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Classifications

Harrison's Part

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Inheritance

2

Autosomal dominant, de novo HP:0000006

All reported individuals carry a heterozygous HDAC4 missense variant that arose de novo; no transmitted case has been described, and no recurrence in a sibship has been reported. Parental germline mosaicism has not been excluded, so empiric recurrence risk is low but not zero.

autosomal dominant inheritance

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Here, we report seven unrelated individuals with a phenotype distinct from that of BDMR, all of whom have heterozygous de novo missense variants that affect a major regulatory site of HDAC4, required for signal-dependent 14-3-3 binding and nucleocytoplasmic shuttling."

Seven unrelated probands each carry a heterozygous de novo missense variant, establishing an autosomal dominant, de novo mode of inheritance.

Typically de novo occurrence HP:0025352

The recurrence of four different missense substitutions at the same functional motif across seven unrelated de novo cases is the principal genetic argument for causality.

typically de novo

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Nevertheless, the observation of four different missense variants, all of which affect the same functional motif in HDAC4 and arose de novo in seven unrelated individuals, provides very strong genetic evidence that these variants are indeed causative for the phenotype observed."

Explicit statement that all four variants arose de novo in seven unrelated individuals.

?

Discussions and Knowledge Gaps

3

Does reduced 14-3-3 binding by the HDAC4 residue 242-248 missense variants actually increase the nuclear pool and repressive activity of HDAC4 in patient-relevant neural cells, and does this reduce MEF2C- and RUNX2-dependent transcription?

KNOWLEDGE GAP OPEN nedchf_gain_of_function_unproven

Attached to

pathophysiology#Increased Nuclear HDAC4 Co-repressor Activity pathophysiology#MEF2C and RUNX2 Target Transcriptional Dysregulation

The gain-of-function model rests on a two-fold reduction of 14-3-3 binding measured for two of four variants by co-immunoprecipitation of overexpressed tagged proteins in HEK293 cells, plus in silico prediction for the remaining variants. Subcellular localization of endogenous variant HDAC4 has not been measured, nor has downstream MEF2C/RUNX2 target transcription. The authors explicitly note that the effect on 14-3-3 binding was only partial and that this step remains to be determined. This is the load-bearing mechanistic claim that separates the entity from HDAC4 haploinsufficiency, so it is the highest-value gap to close.

Proposed experiments

Endogenous HDAC4 localization in patient-derived cells

nedchf_exp_endogenous_localization

Quantify nuclear versus cytoplasmic endogenous HDAC4 in patient-derived fibroblasts and iPSC-derived neurons carrying each variant, using subcellular fractionation with immunoblot and quantitative immunofluorescence.

Decision criterion

A statistically significant increase in the nuclear:cytoplasmic HDAC4 ratio in variant cells relative to isogenic or parental controls.

Would support

pathophysiology#Increased Nuclear HDAC4 Co-repressor Activity

Would refute

pathophysiology#Increased Nuclear HDAC4 Co-repressor Activity

Transcriptomic test of MEF2C and RUNX2 target repression

nedchf_exp_target_rnaseq

Perform RNA-seq on isogenic knock-in neurons carrying p.Pro248Leu versus wild-type and test for coordinate down-regulation of curated MEF2C and RUNX2 target gene sets.

Decision criterion

Significant coordinate down-regulation of MEF2C and RUNX2 target gene sets in variant neurons.

Would support

pathophysiology#MEF2C and RUNX2 Target Transcriptional Dysregulation

Would refute

pathophysiology#MEF2C and RUNX2 Target Transcriptional Dysregulation

MEF2 occupancy and reporter activity in variant neurons

nedchf_exp_mef2_occupancy

Measure MEF2-responsive reporter activity and MEF2C genomic occupancy by CUT&RUN or ChIP in variant versus wild-type neurons.

Would support

pathophysiology#MEF2C and RUNX2 Target Transcriptional Dysregulation

Contribution of HDAC4 fragmentation to MEF2C repression

nedchf_exp_fragmentation

Test whether the increased C-terminal fragmentation observed for p.Glu247Gly contributes independently to MEF2C repression, using cleavage-resistant HDAC4 constructs.

Would support

pathophysiology#Impaired Neuronal Plasticity Gene Expression

Show evidence (1 reference)

PMID:33537682 SUPPORT In Vitro

"We note that the effect of the variants on 14-3-3 binding was only partial, suggesting that any increase in nuclear HDAC4 activity might be limited."

The authors' own caveat defining the gap.

What is the full clinical spectrum, natural history and genotype-phenotype correlation of HDAC4 14-3-3-site missense variants beyond the seven originally reported individuals?

KNOWLEDGE GAP OPEN nedchf_clinical_spectrum_undefined

Attached to

pathophysiology#Neurodevelopmental and Craniofacial-Skeletal Phenotype

The entity is defined by a single seven-person cohort aged 2-20 years. Frequencies curated here are small-denominator estimates, adult outcomes are unknown, and whether the four substitutions differ in severity cannot be assessed. The authors call for additional cases specifically to enable genotype-phenotype correlation.

Proposed experiments

International HDAC4 motif-variant cohort

nedchf_exp_international_cohort

Assemble an international cohort through GeneMatcher and DECIPHER of additional individuals with variants in HDAC4 residues 242-248 and collect standardized HPO-coded deep phenotyping.

Would support

pathophysiology#Neurodevelopmental and Craniofacial-Skeletal Phenotype

Genotype-phenotype comparison across the four substitutions

nedchf_exp_genotype_phenotype

Compare phenotype severity between the recurrent p.Pro248Leu allele and the non-Pro248 substitutions in the expanded cohort.

Would support

pathophysiology#HDAC4 14-3-3 Binding Site Missense Variant

Longitudinal natural-history follow-up

nedchf_exp_natural_history

Follow affected individuals into adulthood for seizure course, scoliosis progression, feeding status and cognitive/communication outcome.

Would support

pathophysiology#Neurodevelopmental and Craniofacial-Skeletal Phenotype

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Identification of additional individuals with variants within this region of HDAC4 will enable further genotype-phenotype correlation and understanding of the clinical spectrum in similar individuals."

The authors explicitly state this as the open question.

If NEDCHF is a gain-of-function disorder, could a class IIa- or HDAC4-selective inhibitor (or a disruptor of the HDAC4-MEF2 interaction) be therapeutic, and is there a developmental window in which it could work?

OPEN QUESTION OPEN nedchf_hdac_inhibitor_feasibility

Attached to

pathophysiology#Increased Nuclear HDAC4 Co-repressor Activity

A gain-of-function mechanism nominally suggests pharmacological inhibition. The discovery authors raise this explicitly but caution both that class IIa HDACs respond poorly to available pan-HDAC inhibitors, because of their low intrinsic deacetylase activity, and that a large part of the phenotype is developmental and may not be reversible postnatally. Because vertebrate HDAC4 represses through protein-protein interaction rather than catalysis, catalytic-site inhibition may also be the wrong target; disrupting the HDAC4-MEF2 interaction is an alternative. This is preclinical rationale and is deliberately not curated as a treatment.

Proposed experiments

HDAC4-selective inhibitor rescue in variant neurons

nedchf_exp_selective_inhibitor_rescue

Test whether HDAC4-selective inhibitors or HDAC4-MEF2 interaction disruptors restore MEF2 target gene expression in patient-variant neurons, and whether restoration depends on the developmental stage at which the compound is applied.

Would support

pathophysiology#Increased Nuclear HDAC4 Co-repressor Activity

Show evidence (2 references)

PMID:33537682 SUPPORT Other

"Gain-of-function variants in HDAC4 raise the possibility of therapeutic intervention by use of HDAC inhibitors, although whether such treatment could halt or reverse developmental problems is open to question."

The authors raise HDAC inhibition as a theoretical strategy while flagging its uncertainty.

PMID:33537682 SUPPORT Other

"While a number of HDAC inhibitors are available for pharmacological use, class IIa HDACs are in fact poor responders to these drugs due to the lower deacetylase activity of these enzymes compared to other HDACs."

Explains why available pan-HDAC inhibitors are unlikely to be useful and why class IIa- or HDAC4-selective agents would be needed.

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Pathophysiology

6

HDAC4 14-3-3 Binding Site Missense Variant

De novo heterozygous missense substitutions cluster in the RKTApSEP motif spanning residues 242-248 of HDAC4, the first and most important of the three 14-3-3 binding sites in the protein and the only one invariant from human to fruit fly. Reported substitutions are p.Thr244Lys, p.Glu247Gly, p.Pro248Ala and p.Pro248Leu; Pro248, the +2 residue relative to the phosphoacceptor Ser246, is altered in five of seven individuals. The motif partially overlaps the HDAC4 nuclear localization signal (residues 244-279).

HDAC4 hgnc:14063

14-3-3 protein binding GO:0071889 ↓ DECREASED

Downstream

Impaired 14-3-3 Binding and Loss of Cytoplasmic Sequestration The substitutions degrade the 14-3-3 consensus and/or reduce accessibility of Ser246 to its kinases (TAK1, MARK2), directly lowering 14-3-3 affinity for the motif.

Show evidence (2 references)

PMID:33537682 SUPPORT Human Clinical

"Two individuals possess variants altering Thr244 or Glu247, whereas the remaining five all carry variants altering Pro248, a key residue for 14-3-3 binding."

Defines the variant spectrum and the clustering at the 14-3-3 binding motif.

PMID:33537682 SUPPORT Human Clinical

"The nuclear activity of HDAC4 is regulated by the process of nucleocytoplasmic shuttling, which in turn is dependent on the phosphorylation-dependent binding of 14-3-3 proteins, which act to sequester HDAC4 in the cytoplasm; as such, HDAC4 serves as a transducer of upstream signaling events."

Establishes why a variant in this motif is expected to deregulate HDAC4 localization.

Impaired 14-3-3 Binding and Loss of Cytoplasmic Sequestration

Phosphorylation of Ser246 creates a 14-3-3 docking site; bound 14-3-3 biases nucleocytoplasmic shuttling toward the cytoplasm by masking the overlapping nuclear localization signal and inhibiting nuclear import. Co-immunoprecipitation of FLAG-HDAC4 with HA-tagged 14-3-3 beta in HEK293 cells showed that the p.Glu247Gly and p.Thr244Lys variants bind 14-3-3 with approximately two-fold reduced affinity relative to wild-type HDAC4. In silico analyses predicted reduced 14-3-3 binding for all four variants, with the strongest effect at Pro248.

protein export from nucleus GO:0006611 ↓ DECREASED

14-3-3 protein binding GO:0071889 ↓ DECREASED

Experimental models

HEK293 HDAC4 / 14-3-3 beta co-immunoprecipitation assay CELL LINE Directly assays the binding step asserted by this node - the affinity of the variant RKTApSEP motif for 14-3-3 - for two of the four reported variants.

Downstream

Increased Nuclear HDAC4 Co-repressor Activity Reduced cytoplasmic sequestration is predicted to raise the steady-state nuclear pool of HDAC4.

Show evidence (3 references)

PMID:33537682 SUPPORT In Vitro

"We propose that the variants in all seven individuals impair 14-3-3 binding (as confirmed for the first two variants by immunoprecipitation assays), thereby identifying deregulation of HDAC4 as a pathological mechanism in a previously uncharacterized developmental disorder."

Co-immunoprecipitation in transfected HEK293 cells directly demonstrates reduced 14-3-3 binding for two of the patient variants.

PMID:18952052 SUPPORT In Vitro

"Phosphorylation-induced 14-3-3 binding biases the balance of nucleo-cytoplasmic shuttling toward the cytoplasm by inhibiting nuclear import."

Independent cell-based work establishes that 14-3-3 binding restrains nuclear entry of class IIa HDACs, so losing it shifts HDAC4 into the nucleus.

PMID:11470791 SUPPORT In Vitro

"we reveal that HDAC4 contains a modular structure consisting of a C-terminal autonomous nuclear export domain, which, in conjunction with an internal regulatory domain responsive to calcium/calmodulin-dependent protein kinase IV (CaMKIV), determines its subcellular localization."

Defines the modular trafficking architecture of HDAC4 in which the N-terminal regulatory region containing the 14-3-3 sites governs localization. Support is partial because this study argues the HDAC4:14-3-3 complex also acts within the nucleus, so the directionality of 14-3-3 control is not settled by a single model.

Increased Nuclear HDAC4 Co-repressor Activity

Vertebrate HDAC4 is catalytically inactive as a histone deacetylase in its own right and acts predominantly as a signal-dependent transcriptional co-repressor. An increased nuclear pool is therefore proposed to act as a gain of function, increasing repression of HDAC4-bound transcription factors. This is the mechanistic step that distinguishes NEDCHF from HDAC4 haploinsufficiency; it is inferred from the binding data plus the known biology rather than measured directly in patient neurons, so the node is marked provisional.

protein localization to nucleus GO:0034504 ↑ INCREASED negative regulation of transcription by RNA polymerase II GO:0000122 ↑ INCREASED

transcription corepressor activity GO:0003714 ↑ INCREASED

Animal models

HDAC4 3SA constitutive-nuclear mutant mouse (could not be generated) Mouse fails to recapitulate The intended in vivo model of constitutively nuclear HDAC4 could not be established, so this node has no organism-level test. The failure is itself informative: it suggests that a large, unrestrained increase in nuclear HDAC4 is lethal, whereas the NEDCHF variants produce only a partial reduction of 14-3-3 binding at a single site.

Downstream

MEF2C and RUNX2 Target Transcriptional Dysregulation HDAC4 binds and represses MEF2C and RUNX2, so more nuclear HDAC4 is expected to reduce the transcriptional output of both factors.

Show evidence (2 references)

PMID:33537682 SUPPORT In Vitro

"As such, we propose that these variants result in a novel gain-of-function effect, leading to increased nuclear activity of HDAC4, and thus differentiating both the molecular mechanism and the outcome of these variants from that of previously reported loss-of-function alleles of HDAC4 that..."

States the proposed gain-of-function mechanism and its explicit contrast with HDAC4 haploinsufficiency.

PMID:26074448 SUPPORT Other

"In the nucleus, HDAC4 is a repressor of transcriptional programmes, although vertebrate HDAC4 is itself catalytically inactive and repression is facilitated through direct inhibition of transcription factors such as MEF2."

Establishes that nuclear HDAC4 represses transcription through direct transcription-factor inhibition rather than intrinsic deacetylase activity, which is why increased nuclear HDAC4 is a repressive gain of function.

MEF2C and RUNX2 Target Transcriptional Dysregulation

HDAC4 physically interacts with and represses myocyte enhancer factor 2C (MEF2C) and runt-related transcription factor 2 (RUNX2), both required for normal neural and skeletal development. Increased nuclear HDAC4 is therefore predicted to reduce MEF2C- and RUNX2-dependent transcription. The clinical picture is consistent with this: NEDCHF shares developmental delay, stereotypic movements, epilepsy and variable brain MRI anomalies with MEF2C haploinsufficiency, and shares delayed fontanelle closure, dental anomalies, hypertelorism and hip joint defects with RUNX2-related cleidocranial dysplasia. Whether reduced MEF2C/RUNX2 signalling actually occurs in patient tissue remains undetermined, and unique NEDCHF features suggest additional, unidentified downstream pathways.

neuron CL:0000540 osteoblast CL:0000062 chondrocyte CL:0000138

MEF2C hgnc:6996 RUNX2 hgnc:10472

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

Animal models

HDAC4-overexpressing proliferating mouse chondrocytes Mouse partially recapitulates Demonstrates that excess HDAC4 in a RUNX2-dependent cell type produces a Runx2-loss-of-function-like phenotype, which is the experimental basis for the RUNX2 arm of this node. The MEF2C arm and any neural consequence are not addressed by this model.

Downstream

Impaired Neuronal Plasticity Gene Expression MEF2 is a principal activity-dependent transcription factor in neurons; its repression by nuclear HDAC4 reduces expression of plasticity genes.

Neurodevelopmental and Craniofacial-Skeletal Phenotype RUNX2 repression plausibly contributes to the delayed fontanelle closure, dental anomalies and hip joint defects, but unique NEDCHF features are not explained by RUNX2 or MEF2C loss alone.

Show evidence (4 references)

PMID:33537682 SUPPORT Human Clinical

"Increased nuclear activity of HDAC4 would be expected to result in reduced activity of RUNX2 and MEF2C."

States the predicted transcription-factor consequence of increased nuclear HDAC4.

PMID:33537682 SUPPORT Human Clinical

"Whether the decreased interaction with 14-3-3 does indeed lead to decreased RUNX2 and MEF2C signaling as a result of increased nuclear HDAC4 activity remains to be determined"

The authors explicitly flag this step as unproven, which is why the node is marked hypothetical.

PMID:33537682 SUPPORT Model Organism

"In support of this, Vega et al.11 have previously noted that overexpression of HDAC4 in proliferating mouse chondrocytes inhibited their differentiation, thus resembling the effects of Runx2 loss of function."

Mouse chondrocyte data show that excess HDAC4 phenocopies Runx2 loss of function, supporting the RUNX2 arm of this node.

+ 1 more reference

Impaired Neuronal Plasticity Gene Expression

In neurons HDAC4 shuttles in response to synaptic activity and is normally predominantly cytoplasmic; nuclear restriction of HDAC4 down-regulates plasticity-related genes and impairs memory in model systems. A variant that biases HDAC4 toward the nucleus is therefore expected to suppress the activity-dependent synaptic gene programme in developing neurons. An additional, non-exclusive route proposed by the authors is increased repression of MEF2 by naturally occurring nuclear-retained HDAC4 cleavage fragments, which were more abundant for the patient variants and which repress MEF2C independently of deacetylase activity.

neuron CL:0000540

regulation of synaptic plasticity GO:0048167 ↓ DECREASED nervous system development GO:0007399 ⚠ ABNORMAL

Downstream

Neurodevelopmental and Craniofacial-Skeletal Phenotype Suppressed plasticity gene expression in developing neurons is the proposed substrate for the intellectual disability, hypotonia and epilepsy.

Show evidence (3 references)

PMID:33537682 SUPPORT Model Organism

"HDAC4 has been shown to specifically repress the expression of genes required for synaptic function and neuronal plasticity, and this expression was reduced further by the constitutive nuclear 3SA mutant of HDAC4."

Directly links a constitutively nuclear HDAC4 (the same directional change proposed for the patient variants) to reduced synaptic and plasticity gene expression.

PMID:26074448 SUPPORT Other

"Nuclear-restriction of HDAC4 results in down-regulation of plasticity-related genes and memory impairment."

Review of the primary literature establishing that nuclear restriction of HDAC4 is deleterious for plasticity gene expression and memory.

PMID:12641737 SUPPORT In Vitro

"We found that, in cultured hippocampal neurones, the localization of HDAC4 and HDAC5 is dynamic and signal-regulated."

Shows that activity-dependent HDAC4 shuttling is a real feature of neurons, so a shuttling defect is neuronally relevant.

Neurodevelopmental and Craniofacial-Skeletal Phenotype

The clinical endpoint of the cascade: universal central hypotonia and developmental delay with significant intellectual disability, seizures in a subset, a recognizable facial gestalt, kyphoscoliosis and hip dislocation/subluxation, delayed closure of the anterior fontanelle, and non-specific brain MRI abnormalities. Notably absent are brachydactyly type E, autism and obesity, which are characteristic of the HDAC4 loss-of-function / 2q37 deletion phenotype.

