Schuurs-Hoeijmakers Syndrome

Mendelian MONDO:0014006 Pathograph 39 Show in embeddings browser Autosomal dominant syndromic intellectual disability

Autosomal dominant neurodevelopmental disorder caused in nearly every reported individual by one recurrent de novo missense variant in PACS1, c.607C>T p.(Arg203Trp), with a second substitution at the same residue, p.(Arg203Gln), in a few individuals. PACS1 is a cytoplasmic sorting protein that routes cargo between endosomes, the trans-Golgi network and the endoplasmic reticulum. Affected individuals have mild to moderate intellectual disability with language more affected than motor skills, a recognizable face (hypertelorism, downslanting palpebral fissures, bulbous nasal tip, wide mouth with downturned corners, thin upper lip, widely spaced teeth), seizures in about half, and variable congenital malformations of the heart, brain, eye, kidney and genitalia, with feeding difficulties and constipation. The variant acts by gain of function rather than by loss of PACS1: the substituted arginine sits in a regulatory loop of the furin-binding region, and its loss strengthens the PACS1-HDAC6 interaction, potentiates HDAC6 deacetylase activity, reduces alpha-tubulin acetylation and impairs dynein-driven transport, fragmenting the Golgi in neurons. A heterozygous multi-exon PACS1 deletion does not reproduce the syndrome. Treatment is supportive; allele-specific RNA silencing and HDAC6 inhibition are preclinical.

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Inheritance

1
Autosomal Dominant HP:0000006
Heterozygous, arising de novo in nearly all reported individuals; parent-to-child transmission has been reported, and parental gonadal mosaicism is the basis of the small recurrence risk quoted to parents of an affected child.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:32672908 SUPPORT Human clinical
"PACS1-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Parent-to-child transmission of a PACS1 pathogenic variant has been reported."
GeneReviews states the inheritance pattern and the usual de novo origin.
PMID:32672908 SUPPORT Human clinical
"If the PACS1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism."
Source of the recurrence risk attributed to parental gonadal mosaicism.
PMID:26842493 SUPPORT Human clinical
"We report on 19 individuals with a recurrent de novo c.607C>T mutation in PACS1."
The delineating cohort, in which every individual carried the same de novo allele.
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Pathophysiology

9
PACS1 Arg203 Gain-of-Function Substitution
The recurrent c.607C>T p.(Arg203Trp) substitution, and the rarer p.(Arg203Gln) at the same residue, lie in the furin-binding region (FBR, residues 101-273) of PACS1. NMR of the FBR shows that a central unstructured segment of PACS1 folds back across the FBR and contacts a positively charged loop that contains Arg203; this intramolecular contact restrains the PACS1-HDAC6 interaction, and the tryptophan substitution disrupts it. The allele is therefore a gain of function. Consistent with this, a three-generation family heterozygous for a deletion of PACS1 exons 12-24 lacked the facial gestalt, intellectual disability and brain anomalies of the syndrome.
PACS1 hgnc:30032 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PACS1 (hgnc:30032). hgnc:30032 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
Animal models
C. elegans pacs-1 knock-in of PACS1 syndrome variants Caenorhabditis elegans measures Shows that the variant alters the protein's subcellular localization in vivo.
Downstream
Enhanced PACS1-HDAC6 Interaction and HDAC6 Hyperactivity
Show evidence (4 references)
PMID:41858172 SUPPORT In vitro / ex vivo
"We present the solution structure of a chimeric PACS-1 FBR and use NMR to demonstrate that the PACS-1/HDAC6 interaction is regulated by an intramolecular mechanism involving the central unstructured region of PACS-1 folding back across the FBR and engaging in contacts with an extended,..."
Structural basis for why Arg203 substitution releases an autoinhibitory contact.
