference_title: CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'We describe 11 unrelated individuals (age range: 9 months to 14 years) with de novo missense variants mapped to the kinase domain of CDK19'
    explanation: Defines the newly reported series; the 14-person aggregate includes the three founding cases.
pathophysiology:
- name: CDK19 Coding Missense Substitutions
  description: Heterozygous coding single-nucleotide substitutions alter conserved residues of the kinase domain, particularly the glycine-rich loop and activation segment. This physical variant class is distinct from its allele-dependent functional consequences.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:33495529
    reference_title: CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'We describe 11 unrelated individuals (age range: 9 months to 14 years) with de novo missense variants mapped to the kinase domain of CDK19'
    explanation: Physical missense variants in the clinical series.
  role: trigger
  gene:
    preferred_term: CDK19
    term:
      id: hgnc:19338
      label: CDK19
  genetic_context:
    gene:
      preferred_term: CDK19
      term:
        id: hgnc:19338
        label: CDK19
    variant_type: single nucleotide variant
    variant_origin: GERMLINE
    genomic_contexts:
    - coding sequence
    notes: Heterozygous de novo variants in the primary series.
  downstream:
  - target: Reduced CDK19 Kinase Activity
    description: Gly28Arg reduces catalytic output in biochemical assays.
    causal_link_type: DIRECT
  - target: Increased CDK19 Kinase Activity
    description: Tyr32His increases catalytic output in biochemical assays.
    causal_link_type: DIRECT
  - target: Impaired CDK19 Functional Complementation
    description: Several variants fail to replace endogenous fly Cdk8 under defined experimental conditions; this does not by itself identify a dominant-negative mechanism.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced CDK19 Kinase Activity
  description: Gly28Arg reduces autophosphorylation and phosphorylation of recombinant RNA-polymerase-II CTD and STAT1. The mutant can still assemble with cyclin C, MED12 and MED13 in the purified module; defective catalysis does not require wholesale loss of the complex.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:33495529
    reference_title: CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein.
    explanation: Direct comparison of variant kinase activities.
  role: central_effector
  gene:
    preferred_term: CDK19
    term:
      id: hgnc:19338
      label: CDK19
    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: Altered Transcriptional Regulation
    description: Altered phosphorylation of transcription-associated substrates provides a plausible route to dysregulated gene expression; patient neuronal transcriptional consequences remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Increased CDK19 Kinase Activity
  description: Tyr32His increases autophosphorylation and substrate phosphorylation in the reported biochemical assays. This increase does not guarantee preserved function in every developmental or cellular readout.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:33495529
    reference_title: CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein.
    explanation: Direct comparison of variant kinase activities.
  role: central_effector
  gene:
    preferred_term: CDK19
    term:
      id: hgnc:19338
      label: CDK19
    modifier: GAIN_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: INCREASED
  downstream:
  - target: Altered Transcriptional Regulation
    description: Altered phosphorylation of transcription-associated substrates provides a plausible route to dysregulated gene expression; patient neuronal transcriptional consequences remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired CDK19 Functional Complementation
  description: Tyr32His and Thr196Ala fail to rescue severe fly Cdk8 depletion or null phenotypes. In milder knockdown conditions, Tyr32His rescues climbing and mitochondrial morphology while failing to normalize lifespan and myofibril width; Thr196Ala remains broadly impaired. A dominant-negative mechanism is a hypothesis rather than proof of interaction with the human wild-type allele.
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: expression of either CDK19 p.Tyr32His or p.Thr196Ala failed to rescue the lethality.
    explanation: Failure of stringent complementation.
  - reference: PMID:41251503
    reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: both variants are unable to rescue the cdk8 depletion muscle myofibril thickening as the wild-type CDK19 can
    explanation: Persistent phenotype despite selective Tyr32His rescue elsewhere.
  gene:
    preferred_term: CDK19
    term:
      id: hgnc:19338
      label: CDK19
  downstream:
  - target: Reduced Drp1 Phosphorylation
    description: Thr196Ala lowers the Drp1 phospho-readout in the sensitized fly background; competition with endogenous Cdk8 is proposed, not directly demonstrated.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired Dendritic Arborization
    description: Fly depletion and rescue studies link deficient CDK19/Cdk8 function to neuronal arbor and synapse defects.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Reduced Synaptic Bouton Formation
    description: Fly neuronal depletion reduces the number of synaptic boutons.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Altered Transcriptional Regulation
  description: CDK19 is a Mediator-associated transcriptional kinase. Variant-dependent phosphorylation changes can alter transcription, but an abnormal neuronal expression program has not been directly delineated in these patients. The cytoplasmic rescue experiments indicate that transcription alone need not account for every phenotype.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:33568421
    reference_title: A novel variant of CDK19 causes a severe neurodevelopmental disorder with infantile spasms.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: We assumed that the disruption of CDK19 kinase activity by pathogenic variants impaired the total transcriptional activity for the CDK module
    explanation: Explicitly proposed transcriptional mechanism.
  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 Dendritic Arborization
    description: Transcriptional dysregulation may disturb neuronal development; the specific intervening gene program has not been established.
    causal_link_type: UNKNOWN
- name: Reduced Drp1 Phosphorylation
  description: Fly Cdk8 depletion can reduce Drp1 Ser616 phosphorylation. Thr196Ala expression reduces this readout in a milder knockdown background where depletion alone does not. Tyr32His shows only a nonsignificant upward trend in that experiment. Direct phosphorylation by an isolated human CDK19 protein was not demonstrated.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:38637532
    reference_title: Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the data show that Cdk8 interacts with Drp1 and promotes phosphorylation of Drp1 at S616
    explanation: Fly protein interaction and phosphorylation support the route.
  - reference: PMID:41251503
    reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the pDrp1:Drp1 ratio is significantly lower in the T196A background
    explanation: Variant-specific fly result.
  downstream:
  - target: Impaired Mitochondrial Fission
    description: Reduced activation of the fission regulator can shift mitochondrial morphology toward fused or elongated networks.
    causal_link_type: DIRECT
- name: Impaired Mitochondrial Fission
  description: Cdk8 depletion produces elongated muscle mitochondria and abnormal neuronal mitochondrial organization. Wild-type and cytoplasmically targeted human CDK19 rescue these defects. Thr196Ala fails to rescue muscle mitochondrial morphology, while Tyr32His can rescue it under milder conditions. A mitochondrial lesion in human patient neurons remains unconfirmed.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:38637532
    reference_title: Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These results show that cytoplasmic CDK19 is sufficient to regulate mitochondrial morphology.
    explanation: Cytoplasmic rescue supports a mechanism beyond nuclear transcription.
  - reference: PMID:41251503
    reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: expression of T196A fails to rescue the mitochondrial dysmorphology
    explanation: Variant-specific complementation outcome.
  biological_processes:
  - preferred_term: mitochondrial fission
    term:
      id: GO:0000266
      label: mitochondrial fission
    modifier: DECREASED
  downstream:
  - target: Reduced Synaptic Mitochondrial Availability
    description: Altered mitochondrial organization can impair transport or retention at neuronal terminals.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Mitochondrial Energetic Stress
    description: Abnormal mitochondrial dynamics accompanies impaired energy production in the neuronal depletion model.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Elevated Cellular Oxidative Stress
    description: Mitochondrial defects can contribute to elevated ROS; their causal contribution has not been isolated in the human variant model.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced Synaptic Mitochondrial Availability
  description: Fly neuronal Cdk8 depletion redistributes mitochondria toward cell bodies and reduces their presence at photoreceptor terminals. The retinal readout is experimental and does not establish a matching patient retinal lesion.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:38637532
    reference_title: Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the number of mitochondria is reduced in photoreceptor terminals
    explanation: Subcellular distribution in the fly model.
  downstream:
  - target: Impaired Synaptic Transmission
    description: Insufficient local mitochondrial support may limit energy-dependent synaptic function.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Mitochondrial Energetic Stress
  description: Neuronal Cdk8 depletion increases mitochondrial Hsp60 and reduces ATP in fly heads. Patient biochemical evidence for this route is lacking.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:38637532
    reference_title: Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we quantified mitochondrial stress by measuring the level of the mitochondrial stress protein Hsp60 ... mitochondrial stress is significantly increased in adult brains. Furthermore, the function of mitochondria is also affected as the ATP synthesis level is significantly reduced upon depletion of Cdk8
    explanation: Neuronal Cdk8 depletion raises the Hsp60 stress marker and reduces ATP synthesis in the fly model.
  downstream:
  - target: Impaired Synaptic Transmission
    description: Reduced energy availability can compromise neurotransmission.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Elevated Cellular Oxidative Stress
  description: ROS is elevated in strong tissue-specific Cdk8 depletion and in the Thr196Ala sensitized fly model. It is not elevated in every knockdown or variant condition. Patient tissue ROS has not been measured in these studies.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:41251503
    reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a significant increase in the mean DHE fluorescent intensity for the escaper T196A flies
    explanation: Increased oxidative-stress readout in the variant model.
  downstream:
  - target: Impaired Neuromuscular Function
    description: Oxidative stress may contribute to dysfunction; antioxidant rescue is partial and assay dependent.
    causal_link_type: UNKNOWN
- name: Impaired Dendritic Arborization
  description: Two fly Cdk8 RNA-interference constructs reduce sensory-neuron dendritic branching. This supports a conserved developmental function but is not patient-neuron histology or a missense-specific assay.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:20563892
    reference_title: CDK19 is disrupted in a female patient with bilateral congenital retinal folds, microcephaly and mild mental retardation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Quantification of dendritic branching revealed a 35% reduction (p < 0.001) in dendrite ends upon Cdk8 knockdown
    explanation: Larval sensory-neuron readout.
  biological_processes:
  - preferred_term: dendrite development
    term:
      id: GO:0016358
      label: dendrite development
    modifier: DECREASED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Global developmental delay
    description: Defective neuronal development provides a candidate explanation for developmental impairment.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Delayed Speech and Language Development
    description: Altered neural circuit development may contribute to language impairment.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intellectual Disability
    description: Neuronal developmental dysfunction is a candidate substrate of intellectual disability.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Absent Speech
    description: Abnormal neural circuit development may contribute to profound language impairment.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced Synaptic Bouton Formation
  description: Neuronal fly Cdk8 depletion reduces neuromuscular-junction boutons by approximately 30% without reducing branch number. This is a distinct synaptic-development readout, not a human histological finding.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we observed a significant decrease (~30%) in the total number of boutons
    explanation: Larval neuromuscular-junction readout.
  biological_processes:
  - preferred_term: synapse organization
    term:
      id: GO:0050808
      label: synapse organization
    modifier: DYSREGULATED
  downstream:
  - target: Impaired Synaptic Transmission
    description: Reduced synaptic connectivity may compromise circuit communication.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Synaptic Transmission
  description: Neuronal Cdk8 depletion nearly abolishes fly electroretinogram on/off transients while preserving response amplitudes, supporting deficient synaptic communication rather than loss of phototransduction. Translation to human seizure networks remains provisional.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:38637532
    reference_title: Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: synaptic transmission is nearly abolished
    explanation: Fly electroretinogram result.
  downstream:
  - target: Seizures
    description: Abnormal neuronal communication may promote network dysfunction, but epileptogenesis has not been directly mapped in patient neurons.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypotonia
    description: Neuronal signaling abnormalities may contribute to reduced tone.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Epileptic Encephalopathy
    description: Abnormal network activity may add an epileptic component to developmental impairment; the patient-specific circuit mechanism remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Developmental Regression
    description: Seizure-associated network dysfunction may contribute to acquired skill loss in the reported case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Neuromuscular Function
  description: Fly depletion models show reduced climbing and altered muscle organization. The contribution of a direct muscle defect versus central neuronal dysfunction to patient hypotonia and gait problems is uncertain.
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:41251503
    reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: flies with depleted cdk8 present with significant climbing defects compared to control flies
    explanation: Model neuromuscular phenotype.
  - reference: PMID:41251503
    reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Under these experimental conditions, ubiquitous depletion of cdk8 yields reduced lifespan, climbing defects, and muscle and mitochondrial dysmorphology.
    explanation: Supports the altered muscle organization clause alongside the climbing defect.
  downstream:
  - target: Hypotonia
    description: Experimental neuromuscular dysfunction offers a candidate route to patient reduced tone.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Gait Disturbance
    description: Altered neuronal and muscle function may contribute to gait and balance abnormalities.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ataxia
    description: Disordered neuronal control of movement may contribute to impaired coordination; the anatomical substrate has not been identified.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
# Frequency bands are taken from the quantitative 14-individual cohort in PMID:33495529
# (universal developmental delay and facial dysmorphism; hypotonia 79%, seizures 64%,
# ophthalmologic anomalies 64%, autism/autistic traits 56%), not from the undifferentiated
# 3-individual narrative in PMID:32330417.
- name: Global developmental delay
  category: Neurologic
  description: Developmental delay was reported in all 14 individuals in the 2021 series, with variable severity; this selected cohort does not establish complete penetrance.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Development delay Yes Yes Yes Yes Yes Yes Yes 14/14 (100%)
    explanation: Developmental delay was reported in all 14 individuals in the 2021 series, with variable severity; this selected cohort does not establish complete penetrance.
  phenotype_contexts:
  - population: 'Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals'
    frequency: OBLIGATE
    notes: 14/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Development delay Yes Yes Yes Yes Yes Yes Yes 14/14 (100%)
      explanation: Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.
- name: Delayed Speech and Language Development
  category: Neurologic
  description: Speech delay ranged from minimal delay to profound language impairment. All 13 assessed individuals in Table 1 were affected.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Speech Delay Nonverbal Nonverbal Nonverbal Minimal delay Nonverbal Nonverbal Delayed 13/13 (100%)
    explanation: Speech delay ranged from minimal delay to profound language impairment. All 13 assessed individuals in Table 1 were affected.
  phenotype_contexts:
  - population: 'Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals'
    frequency: OBLIGATE
    notes: 13/13 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Speech Delay Nonverbal Nonverbal Nonverbal Minimal delay Nonverbal Nonverbal Delayed 13/13 (100%)
      explanation: Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.
- name: Absent Speech
  category: Neurologic
  description: Eight of 11 individuals aged at least three years were nonverbal in the 2021 series; the age-restricted denominator is important.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 8/11 individuals 3 years or older were nonverbal
    explanation: Eight of 11 individuals aged at least three years were nonverbal in the 2021 series; the age-restricted denominator is important.
  phenotype_contexts:
  - population: Individuals aged at least three years in the 2021 clinical series
    frequency: FREQUENT
    notes: 8/11 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: 8/11 individuals 3 years or older were nonverbal
      explanation: Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.
- name: Intellectual Disability
  category: Neurologic
  description: Intellectual disability, including severe disability in the adult founding case, accompanies the developmental disorder. Young children were not all assessable for intellectual disability.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Proband 1 is currently a 25-year-old female with a long-standing history of severe developmental delay and intellectual disability.
    explanation: Intellectual disability, including severe disability in the adult founding case, accompanies the developmental disorder. Young children were not all assessable for intellectual disability.
- name: Hypotonia
  category: Neurologic
  description: Hypotonia often begins in infancy and can be profound. It was present in 11 of 14 individuals in the combined 2021 series.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hypotonia Yes Yes No Yes Yes Yes Yes 11/14 (79%)
    explanation: Hypotonia often begins in infancy and can be profound. It was present in 11 of 14 individuals in the combined 2021 series.
  phenotype_contexts:
  - population: 'Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals'
    frequency: FREQUENT
    notes: 11/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Hypotonia Yes Yes No Yes Yes Yes Yes 11/14 (79%)
      explanation: Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.
- name: Seizures
  category: Neurologic
  description: Epilepsy was reported in nine of 14 individuals in the 2021 cohort; this 64% figure is for seizures, not specifically epileptic encephalopathy. Seizure types and treatment response vary.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Seizures were present in 64% including four individuals with infantile spasms
    explanation: Epilepsy was reported in nine of 14 individuals in the 2021 cohort; this 64% figure is for seizures, not specifically epileptic encephalopathy. Seizure types and treatment response vary.
  phenotype_contexts:
  - population: 'Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals'
    frequency: FREQUENT
    notes: 9/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Seizures were present in 64% including four individuals with infantile spasms
      explanation: Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.
- name: Epileptic Encephalopathy
  category: Neurologic
  description: Severe developmental and epileptic encephalopathy occurs in a subset, including the founding cases. It is not an obligatory presentation of all CDK19 missense variants.
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features.
    explanation: Severe developmental and epileptic encephalopathy occurs in a subset, including the founding cases. It is not an obligatory presentation of all CDK19 missense variants.
- name: Infantile Spasms
  category: Neurologic
  description: Infantile spasms were reported in four of the 14 individuals assessed in 2021; individual reports describe onset during early infancy.