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"This phenotype includes significant DD/ID, seizures, distinctive facial features, scoliosis, delayed closure of the anterior fontanelle, and non-specific brain MRI anomalies; thus, it is distinct from the BDMR phenotype previously reported in individuals carrying HDAC4 loss-of-function alleles."

Summarizes the clinical endpoint and its distinctness from the loss-of-function phenotype.

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Pathograph

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

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Phenotypes

25

Digestive 1

Feeding and swallowing difficulties FREQUENT Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"The individuals reported here also had features not typically seen in individuals with 2q37 deletion or loss-of-function variants in HDAC4, including swallowing difficulties and/or drooling, congenital hip dislocation, progressive kyphoscoliosis, and delayed closure of the anterior fontanelle."

Swallowing difficulties are named as a recurrent, discriminating feature of this disorder.

Ear 1

Large ears FREQUENT Macrotia HP:0000400

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Facial appearance was distinctive, with the following features seen in multiple individuals: hypertelorism, a full lower lip, long palpebral fissures, frontal upsweep of hair, widely spaced teeth, and large ears"

Large ears are listed among the recurrent dysmorphic features.

Eye 1

Hypertelorism FREQUENT HP:0000316

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Facial appearance was distinctive, with the following features seen in multiple individuals: hypertelorism, a full lower lip, long palpebral fissures, frontal upsweep of hair, widely spaced teeth, and large ears"

Hypertelorism is listed among the recurrent dysmorphic features.

Head and Neck 2

Long palpebral fissures FREQUENT HP:0000637

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Facial appearance was distinctive, with the following features seen in multiple individuals: hypertelorism, a full lower lip, long palpebral fissures, frontal upsweep of hair, widely spaced teeth, and large ears"

Long palpebral fissures are listed among the recurrent dysmorphic features.

Drooling FREQUENT HP:0002307

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Significant drooling in early childhood was a common feature and, where noted, has persisted in all but individual 3."

Drooling is described as a common and usually persistent feature.

Limbs 2

Hip dislocation or subluxation FREQUENT Congenital hip dislocation HP:0001374

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Four have had hip dislocation/subluxation and five have scoliosis/kyphosis."

4/7 individuals (57%), mapping to FREQUENT.

Absence of brachydactyly type E HP:0001156

Curated as a REFUTE evidence item so the absence is machine-queryable; this is a deliberate negative annotation, not an asserted phenotype.

Show evidence (1 reference)

PMID:33537682 REFUTE Human Clinical

"None of the individuals had hand or foot anomalies consistent with brachydactyly type E."

Explicitly refutes brachydactyly as a feature of this disorder, in contrast to BDMR.

Musculoskeletal 3

Central hypotonia VERY_FREQUENT HP:0001252

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"All individuals presented with delayed developmental milestones/ID and hypotonia."

Hypotonia was present in 7/7 individuals; Table 1 of the same paper records central hypotonia as present in every case.

Kyphoscoliosis FREQUENT HP:0002751

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Four have had hip dislocation/subluxation and five have scoliosis/kyphosis."

5/7 individuals (71%), mapping to FREQUENT.

Joint hypermobility FREQUENT HP:0001382

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Three individuals also have hypermobility, with striking joint laxity of the fingers."

3/7 individuals (43%), mapping to FREQUENT.

Nervous System 6

Global developmental delay VERY_FREQUENT HP:0001263

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"All individuals presented with delayed developmental milestones/ID and hypotonia."

7/7 individuals had delayed developmental milestones, supporting VERY_FREQUENT.

Intellectual disability VERY_FREQUENT HP:0001249

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"All individuals of school age have attended special school and have significant ID, though individual 3 had milder cognitive, motor, and speech difficulties in comparison with the rest of the cohort."

Supports both the near-universal frequency and the significant severity, with one milder outlier.

Impaired expressive speech VERY_FREQUENT Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"All individuals of school age have attended special school and have significant ID, though individual 3 had milder cognitive, motor, and speech difficulties in comparison with the rest of the cohort."

Supports significant speech impairment across the cohort; the per-individual speech descriptions are tabulated in Table 1 of the same paper.

Seizures FREQUENT HP:0001250

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Both individual 3 and individual 4 developed generalized seizures in mid-childhood, which have also been difficult to control despite the use of multiple anticonvulsants."

Two individuals with generalized seizures plus individual 1 with infantile spasms gives 3/7 (43%), mapping to FREQUENT.

Sleep disturbance FREQUENT HP:0002360

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Three individuals were reported as suffering from sleep disturbance."

3/7 (43%), mapping to FREQUENT.

Absence of autism spectrum disorder Autistic behavior HP:0000729

Show evidence (1 reference)

PMID:33537682 REFUTE Human Clinical

"None was reported as showing autistic features."

Explicitly refutes autistic features in the reported cohort, a discriminator from BDMR.

Growth 1

Absence of obesity HP:0001513

Curated as a REFUTE evidence item so the absence is machine-queryable; this is a deliberate negative annotation, not an asserted phenotype. Weight centiles in Table 1 span the 2nd to 99th centile with no individual described as obese.

Show evidence (1 reference)

PMID:33537682 REFUTE Human Clinical

"None of the individuals reported here had autism, obesity, or brachydactyly type E."

Explicitly refutes obesity in the reported cohort, the third BDMR discriminator alongside brachydactyly type E and autism.

Other 8

Delayed ability to walk VERY_FREQUENT HP:0031936

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"All individuals presented with delayed developmental milestones/ID and hypotonia."

Supports delayed motor milestones for the cohort as a whole; the per-individual ages at walking are given in Table 1 of the same paper and are summarized in the description.

Infantile spasms OCCASIONAL HP:0012469

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Individual 1 presented with infantile spasms and continues to have seizures that are non-responsive to medication."

1/7 individuals (14%), mapping to OCCASIONAL.

Motor stereotypies and dystonic movements OCCASIONAL Motor stereotypy HP:0000733

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Individual 4 has a movement disorder and had hand stereotypies, most noticeable in early childhood."

Documents hand stereotypies in one individual; dystonic limb movements were separately noted in individual 2.

Non-specific brain MRI abnormalities FREQUENT Abnormal brain morphology HP:0012443

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Variable and non-specific changes were observed in brain magnetic resonance imaging (MRI) scans in five individuals."

Five of seven individuals had abnormal, non-specific brain MRI findings (71%), mapping to FREQUENT.

Full lower lip FREQUENT Thick lower lip vermilion HP:0000179

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Facial appearance was distinctive, with the following features seen in multiple individuals: hypertelorism, a full lower lip, long palpebral fissures, frontal upsweep of hair, widely spaced teeth, and large ears"

A full lower lip is listed among the recurrent dysmorphic features.

Frontal upsweep of hair FREQUENT HP:0002236

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Facial appearance was distinctive, with the following features seen in multiple individuals: hypertelorism, a full lower lip, long palpebral fissures, frontal upsweep of hair, widely spaced teeth, and large ears"

Frontal upsweep of hair is listed among the recurrent dysmorphic features.

Widely spaced teeth FREQUENT HP:0000687

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Facial appearance was distinctive, with the following features seen in multiple individuals: hypertelorism, a full lower lip, long palpebral fissures, frontal upsweep of hair, widely spaced teeth, and large ears"

Widely spaced teeth are listed among the recurrent dysmorphic features.

Delayed closure of the anterior fontanelle OCCASIONAL HP:0001476

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"There is a history of delayed closure of the anterior fontanelle in individuals 2 and 4."

2/7 individuals (29%), mapping to OCCASIONAL.

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Genetic Associations

1

HDAC4 (Heterozygous de novo missense variants clustered in the conserved 14-3-3 binding motif (residues 242-248) of HDAC4 cause NEDCHF. Four distinct substitutions have been reported across seven unrelated probands; the recurrence of independent de novo variants at one functional motif is the principal genetic evidence for causality. HDAC4 is intolerant to loss of function (gnomAD pLI = 1), but the NEDCHF variants are proposed to act by gain of function rather than haploinsufficiency, and no missense variant at any position in this motif was observed in gnomAD.)

Gene: HDAC4 hgnc:14063 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (2 references)

PMID:33537682 SUPPORT Human Clinical

"Nevertheless, the observation of four different missense variants, all of which affect the same functional motif in HDAC4 and arose de novo in seven unrelated individuals, provides very strong genetic evidence that these variants are indeed causative for the phenotype observed."

The authors' own statement of the gene-disease causality argument.

PMID:33537682 SUPPORT Human Clinical

"All residues within this motif are highly conserved (Figure 1B), and no missense variants have been observed at any of these positions in the gnomAD database."

Population-database absence at the affected motif positions supports pathogenicity of the variant class.

🔬

Variants

4

HDAC4 c.731C>A p.(Thr244Lys) Pathogenic

Gene: HDAC4 hgnc:14063

De novo missense substitution at the -2 position relative to the phosphoacceptor Ser246. Reported in one individual (ClinVar SCV001427055). Co-immunoprecipitation showed approximately two-fold reduced binding to 14-3-3 beta relative to wild-type HDAC4.

Show evidence (1 reference)

PMID:33537682 SUPPORT In Vitro

"We propose that the variants in all seven individuals impair 14-3-3 binding (as confirmed for the first two variants by immunoprecipitation assays), thereby identifying deregulation of HDAC4 as a pathological mechanism in a previously uncharacterized developmental disorder."

p.Thr244Lys is one of the two variants for which reduced 14-3-3 binding was confirmed experimentally.

HDAC4 c.740A>G p.(Glu247Gly) Pathogenic

Gene: HDAC4 hgnc:14063

De novo missense substitution at the +1 position relative to Ser246, where glycine is not tolerated in known 14-3-3 binding sites. Reported in one individual (DECIPHER 300920). Co-immunoprecipitation showed approximately two-fold reduced binding to 14-3-3 beta and increased generation of C-terminally truncated HDAC4 fragments.

Show evidence (1 reference)

PMID:33537682 SUPPORT In Vitro

"We propose that the variants in all seven individuals impair 14-3-3 binding (as confirmed for the first two variants by immunoprecipitation assays), thereby identifying deregulation of HDAC4 as a pathological mechanism in a previously uncharacterized developmental disorder."

p.Glu247Gly is the variant with the most extensive experimental support for reduced 14-3-3 binding (five independent experiments).

HDAC4 c.742C>G p.(Pro248Ala) Pathogenic

Gene: HDAC4 hgnc:14063

De novo missense substitution at Pro248, the +2 position of the 14-3-3 motif. Reported in one individual (DECIPHER 275175). The 14-3-3-Pred consensus score fell to 45.9% of native.

Show evidence (1 reference)

PMID:33537682 SUPPORT Computational

"Two individuals possess variants altering Thr244 or Glu247, whereas the remaining five all carry variants altering Pro248, a key residue for 14-3-3 binding."

Places p.Pro248Ala within the recurrently altered Pro248 group; the predicted effect on 14-3-3 binding was derived computationally (14-3-3-Pred), not by immunoprecipitation.

HDAC4 c.743C>T p.(Pro248Leu) Pathogenic

Gene: HDAC4 hgnc:14063

Recurrent de novo missense substitution at Pro248, found in four of the seven reported individuals (DECIPHER 286901; ClinVar SCV000741300.1, SCV000574314.5, SCV001427054). The 14-3-3-Pred consensus score fell to 44.5% of native, the largest predicted effect of the four variants.

Show evidence (1 reference)

PMID:33537682 SUPPORT Computational

"Two individuals possess variants altering Thr244 or Glu247, whereas the remaining five all carry variants altering Pro248, a key residue for 14-3-3 binding."

Identifies Pro248 as the recurrently altered residue; the predicted effect on 14-3-3 binding was derived computationally (14-3-3-Pred), not by immunoprecipitation.

💊

Medical Actions

6

Antiseizure Pharmacotherapy

Action: anticonvulsant therapy Ontology label: Anticonvulsant Therapy NCIT:C64172

Agent: anticonvulsant agent NCIT:C264

Seizures in NEDCHF have been difficult to control. The index individual with infantile spasms continued to have medication-non-responsive seizures, and both individuals with mid-childhood generalized seizures remained difficult to control despite multiple anticonvulsants. No disorder-specific antiseizure strategy has been established; management is empiric and seizure-type directed.

Target Phenotypes: Seizure HP:0001250

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Both individual 3 and individual 4 developed generalized seizures in mid-childhood, which have also been difficult to control despite the use of multiple anticonvulsants."

Documents that anticonvulsants are used but that seizure control is often inadequate; support is partial because no efficacy data are reported.

Texture-Modified Diet

Action: texture-modified diet Ontology label: Dietary Intervention NCIT:C15447

Swallowing difficulty, poor suck and oral aversion are common. Reported oral feeding management consisted of texture-modified diets - pureed food, soft food and thickened fluids.

Target Phenotypes: Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"swallowing difficulties, soft food, thickened fluids"

Table 1 records texture modification as the feeding management used in an affected individual. No outcome data are reported, hence PARTIAL.

Gastrostomy Feeding

Action: gastrostomy Ontology label: Gastrostomy NCIT:C52006

Where swallowing difficulty is severe enough that oral intake cannot be maintained, gastrostomy feeding is used; one of the seven reported individuals was gastrostomy-fed. Placement is a procedure and is curated separately from the dietary arm of feeding support.

Target Phenotypes: Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"The individuals reported here also had features not typically seen in individuals with 2q37 deletion or loss-of-function variants in HDAC4, including swallowing difficulties and/or drooling, congenital hip dislocation, progressive kyphoscoliosis, and delayed closure of the anterior fontanelle."

Establishes swallowing difficulty as a recurrent feature of this entity, which is the indication for gastrostomy feeding. Gastrostomy itself is recorded only as a Table 1 cell; a bare cell states no finding and falls below the minimum evidence-snippet length, so it is not quoted as evidence here. No outcome data are reported, hence PARTIAL.

Developmental and Physical Therapy

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Universal hypotonia, delayed or absent independent walking, and severe speech impairment make multidisciplinary developmental support (physical, occupational and speech/communication therapy, special education) the mainstay of care. All school-age individuals attended special school, one used Makaton signing, and two walked only with assistance.

Target Phenotypes: Central hypotonia HP:0001252

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"All individuals presented with delayed developmental milestones/ID and hypotonia."

Establishes the universal motor and developmental impairment that indicates developmental therapy; no intervention trial exists, hence PARTIAL.

Orthopedic Surveillance and Management

Action: orthopedic surgical procedure Ontology label: Orthopedic Surgical Procedure NCIT:C16186

Progressive kyphoscoliosis (5/7) and hip dislocation or subluxation (4/7) warrant spinal and hip surveillance, with orthopedic intervention as clinically indicated. Joint hypermobility may compound instability.

Target Phenotypes: Kyphoscoliosis HP:0002751 Congenital hip dislocation HP:0001374

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Four have had hip dislocation/subluxation and five have scoliosis/kyphosis."

Documents the burden of spinal and hip pathology that motivates orthopedic surveillance; no treatment outcomes are reported, hence PARTIAL.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

All reported variants arose de novo, so recurrence risk for the parents of an affected child is low, though germline mosaicism cannot be excluded. Counseling should distinguish this disorder from HDAC4 haploinsufficiency / 2q37 deletion syndrome, which has a different mechanism, a different clinical course, and different recurrence considerations when a parental balanced rearrangement is present.

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Here, we report seven unrelated individuals with a phenotype distinct from that of BDMR, all of whom have heterozygous de novo missense variants that affect a major regulatory site of HDAC4, required for signal-dependent 14-3-3 binding and nucleocytoplasmic shuttling."

The de novo, unrelated occurrence in all seven probands is the basis for the recurrence-risk counseling message.

🔬

Diagnosis

1

Exome or genome sequencing

All reported individuals were diagnosed by whole-exome sequencing performed for unexplained developmental delay or intellectual disability, either clinically or through the Deciphering Developmental Disorders study, with Sanger confirmation of the HDAC4 variant. Because the phenotype is not specific enough for targeted single-gene testing, broad sequencing with trio analysis (to establish de novo status) is the practical diagnostic route. Chromosomal microarray remains the appropriate test when the phenotype instead suggests a 2q37 deletion.

Show evidence (2 references)

PMID:33537682 SUPPORT Human Clinical

"All individuals reported had been referred for investigation of developmental delay (DD) and/or ID of unknown cause and were each assessed clinically by at least one author."

Ascertainment was through investigation of unexplained developmental delay/ID, i.e. broad sequencing rather than targeted testing.

PMID:33537682 SUPPORT Human Clinical

"Individuals 1, 5, 6, and 7 were evaluated by clinical whole-exome sequencing as previously described."

Documents clinical whole-exome sequencing as the diagnostic modality used for four of the seven probands.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Seven unrelated individuals were reported in the defining 2021 cohort; no population-based prevalence estimate exists. The count reflects reported cases, not an estimated rate.

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"Here, we report seven unrelated individuals with a phenotype distinct from that of BDMR"

Establishes the size of the only reported cohort, supporting an ultra-rare, cases-in-literature prevalence record.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Neurodevelopmental Disorder with Central Hypotonia and Dysmorphic Facies:

2q37 microdeletion syndrome (brachydactyly-mental retardation syndrome) MONDO:0010886

Overlapping Features The other HDAC4-associated phenotype and the principal differential. Brachydactyly-mental retardation syndrome arises from HDAC4 loss of function, usually as part of a contiguous-gene deletion of chromosome 2q37, and is mechanistically distinct from NEDCHF - haploinsufficiency versus a proposed gain of function through increased nuclear HDAC4. The two should not be grouped as a single entity. The dismech entry for the deletion syndrome is 2q37 Microdeletion Syndrome.

Distinguishing Features

Brachydactyly type E is the hallmark of BDMR and is absent in every reported individual with NEDCHF.
Autism spectrum disorder and obesity occur in BDMR but were not seen in NEDCHF.
The BDMR facial gestalt (broad face, brachycephaly, broad upturned nose) differs from the NEDCHF gestalt (hypertelorism, full lower lip, long palpebral fissures, frontal upsweep, widely spaced teeth, large ears).
Swallowing difficulties/drooling, congenital hip dislocation, progressive kyphoscoliosis and delayed anterior fontanelle closure are seen in NEDCHF but are not typical of 2q37 deletion or HDAC4 loss of function.
Developmental delay and intellectual disability are more severe in NEDCHF than in BDMR.
The causal lesion differs - a 2q37 deletion or HDAC4 truncating/whole-gene loss-of-function allele versus a de novo missense variant restricted to the 14-3-3 binding motif at residues 242-248.

Show evidence (3 references)

PMID:33537682 SUPPORT Human Clinical

"Individuals shared facial dysmorphic features that were distinct from the broad face, brachycephaly, and broad, upturned nose described in BDMR. None of the individuals reported here had autism, obesity, or brachydactyly type E."

Enumerates the clinical discriminators between NEDCHF and the BDMR / 2q37 deletion phenotype.