PMID:37848409 SUPPORT Model organism
"Here we use patient fibroblasts, patient-derived NPCs, and mouse models to show that PACS1 is an in vivo effector of HDAC6 and that the R203W substitution represents a gain-of-function (GOF) mutation that increases the interaction between PACS1 and HDAC6 to aberrantly potentiate enzyme activity."
Patient cells and knock-in mice establish the allele as gain of function.
PMID:34373684 SUPPORT INDIRECT Human clinical
"This study might supplement the spectrum of PACS1-NDD and demonstrates that the loss of function variation in PACS1 displays no contributions to the typical SHMS which is caused by the recurrent c.607C > T (p.Arg203Trp) variant."
A heterozygous PACS1 deletion does not cause the syndrome, which argues against haploinsufficiency; the gain-of-function reading follows by exclusion.
+ 1 more reference
Enhanced PACS1-HDAC6 Interaction and HDAC6 Hyperactivity
PACS1 binds the catalytic domains of the class IIb deacetylase HDAC6 through its FBR. Arg203Trp increases this interaction and aberrantly potentiates HDAC6 activity, lowering acetylation of its substrates alpha-tubulin and cortactin in patient-derived neural progenitor cells and mouse neurons.
PACS1 hgnc:30032 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PACS1 (hgnc:30032). hgnc:30032 is a gene from the HUGO Gene Nomenclature Committee. HDAC6 hgnc:14064 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HDAC6 (hgnc:14064). hgnc:14064 is a gene from the HUGO Gene Nomenclature Committee.
tubulin deacetylase activity GO:0042903 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased tubulin deacetylase activity (GO:0042903). GO:0042903 is a molecular function from the Gene Ontology.
Downstream
Alpha-Tubulin and Cortactin Hypoacetylation
Dynein-Mediated Transport Failure
Show evidence (2 references)
PMID:37848409 SUPPORT Model organism
"Here, we use patient cells and PACS1 syndrome mice to show that PACS1 (or PACS-1) is an HDAC6 effector and that the R203W substitution increases the PACS1/HDAC6 interaction, aberrantly potentiating deacetylase activity."
Direct measurement of the increased interaction and deacetylase activity.
PMID:41858172 SUPPORT In vitro / ex vivo
"PACS-1 uses its Furin binding region (FBR: amino acids 101-273) to directly interact with the catalytic domains of HDAC6."
Defines the binding interface the substitution acts on.
Alpha-Tubulin and Cortactin Hypoacetylation
The potentiated HDAC6 lowers acetylation of its substrates alpha-tubulin and cortactin in hippocampal neurons and patient-derived neural progenitor cells. A short exposure to the HDAC6 inhibitor tubacin restores Golgi positioning in patient cells, consistent with deacetylation being upstream of the Golgi defect.
HDAC6 hgnc:14064 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HDAC6 (hgnc:14064). hgnc:14064 is a gene from the HUGO Gene Nomenclature Committee.
tubulin deacetylation GO:0090042 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased tubulin deacetylation (GO:0090042). GO:0090042 is a biological process from the Gene Ontology.
Downstream
Golgi Fragmentation and Dispersal into Dendrites
Show evidence (1 reference)
PMID:37848409 SUPPORT Model organism
"Consequently, PACS1R203W reduces acetylation of α-tubulin and cortactin, causing the Golgi ribbon in hippocampal neurons and patient-derived neural progenitor cells (NPCs) to fragment and overpopulate dendrites, increasing their arborization."
Reduced acetylation of the two HDAC6 substrates.
Dynein-Mediated Transport Failure
PACS1 binds cytoplasmic dynein-1 heavy chain and is needed to keep furin at the trans-Golgi network. The PACS1 Arg203Trp-HDAC6 complex recruits the dynein adaptor BICD2, and the result is a dynein loss-of-function phenotype: cargo motility assays show reduced dynein initiation frequency and velocity, which HDAC6 inhibition or the dynein regulator Lis1 rescues. This places the syndrome among microtubule trafficking disorders.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
microtubule-based transport GO:0099111 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased microtubule-based transport (GO:0099111). GO:0099111 is a biological process from the Gene Ontology.