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Seizures were present in 64% including four individuals with infantile spasms
    explanation: Infantile spasms were reported in four of the 14 individuals assessed in 2021; onset at four to nine months is described in individual reports.
  phenotype_contexts:
  - population: 'Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals'
    frequency: OCCASIONAL
    notes: 4/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Seizures were present in 64% including four individuals with infantile spasms
      explanation: Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.
- name: Hypsarrhythmia
  category: Neurologic
  description: Hypsarrhythmia is documented in children with infantile spasms, including the Tyr32His CSF case.
  phenotype_term:
    preferred_term: Hypsarrhythmia
    term:
      id: HP:0002521
      label: Hypsarrhythmia
  evidence:
  - reference: PMID:33134521
    reference_title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The diagnosis of IS was confirmed by hypsarrhythmia on interictal EEG.
    explanation: Hypsarrhythmia is documented in children with infantile spasms, including the Tyr32His CSF case.
- name: Developmental Regression
  category: Neurologic
  description: The adult Thr196Ala case lost previously acquired speech after seizure onset at 15 months. This individual course does not establish progressive degeneration throughout the disorder.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: At 15 months of age, she developed generalized tonic-clonic seizures that were refractory to multiple anti-epileptic medications and led to neurologic regression with loss of speech.
    explanation: The adult Thr196Ala case lost previously acquired speech after seizure onset at 15 months. This individual course does not establish progressive degeneration throughout the disorder.
- name: Autistic behavior
  category: Behavioral
  description: Autism or autistic traits were reported in five of nine assessed individuals, rather than five of all 14; formal diagnostic status and assessment varied.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Autistic behavior Autistic traits No No No Autism N/A N/A Autism 5/9 (56%)
    explanation: Autism or autistic traits were reported in five of nine assessed individuals, rather than five of all 14; formal diagnostic status and assessment varied.
  phenotype_contexts:
  - population: 'Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals'
    frequency: FREQUENT
    notes: 5/9 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Autistic behavior Autistic traits No No No Autism N/A N/A Autism 5/9 (56%)
      explanation: Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.
- name: Gait Disturbance
  category: Neurologic
  description: Gait or balance abnormalities were present in six of 14 individuals. Some affected children had not yet attained independent walking.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Abnormal gait/balance No Yes No No Yes No No 6/14 (43%)
    explanation: Gait or balance abnormalities were present in six of 14 individuals. Some affected children had not yet attained independent walking.
  phenotype_contexts:
  - population: 'Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals'
    frequency: FREQUENT
    notes: 6/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Abnormal gait/balance No Yes No No Yes No No 6/14 (43%)
      explanation: Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.
- name: Ataxia
  category: Neurologic
  description: Ataxia and a wide-based gait were described in the adult Thr196Ala case.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Her clinical features, including hypotonia, ataxia, mouthing behaviors, constipation, seizures, hand flapping, and absent speech
    explanation: Ataxia and a wide-based gait were described in the adult Thr196Ala case.
- name: Hyporeflexia
  category: Neurologic
  description: Symmetrically reduced reflexes occurred in the adult founding case.
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Her neurological exam was notable for acquired microcephaly, absent speech, diffuse hypotonia, symmetrically reduced reflexes
    explanation: Symmetrically reduced reflexes occurred in the adult founding case.
- name: Brain Atrophy
  category: Neurologic
  description: Brain atrophy occurred in three of 14 individuals in the 2021 aggregate. Serial imaging in a separate Tyr32His case showed nonprogressive atrophy and white-matter abnormalities; atrophy alone does not establish ongoing neurodegeneration.
  phenotype_term:
    preferred_term: Brain atrophy
    term:
      id: HP:0012444
      label: Brain atrophy
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: brain atrophy being the most common in three individuals
    explanation: Brain atrophy occurred in three of 14 individuals in the 2021 aggregate. Serial imaging in a separate Tyr32His case showed nonprogressive atrophy and white-matter abnormalities; atrophy alone does not establish ongoing neurodegeneration.
  phenotype_contexts:
  - population: 'Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals'
    frequency: OCCASIONAL
    notes: 3/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: brain atrophy being the most common in three individuals
      explanation: Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.
- name: Thin Corpus Callosum
  category: Neurologic
  description: A variably reported MRI finding; no reliable feature-specific frequency is available.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Other ﬁndings included thinning of the corpus callosum, delayed myelination, and ventriculomegaly
    explanation: A variably reported MRI finding; no reliable feature-specific frequency is available.
- name: Delayed CNS Myelination
  category: Neurologic
  description: A variably reported MRI finding; no reliable feature-specific frequency is available.
  phenotype_term:
    preferred_term: Delayed CNS myelination
    term:
      id: HP:0002188
      label: Delayed CNS myelination
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Other ﬁndings included thinning of the corpus callosum, delayed myelination, and ventriculomegaly
    explanation: A variably reported MRI finding; no reliable feature-specific frequency is available.
- name: Ventriculomegaly
  category: Neurologic
  description: A variably reported MRI finding; no reliable feature-specific frequency is available.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Other ﬁndings included thinning of the corpus callosum, delayed myelination, and ventriculomegaly
    explanation: A variably reported MRI finding; no reliable feature-specific frequency is available.
- name: Microcephaly
  category: Growth
  description: Microcephaly occurs in some cases, including acquired microcephaly in the adult Thr196Ala case and marked microcephaly in one newly described 2021 individual. Most in the broader series had normal head circumference.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The head circumference was normal except in one subject, who had signi ﬁcant microcephaly
    explanation: Microcephaly occurs in some cases, including acquired microcephaly in the adult Thr196Ala case and marked microcephaly in one newly described 2021 individual. Most in the broader series had normal head circumference.
- name: Tall Stature
  category: Growth
  description: Accelerated linear growth was noted in two Tyr32His cases, suggesting a possible allele-associated feature; the small case count does not establish a genotype-phenotype correlation.
  phenotype_term:
    preferred_term: Tall stature
    term:
      id: HP:0000098
      label: Tall stature
  evidence:
  - reference: PMID:33134521
    reference_title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Tall stature was also identified as another physical feature encountered in our case and 1 of the 3 patients in the previous report.
    explanation: Accelerated linear growth was noted in two Tyr32His cases, suggesting a possible allele-associated feature; the small case count does not establish a genotype-phenotype correlation.
- name: Ophthalmologic anomalies
  category: Ophthalmologic
  description: The clinical spectrum includes strabismus, refractive error, optic atrophy and cortical blindness; individual components are curated separately.
  phenotype_term:
    preferred_term: Abnormality of the eye
    term:
      id: HP:0000478
      label: Abnormality of the eye
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Ophthalmological abnormalities were frequent (64%) including strabismus
    explanation: The clinical spectrum includes strabismus, refractive error, optic atrophy and cortical blindness; individual components are curated separately.
  phenotype_contexts:
  - population: 'Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals'
    frequency: FREQUENT
    notes: 9/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Ophthalmological abnormalities were frequent (64%) including strabismus
      explanation: Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.
- name: Strabismus
  category: Ophthalmologic
  description: Reported in the selected 14-person 2021 series; not an obligatory finding.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)
    explanation: Reported in the selected 14-person 2021 series; not an obligatory finding.
  phenotype_contexts:
  - population: 'Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals'
    frequency: FREQUENT
    notes: 7/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)
      explanation: Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.
- name: Refractive Error
  category: Ophthalmologic
  description: Reported in the selected 14-person 2021 series; not an obligatory finding.
  phenotype_term:
    preferred_term: Abnormality of refraction
    term:
      id: HP:0000539
      label: Abnormality of refraction
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)
    explanation: Reported in the selected 14-person 2021 series; not an obligatory finding.
  phenotype_contexts:
  - population: 'Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals'
    frequency: OCCASIONAL
    notes: 3/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)
      explanation: Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.
- name: Optic Atrophy
  category: Ophthalmologic
  description: Reported in the selected 14-person 2021 series; not an obligatory finding.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)
    explanation: Reported in the selected 14-person 2021 series; not an obligatory finding.
  phenotype_contexts:
  - population: 'Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals'
    frequency: OCCASIONAL
    notes: 1/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)
      explanation: Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.
- name: Cortical Blindness
  category: Ophthalmologic
  description: Reported in the selected 14-person 2021 series; not an obligatory finding.
  phenotype_term:
    preferred_term: Cortical blindness
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)
    explanation: Reported in the selected 14-person 2021 series; not an obligatory finding.
  phenotype_contexts:
  - population: 'Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals'
    frequency: OCCASIONAL
    notes: 1/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)