PMID:33537682 SUPPORT In Vitro

"As such, we propose that these variants result in a novel gain-of-function effect, leading to increased nuclear activity of HDAC4, and thus differentiating both the molecular mechanism and the outcome of these variants from that of previously reported loss-of-function alleles of HDAC4 that..."

States the mechanistic boundary - gain of function here versus haploinsufficiency in BDMR.

PMID:20691407 SUPPORT Human Clinical

"BDMR presents with a range of features, including intellectual disabilities, developmental delays, behavioral abnormalities, sleep disturbance, craniofacial and skeletal abnormalities (including brachydactyly type E), and autism spectrum disorder."

Defines the BDMR/HDAC4-haploinsufficiency phenotype against which NEDCHF is contrasted.

MEF2C haploinsufficiency syndrome Not Yet Curated MONDO:0013266

Overlapping Features MEF2C is a direct repression target of HDAC4, and MEF2C haploinsufficiency (MIM 613443) produces a partly overlapping picture of developmental delay, intellectual disability, stereotypic movements, epilepsy and variable brain MRI anomalies. The overlap is non-specific, and the craniofacial and skeletal features of NEDCHF are not part of the MEF2C phenotype.

Distinguishing Features

A 5q14.3 deletion or MEF2C loss-of-function variant is found rather than an HDAC4 14-3-3-site missense variant.
The distinctive NEDCHF facial gestalt, kyphoscoliosis, hip dislocation and delayed fontanelle closure are not characteristic of MEF2C haploinsufficiency.

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"We noted some non-specific phenotypic overlap between our individuals and those with variants in MEF2C (MIM: 613443), including DD/ID, stereotypic movements, epilepsy, and variable MRI brain scan anomalies."

The authors themselves identify MEF2C-related disorder as the overlapping differential, and characterize the overlap as non-specific.

Cleidocranial dysplasia MONDO:0007340

Overlapping Features RUNX2 is the second direct repression target of HDAC4. Cleidocranial dysplasia (MIM 119600), caused by RUNX2 loss of function, shares delayed closure of the anterior fontanelle, dental anomalies, hypertelorism and hip joint defects with NEDCHF, but the widespread characteristic skeletal defects of cleidocranial dysplasia are largely absent in NEDCHF, and significant intellectual disability is not a feature of cleidocranial dysplasia.

Distinguishing Features

Clavicular hypoplasia/aplasia and supernumerary teeth are characteristic of cleidocranial dysplasia and are not reported in NEDCHF.
Significant developmental delay and intellectual disability are universal in NEDCHF but not features of cleidocranial dysplasia.
A RUNX2 loss-of-function allele is found rather than an HDAC4 14-3-3-site missense variant.

Show evidence (1 reference)

PMID:33537682 SUPPORT Human Clinical

"a feature of which is delayed closure of the anterior fontanelle, which was reported in two of the individuals described here."

Identifies the shared feature and the reason cleidocranial dysplasia is a mechanistically motivated differential.

🧫

Experimental Models

1

HEK293 HDAC4 / 14-3-3 beta co-immunoprecipitation assay CELL_LINE

Transient co-expression of FLAG-tagged wild-type or variant HDAC4 with HA-tagged 14-3-3 beta in HEK293 cells, followed by anti-FLAG co-immunoprecipitation and densitometric quantification of bound 14-3-3 beta on western blots. Only the p.Thr244Lys and p.Glu247Gly alleles were assayed; the two Pro248 substitutions, carried by five of the seven reported individuals, rest on in silico prediction alone. This assay is the only direct functional experiment underpinning the gain-of-function chain curated in this entry.

Organism

human NCBITaxon:9606

Cell source

Immortalized human embryonic kidney cell line (HEK293), transiently transfected with epitope-tagged expression plasmids.

Culture

Two-dimensional monolayer culture; extracts harvested approximately 48 h after transfection for co-immunoprecipitation.

Publication

PMID:33537682

Pathograph links

Impaired 14-3-3 Binding and Loss of Cytoplasmic Sequestration measures fidelity: moderate Directly assays the binding step asserted by this node - the affinity of the variant RKTApSEP motif for 14-3-3 - for two of the four reported variants.

Limitations: Transformed kidney-derived cells with transient overexpression of tagged proteins do not model developing neurons, chondrocytes, or any organism-level phenotype, and the kinase/phosphatase context that sets Ser246 phosphorylation in patient tissue may differ. Two of the four variants, including the recurrent p.Pro248Leu allele, were never assayed. The assay measures binding only: the nuclear-to-cytoplasmic distribution of endogenous HDAC4 was not determined, so the loss of cytoplasmic sequestration remains inferred rather than measured.

Readouts

Variant HDAC4 binding to 14-3-3 beta

Anti-FLAG co-immunoprecipitated HA-tagged 14-3-3 beta, quantified by western blot densitometry relative to HDAC4 and 14-3-3 beta loading controls, for variant versus native HDAC4.

Direction: DECREASED

Interpretation: An approximately two-fold reduction in 14-3-3 binding for both assayed variants is the measured basis for this node; the authors themselves describe the effect as only partial, which is why the downstream nuclear gain-of-function node is marked provisional.

Show evidence (1 reference)

PMID:33537682 SUPPORT In Vitro

"Co-immunoprecipitation assays carried out on cell extracts indicated that both the p.Glu247Gly and p.Thr244Lys variants bound 14-3-3β with approximately two-fold reduced affinity compared to native HDAC4"

Reports the measured binding reduction behind this readout.

Show evidence (1 reference)

PMID:33537682 SUPPORT In Vitro

"To test the effects predicted in silico on the binding of 14-3-3, we co-expressed 14-3-3β with either native or variant HDAC4 in HEK293 cells."

States that the assay was built to test the 14-3-3-binding step, which is why this cell model is treated as informative for this node.

🐁

Animal Models

2

HDAC4-overexpressing proliferating mouse chondrocytes

Overexpression of HDAC4 in proliferating mouse chondrocytes inhibits their differentiation, phenocopying Runx2 loss of function. This is the only experimental system that supports the RUNX2 arm of the MEF2C/RUNX2 node curated in this entry. It is reported here as cited by the NEDCHF discovery paper (Vega et al., reference 11 of PMID:33537682); no animal carrying an HDAC4 14-3-3-motif missense variant has been described.

Species

Mouse

Genotype

HDAC4 overexpression in proliferating chondrocytes

Genes

HDAC4 hgnc:14063

Pathograph links

MEF2C and RUNX2 Target Transcriptional Dysregulation partially recapitulates fidelity: low Demonstrates that excess HDAC4 in a RUNX2-dependent cell type produces a Runx2-loss-of-function-like phenotype, which is the experimental basis for the RUNX2 arm of this node. The MEF2C arm and any neural consequence are not addressed by this model.

Limitations: Supraphysiological overexpression of wild-type HDAC4 in mouse chondrocytes, not a knock-in of a human 14-3-3-motif variant: it models increased HDAC4 dosage rather than impaired 14-3-3 sequestration, covers only the skeletal (RUNX2) arm, and says nothing about neuronal MEF2C targets or the human craniofacial phenotype. It is also cited secondhand through the NEDCHF discovery paper rather than curated from the primary chondrocyte report.

Readouts

Chondrocyte differentiation under HDAC4 overexpression

Differentiation of proliferating mouse chondrocytes overexpressing HDAC4, compared against the Runx2 loss-of-function phenotype.

Direction: DECREASED

Interpretation: Inhibited chondrocyte differentiation resembling Runx2 loss of function is the model's phenotypic correlate of reduced RUNX2 output at this node.

Show evidence (1 reference)

PMID:33537682 SUPPORT Model Organism

"overexpression of HDAC4 in proliferating mouse chondrocytes inhibited their differentiation, thus resembling the effects of Runx2 loss of function"

Reports the differentiation readout and its equivalence to Runx2 loss of function.

Show evidence (1 reference)

PMID:33537682 SUPPORT Model Organism

"In support of this, Vega et al.11 have previously noted that overexpression of HDAC4 in proliferating mouse chondrocytes inhibited their differentiation, thus resembling the effects of Runx2 loss of function."

The NEDCHF authors invoke this model as the support for the RUNX2 arm of the node, which is why it is treated as informative here.

HDAC4 3SA constitutive-nuclear mutant mouse (could not be generated)

The one whole-organism test of constitutively nuclear HDAC4 that has been attempted. Mice carrying the 3SA mutant, in which all three major 14-3-3 sites are mutated to alanine, could not be generated, which the NEDCHF authors read as circumstantial evidence that substantial increases in nuclear HDAC4 activity are incompatible with life. Curated as a model because the negative result bounds the increased-nuclear-HDAC4 node rather than testing it.

Species

Mouse

Genotype

Hdac4 3SA constitutive-nuclear mutant (Ser246, Ser467 and Ser632 of the three major 14-3-3 sites mutated to alanine)

Genes

HDAC4 hgnc:14063

Pathograph links

Increased Nuclear HDAC4 Co-repressor Activity fails to recapitulate fidelity: low The intended in vivo model of constitutively nuclear HDAC4 could not be established, so this node has no organism-level test. The failure is itself informative: it suggests that a large, unrestrained increase in nuclear HDAC4 is lethal, whereas the NEDCHF variants produce only a partial reduction of 14-3-3 binding at a single site.

Limitations: No viable animal was obtained, so nothing was measured - the model provides no data on nuclear HDAC4 levels, MEF2C or RUNX2 target transcription, or phenotype. It also over-models the human lesion: abolishing all three 14-3-3 sites is far more severe than the approximately two-fold reduction in binding at one site measured for the patient variants, so its inviability cannot be read as evidence against the human mechanism, only as a constraint on how large the effect can be.

Show evidence (1 reference)

PMID:33537682 SUPPORT Model Organism

"attempts to generate mice carrying the constitutive nuclear 3SA mutant of HDAC4, in which the serine residues of the three major 14-3-3 sites (Ser246, Ser467, and Ser632) were mutated to alanine, were unsuccessful"

Reports the failed attempt to generate the constitutively nuclear mouse, the negative result this link records.

Structural anchor for the nedchf_gain_of_function_unproven knowledge gap: the absence of any viable in vivo model of increased nuclear HDAC4 is a principal reason the gain-of-function step of the mechanism remains untested.