Downstream
Golgi Fragmentation and Dispersal into Dendrites
Show evidence (1 reference)
PMID:41888583 SUPPORT In vitro / ex vivo
"We demonstrate that PACS1R203W-HDAC6 recruits the adaptor BICD2, forming a complex that disperses the Golgi and impairs dynein function. Cargo motility assays revealed that PACS1R203W reduces dynein initiation frequency and velocity, defects rescued by HDAC6 inhibition or by expressing the..."
Direct measurement of impaired dynein transport and its HDAC6 dependence.
Golgi Fragmentation and Dispersal into Dendrites
In hippocampal neurons and patient-derived neural progenitor cells the Golgi ribbon fragments and Golgi elements overpopulate dendrites. A short exposure to the HDAC6 inhibitor tubacin restores paranuclear Golgi positioning in patient cells.
hippocampal neuron CL:0002608 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hippocampal neuron (CL:0002608). CL:0002608 is a cell type from the Cell Ontology. neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology.
Golgi organization GO:0007030 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Golgi organization (GO:0007030). GO:0007030 is a biological process from the Gene Ontology.
Downstream
Dendritic Overarborization with Reduced Spines and Synapses
Show evidence (2 references)
PMID:37848409 SUPPORT Model organism
"Confocal analysis suggested PACS1R203W profoundly disturbed Golgi (Giantin) positioning and MT organization."
Golgi positioning and microtubule organization are disturbed by the variant.
PMID:37848409 SUPPORT In vitro / ex vivo
"A 24-hr treatment with the HDAC6 inhibitor tubacin reversed this effect, restoring Golgi localization to the paranuclear region."
Reversal by HDAC6 inhibition ties the Golgi phenotype to HDAC6 activity.
Dendritic Overarborization with Reduced Spines and Synapses
In PACS1 syndrome mice, prefrontal cortical neurons carry more elaborate dendrites that are beaded with varicosities and have fewer spines and fewer functional synapses. Antisense oligonucleotides against PACS1 or HDAC6, or HDAC6 inhibitors, restore neuronal structure and synaptic transmission. The increased arborization was not seen in isogenic human iPSC-derived cortical neurons, whose deficit was in network activity instead, so the dendritic branching component is not settled across model systems.
pyramidal neuron CL:0000598 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pyramidal neuron (CL:0000598). CL:0000598 is a cell type from the Cell Ontology.
dendritic spine development GO:0060996 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dendritic spine development (GO:0060996). GO:0060996 is a biological process from the Gene Ontology. dendrite morphogenesis GO:0048813 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal dendrite morphogenesis (GO:0048813). GO:0048813 is a biological process from the Gene Ontology.
Experimental models
Isogenic PACS1(+/R203W) iPSC-derived neurons and cortical organoids IPSC DERIVED MODEL No difference in dendritic arborization by Sholl analysis.
Animal models
PACS1 R203W conditional knock-in mouse Mouse recapitulates Reproduces the dendrite, spine and synapse phenotype and its HDAC6 dependence.
Downstream
Altered Cortical Network Activity
Show evidence (2 references)
PMID:37848409 SUPPORT Model organism
"The dendrites, however, are beset with varicosities, diminished spine density, and fewer functional synapses, characteristic of NDDs."
Mouse and patient-cell dendrite and synapse phenotype.
PMID:38280846 REFUTE In vitro / ex vivo
"Sholl analysis was performed since neuron projection development was a strongly implicated pattern in DEGs (Fig. 3c, d, f) but did not reveal differences in dendritic arborization"
Isogenic human iPSC-derived neurons carrying the variant showed no difference in dendritic arborization, contradicting the increased branching reported in mouse.