      explanation: Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.
- name: Peripheral Edema
  category: Peripheral vascular
  description: Edema of the hands and feet was described in three individuals. A lymphatic mechanism was not established in the missense cohort.
  phenotype_term:
    preferred_term: Peripheral edema
    term:
      id: HP:0012398
      label: Peripheral edema
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: edema of hands and feet was present in three individuals
    explanation: Edema of the hands and feet was described in three individuals. A lymphatic mechanism was not established in the missense cohort.
  phenotype_contexts:
  - population: 'Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals'
    frequency: OCCASIONAL
    notes: 3/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: edema of hands and feet was present in three individuals
      explanation: Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.
- name: Dysmorphic features
  category: Craniofacial
  description: Variable facial differences were recorded in all 14 individuals in the 2021 series; individual facial components and their variability are represented below.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Dysmorphic features Yes Yes Yes Yes Yes Yes Yes 14/14 (100%)
    explanation: Variable facial differences were recorded in all 14 individuals in the 2021 series; individual facial components and their variability are represented below.
  phenotype_contexts:
  - population: 'Fourteen-person 2021 clinical series: 11 new individuals and three previously reported individuals'
    frequency: OBLIGATE
    notes: 14/14 assessed individuals. This is a selected, partly literature-derived cohort, not a population frequency or penetrance estimate.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Dysmorphic features Yes Yes Yes Yes Yes Yes Yes 14/14 (100%)
      explanation: Cohort finding; numerator and assessed denominator are given in the clinical text or Table 1.
- name: Coarse Facial Features
  category: Craniofacial
  description: One of the variably expressed facial findings illustrated in the 2021 cohort.
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Common features included full lips, coarsening of face, thick alea nasi, hypertelorism, low nasal bridge
    explanation: One of the variably expressed facial findings illustrated in the 2021 cohort.
- name: Thick Vermilion Border
  category: Craniofacial
  description: One of the variably expressed facial findings illustrated in the 2021 cohort.
  phenotype_term:
    preferred_term: Thick vermilion border
    term:
      id: HP:0012471
      label: Thick vermilion border
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Common features included full lips, coarsening of face, thick alea nasi, hypertelorism, low nasal bridge
    explanation: One of the variably expressed facial findings illustrated in the 2021 cohort.
- name: Thick Nasal Alae
  category: Craniofacial
  description: One of the variably expressed facial findings illustrated in the 2021 cohort.
  phenotype_term:
    preferred_term: Thick nasal alae
    term:
      id: HP:0009928
      label: Thick nasal alae
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Common features included full lips, coarsening of face, thick alea nasi, hypertelorism, low nasal bridge
    explanation: One of the variably expressed facial findings illustrated in the 2021 cohort.
- name: Depressed Nasal Bridge
  category: Craniofacial
  description: One of the variably expressed facial findings illustrated in the 2021 cohort.
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Common features included full lips, coarsening of face, thick alea nasi, hypertelorism, low nasal bridge
    explanation: One of the variably expressed facial findings illustrated in the 2021 cohort.
- name: Hypertelorism
  category: Craniofacial
  description: Reported in the Tyr32His case and other affected individuals; facial configuration is variable.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:33134521
    reference_title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She had distinct facial dysmorphism characterized by hypertelorism, a prominent nose with a bulbous tip, and a large mouth with widely spaced teeth.
    explanation: Reported in the Tyr32His case and other affected individuals; facial configuration is variable.
- name: Bulbous Nose
  category: Craniofacial
  description: Reported in the Tyr32His case and other affected individuals; facial configuration is variable.
  phenotype_term:
    preferred_term: Bulbous nose
    term:
      id: HP:0000414
      label: Bulbous nose
  evidence:
  - reference: PMID:33134521
    reference_title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She had distinct facial dysmorphism characterized by hypertelorism, a prominent nose with a bulbous tip, and a large mouth with widely spaced teeth.
    explanation: Reported in the Tyr32His case and other affected individuals; facial configuration is variable.
- name: Wide Mouth
  category: Craniofacial
  description: Reported in the Tyr32His case and other affected individuals; facial configuration is variable.
  phenotype_term:
    preferred_term: Wide mouth
    term:
      id: HP:0000154
      label: Wide mouth
  evidence:
  - reference: PMID:33134521
    reference_title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She had distinct facial dysmorphism characterized by hypertelorism, a prominent nose with a bulbous tip, and a large mouth with widely spaced teeth.
    explanation: Reported in the Tyr32His case and other affected individuals; facial configuration is variable.
- name: Widely Spaced Teeth
  category: Craniofacial
  description: Reported in the Tyr32His case and other affected individuals; facial configuration is variable.
  phenotype_term:
    preferred_term: Widely spaced teeth
    term:
      id: HP:0000687
      label: Widely spaced teeth
  evidence:
  - reference: PMID:33134521
    reference_title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She had distinct facial dysmorphism characterized by hypertelorism, a prominent nose with a bulbous tip, and a large mouth with widely spaced teeth.
    explanation: Reported in the Tyr32His case and other affected individuals; facial configuration is variable.
- name: Hypotelorism
  category: Craniofacial
  description: Hypotelorism was present in two founding Thr196Ala cases, whereas hypertelorism occurs in others.
  phenotype_term:
    preferred_term: Hypotelorism
    term:
      id: HP:0000601
      label: Hypotelorism
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Dysmorphic facial features, including hypotelorism and a prominent nose with a bulbous tip, were observed in proband 2.
    explanation: Hypotelorism was present in two founding Thr196Ala cases, whereas hypertelorism occurs in others.
- name: Joint Hypermobility
  category: Musculoskeletal
  description: Reported in the adult Thr196Ala founding case; population frequency and mechanistic specificity remain uncertain.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: she has significant joint laxity resulting in many joint dislocations and a history of severe pica
    explanation: Reported in the adult Thr196Ala founding case; population frequency and mechanistic specificity remain uncertain.
- name: Joint Dislocation
  category: Musculoskeletal
  description: Reported in the adult Thr196Ala founding case; population frequency and mechanistic specificity remain uncertain.
  phenotype_term:
    preferred_term: Joint dislocation
    term:
      id: HP:0001373
      label: Joint dislocation
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: she has significant joint laxity resulting in many joint dislocations and a history of severe pica
    explanation: Reported in the adult Thr196Ala founding case; population frequency and mechanistic specificity remain uncertain.
- name: Pica
  category: Behavioral
  description: Reported in the adult Thr196Ala founding case; population frequency and mechanistic specificity remain uncertain.
  phenotype_term:
    preferred_term: Pica
    term:
      id: HP:0011856
      label: Pica
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: she has significant joint laxity resulting in many joint dislocations and a history of severe pica
    explanation: Reported in the adult Thr196Ala founding case; population frequency and mechanistic specificity remain uncertain.
- name: Scoliosis
  category: Musculoskeletal
  description: Reported in the adult Thr196Ala founding case; population frequency and mechanistic specificity remain uncertain.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She has mild scoliosis. Her neurological exam was notable for acquired microcephaly
    explanation: Reported in the adult Thr196Ala founding case; population frequency and mechanistic specificity remain uncertain.
- name: Constipation
  category: Gastrointestinal
  description: Reported in the adult Thr196Ala founding case; population frequency and mechanistic specificity remain uncertain.
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Her clinical features, including hypotonia, ataxia, mouthing behaviors, constipation, seizures, hand flapping, and absent speech
    explanation: Reported in the adult Thr196Ala founding case; population frequency and mechanistic specificity remain uncertain.
- name: Increased CSF Protein
  category: Laboratory
  description: Observed in one Tyr32His patient. The CSF/plasma glycine ratio was normal and GLDC/AMT testing was negative. This is not a validated diagnostic biomarker or proof of nonketotic hyperglycinemia.
  phenotype_term:
    preferred_term: Increased CSF protein concentration
    term:
      id: HP:0002922
      label: Increased CSF protein concentration
  evidence:
  - reference: PMID:33134521
    reference_title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The CSF examinations performed at 3 years 8 months and at 3 years 11 months reproduced hyperproteinorrachia.
    explanation: Observed in one Tyr32His patient. The CSF/plasma glycine ratio was normal and GLDC/AMT testing was negative. This is not a validated diagnostic biomarker or proof of nonketotic hyperglycinemia.
- name: Increased CSF Glycine
  category: Laboratory
  description: Observed in one Tyr32His patient. The CSF/plasma glycine ratio was normal and GLDC/AMT testing was negative. This is not a validated diagnostic biomarker or proof of nonketotic hyperglycinemia.
  phenotype_term:
    preferred_term: Increased CSF glycine concentration
    term:
      id: HP:0500230
      label: Increased CSF glycine concentration
  evidence:
  - reference: PMID:33134521
    reference_title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: moderate elevation of glycine concentration in the CSF and plasma were identified
    explanation: Observed in one Tyr32His patient. The CSF/plasma glycine ratio was normal and GLDC/AMT testing was negative. This is not a validated diagnostic biomarker or proof of nonketotic hyperglycinemia.
- name: Hyperglycinemia
  category: Laboratory
  description: Observed in one Tyr32His patient. The CSF/plasma glycine ratio was normal and GLDC/AMT testing was negative. This is not a validated diagnostic biomarker or proof of nonketotic hyperglycinemia.