{ }

Source YAML

click to show

name: Neurodevelopmental Disorder with Central Hypotonia and Dysmorphic Facies
creation_date: '2026-08-15T00:00:00Z'
category: Mendelian
synonyms:
- NEDCHF
- HDAC4-related neurodevelopmental disorder
- HDAC4 14-3-3 binding site missense syndrome
description: >-
  Neurodevelopmental disorder with central hypotonia and dysmorphic facies
  (NEDCHF; OMIM:619797) is an autosomal dominant developmental disorder caused
  by de novo heterozygous missense variants that cluster in the conserved
  14-3-3 binding motif spanning residues 242-248 of HDAC4, a class IIa histone
  deacetylase that functions as a signal-responsive transcriptional
  co-repressor. Affected individuals have global developmental delay with
  significant intellectual disability, universal central hypotonia,
  medication-resistant seizures in a subset, a distinctive facial appearance
  (hypertelorism, full lower lip, long palpebral fissures, frontal upsweep of
  hair, widely spaced teeth, large ears), kyphoscoliosis, hip
  dislocation/subluxation, delayed closure of the anterior fontanelle, feeding
  difficulties with drooling, and non-specific brain MRI abnormalities.
  Mechanistically, the variants reduce phosphorylation-dependent 14-3-3 binding
  and therefore cytoplasmic sequestration of HDAC4, and are proposed to act by
  gain of function through increased nuclear HDAC4 co-repressor activity. This
  makes NEDCHF mechanistically distinct from HDAC4 haploinsufficiency and from
  2q37 deletion (brachydactyly-mental retardation) syndrome, and the two should
  not be grouped: no individual with NEDCHF has had brachydactyly type E,
  autism, or obesity.
disease_term:
  preferred_term: neurodevelopmental disorder with central hypotonia and dysmorphic facies
  term:
    id: MONDO:0859232
    label: neurodevelopmental disorder with central hypotonia and dysmorphic facies
parents:
- Neurodevelopmental Disorder
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:33537682
      reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This phenotype includes significant DD/ID, seizures, distinctive facial
        features, scoliosis, delayed closure of the anterior fontanelle, and
        non-specific brain MRI anomalies
      explanation: >-
        The defining features are neurological (developmental delay,
        intellectual disability, hypotonia, seizures, brain MRI anomalies),
        placing the entry in the neurologic chapter.
inheritance:
- name: Autosomal dominant, de novo
  description: >-
    All reported individuals carry a heterozygous HDAC4 missense variant that
    arose de novo; no transmitted case has been described, and no recurrence in
    a sibship has been reported. Parental germline mosaicism has not been
    excluded, so empiric recurrence risk is low but not zero.
  inheritance_term:
    preferred_term: autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report seven unrelated individuals with a phenotype distinct from
      that of BDMR, all of whom have heterozygous de novo missense variants that
      affect a major regulatory site of HDAC4, required for signal-dependent
      14-3-3 binding and nucleocytoplasmic shuttling.
    explanation: >-
      Seven unrelated probands each carry a heterozygous de novo missense
      variant, establishing an autosomal dominant, de novo mode of inheritance.
- name: Typically de novo occurrence
  description: >-
    The recurrence of four different missense substitutions at the same
    functional motif across seven unrelated de novo cases is the principal
    genetic argument for causality.
  inheritance_term:
    preferred_term: typically de novo
    term:
      id: HP:0025352
      label: Typically de novo
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nevertheless, the observation of four different missense variants, all of
      which affect the same functional motif in HDAC4 and arose de novo in seven
      unrelated individuals, provides very strong genetic evidence that these
      variants are indeed causative for the phenotype observed.
    explanation: >-
      Explicit statement that all four variants arose de novo in seven unrelated
      individuals.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Seven unrelated individuals were reported in the defining 2021 cohort; no
    population-based prevalence estimate exists. The count reflects reported
    cases, not an estimated rate.
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report seven unrelated individuals with a phenotype distinct from
      that of BDMR
    explanation: >-
      Establishes the size of the only reported cohort, supporting an
      ultra-rare, cases-in-literature prevalence record.
pathophysiology:
- name: HDAC4 14-3-3 Binding Site Missense Variant
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    De novo heterozygous missense substitutions cluster in the RKTApSEP motif
    spanning residues 242-248 of HDAC4, the first and most important of the
    three 14-3-3 binding sites in the protein and the only one invariant from
    human to fruit fly. Reported substitutions are p.Thr244Lys, p.Glu247Gly,
    p.Pro248Ala and p.Pro248Leu; Pro248, the +2 residue relative to the
    phosphoacceptor Ser246, is altered in five of seven individuals. The motif
    partially overlaps the HDAC4 nuclear localization signal (residues
    244-279).
  genes:
  - preferred_term: HDAC4
    term:
      id: hgnc:14063
      label: HDAC4
  molecular_functions:
  - preferred_term: 14-3-3 protein binding
    term:
      id: GO:0071889
      label: 14-3-3 protein binding
    modifier: DECREASED
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two individuals possess variants altering Thr244 or Glu247, whereas the
      remaining five all carry variants altering Pro248, a key residue for
      14-3-3 binding.
    explanation: >-
      Defines the variant spectrum and the clustering at the 14-3-3 binding
      motif.
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The nuclear activity of HDAC4 is regulated by the process of
      nucleocytoplasmic shuttling, which in turn is dependent on the
      phosphorylation-dependent binding of 14-3-3 proteins, which act to
      sequester HDAC4 in the cytoplasm; as such, HDAC4 serves as a transducer of
      upstream signaling events.
    explanation: >-
      Establishes why a variant in this motif is expected to deregulate HDAC4
      localization.
  downstream:
  - target: Impaired 14-3-3 Binding and Loss of Cytoplasmic Sequestration
    causal_link_type: DIRECT
    description: >-
      The substitutions degrade the 14-3-3 consensus and/or reduce
      accessibility of Ser246 to its kinases (TAK1, MARK2), directly lowering
      14-3-3 affinity for the motif.
- name: Impaired 14-3-3 Binding and Loss of Cytoplasmic Sequestration
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Phosphorylation of Ser246 creates a 14-3-3 docking site; bound 14-3-3
    biases nucleocytoplasmic shuttling toward the cytoplasm by masking the
    overlapping nuclear localization signal and inhibiting nuclear import.
    Co-immunoprecipitation of FLAG-HDAC4 with HA-tagged 14-3-3 beta in HEK293
    cells showed that the p.Glu247Gly and p.Thr244Lys variants bind 14-3-3 with
    approximately two-fold reduced affinity relative to wild-type HDAC4. In
    silico analyses predicted reduced 14-3-3 binding for all four variants, with
    the strongest effect at Pro248.
  molecular_functions:
  - preferred_term: 14-3-3 protein binding
    term:
      id: GO:0071889
      label: 14-3-3 protein binding
    modifier: DECREASED
  biological_processes:
  - preferred_term: protein export from nucleus
    term:
      id: GO:0006611
      label: protein export from nucleus
    modifier: DECREASED
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We propose that the variants in all seven individuals impair 14-3-3
      binding (as confirmed for the first two variants by immunoprecipitation
      assays), thereby identifying deregulation of HDAC4 as a pathological
      mechanism in a previously uncharacterized developmental disorder.
    explanation: >-
      Co-immunoprecipitation in transfected HEK293 cells directly demonstrates
      reduced 14-3-3 binding for two of the patient variants.
  - reference: PMID:18952052
    reference_title: 14-3-3 regulates the nuclear import of class IIa histone deacetylases.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Phosphorylation-induced 14-3-3 binding biases the balance of
      nucleo-cytoplasmic shuttling toward the cytoplasm by inhibiting nuclear
      import.
    explanation: >-
      Independent cell-based work establishes that 14-3-3 binding restrains
      nuclear entry of class IIa HDACs, so losing it shifts HDAC4 into the
      nucleus.
  - reference: PMID:11470791
    reference_title: The modular nature of histone deacetylase HDAC4 confers phosphorylation-dependent intracellular trafficking.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we reveal that HDAC4 contains a modular structure consisting of a
      C-terminal autonomous nuclear export domain, which, in conjunction with an
      internal regulatory domain responsive to calcium/calmodulin-dependent
      protein kinase IV (CaMKIV), determines its subcellular localization.
    explanation: >-
      Defines the modular trafficking architecture of HDAC4 in which the
      N-terminal regulatory region containing the 14-3-3 sites governs
      localization. Support is partial because this study argues the
      HDAC4:14-3-3 complex also acts within the nucleus, so the directionality
      of 14-3-3 control is not settled by a single model.
  downstream:
  - target: Increased Nuclear HDAC4 Co-repressor Activity
    causal_link_type: DIRECT
    description: >-
      Reduced cytoplasmic sequestration is predicted to raise the steady-state
      nuclear pool of HDAC4.
- name: Increased Nuclear HDAC4 Co-repressor Activity
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Vertebrate HDAC4 is catalytically inactive as a histone deacetylase in its
    own right and acts predominantly as a signal-dependent transcriptional
    co-repressor. An increased nuclear pool is therefore proposed to act as a
    gain of function, increasing repression of HDAC4-bound transcription
    factors. This is the mechanistic step that distinguishes NEDCHF from HDAC4
    haploinsufficiency; it is inferred from the binding data plus the known
    biology rather than measured directly in patient neurons, so the node is
    marked provisional.
  molecular_functions:
  - preferred_term: transcription corepressor activity
    term:
      id: GO:0003714
      label: transcription corepressor activity
    modifier: INCREASED
  biological_processes:
  - preferred_term: protein localization to nucleus
    term:
      id: GO:0034504
      label: protein localization to nucleus
    modifier: INCREASED
  - preferred_term: negative regulation of transcription by RNA polymerase II
    term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    modifier: INCREASED
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      As such, we propose that these variants result in a novel gain-of-function
      effect, leading to increased nuclear activity of HDAC4, and thus
      differentiating both the molecular mechanism and the outcome of these
      variants from that of previously reported loss-of-function alleles of
      HDAC4 that result in haploinsufficiency.
    explanation: >-
      States the proposed gain-of-function mechanism and its explicit contrast
      with HDAC4 haploinsufficiency.
  - reference: PMID:26074448
    reference_title: "The Class IIa histone deacetylase HDAC4 and neuronal function: Nuclear nuisance and cytoplasmic stalwart?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In the nucleus, HDAC4 is a repressor of transcriptional programmes,
      although vertebrate HDAC4 is itself catalytically inactive and repression
      is facilitated through direct inhibition of transcription factors such as
      MEF2.
    explanation: >-
      Establishes that nuclear HDAC4 represses transcription through direct
      transcription-factor inhibition rather than intrinsic deacetylase
      activity, which is why increased nuclear HDAC4 is a repressive gain of
      function.
  notes: >-
    The authors caution that the effect on 14-3-3 binding was only partial, so
    any increase in nuclear HDAC4 activity may be modest; they also note that
    mice carrying the constitutively nuclear 3SA HDAC4 mutant could not be
    generated, suggesting large increases may be lethal.
  downstream:
  - target: MEF2C and RUNX2 Target Transcriptional Dysregulation
    causal_link_type: DIRECT
    description: >-
      HDAC4 binds and represses MEF2C and RUNX2, so more nuclear HDAC4 is
      expected to reduce the transcriptional output of both factors.
- name: MEF2C and RUNX2 Target Transcriptional Dysregulation
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    HDAC4 physically interacts with and represses myocyte enhancer factor 2C
    (MEF2C) and runt-related transcription factor 2 (RUNX2), both required for
    normal neural and skeletal development. Increased nuclear HDAC4 is
    therefore predicted to reduce MEF2C- and RUNX2-dependent transcription. The
    clinical picture is consistent with this: NEDCHF shares developmental
    delay, stereotypic movements, epilepsy and variable brain MRI anomalies
    with MEF2C haploinsufficiency, and shares delayed fontanelle closure,
    dental anomalies, hypertelorism and hip joint defects with RUNX2-related
    cleidocranial dysplasia. Whether reduced MEF2C/RUNX2 signalling actually
    occurs in patient tissue remains undetermined, and unique NEDCHF features
    suggest additional, unidentified downstream pathways.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  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
  genes:
  - preferred_term: MEF2C
    term:
      id: hgnc:6996
      label: MEF2C
  - preferred_term: RUNX2
    term:
      id: hgnc:10472
      label: RUNX2
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increased nuclear activity of HDAC4 would be expected to result in reduced
      activity of RUNX2 and MEF2C.
    explanation: >-
      States the predicted transcription-factor consequence of increased nuclear
      HDAC4.
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whether the decreased interaction with 14-3-3 does indeed lead to
      decreased RUNX2 and MEF2C signaling as a result of increased nuclear HDAC4
      activity remains to be determined
    explanation: >-
      The authors explicitly flag this step as unproven, which is why the node
      is marked hypothetical.
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In support of this, Vega et al.11 have previously noted that
      overexpression of HDAC4 in proliferating mouse chondrocytes inhibited
      their differentiation, thus resembling the effects of Runx2 loss of
      function.
    explanation: >-
      Mouse chondrocyte data show that excess HDAC4 phenocopies Runx2 loss of
      function, supporting the RUNX2 arm of this node.
  - reference: PMID:12641737
    reference_title: Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The class II histone deacetylases, HDAC4 and HDAC5, directly bind to and
      repress myogenic transcription factors of the myocyte enhancer factor-2
      (MEF-2) family thereby inhibiting skeletal myogenesis.
    explanation: >-
      Independent evidence that HDAC4 directly binds and represses MEF2-family
      transcription factors.
  downstream:
  - target: Impaired Neuronal Plasticity Gene Expression
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced MEF2-dependent transcription of synaptic genes
    description: >-
      MEF2 is a principal activity-dependent transcription factor in neurons;
      its repression by nuclear HDAC4 reduces expression of plasticity genes.
  - target: Neurodevelopmental and Craniofacial-Skeletal Phenotype
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced RUNX2-dependent osteogenic transcription
    - as-yet-unidentified HDAC4 downstream pathways
    description: >-
      RUNX2 repression plausibly contributes to the delayed fontanelle closure,
      dental anomalies and hip joint defects, but unique NEDCHF features are not
      explained by RUNX2 or MEF2C loss alone.
- name: Impaired Neuronal Plasticity Gene Expression
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    In neurons HDAC4 shuttles in response to synaptic activity and is normally
    predominantly cytoplasmic; nuclear restriction of HDAC4 down-regulates
    plasticity-related genes and impairs memory in model systems. A variant that
    biases HDAC4 toward the nucleus is therefore expected to suppress the
    activity-dependent synaptic gene programme in developing neurons. An
    additional, non-exclusive route proposed by the authors is increased
    repression of MEF2 by naturally occurring nuclear-retained HDAC4 cleavage
    fragments, which were more abundant for the patient variants and which
    repress MEF2C independently of deacetylase activity.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: regulation of synaptic plasticity
    term:
      id: GO:0048167
      label: regulation of synaptic plasticity
    modifier: DECREASED
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      HDAC4 has been shown to specifically repress the expression of genes
      required for synaptic function and neuronal plasticity, and this
      expression was reduced further by the constitutive nuclear 3SA mutant of
      HDAC4.
    explanation: >-
      Directly links a constitutively nuclear HDAC4 (the same directional change
      proposed for the patient variants) to reduced synaptic and plasticity gene
      expression.
  - reference: PMID:26074448
    reference_title: "The Class IIa histone deacetylase HDAC4 and neuronal function: Nuclear nuisance and cytoplasmic stalwart?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Nuclear-restriction of HDAC4 results in down-regulation of
      plasticity-related genes and memory impairment.
    explanation: >-
      Review of the primary literature establishing that nuclear restriction of
      HDAC4 is deleterious for plasticity gene expression and memory.
  - reference: PMID:12641737
    reference_title: Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found that, in cultured hippocampal neurones, the localization of HDAC4
      and HDAC5 is dynamic and signal-regulated.
    explanation: >-
      Shows that activity-dependent HDAC4 shuttling is a real feature of
      neurons, so a shuttling defect is neuronally relevant.
  downstream:
  - target: Neurodevelopmental and Craniofacial-Skeletal Phenotype
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered activity-dependent synaptic gene programmes during development
    description: >-
      Suppressed plasticity gene expression in developing neurons is the
      proposed substrate for the intellectual disability, hypotonia and
      epilepsy.
- name: Neurodevelopmental and Craniofacial-Skeletal Phenotype
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    The clinical endpoint of the cascade: universal central hypotonia and
    developmental delay with significant intellectual disability, seizures in a
    subset, a recognizable facial gestalt, kyphoscoliosis and hip
    dislocation/subluxation, delayed closure of the anterior fontanelle, and
    non-specific brain MRI abnormalities. Notably absent are brachydactyly type
    E, autism and obesity, which are characteristic of the HDAC4
    loss-of-function / 2q37 deletion phenotype.
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This phenotype includes significant DD/ID, seizures, distinctive facial
      features, scoliosis, delayed closure of the anterior fontanelle, and
      non-specific brain MRI anomalies; thus, it is distinct from the BDMR
      phenotype previously reported in individuals carrying HDAC4
      loss-of-function alleles.
    explanation: >-
      Summarizes the clinical endpoint and its distinctness from the
      loss-of-function phenotype.
phenotypes:
- category: Nervous System
  name: Global developmental delay
  description: >-
    All seven reported individuals were ascertained for developmental delay
    and/or intellectual disability of unknown cause, and all presented with
    delayed developmental milestones.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All individuals presented with delayed developmental milestones/ID and hypotonia.
    explanation: 7/7 individuals had delayed developmental milestones, supporting VERY_FREQUENT.
- category: Nervous System
  name: Intellectual disability
  description: >-
    All individuals of school age attended special school and had significant
    intellectual disability; one individual (individual 3) had comparatively
    milder cognitive, motor and speech difficulties. The degree of impairment
    was greater than that typically reported in brachydactyly-mental
    retardation syndrome.
  frequency: VERY_FREQUENT
  severity: SEVERE
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals of school age have attended special school and have
      significant ID, though individual 3 had milder cognitive, motor, and
      speech difficulties in comparison with the rest of the cohort.
    explanation: >-
      Supports both the near-universal frequency and the significant severity,
      with one milder outlier.
- category: Nervous System
  name: Central hypotonia
  description: >-
    Central hypotonia was recorded as present in all seven individuals and is
    the feature for which the disorder is named. HP:0011398 (Central hypotonia)
    is obsolete in the current HPO and is replaced by HP:0001252 (Hypotonia);
    the more specific clinical descriptor is retained in preferred_term.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Central hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All individuals presented with delayed developmental milestones/ID and hypotonia.
    explanation: >-
      Hypotonia was present in 7/7 individuals; Table 1 of the same paper
      records central hypotonia as present in every case.
- category: Nervous System
  name: Delayed ability to walk
  description: >-
    Independent walking had not been achieved in the majority of individuals;
    two walked only with assistance, and the least severely affected individual
    walked at 18 months.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Delayed ability to walk
    term:
      id: HP:0031936
      label: Delayed ability to walk
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All individuals presented with delayed developmental milestones/ID and hypotonia.
    explanation: >-
      Supports delayed motor milestones for the cohort as a whole; the
      per-individual ages at walking are given in Table 1 of the same paper and
      are summarized in the description.
- category: Nervous System
  name: Impaired expressive speech
  description: >-
    Speech was severely affected in most individuals: three were non-verbal and
    three had only single words or a few single words; one individual was
    fluent with first words at 18 months.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals of school age have attended special school and have
      significant ID, though individual 3 had milder cognitive, motor, and
      speech difficulties in comparison with the rest of the cohort.
    explanation: >-
      Supports significant speech impairment across the cohort; the
      per-individual speech descriptions are tabulated in Table 1 of the same
      paper.
- category: Nervous System
  name: Seizures
  description: >-
    Three of seven individuals had seizures. One presented with infantile
    spasms progressing to multiple medication-resistant seizure types; two
    developed generalized seizures in mid-childhood (with drop attacks in one
    and generalized tonic-clonic seizures in the other) that were also
    difficult to control with multiple anticonvulsants.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both individual 3 and individual 4 developed generalized seizures in
      mid-childhood, which have also been difficult to control despite the use
      of multiple anticonvulsants.
    explanation: >-
      Two individuals with generalized seizures plus individual 1 with infantile
      spasms gives 3/7 (43%), mapping to FREQUENT.
- category: Nervous System
  name: Infantile spasms
  description: >-
    One individual presented with infantile spasms in infancy and continued to
    have multiple, medication-resistant seizure types.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual 1 presented with infantile spasms and continues to have
      seizures that are non-responsive to medication.
    explanation: 1/7 individuals (14%), mapping to OCCASIONAL.
- category: Nervous System
  name: Motor stereotypies and dystonic movements
  description: >-
    One individual had a movement disorder with hand stereotypies most
    noticeable in early childhood; another was described as having dystonic
    limb movements.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Motor stereotypy
    term:
      id: HP:0000733
      label: Motor stereotypy
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual 4 has a movement disorder and had hand stereotypies, most
      noticeable in early childhood.
    explanation: >-
      Documents hand stereotypies in one individual; dystonic limb movements
      were separately noted in individual 2.
- category: Nervous System
  name: Sleep disturbance
  description: Three of seven individuals were reported to have sleep disturbance.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Three individuals were reported as suffering from sleep disturbance.
    explanation: 3/7 (43%), mapping to FREQUENT.
- category: Nervous System
  name: Non-specific brain MRI abnormalities
  description: >-
    Brain MRI showed variable, non-specific changes in five individuals,
    including cerebral and cerebellar atrophy, brainstem signal abnormality,
    thin corpus callosum, ventriculomegaly and generalized paucity of brain
    matter; two scans were normal.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal brain morphology
    term:
      id: HP:0012443
      label: Abnormal brain morphology
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variable and non-specific changes were observed in brain magnetic
      resonance imaging (MRI) scans in five individuals.
    explanation: >-
      Five of seven individuals had abnormal, non-specific brain MRI findings
      (71%), mapping to FREQUENT.
- category: Head and Neck
  name: Hypertelorism
  description: >-
    Hypertelorism was part of the distinctive facial gestalt seen in multiple
    individuals.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial appearance was distinctive, with the following features seen in
      multiple individuals: hypertelorism, a full lower lip, long palpebral
      fissures, frontal upsweep of hair, widely spaced teeth, and large ears
    explanation: Hypertelorism is listed among the recurrent dysmorphic features.
- category: Head and Neck
  name: Full lower lip
  description: >-
    A full (thick) lower lip vermilion was one of the recurrent facial features
    illustrated in the published photographs.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Full lower lip
    term:
      id: HP:0000179
      label: Thick lower lip vermilion
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial appearance was distinctive, with the following features seen in
      multiple individuals: hypertelorism, a full lower lip, long palpebral
      fissures, frontal upsweep of hair, widely spaced teeth, and large ears
    explanation: A full lower lip is listed among the recurrent dysmorphic features.
- category: Head and Neck
  name: Long palpebral fissures
  description: Relatively long palpebral fissures were seen in multiple individuals.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Long palpebral fissure
    term:
      id: HP:0000637
      label: Long palpebral fissure
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial appearance was distinctive, with the following features seen in
      multiple individuals: hypertelorism, a full lower lip, long palpebral
      fissures, frontal upsweep of hair, widely spaced teeth, and large ears
    explanation: Long palpebral fissures are listed among the recurrent dysmorphic features.
- category: Head and Neck
  name: Frontal upsweep of hair
  description: A frontal upsweep of the hair was a recurrent feature of the facial gestalt.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Frontal upsweep of hair
    term:
      id: HP:0002236
      label: Frontal upsweep of hair
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial appearance was distinctive, with the following features seen in
      multiple individuals: hypertelorism, a full lower lip, long palpebral
      fissures, frontal upsweep of hair, widely spaced teeth, and large ears
    explanation: Frontal upsweep of hair is listed among the recurrent dysmorphic features.
- category: Head and Neck
  name: Widely spaced teeth
  description: >-
    Widely spaced teeth were seen in multiple individuals; delayed dentition was
    additionally recorded in two.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Widely spaced teeth
    term:
      id: HP:0000687
      label: Widely spaced teeth
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial appearance was distinctive, with the following features seen in
      multiple individuals: hypertelorism, a full lower lip, long palpebral
      fissures, frontal upsweep of hair, widely spaced teeth, and large ears
    explanation: Widely spaced teeth are listed among the recurrent dysmorphic features.
- category: Head and Neck
  name: Large ears
  description: Large ears were part of the recurrent facial gestalt.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Large ears
    term:
      id: HP:0000400
      label: Macrotia
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial appearance was distinctive, with the following features seen in
      multiple individuals: hypertelorism, a full lower lip, long palpebral
      fissures, frontal upsweep of hair, widely spaced teeth, and large ears
    explanation: Large ears are listed among the recurrent dysmorphic features.
- category: Head and Neck
  name: Delayed closure of the anterior fontanelle
  description: >-
    Two of seven individuals had a documented history of delayed closure of the
    anterior fontanelle, a feature not typical of 2q37 deletion or HDAC4
    loss-of-function and one that overlaps RUNX2-related cleidocranial
    dysplasia.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Delayed closure of the anterior fontanelle
    term:
      id: HP:0001476
      label: Delayed closure of the anterior fontanelle
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is a history of delayed closure of the anterior fontanelle in
      individuals 2 and 4.
    explanation: 2/7 individuals (29%), mapping to OCCASIONAL.
- category: Musculoskeletal
  name: Kyphoscoliosis
  description: >-
    Five of seven individuals had scoliosis and/or kyphosis, including
    progressive thoracolumbar scoliosis in one and postural thoracolumbar
    kyphosis in another.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Kyphoscoliosis
    term:
      id: HP:0002751
      label: Kyphoscoliosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Four have had hip dislocation/subluxation and five have scoliosis/kyphosis.
    explanation: 5/7 individuals (71%), mapping to FREQUENT.
- category: Musculoskeletal
  name: Hip dislocation or subluxation
  description: >-
    Four of seven individuals had hip dislocation or subluxation, including two
    with congenital hip dislocation and two with femoral head subluxation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Congenital hip dislocation
    term:
      id: HP:0001374
      label: Congenital hip dislocation
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Four have had hip dislocation/subluxation and five have scoliosis/kyphosis.
    explanation: 4/7 individuals (57%), mapping to FREQUENT.
- category: Musculoskeletal
  name: Joint hypermobility
  description: >-
    Three of seven individuals had hypermobility with striking joint laxity of
    the fingers.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three individuals also have hypermobility, with striking joint laxity of
      the fingers.
    explanation: 3/7 individuals (43%), mapping to FREQUENT.
- category: Digestive
  name: Feeding and swallowing difficulties
  description: >-
    Swallowing difficulties, poor suck, texture-modified diets, oral aversion
    and gastrostomy feeding were recorded across the cohort. These are features
    not typically seen with 2q37 deletion or HDAC4 loss of function.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individuals reported here also had features not typically seen in
      individuals with 2q37 deletion or loss-of-function variants in HDAC4,
      including swallowing difficulties and/or drooling, congenital hip
      dislocation, progressive kyphoscoliosis, and delayed closure of the
      anterior fontanelle.
    explanation: >-
      Swallowing difficulties are named as a recurrent, discriminating feature
      of this disorder.
- category: Digestive
  name: Drooling
  description: >-
    Significant drooling in early childhood was a common feature and, where
    noted, persisted in all but one individual.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Drooling
    term:
      id: HP:0002307
      label: Drooling
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Significant drooling in early childhood was a common feature and, where
      noted, has persisted in all but individual 3.
    explanation: Drooling is described as a common and usually persistent feature.
- category: Limbs
  name: Absence of brachydactyly type E
  description: >-
    No individual had hand or foot anomalies consistent with brachydactyly type
    E. This negative finding is diagnostically important because brachydactyly
    type E is the hallmark of the HDAC4 loss-of-function / 2q37 deletion
    (brachydactyly-mental retardation) phenotype.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of the individuals had hand or foot anomalies consistent with
      brachydactyly type E.
    explanation: >-
      Explicitly refutes brachydactyly as a feature of this disorder, in
      contrast to BDMR.
  notes: >-
    Curated as a REFUTE evidence item so the absence is machine-queryable; this
    is a deliberate negative annotation, not an asserted phenotype.
- category: Nervous System
  name: Absence of autism spectrum disorder
  description: >-
    None of the seven individuals was reported as showing autistic features,
    despite autism spectrum disorder being a recognized feature of the 2q37
    deletion / HDAC4 loss-of-function phenotype.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: None was reported as showing autistic features.
    explanation: >-
      Explicitly refutes autistic features in the reported cohort, a
      discriminator from BDMR.
- category: Growth
  name: Absence of obesity
  description: >-
    No individual in the reported cohort was obese. With brachydactyly type E
    and autism spectrum disorder, obesity completes the triad of features that
    are characteristic of the HDAC4 loss-of-function / 2q37 deletion
    (brachydactyly-mental retardation) phenotype and are absent from NEDCHF.
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of the individuals reported here had autism, obesity, or
      brachydactyly type E.
    explanation: >-
      Explicitly refutes obesity in the reported cohort, the third BDMR
      discriminator alongside brachydactyly type E and autism.
  notes: >-
    Curated as a REFUTE evidence item so the absence is machine-queryable; this
    is a deliberate negative annotation, not an asserted phenotype. Weight
    centiles in Table 1 span the 2nd to 99th centile with no individual
    described as obese.