Altered Cortical Network Activity
Mature PACS1(+/R203W) glutamatergic neurons and cortical organoids differentiated from isogenic stem cells show reduced expression of synaptic signaling genes and prolonged network bursts with longer interspike intervals on multielectrode arrays and calcium imaging. Neural precursors show few changes, so the deficit appears with neuronal maturation. Organoid proteomics converge on the same developmental processes and on known neurodevelopmental disorder and autism risk genes. This node is the proposed substrate for intellectual disability, autism and seizures; no study has yet connected a specific circuit change to a specific clinical feature.
glutamatergic neuron CL:0000679 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glutamatergic neuron (CL:0000679). CL:0000679 is a cell type from the Cell Ontology.
chemical synaptic transmission GO:0007268 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chemical synaptic transmission (GO:0007268). GO:0007268 is a biological process from the Gene Ontology.
Experimental models
Isogenic PACS1(+/R203W) iPSC-derived neurons and cortical organoids IPSC DERIVED MODEL Measures the network-burst phenotype in human neurons.
Downstream
Intellectual Disability
Delayed Speech and Language Development
Seizures
Autism
Show evidence (3 references)
PMID:38280846 SUPPORT In vitro / ex vivo
"While few deleterious effects were detected in PACS1(+/R203W) neural precursors, mature PACS1(+/R203W) glutamatergic neurons exhibited impaired expression of genes involved in synaptic signaling processes."
Synaptic gene expression is impaired in mature variant neurons.
PMID:38280846 SUPPORT In vitro / ex vivo
"Subsequent characterization of neural activity using calcium imaging and multielectrode arrays revealed the p.R203W PACS1 variant leads to a prolonged neuronal network burst duration mediated by an increased interspike interval."
Functional network phenotype in human neurons.
PMID:42835086 SUPPORT In vitro / ex vivo
"Key dysregulated transcripts and proteins in PACS1(+/R203W) organoids were classified as NDD-causative and ASD-risk genes."
Organoid proteome changes converge on neurodevelopmental disorder genes.
Aberrant Cranial Neural Crest Specification and Migration
In zebrafish embryos, mRNA encoding the mutant PACS1 induces craniofacial cartilage defects, most likely in a dominant-negative fashion, through aberrant specification and migration of SOX10-positive cranial neural crest cells, while enteric neural crest is spared. In transfected cells the mutant protein forms cytoplasmic aggregates with increased stability. This is the proposed basis of the facial gestalt. The model is overexpression of human mRNA in fish, and the result predates the HDAC6 mechanism; how the two connect has not been tested.
neural crest cell CL:0011012 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural crest cell (CL:0011012). CL:0011012 is a cell type from the Cell Ontology.
neural crest cell migration GO:0001755 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal neural crest cell migration (GO:0001755). GO:0001755 is a biological process from the Gene Ontology.
Downstream
Characteristic Facial Gestalt
Show evidence (2 references)
PMID:23159249 SUPPORT Model organism
"Furthermore, consistent with the human pathology, expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion. This phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells."
Zebrafish overexpression model of the craniofacial phenotype.
PMID:23159249 SUPPORT In vitro / ex vivo
"Altered PACS1 forms cytoplasmic aggregates in vitro with concomitant increased protein stability"
Mutant protein behavior in cultured cells.
Extracellular Matrix Dysregulation in Fibroblasts
Transcriptomes of patient fibroblasts show altered extracellular matrix organization, including raised COL8A1 expression and deposition, which an allele-specific siRNA against the c.607C>T transcript corrects. How this relates to the HDAC6 mechanism, and which clinical feature it contributes to, has not been established.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
extracellular matrix organization GO:0030198 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:40972577 SUPPORT In vitro / ex vivo
"Furthermore, transcriptomic analysis of SHMS fibroblasts revealed alterations in extracellular matrix organization in mutant cells, including elevated COL8A1 expression and extracellular deposition."