  phenotype_term:
    preferred_term: Hyperglycinemia
    term:
      id: HP:0002154
      label: Hyperglycinemia
  evidence:
  - reference: PMID:33134521
    reference_title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: moderate elevation of glycine concentration in the CSF and plasma were identified
    explanation: Observed in one Tyr32His patient. The CSF/plasma glycine ratio was normal and GLDC/AMT testing was negative. This is not a validated diagnostic biomarker or proof of nonketotic hyperglycinemia.
- name: High Palate
  category: Craniofacial
  description: A high-arched palate was reported in the Tyr32His and Thr31Asn cases.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:33568421
    reference_title: A novel variant of CDK19 causes a severe neurodevelopmental disorder with infantile spasms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: hypertelorism, a prominent nose with a bulbous tip and low nasal bridge, and high-arched palate
    explanation: Palatal finding in the Thr31Asn case.
genetic:
- name: CDK19
  association: Heterozygous de novo kinase-domain missense variants cause a variable neurodevelopmental disorder. Recurrent alleles cluster in the glycine-rich ATP-binding loop and activation segment. The direction of biochemical activity and the ability to substitute for fly Cdk8 depend on allele and assay. Neither a universal loss-of-function mechanism nor simple haploinsufficiency explains all reported variants.
  gene_term:
    preferred_term: CDK19
    term:
      id: hgnc:19338
      label: CDK19
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:32330417
      reference_title: "De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified three unrelated individuals with de novo missense variants in CDK19"
      explanation: Heterozygous de novo CDK19 missense variants are consistent with autosomal dominant inheritance.
    description: The missense series consists predominantly of confirmed de novo heterozygous variants. A de novo result does not make recurrence risk zero because parental germline mosaicism cannot be excluded; penetrance and family recurrence rates have not been quantified.
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We identified three unrelated individuals with de novo missense variants in CDK19
    explanation: Human case-level evidence for the de novo disorder.
  - reference: PMID:33495529
    reference_title: CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein.
    explanation: Opposite biochemical effects do not support a uniformly decreased activity annotation.
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: G2P classifies the autosomal dominant CDK19–DEE87 relationship as Strong (evaluated 14 January 2025; GenCC SGC-123798.1). ClinGen has not published its own CDK19 validity curation. An earlier pericentric chromosome-6 inversion disrupted CDK19 and reduced transcript abundance in a patient with retinal folds, microcephaly and milder intellectual disability; that single structural case does not establish that all deletions or truncating alleles cause the missense-associated syndrome.
  gene_disease_validity:
  - validity_classification: STRONG
    classified_by: G2P
    external_id: G2P02961
    notes: G2P assertion represented by GenCC SGC-123798.1; evaluated 2025-01-14. Historical classifications by other submitters differ.
    evidence:
    - reference: url:https://thegencc.org/submissions/SGC-123798.1
      reference_title: CDK19 | developmental and epileptic encephalopathy, 87 | Autosomal dominant by G2P submission information facts
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: 'Classification: ... Strong ... Gene: ... CDK19 ... Disease: ... developmental and epileptic encephalopathy, 87'
      explanation: Records the external G2P assertion, not a new dismech validity assessment.
  variants:
  - name: p.Gly28Arg
    description: Recurrent ATP-loop substitution encoded by c.82G>C or c.82G>A in the 2021 cohort. Autophosphorylation and substrate phosphorylation are reduced.
    evidence:
    - reference: PMID:33495529
      reference_title: CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein.
      explanation: Measured biochemical effects.
  - name: c.94T>C (p.Tyr32His)
    description: Recurrent ATP-loop allele with increased activity in biochemical assays. It fails stringent fly rescue assays but restores selected functions under milder knockdown conditions; lifespan and myofibril defects can remain.
    evidence:
    - reference: PMID:41251503
      reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Y32H can functionally compensate for Cdk8 depletion in a manner similar to wild-type CDK19.
      explanation: Supports restoration of selected functions under the milder knockdown conditions of this study.
    - reference: PMID:41251503
      reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      directness: DIRECT
      snippet: Y32H and T196A were unable to rescue lethality caused by cdk8 deficiency or aberrant phenotypes caused by severe cdk8 depletion in the way that wild-type CDK19 could
      explanation: Restates the earlier stringent rescue result (lethality and severe depletion) that Tyr32His failed.
    - reference: PMID:41251503
      reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Expression of wild-type CDK19 in the cdk8 depleted background rescued lifespan with 50% viability climbing to around day 46, while the Y32H and T196A backgrounds reached 50% viability around day 27 and day 12 respectively
      explanation: Lifespan is not restored by Tyr32His.
    - reference: PMID:41251503
      reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: both Y32H and T196A fail to rescue this phenotype as these backgrounds harbour myofibrils significantly thicker than the wild-type CDK19 background
      explanation: The myofibril defect remains with Tyr32His.
  - name: c.586A>G (p.Thr196Ala)
    description: Activation-segment substitution in two founding patients. It fails functional rescue and decreases Drp1 phosphorylation in the sensitized fly model; a dominant-negative mechanism is proposed but not directly established in human cells.
    evidence:
    - reference: PMID:32330417
      reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: p.Thr196Ala identified in probands 1 and 2
      explanation: Recurrent founding allele.
  - name: c.92C>A (p.Thr31Asn)
    description: De novo variant classified as likely pathogenic in the infantile-spasm case. ATP-pocket effects were modeled computationally; kinase activity was not directly measured in that report.
    evidence:
    - reference: PMID:33568421
      reference_title: A novel variant of CDK19 causes a severe neurodevelopmental disorder with infantile spasms.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: We identified a novel de novo missense variant c.92C > A (p.Thr31Asn) in CDK19 that was classified as a likely pathogenic disease-causing variant.
      explanation: Case-level classification and variant identity.
    clinical_significance: LIKELY_PATHOGENIC
  - name: Additional kinase-domain substitutions
    description: The 2021 series also reports p.Gly28Ala, p.Tyr32Cys, p.Phe197Leu, p.Trp198Cys and p.Arg200Trp. Direct biochemical results for Gly28Arg or Tyr32His should not be assigned to each untested allele.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The additional substitutions reported here, p.Phe197Leu, p.Trp198Cys, and p.Arg200Trp
      explanation: Activation-segment variants in the primary cohort.
  - name: Historical CDK19-disrupting pericentric inversion
    description: A de novo inversion with a breakpoint mapped within intron 1 was associated with reduced CDK19 RNA in EBV-transformed lymphoblasts. Its retinal/microcephaly phenotype and dosage mechanism should be considered separately from the better-supported kinase-domain missense series.
    evidence:
    - reference: PMID:20563892
      reference_title: CDK19 is disrupted in a female patient with bilateral congenital retinal folds, microcephaly and mild mental retardation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The transcript level for CDK19 in the patient was found to be 54% (p = 0.022) when compared with the control mean
      explanation: Measured transcript decrease in the inversion case; not a direct kinase assay.
treatments:
- name: Antiseizure Pharmacotherapy
  description: Antiseizure regimens are individualized. Reported agents include valproate, clonazepam, topiramate, levetiracetam and lamotrigine, often in combination. Some patients remain drug resistant; a transient partial response to topiramate in the Thr31Asn case does not establish sustained or allele-specific efficacy.
  therapeutic_modality: SMALL_MOLECULE
  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: clonazepam
      term:
        id: CHEBI:3756
        label: clonazepam
    - preferred_term: topiramate
      term:
        id: CHEBI:63631
        label: topiramate
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
    - preferred_term: lamotrigine
      term:
        id: CHEBI:6367
        label: lamotrigine
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Current antiepileptic medications include daily valproic acid and clonazepam as needed.
    explanation: Documented regimen; seizure control remained incomplete.
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Currently, a combination of sodium valproate, topiramate, and lamotrigine are being used.
    explanation: Combination use does not isolate efficacy of any one agent.
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: At 16 months of age, levetiracetam was added but was ineffective.
    explanation: Negative evidence for successful seizure control in the reported individual; it does not establish lack of benefit in every patient.
  - reference: PMID:33568421
    reference_title: A novel variant of CDK19 causes a severe neurodevelopmental disorder with infantile spasms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: oral treatment with topiramate was able to alleviate seizures for a few months
    explanation: Temporary partial benefit; refractory seizures subsequently persisted.
- name: ACTH for Infantile Spasms
  description: ACTH was tried for infantile spasms or severe early epilepsy. It failed to control seizures in one Thr196Ala child and was stopped after one week in a Tyr32His child because of an intercurrent infection and immunosuppression concerns. The latter is a tolerability/interruption observation, not proof of inefficacy.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticotropin
      term:
        id: CHEBI:3892
        label: corticotropin
  target_phenotypes:
  - preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Parenteral adrenocorticotropic hormone (ACTH) injections and oral antiepileptic drugs, including sodium valproate and topiramate, failed to control the seizures.
    explanation: Negative evidence for successful seizure control in the reported individual; it does not establish lack of benefit in every patient.
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: After he was given ACTH for 1 week, the drug was stopped because of a concomitant infection and immunosuppression concerns.
    explanation: Treatment was interrupted for infection and immunosuppression concerns, so this observation does not establish efficacy or inefficacy.