genetic:
- name: HDAC4
  gene_term:
    preferred_term: HDAC4
    term:
      id: hgnc:14063
      label: HDAC4
  presence: PRESENT
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  association: >-
    Heterozygous de novo missense variants clustered in the conserved 14-3-3
    binding motif (residues 242-248) of HDAC4 cause NEDCHF. Four distinct
    substitutions have been reported across seven unrelated probands; the
    recurrence of independent de novo variants at one functional motif is the
    principal genetic evidence for causality. HDAC4 is intolerant to loss of
    function (gnomAD pLI = 1), but the NEDCHF variants are proposed to act by
    gain of function rather than haploinsufficiency, and no missense variant at
    any position in this motif was observed in gnomAD.
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nevertheless, the observation of four different missense variants, all of
      which affect the same functional motif in HDAC4 and arose de novo in seven
      unrelated individuals, provides very strong genetic evidence that these
      variants are indeed causative for the phenotype observed.
    explanation: The authors' own statement of the gene-disease causality argument.
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All residues within this motif are highly conserved (Figure 1B), and no
      missense variants have been observed at any of these positions in the
      gnomAD database.
    explanation: >-
      Population-database absence at the affected motif positions supports
      pathogenicity of the variant class.
variants:
- name: HDAC4 c.731C>A p.(Thr244Lys)
  description: >-
    De novo missense substitution at the -2 position relative to the
    phosphoacceptor Ser246. Reported in one individual (ClinVar SCV001427055).
    Co-immunoprecipitation showed approximately two-fold reduced binding to
    14-3-3 beta relative to wild-type HDAC4.
  gene:
    preferred_term: HDAC4
    term:
      id: hgnc:14063
      label: HDAC4
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We propose that the variants in all seven individuals impair 14-3-3
      binding (as confirmed for the first two variants by immunoprecipitation
      assays), thereby identifying deregulation of HDAC4 as a pathological
      mechanism in a previously uncharacterized developmental disorder.
    explanation: >-
      p.Thr244Lys is one of the two variants for which reduced 14-3-3 binding
      was confirmed experimentally.
- name: HDAC4 c.740A>G p.(Glu247Gly)
  description: >-
    De novo missense substitution at the +1 position relative to Ser246, where
    glycine is not tolerated in known 14-3-3 binding sites. Reported in one
    individual (DECIPHER 300920). Co-immunoprecipitation showed approximately
    two-fold reduced binding to 14-3-3 beta and increased generation of
    C-terminally truncated HDAC4 fragments.
  gene:
    preferred_term: HDAC4
    term:
      id: hgnc:14063
      label: HDAC4
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We propose that the variants in all seven individuals impair 14-3-3
      binding (as confirmed for the first two variants by immunoprecipitation
      assays), thereby identifying deregulation of HDAC4 as a pathological
      mechanism in a previously uncharacterized developmental disorder.
    explanation: >-
      p.Glu247Gly is the variant with the most extensive experimental support
      for reduced 14-3-3 binding (five independent experiments).
- name: HDAC4 c.742C>G p.(Pro248Ala)
  description: >-
    De novo missense substitution at Pro248, the +2 position of the 14-3-3
    motif. Reported in one individual (DECIPHER 275175). The 14-3-3-Pred
    consensus score fell to 45.9% of native.
  gene:
    preferred_term: HDAC4
    term:
      id: hgnc:14063
      label: HDAC4
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Two individuals possess variants altering Thr244 or Glu247, whereas the
      remaining five all carry variants altering Pro248, a key residue for
      14-3-3 binding.
    explanation: >-
      Places p.Pro248Ala within the recurrently altered Pro248 group; the
      predicted effect on 14-3-3 binding was derived computationally
      (14-3-3-Pred), not by immunoprecipitation.
- name: HDAC4 c.743C>T p.(Pro248Leu)
  description: >-
    Recurrent de novo missense substitution at Pro248, found in four of the
    seven reported individuals (DECIPHER 286901; ClinVar SCV000741300.1,
    SCV000574314.5, SCV001427054). The 14-3-3-Pred consensus score fell to
    44.5% of native, the largest predicted effect of the four variants.
  gene:
    preferred_term: HDAC4
    term:
      id: hgnc:14063
      label: HDAC4
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Two individuals possess variants altering Thr244 or Glu247, whereas the
      remaining five all carry variants altering Pro248, a key residue for
      14-3-3 binding.
    explanation: >-
      Identifies Pro248 as the recurrently altered residue; the predicted effect
      on 14-3-3 binding was derived computationally (14-3-3-Pred), not by
      immunoprecipitation.
diagnosis:
- name: Exome or genome sequencing
  description: >-
    All reported individuals were diagnosed by whole-exome sequencing performed
    for unexplained developmental delay or intellectual disability, either
    clinically or through the Deciphering Developmental Disorders study, with
    Sanger confirmation of the HDAC4 variant. Because the phenotype is not
    specific enough for targeted single-gene testing, broad sequencing with
    trio analysis (to establish de novo status) is the practical diagnostic
    route. Chromosomal microarray remains the appropriate test when the
    phenotype instead suggests a 2q37 deletion.
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals reported had been referred for investigation of
      developmental delay (DD) and/or ID of unknown cause and were each assessed
      clinically by at least one author.
    explanation: >-
      Ascertainment was through investigation of unexplained developmental
      delay/ID, i.e. broad sequencing rather than targeted testing.
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals 1, 5, 6, and 7 were evaluated by clinical whole-exome
      sequencing as previously described.
    explanation: >-
      Documents clinical whole-exome sequencing as the diagnostic modality used
      for four of the seven probands.
differential_diagnoses:
- name: 2q37 microdeletion syndrome (brachydactyly-mental retardation syndrome)
  description: >-
    The other HDAC4-associated phenotype and the principal differential.
    Brachydactyly-mental retardation syndrome arises from HDAC4 loss of
    function, usually as part of a contiguous-gene deletion of chromosome 2q37,
    and is mechanistically distinct from NEDCHF - haploinsufficiency versus a
    proposed gain of function through increased nuclear HDAC4. The two should
    not be grouped as a single entity. The dismech entry for the deletion
    syndrome is 2q37 Microdeletion Syndrome.
  distinguishing_features:
  - "Brachydactyly type E is the hallmark of BDMR and is absent in every reported individual with NEDCHF."
  - "Autism spectrum disorder and obesity occur in BDMR but were not seen in NEDCHF."
  - "The BDMR facial gestalt (broad face, brachycephaly, broad upturned nose) differs from the NEDCHF gestalt (hypertelorism, full lower lip, long palpebral fissures, frontal upsweep, widely spaced teeth, large ears)."
  - "Swallowing difficulties/drooling, congenital hip dislocation, progressive kyphoscoliosis and delayed anterior fontanelle closure are seen in NEDCHF but are not typical of 2q37 deletion or HDAC4 loss of function."
  - "Developmental delay and intellectual disability are more severe in NEDCHF than in BDMR."
  - "The causal lesion differs - a 2q37 deletion or HDAC4 truncating/whole-gene loss-of-function allele versus a de novo missense variant restricted to the 14-3-3 binding motif at residues 242-248."
  disease_term:
    preferred_term: 2q37 microdeletion syndrome
    term:
      id: MONDO:0010886
      label: 2q37 microdeletion syndrome
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals shared facial dysmorphic features that were distinct from the
      broad face, brachycephaly, and broad, upturned nose described in BDMR.
      None of the individuals reported here had autism, obesity, or
      brachydactyly type E.
    explanation: >-
      Enumerates the clinical discriminators between NEDCHF and the BDMR / 2q37
      deletion phenotype.
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      As such, we propose that these variants result in a novel gain-of-function
      effect, leading to increased nuclear activity of HDAC4, and thus
      differentiating both the molecular mechanism and the outcome of these
      variants from that of previously reported loss-of-function alleles of
      HDAC4 that result in haploinsufficiency.
    explanation: >-
      States the mechanistic boundary - gain of function here versus
      haploinsufficiency in BDMR.
  - reference: PMID:20691407
    reference_title: Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BDMR presents with a range of features, including intellectual
      disabilities, developmental delays, behavioral abnormalities, sleep
      disturbance, craniofacial and skeletal abnormalities (including
      brachydactyly type E), and autism spectrum disorder.
    explanation: >-
      Defines the BDMR/HDAC4-haploinsufficiency phenotype against which NEDCHF
      is contrasted.
  notes: >-
    The 2q37 Microdeletion Syndrome entry in this knowledge base already records
    NEDCHF as a reciprocal differential and states that de novo HDAC4 missense
    variants affecting the 14-3-3-binding regulatory region should not be
    grouped with HDAC4 loss of function or 2q37 deletion. This entry honors that
    boundary.
- name: MEF2C haploinsufficiency syndrome
  description: >-
    MEF2C is a direct repression target of HDAC4, and MEF2C haploinsufficiency
    (MIM 613443) produces a partly overlapping picture of developmental delay,
    intellectual disability, stereotypic movements, epilepsy and variable brain
    MRI anomalies. The overlap is non-specific, and the craniofacial and
    skeletal features of NEDCHF are not part of the MEF2C phenotype.
  distinguishing_features:
  - "A 5q14.3 deletion or MEF2C loss-of-function variant is found rather than an HDAC4 14-3-3-site missense variant."
  - "The distinctive NEDCHF facial gestalt, kyphoscoliosis, hip dislocation and delayed fontanelle closure are not characteristic of MEF2C haploinsufficiency."
  disease_term:
    preferred_term: MEF2C haploinsufficiency syndrome
    term:
      id: MONDO:0013266
      label: neurodevelopmental disorder with hypotonia, stereotypic hand movements,
        and impaired language
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We noted some non-specific phenotypic overlap between our individuals and
      those with variants in MEF2C (MIM: 613443), including DD/ID, stereotypic
      movements, epilepsy, and variable MRI brain scan anomalies.
    explanation: >-
      The authors themselves identify MEF2C-related disorder as the overlapping
      differential, and characterize the overlap as non-specific.
- name: Cleidocranial dysplasia
  description: >-
    RUNX2 is the second direct repression target of HDAC4. Cleidocranial
    dysplasia (MIM 119600), caused by RUNX2 loss of function, shares delayed
    closure of the anterior fontanelle, dental anomalies, hypertelorism and hip
    joint defects with NEDCHF, but the widespread characteristic skeletal
    defects of cleidocranial dysplasia are largely absent in NEDCHF, and
    significant intellectual disability is not a feature of cleidocranial
    dysplasia.
  distinguishing_features:
  - "Clavicular hypoplasia/aplasia and supernumerary teeth are characteristic of cleidocranial dysplasia and are not reported in NEDCHF."
  - "Significant developmental delay and intellectual disability are universal in NEDCHF but not features of cleidocranial dysplasia."
  - "A RUNX2 loss-of-function allele is found rather than an HDAC4 14-3-3-site missense variant."
  disease_term:
    preferred_term: cleidocranial dysplasia
    term:
      id: MONDO:0007340
      label: cleidocranial dysplasia 1
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a feature of which is delayed closure of the anterior fontanelle, which
      was reported in two of the individuals described here.
    explanation: >-
      Identifies the shared feature and the reason cleidocranial dysplasia is a
      mechanistically motivated differential.
treatments:
- name: Antiseizure Pharmacotherapy
  description: >-
    Seizures in NEDCHF have been difficult to control. The index individual with
    infantile spasms continued to have medication-non-responsive seizures, and
    both individuals with mid-childhood generalized seizures remained difficult
    to control despite multiple anticonvulsants. No disorder-specific antiseizure
    strategy has been established; management is empiric and seizure-type
    directed.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: anticonvulsant therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
    therapeutic_agent:
    - preferred_term: anticonvulsant agent
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both individual 3 and individual 4 developed generalized seizures in
      mid-childhood, which have also been difficult to control despite the use
      of multiple anticonvulsants.
    explanation: >-
      Documents that anticonvulsants are used but that seizure control is often
      inadequate; support is partial because no efficacy data are reported.
- name: Texture-Modified Diet
  description: >-
    Swallowing difficulty, poor suck and oral aversion are common. Reported oral
    feeding management consisted of texture-modified diets - pureed food, soft
    food and thickened fluids.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: texture-modified diet
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: swallowing difficulties, soft food, thickened fluids
    explanation: >-
      Table 1 records texture modification as the feeding management used in an
      affected individual. No outcome data are reported, hence PARTIAL.
- name: Gastrostomy Feeding
  description: >-
    Where swallowing difficulty is severe enough that oral intake cannot be
    maintained, gastrostomy feeding is used; one of the seven reported
    individuals was gastrostomy-fed. Placement is a procedure and is curated
    separately from the dietary arm of feeding support.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: gastrostomy
    term:
      id: NCIT:C52006
      label: Gastrostomy
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individuals reported here also had features not typically seen in
      individuals with 2q37 deletion or loss-of-function variants in HDAC4,
      including swallowing difficulties and/or drooling, congenital hip
      dislocation, progressive kyphoscoliosis, and delayed closure of the
      anterior fontanelle.
    explanation: >-
      Establishes swallowing difficulty as a recurrent feature of this entity,
      which is the indication for gastrostomy feeding. Gastrostomy itself is
      recorded only as a Table 1 cell; a bare cell states no finding and falls
      below the minimum evidence-snippet length, so it is not quoted as
      evidence here. No outcome data are reported, hence PARTIAL.
- name: Developmental and Physical Therapy
  description: >-
    Universal hypotonia, delayed or absent independent walking, and severe
    speech impairment make multidisciplinary developmental support (physical,
    occupational and speech/communication therapy, special education) the
    mainstay of care. All school-age individuals attended special school, one
    used Makaton signing, and two walked only with assistance.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Central hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All individuals presented with delayed developmental milestones/ID and hypotonia.
    explanation: >-
      Establishes the universal motor and developmental impairment that
      indicates developmental therapy; no intervention trial exists, hence
      PARTIAL.
- name: Orthopedic Surveillance and Management
  description: >-
    Progressive kyphoscoliosis (5/7) and hip dislocation or subluxation (4/7)
    warrant spinal and hip surveillance, with orthopedic intervention as
    clinically indicated. Joint hypermobility may compound instability.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_phenotypes:
  - preferred_term: Kyphoscoliosis
    term:
      id: HP:0002751
      label: Kyphoscoliosis
  - preferred_term: Congenital hip dislocation
    term:
      id: HP:0001374
      label: Congenital hip dislocation
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Four have had hip dislocation/subluxation and five have scoliosis/kyphosis.
    explanation: >-
      Documents the burden of spinal and hip pathology that motivates orthopedic
      surveillance; no treatment outcomes are reported, hence PARTIAL.
- name: Genetic Counseling
  description: >-
    All reported variants arose de novo, so recurrence risk for the parents of
    an affected child is low, though germline mosaicism cannot be excluded.
    Counseling should distinguish this disorder from HDAC4 haploinsufficiency /
    2q37 deletion syndrome, which has a different mechanism, a different
    clinical course, and different recurrence considerations when a parental
    balanced rearrangement is present.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report seven unrelated individuals with a phenotype distinct from
      that of BDMR, all of whom have heterozygous de novo missense variants that
      affect a major regulatory site of HDAC4, required for signal-dependent
      14-3-3 binding and nucleocytoplasmic shuttling.
    explanation: >-
      The de novo, unrelated occurrence in all seven probands is the basis for
      the recurrence-risk counseling message.
animal_models:
- name: HDAC4-overexpressing proliferating mouse chondrocytes
  species: Mouse
  genotype: HDAC4 overexpression in proliferating chondrocytes
  genes:
  - preferred_term: HDAC4
    term:
      id: hgnc:14063
      label: HDAC4
  description: >-
    Overexpression of HDAC4 in proliferating mouse chondrocytes inhibits their
    differentiation, phenocopying Runx2 loss of function. This is the only
    experimental system that supports the RUNX2 arm of the MEF2C/RUNX2 node
    curated in this entry. It is reported here as cited by the NEDCHF discovery
    paper (Vega et al., reference 11 of PMID:33537682); no animal carrying an
    HDAC4 14-3-3-motif missense variant has been described.
  modeled_mechanisms:
  - target: MEF2C and RUNX2 Target Transcriptional Dysregulation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Demonstrates that excess HDAC4 in a RUNX2-dependent cell type produces a
      Runx2-loss-of-function-like phenotype, which is the experimental basis for
      the RUNX2 arm of this node. The MEF2C arm and any neural consequence are
      not addressed by this model.
    limitations: >-
      Supraphysiological overexpression of wild-type HDAC4 in mouse
      chondrocytes, not a knock-in of a human 14-3-3-motif variant: it models
      increased HDAC4 dosage rather than impaired 14-3-3 sequestration, covers
      only the skeletal (RUNX2) arm, and says nothing about neuronal MEF2C
      targets or the human craniofacial phenotype. It is also cited secondhand
      through the NEDCHF discovery paper rather than curated from the primary
      chondrocyte report.
    readouts:
    - name: Chondrocyte differentiation under HDAC4 overexpression
      target: MEF2C and RUNX2 Target Transcriptional Dysregulation
      description: >-
        Differentiation of proliferating mouse chondrocytes overexpressing
        HDAC4, compared against the Runx2 loss-of-function phenotype.
      direction: DECREASED
      interpretation: >-
        Inhibited chondrocyte differentiation resembling Runx2 loss of function
        is the model's phenotypic correlate of reduced RUNX2 output at this
        node.
      evidence:
      - reference: PMID:33537682
        reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          overexpression of HDAC4 in proliferating mouse chondrocytes inhibited
          their differentiation, thus resembling the effects of Runx2 loss of
          function
        explanation: >-
          Reports the differentiation readout and its equivalence to Runx2 loss
          of function.
    evidence:
    - reference: PMID:33537682
      reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In support of this, Vega et al.11 have previously noted that
        overexpression of HDAC4 in proliferating mouse chondrocytes inhibited
        their differentiation, thus resembling the effects of Runx2 loss of
        function.
      explanation: >-
        The NEDCHF authors invoke this model as the support for the RUNX2 arm of
        the node, which is why it is treated as informative here.
- name: HDAC4 3SA constitutive-nuclear mutant mouse (could not be generated)
  species: Mouse
  genotype: >-
    Hdac4 3SA constitutive-nuclear mutant (Ser246, Ser467 and Ser632 of the
    three major 14-3-3 sites mutated to alanine)
  genes:
  - preferred_term: HDAC4
    term:
      id: hgnc:14063
      label: HDAC4
  description: >-
    The one whole-organism test of constitutively nuclear HDAC4 that has been
    attempted. Mice carrying the 3SA mutant, in which all three major 14-3-3
    sites are mutated to alanine, could not be generated, which the NEDCHF
    authors read as circumstantial evidence that substantial increases in
    nuclear HDAC4 activity are incompatible with life. Curated as a model
    because the negative result bounds the increased-nuclear-HDAC4 node rather
    than testing it.
  modeled_mechanisms:
  - target: Increased Nuclear HDAC4 Co-repressor Activity
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The intended in vivo model of constitutively nuclear HDAC4 could not be
      established, so this node has no organism-level test. The failure is
      itself informative: it suggests that a large, unrestrained increase in
      nuclear HDAC4 is lethal, whereas the NEDCHF variants produce only a
      partial reduction of 14-3-3 binding at a single site.
    limitations: >-
      No viable animal was obtained, so nothing was measured - the model
      provides no data on nuclear HDAC4 levels, MEF2C or RUNX2 target
      transcription, or phenotype. It also over-models the human lesion:
      abolishing all three 14-3-3 sites is far more severe than the
      approximately two-fold reduction in binding at one site measured for the
      patient variants, so its inviability cannot be read as evidence against
      the human mechanism, only as a constraint on how large the effect can be.
    evidence:
    - reference: PMID:33537682
      reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        attempts to generate mice carrying the constitutive nuclear 3SA mutant
        of HDAC4, in which the serine residues of the three major 14-3-3 sites
        (Ser246, Ser467, and Ser632) were mutated to alanine, were unsuccessful
      explanation: >-
        Reports the failed attempt to generate the constitutively nuclear mouse,
        the negative result this link records.
  notes: >-
    Structural anchor for the nedchf_gain_of_function_unproven knowledge gap:
    the absence of any viable in vivo model of increased nuclear HDAC4 is a
    principal reason the gain-of-function step of the mechanism remains
    untested.
experimental_models:
- name: HEK293 HDAC4 / 14-3-3 beta co-immunoprecipitation assay
  description: >-
    Transient co-expression of FLAG-tagged wild-type or variant HDAC4 with
    HA-tagged 14-3-3 beta in HEK293 cells, followed by anti-FLAG
    co-immunoprecipitation and densitometric quantification of bound 14-3-3
    beta on western blots. Only the p.Thr244Lys and p.Glu247Gly alleles were
    assayed; the two Pro248 substitutions, carried by five of the seven reported
    individuals, rest on in silico prediction alone. This assay is the only
    direct functional experiment underpinning the gain-of-function chain curated
    in this entry.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: >-
    Immortalized human embryonic kidney cell line (HEK293), transiently
    transfected with epitope-tagged expression plasmids.
  culture_system: >-
    Two-dimensional monolayer culture; extracts harvested approximately 48 h
    after transfection for co-immunoprecipitation.
  conditions:
  - Wild-type FLAG-HDAC4 co-expressed with HA-tagged 14-3-3 beta
  - FLAG-HDAC4 p.Thr244Lys co-expressed with HA-tagged 14-3-3 beta
  - FLAG-HDAC4 p.Glu247Gly co-expressed with HA-tagged 14-3-3 beta
  publication: PMID:33537682
  modeled_mechanisms:
  - target: Impaired 14-3-3 Binding and Loss of Cytoplasmic Sequestration
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Directly assays the binding step asserted by this node - the affinity of
      the variant RKTApSEP motif for 14-3-3 - for two of the four reported
      variants.
    limitations: >-
      Transformed kidney-derived cells with transient overexpression of tagged
      proteins do not model developing neurons, chondrocytes, or any
      organism-level phenotype, and the kinase/phosphatase context that sets
      Ser246 phosphorylation in patient tissue may differ. Two of the four
      variants, including the recurrent p.Pro248Leu allele, were never assayed.
      The assay measures binding only: the nuclear-to-cytoplasmic distribution
      of endogenous HDAC4 was not determined, so the loss of cytoplasmic
      sequestration remains inferred rather than measured.
    readouts:
    - name: Variant HDAC4 binding to 14-3-3 beta
      target: Impaired 14-3-3 Binding and Loss of Cytoplasmic Sequestration
      description: >-
        Anti-FLAG co-immunoprecipitated HA-tagged 14-3-3 beta, quantified by
        western blot densitometry relative to HDAC4 and 14-3-3 beta loading
        controls, for variant versus native HDAC4.
      direction: DECREASED
      interpretation: >-
        An approximately two-fold reduction in 14-3-3 binding for both assayed
        variants is the measured basis for this node; the authors themselves
        describe the effect as only partial, which is why the downstream nuclear
        gain-of-function node is marked provisional.
      evidence:
      - reference: PMID:33537682
        reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Co-immunoprecipitation assays carried out on cell extracts indicated
          that both the p.Glu247Gly and p.Thr244Lys variants bound 14-3-3β
          with approximately two-fold reduced affinity compared to native HDAC4
        explanation: Reports the measured binding reduction behind this readout.
    evidence:
    - reference: PMID:33537682
      reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        To test the effects predicted in silico on the binding of 14-3-3, we
        co-expressed 14-3-3β with either native or variant HDAC4 in HEK293
        cells.
      explanation: >-
        States that the assay was built to test the 14-3-3-binding step, which
        is why this cell model is treated as informative for this node.
discussions:
- discussion_id: nedchf_gain_of_function_unproven
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does reduced 14-3-3 binding by the HDAC4 residue 242-248 missense variants
    actually increase the nuclear pool and repressive activity of HDAC4 in
    patient-relevant neural cells, and does this reduce MEF2C- and
    RUNX2-dependent transcription?
  attaches_to:
  - pathophysiology#Increased Nuclear HDAC4 Co-repressor Activity
  - pathophysiology#MEF2C and RUNX2 Target Transcriptional Dysregulation
  rationale: >-
    The gain-of-function model rests on a two-fold reduction of 14-3-3 binding
    measured for two of four variants by co-immunoprecipitation of overexpressed
    tagged proteins in HEK293 cells, plus in silico prediction for the remaining
    variants. Subcellular localization of endogenous variant HDAC4 has not been
    measured, nor has downstream MEF2C/RUNX2 target transcription. The authors
    explicitly note that the effect on 14-3-3 binding was only partial and that
    this step remains to be determined. This is the load-bearing mechanistic
    claim that separates the entity from HDAC4 haploinsufficiency, so it is the
    highest-value gap to close.
  proposed_experiments:
  - experiment_id: nedchf_exp_endogenous_localization
    name: Endogenous HDAC4 localization in patient-derived cells
    description: >-
      Quantify nuclear versus cytoplasmic endogenous HDAC4 in patient-derived
      fibroblasts and iPSC-derived neurons carrying each variant, using
      subcellular fractionation with immunoblot and quantitative
      immunofluorescence.
    decision_criterion: >-
      A statistically significant increase in the nuclear:cytoplasmic HDAC4
      ratio in variant cells relative to isogenic or parental controls.
    would_support:
    - pathophysiology#Increased Nuclear HDAC4 Co-repressor Activity
    would_refute:
    - pathophysiology#Increased Nuclear HDAC4 Co-repressor Activity
  - experiment_id: nedchf_exp_target_rnaseq
    name: Transcriptomic test of MEF2C and RUNX2 target repression
    description: >-
      Perform RNA-seq on isogenic knock-in neurons carrying p.Pro248Leu versus
      wild-type and test for coordinate down-regulation of curated MEF2C and
      RUNX2 target gene sets.
    decision_criterion: >-
      Significant coordinate down-regulation of MEF2C and RUNX2 target gene sets
      in variant neurons.
    would_support:
    - pathophysiology#MEF2C and RUNX2 Target Transcriptional Dysregulation
    would_refute:
    - pathophysiology#MEF2C and RUNX2 Target Transcriptional Dysregulation
  - experiment_id: nedchf_exp_mef2_occupancy
    name: MEF2 occupancy and reporter activity in variant neurons
    description: >-
      Measure MEF2-responsive reporter activity and MEF2C genomic occupancy by
      CUT&RUN or ChIP in variant versus wild-type neurons.
    would_support:
    - pathophysiology#MEF2C and RUNX2 Target Transcriptional Dysregulation
  - experiment_id: nedchf_exp_fragmentation
    name: Contribution of HDAC4 fragmentation to MEF2C repression
    description: >-
      Test whether the increased C-terminal fragmentation observed for
      p.Glu247Gly contributes independently to MEF2C repression, using
      cleavage-resistant HDAC4 constructs.
    would_support:
    - pathophysiology#Impaired Neuronal Plasticity Gene Expression
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We note that the effect of the variants on 14-3-3 binding was only
      partial, suggesting that any increase in nuclear HDAC4 activity might be
      limited.
    explanation: The authors' own caveat defining the gap.
- discussion_id: nedchf_clinical_spectrum_undefined
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the full clinical spectrum, natural history and genotype-phenotype
    correlation of HDAC4 14-3-3-site missense variants beyond the seven
    originally reported individuals?
  attaches_to:
  - pathophysiology#Neurodevelopmental and Craniofacial-Skeletal Phenotype
  rationale: >-
    The entity is defined by a single seven-person cohort aged 2-20 years.
    Frequencies curated here are small-denominator estimates, adult outcomes are
    unknown, and whether the four substitutions differ in severity cannot be
    assessed. The authors call for additional cases specifically to enable
    genotype-phenotype correlation.
  proposed_experiments:
  - experiment_id: nedchf_exp_international_cohort
    name: International HDAC4 motif-variant cohort
    description: >-
      Assemble an international cohort through GeneMatcher and DECIPHER of
      additional individuals with variants in HDAC4 residues 242-248 and collect
      standardized HPO-coded deep phenotyping.
    would_support:
    - pathophysiology#Neurodevelopmental and Craniofacial-Skeletal Phenotype
  - experiment_id: nedchf_exp_genotype_phenotype
    name: Genotype-phenotype comparison across the four substitutions
    description: >-
      Compare phenotype severity between the recurrent p.Pro248Leu allele and
      the non-Pro248 substitutions in the expanded cohort.
    would_support:
    - pathophysiology#HDAC4 14-3-3 Binding Site Missense Variant
  - experiment_id: nedchf_exp_natural_history
    name: Longitudinal natural-history follow-up
    description: >-
      Follow affected individuals into adulthood for seizure course, scoliosis
      progression, feeding status and cognitive/communication outcome.
    would_support:
    - pathophysiology#Neurodevelopmental and Craniofacial-Skeletal Phenotype
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identification of additional individuals with variants within this region
      of HDAC4 will enable further genotype-phenotype correlation and
      understanding of the clinical spectrum in similar individuals.
    explanation: The authors explicitly state this as the open question.
- discussion_id: nedchf_hdac_inhibitor_feasibility
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    If NEDCHF is a gain-of-function disorder, could a class IIa- or
    HDAC4-selective inhibitor (or a disruptor of the HDAC4-MEF2 interaction) be
    therapeutic, and is there a developmental window in which it could work?
  attaches_to:
  - pathophysiology#Increased Nuclear HDAC4 Co-repressor Activity
  rationale: >-
    A gain-of-function mechanism nominally suggests pharmacological inhibition.
    The discovery authors raise this explicitly but caution both that class IIa
    HDACs respond poorly to available pan-HDAC inhibitors, because of their low
    intrinsic deacetylase activity, and that a large part of the phenotype is
    developmental and may not be reversible postnatally. Because vertebrate
    HDAC4 represses through protein-protein interaction rather than catalysis,
    catalytic-site inhibition may also be the wrong target; disrupting the
    HDAC4-MEF2 interaction is an alternative. This is preclinical rationale and
    is deliberately not curated as a treatment.
  proposed_experiments:
  - experiment_id: nedchf_exp_selective_inhibitor_rescue
    name: HDAC4-selective inhibitor rescue in variant neurons
    description: >-
      Test whether HDAC4-selective inhibitors or HDAC4-MEF2 interaction
      disruptors restore MEF2 target gene expression in patient-variant neurons,
      and whether restoration depends on the developmental stage at which the
      compound is applied.
    would_support:
    - pathophysiology#Increased Nuclear HDAC4 Co-repressor Activity
  evidence:
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Gain-of-function variants in HDAC4 raise the possibility of therapeutic
      intervention by use of HDAC inhibitors, although whether such treatment
      could halt or reverse developmental problems is open to question.
    explanation: >-
      The authors raise HDAC inhibition as a theoretical strategy while flagging
      its uncertainty.
  - reference: PMID:33537682
    reference_title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      While a number of HDAC inhibitors are available for pharmacological use,
      class IIa HDACs are in fact poor responders to these drugs due to the lower
      deacetylase activity of these enzymes compared to other HDACs.
    explanation: >-
      Explains why available pan-HDAC inhibitors are unlikely to be useful and
      why class IIa- or HDAC4-selective agents would be needed.
notes: >-
  Scope boundary: this entry covers only the de novo missense variants in the
  HDAC4 14-3-3 binding motif (residues 242-248). HDAC4 loss of function
  (truncating variants, whole-gene deletion, 2q37 contiguous-gene deletion) is
  curated separately under 2q37 Microdeletion Syndrome and must not be merged
  with this entry; the two have opposite proposed directions of effect on HDAC4
  activity.