- name: Ketogenic Diet
  description: Responses differ between reported cases. The adult Thr196Ala patient previously responded well, whereas another Thr196Ala child and the Tyr32His CSF case had no adequate seizure response. These uncontrolled observations do not identify a uniformly effective or ineffective diet.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Ketogenic Diet
    term:
      id: NCIT:C173168
      label: Ketogenic Diet
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Her seizures had previously responded well to a ketogenic diet.
    explanation: Reported benefit in one patient.
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: A ketogenic diet was tried but did not help to control seizures.
    explanation: Negative evidence for successful seizure control in the reported individual; it does not establish lack of benefit in every patient.
  - reference: PMID:33134521
    reference_title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Her epilepsy was refractory to conventional antiepileptic drugs and ketogenic diet.
    explanation: Negative evidence for successful seizure control in the reported individual; it does not establish lack of benefit in every patient.
- name: Dextromethorphan (Unsuccessful Case Trial)
  description: An NMDA-receptor antagonist was used at age four years in the Tyr32His patient with elevated CSF and plasma glycine, without clinical success. This is not an established treatment for CDK19-related disorder, and a glycine-driven mechanism remains unconfirmed.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dextromethorphan
      term:
        id: CHEBI:4470
        label: dextromethorphan
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33134521
    reference_title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Oral dextromethorphan administration was initiated at 4 years of age but was unsuccessful.
    explanation: Negative evidence for successful seizure control in the reported individual; it does not establish lack of benefit in every patient.
- name: N-Acetylcysteine Amide (Experimental Fly Intervention)
  description: Dietary N-acetylcysteine amide (NACA), distinct from N-acetylcysteine, reduced muscle ROS in Thr196Ala-expressing flies and shortened mitochondria across all tested genotypes. Myofibril width was not rescued. The proportion reaching the climbing endpoint did not significantly improve, although per-assay climbing distributions showed mild improvement. No human efficacy or seizure benefit was tested.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: N-Acetylcysteine amide
      term:
        id: CHEBI:231847
        label: N-Acetylcysteine amide
  target_mechanisms:
  - target: Elevated Cellular Oxidative Stress
    treatment_effect: INHIBITS
    description: Reduced DHE fluorescence in the sensitized Thr196Ala fly background; human translation is untested.
    evidence:
    - reference: PMID:41251503
      reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: expression of T196A is contributing to elevated muscular ROS that NACA can suppress
      explanation: Model-specific antioxidant effect.
  evidence:
  - reference: PMID:41251503
    reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: NACA can indiscriminately induce mitochondrial fission in all backgrounds regardless of the mitochondrial morphology and counteract the T196A failure to rescue the cdk8 depletion mitochondrial morphology
    explanation: Supports the shortened mitochondria across all tested fly genotypes; an experimental fly exposure, not a human dose recommendation.
  - reference: PMID:41251503
    reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: there is no significant difference in the adult IFM myofibril width from adults raised with or without NACA supplementation
    explanation: Refutes structural myofibril rescue by NACA. The ROS and mitochondrial effects are separate readouts supported by their own evidence.
- name: Supportive Developmental and Mobility Care
  description: Care addresses developmental, communication and mobility needs. Orthotics helped the adult founding patient attain walking at age five; that observation does not establish the efficacy of a specific rehabilitation protocol.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: She walked at 5 years of age with the help of orthotics.
    explanation: Individual mobility-support observation.
- name: Genetic Counseling
  description: Variant interpretation and parental testing inform counseling. Most reported missense cases are de novo, but a negative parental blood result does not exclude germline mosaicism. A quantitative recurrence or penetrance estimate is not established by these reports.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We identified three unrelated individuals with de novo missense variants in CDK19
    explanation: De novo case evidence informs counseling; this is not a measured recurrence-risk estimate.
diagnosis:
- name: Molecular Diagnosis and Parental Testing
  description: Trio exome or genome sequencing identified heterozygous de novo kinase-domain missense variants. Earlier nondiagnostic testing does not exclude CDK19 disease. Variant assessment should integrate phenotype, inheritance and allele-specific evidence rather than treating any rare CDK19 variant as causal.
  diagnosis_term:
    preferred_term: Whole Exome Sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:33134521
    reference_title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: identified using trio-based whole-exome sequencing
    explanation: Trio sequencing confirmed the recurrent Tyr32His allele.
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a de novo coding variant was identified in CDK19
    explanation: Genome-based diagnosis in the founding adult.
- name: Electroencephalography
  description: EEG characterizes seizure type and epileptic encephalopathy. Hypsarrhythmia, sometimes with burst suppression, occurs in affected infants; an EEG abnormality is not required in individuals without epilepsy.
  diagnosis_term:
    preferred_term: Electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Electroencephalogram (EEG) showed hypsarrhythmia with burst suppression.
    explanation: Documented infant EEG finding.
- name: Brain MRI
  description: Imaging may demonstrate atrophy, thin corpus callosum, delayed myelination or ventriculomegaly. Findings are variable and nonspecific; a normal scan does not exclude the disorder. Atrophy was stable on repeat imaging in one Tyr32His patient.
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:33134521
    reference_title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Nonprogressive brain atrophy was concomitant with white matter abnormalities that were suggestive of delayed myelination.
    explanation: Serial imaging in one case.
- name: Ophthalmologic Assessment
  description: Eye evaluation characterizes strabismus, refractive errors, optic atrophy and cortical visual impairment. These are overlapping clinical findings rather than a unique diagnostic signature.
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: including strabismus ( n = 7), refractive errors ( n = 3), optic nerve atrophy ( n = 1), and/or cortical blindness ( n = 1)
    explanation: Multiple ocular findings in the clinical cohort.
- name: Biochemical Assessment of Atypical Cases
  description: One Tyr32His case had persistently elevated CSF protein and later elevated CSF/plasma glycine, prompting evaluation for nonketotic hyperglycinemia. These case-specific results do not establish a screening biomarker or justify routine invasive CSF testing for every CDK19 diagnosis.
  evidence:
  - reference: PMID:33134521
    reference_title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The CSF/plasma glycine ratio was normal, and genetic testing for GLDC and AMT, the responsible genes for nonketotic hyperglycinemia (NKH), was negative.
    explanation: The reported case was not confirmed to have NKH.
differential_diagnoses:
- name: Angelman Syndrome
  description: Severe speech impairment, ataxia, mouthing and hand-flapping behaviors in the adult Thr196Ala case resembled Angelman syndrome. Appropriate Angelman molecular testing was negative before CDK19 diagnosis.
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'were considered to be similar to those of Angelman syndrome (MIM: 105830), but genetic testing for that syndrome was negative.'
    explanation: Documented diagnostic overlap, not a proposed alternative in molecularly confirmed CDK19 disease.
- name: Nonketotic Hyperglycinemia
  description: Elevated glycine prompted this differential in a Tyr32His case, but normal CSF/plasma ratio and negative GLDC/AMT testing did not support that diagnosis. The source does not establish glycine-cleavage deficiency as a CDK19 mechanism.
  evidence:
  - reference: PMID:33134521
    reference_title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The CSF/plasma glycine ratio was normal, and genetic testing for GLDC and AMT, the responsible genes for nonketotic hyperglycinemia (NKH), was negative.
    explanation: Case-specific differential workup.
animal_models:
- name: Fly Sensory-Neuron Cdk8 Knockdown
  species: Drosophila melanogaster
  genotype: 477-Gal4-directed Cdk8 RNA interference, two independent constructs
  publication: PMID:20563892
  description: Larval type-IV multidendritic sensory neurons have fewer branches and reduced dendritic fields after Cdk8 knockdown. One fly ortholog represents functions divided between mammalian CDK8 and CDK19.
  modeled_mechanisms:
  - target: Impaired Dendritic Arborization
    description: Reduced dendritic branching after endogenous Cdk8 depletion.
    evidence:
    - reference: PMID:20563892
      reference_title: CDK19 is disrupted in a female patient with bilateral congenital retinal folds, microcephaly and mild mental retardation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Quantification of dendritic branching revealed a 35% reduction (p < 0.001) in dendrite ends upon Cdk8 knockdown
      explanation: Sensory-neuron branching assay.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Knockdown is not a patient missense allele, and fly sensory neurons do not model all human cortical cell types.
    fidelity: MODERATE
  evidence:
  - reference: PMID:20563892
    reference_title: CDK19 is disrupted in a female patient with bilateral congenital retinal folds, microcephaly and mild mental retardation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Quantification of dendritic branching revealed a 35% reduction (p < 0.001) in dendrite ends upon Cdk8 knockdown
    explanation: Sensory-neuron branching assay.
- name: Fly Cdk8 Null and Strong Neuronal Depletion with Human Rescue
  species: Drosophila melanogaster
  genotype: Cdk8-null or neuronal Cdk8 RNA interference; reference, Tyr32His or Thr196Ala human CDK19 transgenes
  publication: PMID:32330417
  description: Reference human CDK19 rescues stringent complementation, neuronal bang sensitivity and shortened lifespan; the two patient variants fail these readouts. Neuronal depletion reduces NMJ boutons. Glial depletion did not reproduce neuronal lethality or locomotor/lifespan defects.
  modeled_mechanisms:
  - target: Impaired CDK19 Functional Complementation
    description: Reference but not variant CDK19 restores the severe depletion/null phenotype.
    evidence:
    - reference: PMID:32330417
      reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: expression of either CDK19 p.Tyr32His or p.Thr196Ala failed to rescue the lethality.
      explanation: Variant complementation failure.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: A sensitized ortholog-loss/transgene assay is not an endogenous human heterozygous allele and does not prove dominant-negative interaction.
    fidelity: MODERATE
  - target: Reduced Synaptic Bouton Formation
    description: Neuronal Cdk8 depletion reduces bouton number.
    evidence:
    - reference: PMID:32330417
      reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: we observed a significant decrease (~30%) in the total number of boutons
      explanation: Synapse-development readout.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Larval motor synapses differ from human cortical networks; branch number was unchanged.
    fidelity: MODERATE
  evidence:
  - reference: PMID:32330417
    reference_title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Flies that lost Cdk8 in neurons exhibit strong bang sensitivity
    explanation: Seizure-like fly stress response.
- name: Fly Tissue-Specific Cdk8 Depletion and Cytoplasmic CDK19 Rescue
  species: Drosophila melanogaster
  genotype: Neuronal or muscle Cdk8 RNA interference; human CDK19WT or CDK19ΔNLS transgenes
  publication: PMID:38637532
  description: Tissue-specific depletion perturbs mitochondrial morphology, neuronal energy state and synaptic transmission. Cytoplasmically targeted human CDK19 rescues several phenotypes, supporting a nonnuclear function. These experiments precede the direct comparison of patient variants.
  modeled_mechanisms:
  - target: Impaired Mitochondrial Fission
    description: Cytoplasmic human CDK19 rescues the knockdown mitochondrial morphology.
    evidence:
    - reference: PMID:38637532
      reference_title: Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: These results show that cytoplasmic CDK19 is sufficient to regulate mitochondrial morphology.
      explanation: Nonnuclear rescue.
    relationship: RESCUES
    model_scale: CELLULAR
    limitations: Fly ortholog depletion and transgenic rescue do not establish mitochondrial abnormalities in patient neurons.
    fidelity: MODERATE
  - target: Impaired Synaptic Transmission
    description: Photoreceptor synaptic transients are severely reduced while response amplitudes are retained.
    evidence:
    - reference: PMID:38637532
      reference_title: Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: synaptic transmission is nearly abolished
      explanation: Electroretinographic readout.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: A visual synapse assay does not directly measure epileptic network activity.
    fidelity: MODERATE
  evidence:
  - reference: PMID:38637532
    reference_title: Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These results show that cytoplasmic CDK19 is sufficient to regulate mitochondrial morphology.
    explanation: Nonnuclear rescue.
- name: Fly Sensitized Cdk8 Depletion with Tyr32His or Thr196Ala
  species: Drosophila melanogaster
  genotype: da-Gal4-driven ubiquitous Cdk8 RNA interference plus human reference, Tyr32His or Thr196Ala CDK19
  publication: PMID:41251503
  description: The milder 25°C background preserves approximately 30% endogenous cdk8 expression. Tyr32His rescues climbing and mitochondrial length but not lifespan or myofibril width; Thr196Ala has broader defects and increased muscle ROS. More severe 29°C eclosion experiments impair both variants. Antioxidant NACA lowers Thr196Ala ROS with partial, readout-dependent benefits.
  modeled_mechanisms:
  - target: Impaired CDK19 Functional Complementation
    description: Complementation varies by variant, residual ortholog expression and measured trait.
    evidence:
    - reference: PMID:41251503
      reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: both variants are unable to rescue the cdk8 depletion muscle myofibril thickening as the wild-type CDK19 can
      explanation: Persistent muscle-width defect despite selective rescue of other readouts.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Driver, temperature and RNAi strength change the phenotype. Neither construct recreates a patient heterozygous genomic state.
    fidelity: MODERATE
  - target: Reduced Drp1 Phosphorylation
    description: Thr196Ala lowers the Drp1 phospho-readout in this sensitized background.
    evidence:
    - reference: PMID:41251503
      reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: the pDrp1:Drp1 ratio is significantly lower in the T196A background
      explanation: Variant-dependent phospho-readout.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Tyr32His upward trend was nonsignificant; mild depletion alone did not lower this readout.
    fidelity: MODERATE
  - target: Elevated Cellular Oxidative Stress
    description: NACA suppresses the elevated muscle ROS of Thr196Ala flies.
    evidence:
    - reference: PMID:41251503
      reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: expression of T196A is contributing to elevated muscular ROS that NACA can suppress
      explanation: Experimental rescue.
    relationship: RESCUES
    model_scale: CELLULAR
    limitations: Biochemical rescue is not clinical efficacy or evidence that every motor phenotype is ROS dependent.
    fidelity: MODERATE
  evidence:
  - reference: PMID:41251503
    reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: both variants are unable to rescue the cdk8 depletion muscle myofibril thickening as the wild-type CDK19 can
    explanation: Persistent muscle-width defect despite selective rescue of other readouts.
- name: Zebrafish CDK19 mRNA Overexpression
  species: Danio rerio
  genotype: One-cell injection of human wild-type, Gly28Arg or Tyr32His CDK19 mRNA
  publication: PMID:33495529
  description: At five days postfertilization, approximately 35% of Gly28Arg-injected and 45% of Tyr32His-injected embryos had abnormalities, versus 17% after reference CDK19 mRNA. Short body axis, hypoplastic anterior structures, abnormal tails and increased lethality support developmental perturbation but do not reproduce human epilepsy.
  modeled_mechanisms:
  - target: CDK19 Coding Missense Substitutions
    description: Tests developmental effects of coding-variant overexpression.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: injection of CDK19 mRNA with the Tyr32His variant and the Gly28Arg variant markedly ... increased the fraction of embryos with these morphological changes to 45%
      explanation: Developmental perturbation from mRNA overexpression.
    relationship: PERTURBS
    model_scale: ORGANISM
    limitations: Wild-type overexpression itself is abnormal in a subset. Dosage and injection toxicity limit mechanistic inference; endogenous heterozygous alleles were not tested.
    fidelity: LOW
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: injection of CDK19 mRNA with the Tyr32His variant and the Gly28Arg variant markedly ... increased the fraction of embryos with these morphological changes to 45%
    explanation: Developmental perturbation from mRNA overexpression.
- name: Zebrafish cdk8 and cdk19 Morpholino Knockdown
  species: Danio rerio
  genotype: cdk8 and/or cdk19 morpholino-mediated knockdown
  publication: PMID:33495529
  description: Combined morpholino knockdown produced more head abnormalities than either single knockdown, suggesting partially overlapping developmental functions. This is transient knockdown, not a genomic knockout or a patient-variant model.
  modeled_mechanisms:
  - target: Impaired CDK19 Functional Complementation
    description: Perturbs partially redundant kinase functions during development.
    evidence:
    - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
      reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Double knockdown of cdk8 and cdk19 (cdk8/19) showed anatomical defects, especially in the head region
      explanation: Combined ortholog depletion.
    relationship: PERTURBS
    model_scale: ORGANISM
    limitations: No patient allele or epileptic phenotype was tested; morpholino effects and paralog depletion differ from human de novo missense variation.
    fidelity: LOW
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Double knockdown of cdk8 and cdk19 (cdk8/19) showed anatomical defects, especially in the head region
    explanation: Combined ortholog depletion.
experimental_models:
- name: HEK293 CDK19 Autophosphorylation Assay
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Transfected HEK293 cells expressing reference or variant CDK19 with cyclin C
  publication: PMID:33495529
  description: Immunoprecipitated kinase was assayed for autophosphorylation. Gly28Arg had lower and Tyr32His higher activity than reference CDK19; the Tyr32His increase was statistically significant in this assay.
  modeled_mechanisms:
  - target: Reduced CDK19 Kinase Activity
    description: Measures allele-dependent catalytic output.
    evidence:
    - reference: PMID:33495529
      reference_title: CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein.
      explanation: Variant catalytic assay.
    relationship: MEASURES
    model_scale: MOLECULAR
    limitations: Overexpression in a nonneuronal line and autophosphorylation do not define the complete neuronal phenotype.
    fidelity: MODERATE
  - target: Increased CDK19 Kinase Activity
    description: Measures allele-dependent catalytic output.
    evidence:
    - reference: PMID:33495529
      reference_title: CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein.
      explanation: Variant catalytic assay.
    relationship: MEASURES
    model_scale: MOLECULAR
    limitations: Overexpression in a nonneuronal line and autophosphorylation do not define the complete neuronal phenotype.
    fidelity: MODERATE
  evidence:
  - reference: PMID:33495529
    reference_title: CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein.
    explanation: Variant catalytic assay.
- name: Reconstituted CDK19 Kinase Module
  experimental_model_type: OTHER
  cell_source: Baculovirus-produced recombinant human CDK19, cyclin C, MED12 and MED13 complex
  publication: PMID:33495529
  description: Purified modules phosphorylated recombinant RNA-polymerase-II CTD and STAT1 substrates. Gly28Arg reduced substrate phosphorylation despite retained module assembly; Tyr32His increased catalytic output.
  modeled_mechanisms:
  - target: Reduced CDK19 Kinase Activity
    description: Purified-complex substrate phosphorylation provides a biochemical readout.
    evidence:
    - reference: PMID:33495529
      reference_title: CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein.
      explanation: Variant catalytic assay.
    relationship: MEASURES
    model_scale: MOLECULAR
    limitations: Artificial substrate concentrations and reconstituted complexes do not establish a patient transcriptional signature.
    fidelity: MODERATE
  - target: Increased CDK19 Kinase Activity
    description: Purified-complex substrate phosphorylation provides a biochemical readout.
    evidence:
    - reference: PMID:33495529