  Other HDAC4 loss-of-function reports, including a de novo frameshift
  (p.Gln1046AspfsTer29) associated with Lennox-Gastaut syndrome and
  polymicrogyria-like cortical malformation (PMID:40167013), belong to the
  loss-of-function arm and are deliberately not used as evidence here.

  No GeneReviews chapter exists for this disorder. A PubMed search for "HDAC4
  GeneReviews[All Fields]" returns only the retired 2q37 microdeletion syndrome
  chapter (PMID:20301337), which describes the deletion/loss-of-function entity
  rather than NEDCHF, and is therefore not used as a phenotype baseline for this
  entry.

  Frequency values are derived from the denominator of seven reported
  individuals and should be treated as provisional small-cohort estimates.

  Named-entity-confusion preflight: MONDO:0859232 was verified with OAK to carry
  xref OMIM:619797 and relationship RO:0004003 to HGNC:14063 (HDAC4), matching
  the gene and OMIM identity asserted throughout this entry. The falcon
  deep-research report was additionally checked with `just preflight-dr` and
  passed (HDAC4 mentioned 47 times, top gene; OMIM 619797 present).

  Treatment-term ontology: MAXO was removed from dismech and every former MAXO
  treatment term was remapped to its NCIT equivalent, so the schema's
  `TreatmentActionTerm` dynamic enum is reachable only from NCIT:C25218
  (Clinical Intervention or Procedure). All treatments here therefore use NCIT
  action terms (NCIT:C64172 Anticonvulsant Therapy, NCIT:C15447 Dietary
  Intervention, NCIT:C52006 Gastrostomy, NCIT:C15302 Physical Therapy,
  NCIT:C16186 Orthopedic Surgical Procedure, NCIT:C15240 Genetic Counseling).

  Model systems: the three systems relevant to this disorder are curated as
  first-class models linked to the pathograph rather than left as evidence
  items - the HEK293 co-immunoprecipitation assay (the only direct functional
  experiment, MEASURES the 14-3-3-binding node), HDAC4 overexpression in
  proliferating mouse chondrocytes (PARTIALLY_RECAPITULATES the RUNX2 arm), and
  the 3SA constitutive-nuclear mouse that could not be generated
  (FAILS_TO_RECAPITULATE, the negative in vivo result behind the
  gain-of-function knowledge gap). No patient-derived cell line, iPSC model or
  variant knock-in animal has been reported.

  Ontology-term caution: the falcon deep-research report suggested HP:0011443
  for central hypotonia and HP:0000639 for long palpebral fissure. Both were
  rejected after OAK verification (HP:0011398 Central hypotonia is obsolete and
  replaced by HP:0001252 Hypotonia; the correct long palpebral fissure term is
  HP:0000637). The verified terms are used here.

📚

References & Deep Research

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 13 citations 2026-08-15T08:43:05.720240

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Neurodevelopmental Disorder with Central Hypotonia and Dysmorphic Facies
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Neurodevelopmental Disorder with Central Hypotonia and Dysmorphic Facies covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Neurodevelopmental Disorder with Central Hypotonia and Dysmorphic Facies

Executive summary

Neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHDF) is an exceptionally rare, monogenic developmental chromatinopathy caused by heterozygous, usually de novo missense variants in the major 14-3-3-binding motif of HDAC4. The defining evidence remains a 2021 series of seven unrelated individuals; consequently, prevalence, penetrance, survival, long-term natural history, and treatment-response estimates are not established. The disorder must not be conflated with 2q37 deletion/brachydactyly–mental retardation syndrome, which usually reflects HDAC4 haploinsufficiency or a larger contiguous-gene deletion and has a different phenotype and molecular mechanism. Open Targets maps the disease to MONDO:0859232, HDAC4 (ENSG00000068024), and literature including PMID 33537682. (OpenTargets Search: Neurodevelopmental disorder with central hypotonia and dysmorphic facies, wakeling2021missensesubstitutionsat pages 1-6)

The best-supported pathogenic chain is: variant in HDAC4 residues 242–248 → impaired phosphorylation-dependent 14-3-3 binding → reduced cytoplasmic sequestration → inferred increase in nuclear HDAC4/corepressor activity → altered developmental transcription, probably including excessive repression of MEF2C- and RUNX2-dependent programs → neurodevelopmental, craniofacial, and skeletal manifestations. Only the impaired binding step has been directly demonstrated for selected variants; increased nuclear activity and downstream transcriptional effects remain compelling but incompletely tested hypotheses. (wakeling2021missensesubstitutionsat pages 12-17, wakeling2021missensesubstitutionsat pages 9-12)

The defining evidence is summarized below.

Domain	Established findings	Quantitative evidence in defining 7-person cohort	Suggested ontology terms	Evidence limitations
Disease identity	Distinct Mendelian neurodevelopmental disorder caused by HDAC4 missense variants affecting the major 14-3-3 regulatory motif; distinguished from HDAC4 haploinsufficiency/2q37 deletion syndrome (BDMR) by phenotype and proposed mechanism (wakeling2021missensesubstitutionsat pages 1-6, wakeling2021missensesubstitutionsat pages 9-12)	Defining cohort: 7 unrelated individuals (wakeling2021missensesubstitutionsat pages 1-6, wakeling2021missensesubstitutionsat pages 6-9)	Suggested: MONDO:0859232; OMIM:619797; NCBI Gene/ HGNC for HDAC4	MONDO/OMIM identifiers are disease-resource mappings; cohort size comes from one discovery report
Causal gene / variant class	Heterozygous de novo missense variants in HDAC4 clustering at residues 242-248 around phospho-Ser246 within the 14-3-3 binding site; variants reported to alter Thr244, Glu247, or Pro248 (wakeling2021missensesubstitutionsat pages 1-6, wakeling2021missensesubstitutionsat pages 6-9)	7/7 de novo; 5/7 affect Pro248 (wakeling2021missensesubstitutionsat pages 1-6, wakeling2021missensesubstitutionsat pages 6-9)	Suggested: Sequence Ontology missense_variant; HP suggested De novo mutation if phenotype-modeling requires; GO suggested protein binding, protein localization	Full per-patient HGVS list was not fully recoverable from the parsed table extract
Core neurodevelopmental phenotype	Universal developmental delay / intellectual disability with central hypotonia; all school-age individuals required special education, with one relatively milder case (wakeling2021missensesubstitutionsat pages 6-9)	DD/ID 7/7; hypotonia 7/7 (wakeling2021missensesubstitutionsat pages 6-9)	Suggested HPO: Developmental delay (HP:0001263), Intellectual disability (HP:0001249), Central hypotonia (HP:0011443)	Severity stratification and milestone ages were incompletely extractable from the malformed table
Seizures / neurologic features	Epilepsy is common; one case had infantile spasms refractory to medication, two had generalized seizures beginning in mid-childhood; movement abnormalities included hand stereotypies or dystonic limb movements (wakeling2021missensesubstitutionsat pages 6-9)	Seizures 3/7 (wakeling2021missensesubstitutionsat pages 6-9)	Suggested HPO: Seizure (HP:0001250), Infantile spasms (HP:0012469), Stereotypy (HP:0000733), Dystonia (HP:0001332)	Frequency for movement disorder/stereotypies was described narratively, not fully tabulated in available extract
Sleep	Sleep disturbance reported in a subset (wakeling2021missensesubstitutionsat pages 6-9)	3/7 (wakeling2021missensesubstitutionsat pages 6-9)	Suggested HPO: Sleep disturbance (HP:0002360)	Type/severity of sleep disorder not consistently specified
Brain imaging	Variable, nonspecific brain MRI abnormalities occurred in most imaged cases (wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 12-17)	MRI nonspecific changes 5/7 (wakeling2021missensesubstitutionsat pages 6-9)	Suggested HPO: Abnormality of brain MRI (HP:0410263)	Specific neuroanatomical lesions were not consistently detailed in accessible text
Craniofacial / oral phenotype	Recurrent facial features included hypertelorism, full lower lip, long palpebral fissures, frontal hair upsweep, widely spaced teeth, and large ears; significant drooling in early childhood was common (wakeling2021missensesubstitutionsat pages 6-9)	Multi-case recurrent features reported qualitatively; exact counts not fully recoverable except statement that at least 6/7 had dental anomalies, hypertelorism and/or hip defects (wakeling2021missensesubstitutionsat pages 12-17, wakeling2021missensesubstitutionsat pages 9-12)	Suggested HPO: Hypertelorism (HP:0000316), Long palpebral fissure (HP:0000639), Full lower lip (HP:0000179), Widely spaced teeth (HP:0000687), Large ears (HP:0000400), Drooling (HP:0002307)	Individual feature frequencies are incompletely extractable from the parsed PDF table
Feeding / swallowing	Swallowing difficulties and/or drooling are highlighted as distinguishing features compared with BDMR (wakeling2021missensesubstitutionsat pages 9-12)	Cohort-wide count not fully extractable; described as clinically recurrent/common (wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 9-12)	Suggested HPO: Dysphagia (HP:0002015), Feeding difficulties (HP:0011968), Drooling (HP:0002307)	Exact numerator/denominator for swallowing problems unavailable in accessible text
Skeletal / orthopedic phenotype	Hip dislocation or subluxation, progressive scoliosis/kyphosis, and joint laxity/hypermobility were frequent; delayed anterior fontanel closure seen in two cases (wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 9-12)	Hip dislocation/subluxation 4/7; scoliosis/kyphosis 5/7; delayed fontanel closure 2/7 (wakeling2021missensesubstitutionsat pages 6-9)	Suggested HPO: Hip dislocation (HP:0002827), Hip subluxation (HP:0001388), Scoliosis (HP:0002650), Kyphosis (HP:0002808), Joint hypermobility (HP:0001382), Delayed closure of the anterior fontanelle (HP:0001476)	Progression details were narrative; some features grouped together (e.g., scoliosis/kyphosis)
Growth	Growth was generally unremarkable except relatively large head size in one case (wakeling2021missensesubstitutionsat pages 6-9)	No robust abnormal-growth frequency; authors state growth parameters were “generally unremarkable” (wakeling2021missensesubstitutionsat pages 6-9)	Suggested HPO: Relative macrocephaly (HP:0004482) if supported case-wise	Limited anthropometric summary only
Negative / distinguishing features	Unlike BDMR/2q37 deletion syndrome, the cohort lacked reported autism, obesity, and brachydactyly type E; also lacked BDMR-typical broad face/brachycephaly/broad upturned nose (wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 9-12)	Autism 0/7 reported; obesity 0/7 reported; brachydactyly type E 0/7 reported (wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 9-12)	Suggested HPO negatives for curation only if allowed: absence of Autistic behavior (HP:0000729), Obesity (HP:0001513), Brachydactyly type E (HP:0005863)	These are reported absences in a small cohort, not proof of impossibility
Molecular mechanism	Variants impair phosphorylation-dependent 14-3-3 interaction at the key HDAC4 shuttling motif, reducing cytoplasmic sequestration and supporting a gain-of-function via increased nuclear HDAC4 activity; downstream effects on RUNX2 and MEF2C are proposed (wakeling2021missensesubstitutionsat pages 9-12, wakeling2021missensesubstitutionsat pages 12-17, wakeling2021missensesubstitutionsat pages 6-9)	Functional assay showed ~2-fold reduced 14-3-3β binding for p.Thr244Lys and p.Glu247Gly in HEK-293 co-immunoprecipitation assays (wakeling2021missensesubstitutionsat pages 9-12)	Suggested GO: protein binding (GO:0005515), protein localization to nucleus / nucleocytoplasmic transport (suggested only), negative regulation of transcription by RNA polymerase II (GO:0000122); suggested CL: HEK-293 cell not a CL term, so avoid strict CL assertion	Reduced binding is experimentally shown only for two variants; increased nuclear activity and transcriptional consequences are strongly inferred/proposed rather than directly measured in patient tissue
Differential diagnosis	Should be distinguished from 2q37 deletion syndrome / brachydactyly-mental retardation syndrome (BDMR) caused by HDAC4 loss-of-function or larger deletions; defining differences include more severe DD/ID and presence of swallowing difficulties/drooling, congenital hip defects, progressive kyphoscoliosis, delayed fontanel closure, and absence of autism/obesity/brachydactyly E (wakeling2021missensesubstitutionsat pages 1-6, wakeling2021missensesubstitutionsat pages 9-12, le2019genotypeandphenotype pages 6-7)	Comparator evidence includes a 103-individual 2q37 deletion cohort supporting HDAC4 as major contributor to BDMR but with different/overlapping features (le2019genotypeandphenotype pages 6-7, le2019genotypeandphenotype pages 2-3)	Suggested MONDO/OMIM differential: 2q37 deletion syndrome / BDMR (OMIM:600430)	Differential interpretation depends on small n for OMIM 619797 and heterogeneous comparator deletions
Diagnostics / management implication	Diagnosis currently depends on sequencing-based detection of HDAC4 missense variants in the 242-248 motif and clinical correlation; no disease-specific interventional trial or established targeted therapy identified in available evidence (wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 12-17)	Cohort identified by WES/clinical exome sequencing, with Sanger confirmation (wakeling2021missensesubstitutionsat pages 6-9)	Suggested NCIT: Whole Exome Sequencing, Sanger Sequencing	No validated biomarker, natural-history study, or evidence-based treatment algorithm found in retrieved sources

Table: This table summarizes the defining clinical and mechanistic evidence for Neurodevelopmental Disorder with Central Hypotonia and Dysmorphic Facies (OMIM 619797) from the foundational 7-person cohort. It is useful for rapid knowledge-base curation because it separates established observations, explicit cohort counts, suggested ontology mappings, and evidence limitations.

1. Disease information

Definition and identifiers

NEDCHDF is a congenital/early-childhood neurodevelopmental syndrome characterized by developmental delay or intellectual disability, central hypotonia, distinctive facial appearance, and frequent neurologic and orthopedic abnormalities. The defining report called it a “novel intellectual disability syndrome.” Its accepted identifiers are:

OMIM: 619797.
MONDO: MONDO:0859232.
Causal gene: HDAC4, histone deacetylase 4; OMIM gene 605314; Ensembl ENSG00000068024.
Common names: neurodevelopmental disorder with central hypotonia and dysmorphic facies; HDAC4-related neurodevelopmental disorder; HDAC4 14-3-3-binding-site disorder; the discovery-paper designation “novel intellectual disability syndrome.” (OpenTargets Search: Neurodevelopmental disorder with central hypotonia and dysmorphic facies, wakeling2021missensesubstitutionsat pages 1-6)
Orphanet, MeSH, ICD-10/ICD-11: no disease-specific identifier was established in the retrieved evidence. Coding will generally fall under broader intellectual-disability, developmental-disorder, hypotonia, or congenital-malformation categories.

The present description is aggregated disease-level information derived from a very small published patient series, not from an EHR population or registry. The foundational article was received September 18, 2020, accepted November 16, 2020, and published in January 2021: Wakeling et al., Human Genetics and Genomics Advances 2:100015, DOI: 10.1016/j.xhgg.2020.100015, PMID 33537682. (OpenTargets Search: Neurodevelopmental disorder with central hypotonia and dysmorphic facies, wakeling2021missensesubstitutionsat pages 1-6)

Critical nosologic distinction

NEDCHDF is distinct from 2q37 deletion syndrome/brachydactyly–mental retardation syndrome (BDMR; OMIM 600430). BDMR commonly results from HDAC4 loss of function or larger 2q37 deletions and classically includes brachydactyly type E, mild-to-moderate ID, obesity, autistic features, and broad facial morphology. The NEDCHDF cohort instead had more substantial DD/ID, dysphagia/drooling, hip defects, progressive kyphoscoliosis, and occasional delayed fontanel closure, without reported obesity, autism, or brachydactyly E. (wakeling2021missensesubstitutionsat pages 1-6, wakeling2021missensesubstitutionsat pages 9-12)

2. Etiology, risk, and protective factors

Causal factor

The established cause is a germline heterozygous de novo missense variant in HDAC4, clustered in the invariant 14-3-3-binding motif spanning amino acids 242–248 around phospho-Ser246. Four distinct variants affecting Thr244, Glu247, or Pro248 were reported among seven unrelated individuals; five of seven variants affected Pro248. Explicitly discussed protein changes include p.Thr244Lys, p.Glu247Gly, p.Pro248Ala, and p.Pro248Leu. (wakeling2021missensesubstitutionsat pages 1-6, wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 9-12)

Risk and protective factors

Genetic risk: presence of a pathogenic motif-disrupting HDAC4 allele. The founding variants were absent from gnomAD at the affected motif positions, and HDAC4 was highly constrained against loss-of-function variation (reported pLI=1), although that constraint metric pertains more directly to haploinsufficiency. (wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 1-6)
Environmental, infectious, lifestyle, occupational, sex, or ancestry risk factors: none established.
Protective alleles, modifier genes, diet, or lifestyle factors: none established.
Gene–environment interaction: no disease-specific evidence. HDAC4 is a signal-responsive nucleocytoplasmic shuttle, so cellular signaling can regulate its localization, but this is not evidence for a clinical environmental modifier. (wakeling2021missensesubstitutionsat pages 6-9)

Because most variants arose de novo, advanced parental age could not be evaluated in the seven-person series and should not be asserted as a risk factor.

3. Phenotypes

Core and recurrent findings

The following frequencies come only from the defining seven-person cohort and therefore have wide uncertainty:

Developmental delay/intellectual disability: 7/7. All school-age individuals attended special schools; severity was generally substantial, although one individual had milder cognitive, motor, and speech impairment. Suggested HPO: HP:0001263 Developmental delay, HP:0001249 Intellectual disability, HP:0000750 Delayed speech and language development. (wakeling2021missensesubstitutionsat pages 6-9)
Hypotonia: 7/7, described as central in the disease name. Suggested HPO: HP:0011443 Central hypotonia. (wakeling2021missensesubstitutionsat pages 6-9)
Epilepsy: 3/7. One patient had infantile spasms continuing despite medication; two developed difficult-to-control generalized seizures in mid-childhood. Suggested HPO: HP:0001250 Seizure, HP:0012469 Infantile spasms, HP:0002197 Generalized-onset seizure, HP:0002345 Action tremor only if separately documented—not a core term. (wakeling2021missensesubstitutionsat pages 6-9)
Nonspecific brain-MRI abnormalities: 5/7. Suggested HPO: HP:0410263 Abnormality of brain MRI; the available evidence does not support one consistent structural lesion. (wakeling2021missensesubstitutionsat pages 6-9)
Sleep disturbance: 3/7. Suggested HPO: HP:0002360 Sleep disturbance. (wakeling2021missensesubstitutionsat pages 6-9)
Movement/behavioral findings: hand stereotypies in one patient and dystonic limb movements in another. No autistic features were reported. Suggested HPO: HP:0000733 Stereotypy, HP:0001332 Dystonia; record autistic behavior as an observed-negative finding, not an exclusion criterion. (wakeling2021missensesubstitutionsat pages 6-9)
Craniofacial/oral features: hypertelorism, long palpebral fissures, full lower lip, frontal hair upsweep, widely spaced teeth, large ears, and dental anomalies. Suggested HPO: HP:0000316 Hypertelorism, HP:0000639 Long palpebral fissure, HP:0000179 Full lower lip, HP:0000687 Widely spaced teeth, HP:0000400 Large ears, and HP:0000164 Abnormality of the dentition. At least 6/7 had dental anomalies, hypertelorism, and/or hip-joint defects, but that composite count must not be interpreted as the frequency of each component. (wakeling2021missensesubstitutionsat pages 12-17, wakeling2021missensesubstitutionsat pages 6-9)
Feeding/oromotor involvement: dysphagia and significant childhood drooling were recurrent; drooling generally persisted except in one patient. Suggested HPO: HP:0002015 Dysphagia, HP:0011968 Feeding difficulties, HP:0002307 Drooling. Exact individual frequencies were not recoverable from the published table extract. (wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 9-12)
Orthopedic findings: hip dislocation/subluxation 4/7, scoliosis/kyphosis 5/7, and joint hypermobility/laxity 3/7. Suggested HPO: HP:0002827 Hip dislocation, HP:0001388 Hip subluxation, HP:0002650 Scoliosis, HP:0002808 Kyphosis, HP:0001382 Joint hypermobility. (wakeling2021missensesubstitutionsat pages 6-9)
Delayed anterior-fontanel closure: 2/7; suggested HPO HP:0001476. (wakeling2021missensesubstitutionsat pages 6-9)
Growth: generally unremarkable; one individual had a relatively large head. Obesity was absent in this small cohort. Suggested case-specific HPO: HP:0004482 Relative macrocephaly. (wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 9-12)

Severity, progression, and quality of life

Manifestations begin in infancy or early childhood through hypotonia and delayed milestones. Neurodevelopmental disability is chronic; seizure onset ranged from infancy to mid-childhood. Progressive kyphoscoliosis was explicitly noted, whereas the cognitive course was not shown to be neurodegenerative. Functional burden includes special-education needs, impaired mobility, communication limitations, feeding/swallowing problems, drooling, sleep disturbance, epilepsy, and orthopedic care. No disease-specific EQ-5D, SF-36, PROMIS, caregiver-burden, or adaptive-function study is available. (wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 9-12)

4. Genetic and molecular information

HDAC4 encodes a class IIa histone deacetylase/transcriptional corepressor with an N-terminal regulatory region and C-terminal deacetylase domain. The disorder-associated variants are germline missense substitutions, not somatic variants or recurrent chromosomal abnormalities. All seven founding cases were de novo. Formal ClinVar classifications and exact genomic/cDNA HGVS expressions should be verified against the current transcript NM_006037.4 before database ingestion; the source confirms Sanger validation but the retrieved table did not permit reliable extraction of every cDNA coordinate. (wakeling2021missensesubstitutionsat pages 6-9)

The variants are best interpreted as motif-specific gain-of-function/dysregulating alleles, not simple HDAC4 haploinsufficiency. No affected-position missense variant was present in gnomAD in the report. No founder variant, modifier gene, protective allele, pathogenic mosaic case, epigenetic “episignature,” or recurrent large-scale rearrangement specific to NEDCHDF has been demonstrated. (wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 9-12)

For contrast, HDAC4 haploinsufficiency and 2q37 deletions constitute a related but different disorder. A 103-person 2q37 analysis found incomplete penetrance and variable expressivity; reported aggregate frequencies included craniofacial dysmorphism 86%, cognitive/behavioral issues 79%, brachydactyly E 48%, and overweight/obesity 34%. HDAC4-specific loss-of-function examples included c.2399_2400insC (p.Gly801Trpfs*77) and an intragenic 65-bp deletion. (le2019genotypeandphenotype pages 6-7, le2019genotypeandphenotype pages 2-3)

5. Environmental information

No toxin, radiation, pollution, maternal exposure, diet, smoking, alcohol, physical-activity pattern, occupational agent, or infectious organism is known to cause or trigger NEDCHDF. It is not infectious or zoonotic. Environmental interventions cannot prevent a de novo germline variant, although standard supportive environments and early developmental services may reduce secondary disability.

6. Mechanism and pathophysiology

Upstream molecular defect

HDAC4 normally shuttles between nucleus and cytoplasm. Phosphorylation of Ser246, Ser467, and Ser632 creates 14-3-3-binding sites; the residues 242–248 motif makes a major contribution to cytoplasmic sequestration. The disease variants alter residues around Ser246, potentially reducing phosphorylation and/or direct 14-3-3 affinity. (wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 9-12)

In HEK-293 cells, co-immunoprecipitation showed that p.Thr244Lys and p.Glu247Gly had approximately twofold lower affinity for 14-3-3β than wild-type HDAC4. In-silico 14-3-3 scores were 88.6% of wild type for p.Glu247Gly, 45.9% for p.Pro248Ala, 44.5% for p.Pro248Leu, and 94.2% for p.Thr244Lys; those predictions are supportive rather than equivalent to functional validation. (wakeling2021missensesubstitutionsat pages 9-12)

Downstream chain

Reduced 14-3-3 binding is predicted to decrease cytoplasmic retention and increase nuclear HDAC4. Nuclear HDAC4 acts predominantly as a transcriptional corepressor and interacts with MEF2C and RUNX2. Increased repression of MEF2C-related neuronal/synaptic programs plausibly contributes to DD/ID, seizures, stereotypies, and MRI abnormalities; increased RUNX2 repression plausibly contributes to hip defects, delayed fontanel closure, dental abnormalities, and scoliosis. The paper emphasized that these downstream effects “remain to be determined” and may involve additional unidentified pathways. (wakeling2021missensesubstitutionsat pages 12-17, wakeling2021missensesubstitutionsat pages 9-12)

Suggested ontology annotations include GO:0005515 protein binding, GO:0000122 negative regulation of transcription by RNA polymerase II, GO:0051170 import into nucleus, GO:0051168 nuclear export, GO:0001501 skeletal system development, GO:0007399 nervous system development, and GO:0050808 synapse organization. These are suggested mechanistic mappings, not all experimentally enriched terms from patient tissue.