      reference_title: CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein.
      explanation: Variant catalytic assay.
    relationship: MEASURES
    model_scale: MOLECULAR
    limitations: Artificial substrate concentrations and reconstituted complexes do not establish a patient transcriptional signature.
    fidelity: MODERATE
  evidence:
  - reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
    reference_title: https://www.nature.com/articles/s41436-020-01091-9.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: this mutant still can form the complex with other subunits (cyclin C, MED12, and MED13)
    explanation: Gly28Arg complex assembly remains possible.
- name: S2R+ Cdk8–Drp1 Interaction and Kinase Assay
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Drosophila melanogaster
    term:
      id: NCBITaxon:7227
      label: Drosophila melanogaster
  cell_source: Transfected Drosophila S2R+ insect cells
  publication: PMID:38637532
  description: Cytoplasmic Cdk8/Drp1 immunoprecipitates show protein association and ATP-dependent Drp1 Ser616 phosphorylation. An associated kinase cannot be excluded by an immunoprecipitate experiment alone.
  modeled_mechanisms:
  - target: Reduced Drp1 Phosphorylation
    description: Measures the Cdk8-associated Drp1 phosphorylation reaction relevant to the proposed route.
    evidence:
    - reference: PMID:38637532
      reference_title: Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: phosphorylation of co-immunoprecipitated cytoplasmic Drp1 is significantly elevated in the presence of ATP
      explanation: ATP-dependent in-vitro phosphorylation.
    relationship: MEASURES
    model_scale: MOLECULAR
    limitations: Uses fly Cdk8 rather than isolated human CDK19, and neither patient variant is tested.
    fidelity: LOW
  evidence:
  - reference: PMID:38637532
    reference_title: Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Drp1 was pulled down with Cdk8 in the Myc-tagged Cdk8 immunoprecipitation (IP), while Drp1 was absent from the control IgG IP. Cdk8 was also pulled down in the reciprocal pulldown using HA-tagged Drp1
    explanation: Reciprocal co-immunoprecipitation in transfected S2R+ cells shows the Cdk8-Drp1 association.
computational_models:
- name: Thr31Asn CDK19–Cyclin C Structural Prediction
  model_type: STRUCTURAL_PREDICTION
  publication: PMID:33568421
  description: PyMOL-based structural analysis places Thr31 near ATP-positioning residues in the glycine-rich loop. Reduced ATP affinity and kinase activity were proposed, not measured. The paper also speculated that Tyr32His would reduce activity, which is not supported by the separate biochemical assays showing increased catalytic output.
  modeled_mechanisms:
  - target: Reduced CDK19 Kinase Activity
    description: Predicts an impaired ATP-binding/catalytic consequence for Thr31Asn.
    evidence:
    - reference: PMID:33568421
      reference_title: A novel variant of CDK19 causes a severe neurodevelopmental disorder with infantile spasms.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: We built a CDK19 protein model in complex with cyclin C with the presence of ATP using the program PyMOL
      explanation: Protein structural model.
    relationship: MEASURES
    model_scale: MOLECULAR
    limitations: Computational localization and structural speculation do not demonstrate catalytic loss or prove a dominant-negative effect.
    fidelity: LOW
  evidence:
  - reference: PMID:33568421
    reference_title: A novel variant of CDK19 causes a severe neurodevelopmental disorder with infantile spasms.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We built a CDK19 protein model in complex with cyclin C with the presence of ATP using the program PyMOL
    explanation: Protein structural model.
discussions:
- discussion_id: allele_assay_dependence
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: How do kinase activity, substrate choice and cellular context determine the clinical effects of distinct CDK19 missense alleles?
  attaches_to:
  - pathophysiology#Reduced CDK19 Kinase Activity
  - pathophysiology#Increased CDK19 Kinase Activity
  - pathophysiology#Impaired CDK19 Functional Complementation
  rationale: Tyr32His increases catalytic output in biochemical assays while its rescue varies across fly tissues, temperatures and residual ortholog expression. Failed complementation, overexpression toxicity and reduced catalytic activity are distinct observations. Dominant-negative interaction with the normal human allele remains unproven.
  evidence:
  - reference: PMID:33495529
    reference_title: CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein.
    explanation: Variant catalytic assay.
  - reference: PMID:41251503
    reference_title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: both variants are unable to rescue the cdk8 depletion muscle myofibril thickening as the wild-type CDK19 can
    explanation: Readout-specific persistent defect.
- discussion_id: human_mitochondrial_translation
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Do CDK19 patient neurons share the mitochondrial and Drp1 abnormalities found in sensitized fly models?
  attaches_to:
  - pathophysiology#Impaired Mitochondrial Fission
  - pathophysiology#Reduced Drp1 Phosphorylation
  - pathophysiology#Elevated Cellular Oxidative Stress
  rationale: Cytoplasmic rescue and patient-variant fly experiments support a route beyond transcription. Patient-neuron mitochondrial morphology, phosphorylation and energy defects have not been established in these studies. NACA effects in flies provide a hypothesis for further testing, not a validated human therapy.
  evidence:
  - reference: PMID:38637532
    reference_title: Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These results show that cytoplasmic CDK19 is sufficient to regulate mitochondrial morphology.
    explanation: Model evidence underlying the translational gap.
- discussion_id: glycine_biomarker_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Are CSF protein and glycine abnormalities reproducible CDK19-associated findings, and do they contribute to seizures?
  attaches_to:
  - phenotypes#Increased CSF Protein
  - phenotypes#Increased CSF Glycine
  rationale: These biochemical findings come from one Tyr32His case. A normal CSF/plasma ratio, negative GLDC/AMT testing and unsuccessful dextromethorphan treatment limit an NKH-like mechanistic interpretation. Replication and direct metabolic studies are needed before these values can be used as diagnostic or treatment biomarkers.
  evidence:
  - reference: PMID:33134521
    reference_title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The mechanism through which the CDK19 variant leads to the CSF abnormalities remains unknown.
    explanation: Explicit uncertainty in the primary report.
- discussion_id: structural_allele_scope
  kind: INTERPRETATION
  status: OPEN
  prompt: How does the historical CDK19-disrupting inversion relate to the later kinase-domain missense syndrome?
  attaches_to:
  - genetic#CDK19
  rationale: The pericentric inversion was mapped to CDK19 intron 1 and reduced transcript levels in transformed lymphoblasts, supporting a dosage effect. Retinal folds, microcephaly and milder intellectual disability without reported epilepsy differ from many missense cases. Breakpoint mapping did not establish a nucleotide-resolved junction, and the isolated structural case does not establish pathogenicity of all CDK19 deletions or truncations.
  evidence:
  - reference: PMID:20563892
    reference_title: CDK19 is disrupted in a female patient with bilateral congenital retinal folds, microcephaly and mild mental retardation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The transcript level for CDK19 in the patient was found to be 54% (p = 0.022) when compared with the control mean
    explanation: Inversion-associated RNA decrease.
notes: Reported frequencies come from selected clinical series, with overlap between the founding cases and later aggregates. Seizures and epileptic encephalopathy are not synonymous, and absence of epilepsy does not exclude a CDK19 missense-associated neurodevelopmental disorder. No clinically established subtypes or robust allele-specific severity predictions follow from these small series. The historical inversion-associated retinal phenotype is retained as a qualified genetic observation rather than pooled into missense-cohort frequencies. Patient-derived neuronal histology and a unified transcriptional or mitochondrial mechanism remain unresolved. The Nature-hosted PDF reference is the full text of PMID:33495529; the PubMed cache contains its abstract.
references:
- reference: PMID:20563892
  title: CDK19 is disrupted in a female patient with bilateral congenital retinal folds, microcephaly and mild mental retardation.
- reference: PMID:32330417
  title: De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.
- reference: PMID:33134521
  title: Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.
- reference: PMID:33495529
  title: CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.
- reference: PMID:33568421
  title: A novel variant of CDK19 causes a severe neurodevelopmental disorder with infantile spasms.
- reference: PMID:38637532
  title: Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.
- reference: PMID:41251503
  title: Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.
- reference: url:https://thegencc.org/submissions/SGC-123798.1
  title: CDK19 | developmental and epileptic encephalopathy, 87 | Autosomal dominant by G2P submission information facts
- reference: url:https://www.nature.com/articles/s41436-020-01091-9.pdf
  title: https://www.nature.com/articles/s41436-020-01091-9.pdf

📚

References & Deep Research

References

9

PMID:20563892

CDK19 is disrupted in a female patient with bilateral congenital retinal folds, microcephaly and mild mental retardation.

No top-level findings curated for this source.

PMID:32330417

De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.

No top-level findings curated for this source.

PMID:33134521

Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant.

No top-level findings curated for this source.

PMID:33495529

CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.

No top-level findings curated for this source.

PMID:33568421

A novel variant of CDK19 causes a severe neurodevelopmental disorder with infantile spasms.

No top-level findings curated for this source.

PMID:38637532

Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.

No top-level findings curated for this source.

PMID:41251503

Uncovering functional insights into human pathogenic variants in CDK19 using Drosophila models.

No top-level findings curated for this source.

url:https://thegencc.org/submissions/SGC-123798.1

CDK19 | developmental and epileptic encephalopathy, 87 | Autosomal dominant by G2P submission information facts

No top-level findings curated for this source.

url:https://www.nature.com/articles/s41436-020-01091-9.pdf

https://www.nature.com/articles/s41436-020-01091-9.pdf

No top-level findings curated for this source.

CDK19-Related Disorder

Ask OpenScientist

OpenScientist Report

Classifications

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Computational Models

Source YAML

References & Deep Research

References