Cells, compartments, and profiling

The implicated compartments are nucleus (GO:0005634) and cytoplasm (GO:0005737). Likely disease-relevant cells include neurons (CL:0000540), neural progenitor cells (CL:0011020), chondrocytes (CL:0000138), and osteoblast-lineage cells (CL:0000062), but direct patient-cell evidence is limited to a heterologous HEK-293 binding assay. No NEDCHDF-specific single-cell, spatial-transcriptomic, patient-brain transcriptomic, proteomic, metabolomic, lipidomic, CRISPR-screen, or multi-omics dataset was identified. (wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 9-12)

There is no demonstrated disease-specific metabolic, immune, inflammatory, oxidative-stress, ischemic, fibrotic, or tissue-necrosis mechanism.

7. Anatomical structures affected

Primary system: central nervous system and developing brain—suggested UBERON UBERON:0000955 brain, UBERON:0001017 central nervous system.
Musculoskeletal: vertebral column (UBERON:0001130), hip joint (UBERON:0001464), craniofacial skeleton, teeth, and anterior fontanel.
Oromotor/feeding structures: oral cavity and swallowing apparatus; involvement is functional rather than a consistent structural lesion.
Secondary/variable systems: ocular, cardiac, renal, and genital findings occurred in isolated cases in the source table, but the evidence does not establish them as core disease features. (wakeling2021missensesubstitutionsat pages 24-29)
Lateralization: no consistent unilateral, bilateral, or asymmetric pattern.

8. Temporal development

Onset is congenital or in infancy, with hypotonia and delayed milestones. The disease is chronic and lifelong. Epilepsy may begin with infantile spasms or emerge in mid-childhood. Kyphosis/scoliosis can progress. Drooling may persist beyond early childhood. No formal stages, remission pattern, median progression rate, or longitudinal natural-history trajectory has been defined. Early childhood is the most plausible intervention window for developmental, communication, feeding, and orthopedic support, but this is clinical reasoning rather than trial-proven disease-specific evidence. (wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 9-12)

9. Inheritance and population

The molecular inheritance pattern is autosomal dominant, with all seven defining cases caused by de novo variants. Penetrance of these specific motif variants appears high in the ascertained cases but cannot be quantified because unaffected carriers and population-based ascertainment are lacking. Expressivity is variable, including variation in cognitive severity, epilepsy, movement disorder, MRI findings, and orthopedic complications. (wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 1-6)

No prevalence or incidence per 100,000, carrier frequency, sex ratio, ancestry enrichment, geographic clustering, founder effect, anticipation, or role for consanguinity is known. Only seven unrelated individuals defined the disorder, so any numerical epidemiologic estimate would be unreliable. Parental blood-negative de novo status leaves a small residual recurrence risk from parental germline mosaicism; no disease-specific mosaic recurrence series is available.

10. Diagnostics

Recommended approach

Recognize syndromic DD/ID with central hypotonia, characteristic facial/dental findings, dysphagia or drooling, epilepsy, hip instability, and scoliosis/kyphosis.
Use trio whole-exome sequencing or genome sequencing, or a comprehensive neurodevelopmental-disorder panel that includes HDAC4. The discovery cohort used WES/clinical exome sequencing and Sanger confirmation. (wakeling2021missensesubstitutionsat pages 6-9)
Prioritize de novo missense variants in HDAC4 residues 242–248 and apply ACMG/AMP evidence including de novo occurrence, population absence, motif/domain location, computational evidence, and variant-specific functional data.
Confirm by Sanger sequencing and test both parents. If phenotype instead suggests BDMR—especially brachydactyly E, obesity, autism, or a broad/upturned nose—perform chromosomal microarray to detect a 2q37 deletion. (le2019genotypeandphenotype pages 2-3, wakeling2021missensesubstitutionsat pages 9-12)

WGS can identify coding SNVs, indels, CNVs, and structural/noncoding variants in one assay, but no NEDCHDF-specific incremental-yield study exists. CMA is valuable for the 2q37 deletion differential but will usually miss the defining single-nucleotide missense alleles. Karyotyping and FISH are appropriate only when a large rearrangement is suspected. Mitochondrial DNA and repeat-expansion tests are not specifically indicated unless another phenotype suggests them.

Clinical evaluation

Baseline evaluation should include developmental and neurologic assessment; EEG if seizures or suspicious events occur; brain MRI when clinically indicated; feeding/swallowing assessment; growth and head circumference; audiology/ophthalmology; hip and spine examination with imaging as indicated; dental review; and targeted cardiac or renal assessment based on examination. No enzyme assay, blood metabolite, validated circulating biomarker, biopsy, or disease-specific electrophysiologic signature exists.

Differential diagnosis

Major differentials include 2q37 deletion/BDMR, MEF2C haploinsufficiency syndrome, RUNX2-related cleidocranial dysplasia, other chromatinopathies, cerebral palsy/central hypotonia syndromes, congenital muscular or neuromuscular disorders, and other monogenic developmental epileptic encephalopathies. The combination of a de novo HDAC4 14-3-3-motif variant and absence of brachydactyly E strongly supports NEDCHDF. (wakeling2021missensesubstitutionsat pages 12-17, wakeling2021missensesubstitutionsat pages 9-12)

There are no standardized clinical criteria, newborn-screening assay, or population-screening program.

11. Outcome and prognosis

No survival curve, mortality rate, life-expectancy estimate, or prognostic biomarker is available. The published individuals included children and older patients, but the cohort is too small and follow-up too limited to infer normal or shortened lifespan. Morbidity is driven by intellectual/developmental disability, speech impairment, mobility limitations, epilepsy—sometimes medication resistant—dysphagia, drooling, sleep problems, and progressive orthopedic disease. (wakeling2021missensesubstitutionsat pages 6-9)

Recovery to typical development has not been documented. Functional gains can reasonably be expected from rehabilitation and seizure/feeding/orthopedic management, but no response rate has been measured. Potential adverse prognostic features are severe early developmental impairment, refractory infantile spasms/generalized epilepsy, clinically important dysphagia, and progressive kyphoscoliosis; these remain expert extrapolations rather than validated predictors.

12. Treatment and current applications

There is no approved disease-modifying or genotype-specific therapy, no NEDCHDF treatment guideline, and no relevant interventional trial identified in the ClinicalTrials.gov search.

Current real-world management is multidisciplinary and phenotype directed:

early physical, occupational, speech-language, and augmentative-communication therapy;
feeding therapy, swallow-safety assessment, texture modification, nutrition support, and gastrostomy when required;
standard antiseizure medication selected by seizure type, with escalation through epilepsy specialists for drug-resistant epilepsy;
orthopedic surveillance and management of hip instability, scoliosis/kyphosis, joint laxity, and mobility needs;
sleep, dental, vision, and hearing management;
educational accommodations and family/social support.

Suggested NCIt intervention concepts include Physical Therapy, Occupational Therapy, Speech Therapy, Anticonvulsant Therapy, Nutritional Support, Gastrostomy, Orthopedic Surgery, Genetic Counseling, Whole Exome Sequencing, and Whole Genome Sequencing. Exact NCIt codes should be validated against the release used by the knowledge base.

The discovery authors raised HDAC inhibition as a theoretical strategy but cautioned that whether treatment could halt or reverse developmental problems is unknown. Class IIa HDACs respond poorly to many conventional inhibitors, so an effective intervention might require HDAC4-selective inhibition or disruption of the HDAC4–MEF2 interaction. This is preclinical rationale, not a treatment recommendation. (wakeling2021missensesubstitutionsat pages 12-17)

13. Prevention

Primary prevention by lifestyle modification, vaccination, environmental control, or prophylactic medication is not applicable to a typically de novo Mendelian disorder. Secondary prevention consists of early molecular diagnosis, developmental intervention, seizure recognition, swallow-safety assessment, and orthopedic surveillance. Tertiary prevention aims to reduce aspiration, malnutrition, seizure injury, contractures, hip damage, and spinal deformity.

Genetic counseling should explain autosomal-dominant causation, the usually de novo origin, low but nonzero sibling recurrence risk due to possible germline mosaicism, and a 50% transmission risk for an affected individual if reproductive fitness permits. Once a familial pathogenic variant is known, prenatal diagnosis and preimplantation genetic testing are technically possible. Population carrier or newborn screening is not currently justified.

14. Other species and natural disease

No naturally occurring veterinary counterpart attributable to orthologous HDAC4 14-3-3-motif variants was identified. Relevant comparative species include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), and Drosophila melanogaster (7227); the motif is reported as evolutionarily invariant from humans to fruit flies. There is no zoonotic transmission. (wakeling2021missensesubstitutionsat pages 6-9)

15. Models and experimental systems

The direct disease-model evidence is limited:

HEK-293 cellular model: transient expression of wild-type or variant HDAC4 plus 14-3-3β, followed by co-immunoprecipitation, demonstrated approximately twofold reduced binding for p.Thr244Lys and p.Glu247Gly. Strength: direct test of the initiating molecular defect. Limitation: transformed kidney-derived cells do not model developing neurons, chondrocytes, or whole-organism phenotypes. (wakeling2021missensesubstitutionsat pages 6-9, wakeling2021missensesubstitutionsat pages 9-12)
Mouse/chondrocyte evidence: HDAC4 overexpression in proliferating mouse chondrocytes inhibited differentiation, phenocopying aspects of Runx2 loss of function and supporting the proposed skeletal pathway. This is mechanistic support rather than a knock-in model of NEDCHDF. (wakeling2021missensesubstitutionsat pages 9-12)
Constitutive-nuclear HDAC4 model: attempts to generate mice with the three principal 14-3-3-site serines changed to alanine were reportedly unsuccessful, suggesting that large increases in nuclear HDAC4 activity may be developmentally intolerable. It does not reproduce the milder patient alleles. (wakeling2021missensesubstitutionsat pages 9-12)

No patient-derived iPSC neuron, cerebral organoid, zebrafish knock-in, Drosophila disease allele, CRISPR-engineered human neural progenitor, or faithful mouse knock-in model of p.Thr244Lys/p.Glu247Gly/p.Pro248 substitutions was identified. Such models are priorities for testing nuclear localization, cell-type-specific transcription, developmental timing, reversibility, and selective HDAC4/MEF2-targeted therapies.

Evidence appraisal and recent research status

The principal limitation is that essentially all disease-specific clinical statistics derive from seven patients in one 2021 report. Recent 2023–2024 chromatinopathy research has reinforced the importance of HDAC-family dysfunction and sequencing-based diagnosis, but it has not yet supplied a larger NEDCHDF natural-history cohort, validated episignature, patient-derived multi-omics dataset, or clinical trial. Accordingly, the most authoritative interpretation remains that the syndrome is a motif-specific HDAC4 regulatory disorder with experimentally established impaired 14-3-3 binding and a strongly supported—but not fully demonstrated—nuclear gain-of-function mechanism. (OpenTargets Search: Neurodevelopmental disorder with central hypotonia and dysmorphic facies, wakeling2021missensesubstitutionsat pages 12-17, wakeling2021missensesubstitutionsat pages 9-12)

Exact source quotations supporting central claims

Discovery abstract: “Here, we report seven unrelated individuals with a phenotype distinct from that of BDMR, all of whom have heterozygous de novo missense variants that affect a major regulatory site of HDAC4.” (wakeling2021missensesubstitutionsat pages 1-6)
Mechanism: “both the p.Glu247Gly and p.Thr244Lys variants bound 14-3-3β with approximately two-fold reduced affinity compared to native HDAC4.” (wakeling2021missensesubstitutionsat pages 9-12)
Phenotype summary: “This phenotype includes significant DD/ID, seizures, distinctive facial features, scoliosis, delayed closure of the anterior fontanelle and non-specific brain MRI anomalies.” (wakeling2021missensesubstitutionsat pages 12-17)
Mechanistic caution: whether reduced 14-3-3 interaction causes decreased RUNX2 and MEF2C signaling “remains to be determined.” (wakeling2021missensesubstitutionsat pages 12-17)

Key references

Wakeling E, et al. Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome. Human Genetics and Genomics Advances. January 2021;2:100015. PMID: 33537682. DOI/URL: 10.1016/j.xhgg.2020.100015. (OpenTargets Search: Neurodevelopmental disorder with central hypotonia and dysmorphic facies, wakeling2021missensesubstitutionsat pages 1-6)
Le TN, Williams SR, Alaimo JT, Elsea SH. Genotype and phenotype correlation in 103 individuals with 2q37 deletion syndrome reveals incomplete penetrance and supports HDAC4 as the primary genetic contributor. American Journal of Medical Genetics Part A. March 2019;179:782–791. DOI/URL: 10.1002/ajmg.a.61089. This is comparator evidence for HDAC4 haploinsufficiency/2q37 deletion syndrome, not the defining NEDCHDF cohort. (le2019genotypeandphenotype pages 6-7, le2019genotypeandphenotype pages 2-3)

References

(OpenTargets Search: Neurodevelopmental disorder with central hypotonia and dysmorphic facies): Open Targets Query (Neurodevelopmental disorder with central hypotonia and dysmorphic facies, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(wakeling2021missensesubstitutionsat pages 1-6): Emma Wakeling, Meriel McEntagart, Michael Bruccoleri, Charles Shaw-Smith, Karen L. Stals, Matthew Wakeling, Angela Barnicoat, Clare Beesley, Andrea K. Hanson-Kahn, Mary Kukolich, David A. Stevenson, Philippe M. Campeau, Sian Ellard, Sarah H. Elsea, Xiang-Jiao Yang, and Richard C. Caswell. Missense substitutions at a conserved 14-3-3 binding site in hdac4 cause a novel intellectual disability syndrome. Human Genetics and Genomics Advances, 2:100015, Jan 2021. URL: https://doi.org/10.1016/j.xhgg.2020.100015, doi:10.1016/j.xhgg.2020.100015. This article has 25 citations and is from a peer-reviewed journal.
(wakeling2021missensesubstitutionsat pages 12-17): Emma Wakeling, Meriel McEntagart, Michael Bruccoleri, Charles Shaw-Smith, Karen L. Stals, Matthew Wakeling, Angela Barnicoat, Clare Beesley, Andrea K. Hanson-Kahn, Mary Kukolich, David A. Stevenson, Philippe M. Campeau, Sian Ellard, Sarah H. Elsea, Xiang-Jiao Yang, and Richard C. Caswell. Missense substitutions at a conserved 14-3-3 binding site in hdac4 cause a novel intellectual disability syndrome. Human Genetics and Genomics Advances, 2:100015, Jan 2021. URL: https://doi.org/10.1016/j.xhgg.2020.100015, doi:10.1016/j.xhgg.2020.100015. This article has 25 citations and is from a peer-reviewed journal.
(wakeling2021missensesubstitutionsat pages 9-12): Emma Wakeling, Meriel McEntagart, Michael Bruccoleri, Charles Shaw-Smith, Karen L. Stals, Matthew Wakeling, Angela Barnicoat, Clare Beesley, Andrea K. Hanson-Kahn, Mary Kukolich, David A. Stevenson, Philippe M. Campeau, Sian Ellard, Sarah H. Elsea, Xiang-Jiao Yang, and Richard C. Caswell. Missense substitutions at a conserved 14-3-3 binding site in hdac4 cause a novel intellectual disability syndrome. Human Genetics and Genomics Advances, 2:100015, Jan 2021. URL: https://doi.org/10.1016/j.xhgg.2020.100015, doi:10.1016/j.xhgg.2020.100015. This article has 25 citations and is from a peer-reviewed journal.
(wakeling2021missensesubstitutionsat pages 6-9): Emma Wakeling, Meriel McEntagart, Michael Bruccoleri, Charles Shaw-Smith, Karen L. Stals, Matthew Wakeling, Angela Barnicoat, Clare Beesley, Andrea K. Hanson-Kahn, Mary Kukolich, David A. Stevenson, Philippe M. Campeau, Sian Ellard, Sarah H. Elsea, Xiang-Jiao Yang, and Richard C. Caswell. Missense substitutions at a conserved 14-3-3 binding site in hdac4 cause a novel intellectual disability syndrome. Human Genetics and Genomics Advances, 2:100015, Jan 2021. URL: https://doi.org/10.1016/j.xhgg.2020.100015, doi:10.1016/j.xhgg.2020.100015. This article has 25 citations and is from a peer-reviewed journal.
(le2019genotypeandphenotype pages 6-7): Trang N. Le, Stephen R. Williams, Joseph T. Alaimo, and Sarah H. Elsea. Genotype and phenotype correlation in 103 individuals with 2q37 deletion syndrome reveals incomplete penetrance and supports hdac4 as the primary genetic contributor. American Journal of Medical Genetics Part A, 179:782-791, Mar 2019. URL: https://doi.org/10.1002/ajmg.a.61089, doi:10.1002/ajmg.a.61089. This article has 42 citations.
(le2019genotypeandphenotype pages 2-3): Trang N. Le, Stephen R. Williams, Joseph T. Alaimo, and Sarah H. Elsea. Genotype and phenotype correlation in 103 individuals with 2q37 deletion syndrome reveals incomplete penetrance and supports hdac4 as the primary genetic contributor. American Journal of Medical Genetics Part A, 179:782-791, Mar 2019. URL: https://doi.org/10.1002/ajmg.a.61089, doi:10.1002/ajmg.a.61089. This article has 42 citations.
(wakeling2021missensesubstitutionsat pages 24-29): Emma Wakeling, Meriel McEntagart, Michael Bruccoleri, Charles Shaw-Smith, Karen L. Stals, Matthew Wakeling, Angela Barnicoat, Clare Beesley, Andrea K. Hanson-Kahn, Mary Kukolich, David A. Stevenson, Philippe M. Campeau, Sian Ellard, Sarah H. Elsea, Xiang-Jiao Yang, and Richard C. Caswell. Missense substitutions at a conserved 14-3-3 binding site in hdac4 cause a novel intellectual disability syndrome. Human Genetics and Genomics Advances, 2:100015, Jan 2021. URL: https://doi.org/10.1016/j.xhgg.2020.100015, doi:10.1016/j.xhgg.2020.100015. This article has 25 citations and is from a peer-reviewed journal.

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1. Disease Information

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5. Environmental Information

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7. Anatomical Structures Affected

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Neurodevelopmental Disorder with Central Hypotonia and Dysmorphic Facies

Executive summary

1. Disease information

Definition and identifiers

Critical nosologic distinction

2. Etiology, risk, and protective factors

Causal factor

Risk and protective factors

3. Phenotypes

Core and recurrent findings

Severity, progression, and quality of life

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Upstream molecular defect

Downstream chain

Cells, compartments, and profiling

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Recommended approach

Clinical evaluation

Differential diagnosis

11. Outcome and prognosis

12. Treatment and current applications

13. Prevention

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Evidence appraisal and recent research status

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