Patient fibroblast transcriptomic and deposition finding.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Schuurs-Hoeijmakers Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

31
Cardiovascular 3
Congenital Heart Defect FREQUENT Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Sequelae: Atrial Septal Defect Ventricular Septal Defect
Show evidence (2 references)
PMID:26842493 SUPPORT Human clinical
"Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males)."
Heart malformation in 10 of 19.
PMID:37373745 SUPPORT Human clinical
"In the literature review, almost 42% (42/100) of individuals with PACS1-NDD reportedly experienced HD. Septal defects were the most common malformation, followed by patent ductus arteriosus."
Pooled literature frequency and spectrum of heart disease.
Atrial Septal Defect OCCASIONAL HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28111752 SUPPORT Human clinical
"Cardiac defects were noted in four individuals, including two individuals with atrial septal defects, three with ventricular septal defects, and one individual with a dilated pulmonary artery."
Atrial septal defects in two of eight individuals.
Ventricular Septal Defect OCCASIONAL HP:0001629 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular septal defect (HP:0001629). HP:0001629 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28111752 SUPPORT Human clinical
"Cardiac defects were noted in four individuals, including two individuals with atrial septal defects, three with ventricular septal defects, and one individual with a dilated pulmonary artery."
Ventricular septal defects in three of eight individuals.
Digestive 3
Feeding Difficulties VERY_FREQUENT HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41882293 SUPPORT Human clinical
"Our study expands the phenotypic spectrum of PACS1-RD by reporting median age at independent walking and first spoken words (both 24 months), cross-sectional growth parameters, and previously undescribed clinical features, including congenital kidney malformations (25%) and feeding difficulties (75%)."
Feeding difficulties in 75 percent.
PMID:26842493 SUPPORT Human clinical
"Feeding dysfunction is presenting in infancy with failure to thrive (5/19), gastroesophageal reflux (6/19), and gastrostomy tube placement (4/19)."
Infant feeding dysfunction in the delineating cohort.
Gastroesophageal Reflux FREQUENT HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26842493 SUPPORT Human clinical
"Feeding dysfunction is presenting in infancy with failure to thrive (5/19), gastroesophageal reflux (6/19), and gastrostomy tube placement (4/19)."
Reflux in 6 of 19.
Constipation HP:0002019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constipation (HP:0002019). HP:0002019 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28111752 SUPPORT Human clinical
"The majority of individuals in our series had gastroesophageal reflux, and constipation was common."
Constipation common in an eight-person series.
Ear 1
Low-Set Ears VERY_FREQUENT HP:0000369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-set ears (HP:0000369). HP:0000369 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32672908 SUPPORT Human clinical
"Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
GeneReviews lists low-set and simple ears.
Eye 3
Hypertelorism VERY_FREQUENT HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32672908 SUPPORT Human clinical
"Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
GeneReviews lists hypertelorism among the common facial features.
Ptosis VERY_FREQUENT HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26842493 SUPPORT Human clinical
"There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy"..."
Ptosis is part of the facial gestalt in the delineating cohort.
Coloboma HP:0000589 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coloboma (HP:0000589). HP:0000589 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33369122 SUPPORT Human clinical
"Clinically, coloboma has been described as a feature in a WDR37-related disorder and a PACS1-related disorder (Schuurs-Hoeijmakers syndrome), but not in a PACS2-related disorder."
Coloboma is a recognized feature of the PACS1 disorder.
Genitourinary 2
Cryptorchidism FREQUENT HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26842493 SUPPORT Human clinical
"Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males)."
Cryptorchidism in 6 of 12 males.
PMID:41882293 SUPPORT Human clinical
"Compared with the literature, our series showed a higher prevalence of cryptorchidism (77.8%), congenital heart defect (45.8%), and hypotonia (75%)."
Higher frequency in a second series of 24.
Congenital Kidney Malformation OCCASIONAL Abnormal renal morphology HP:0012210 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital kidney malformation, annotated with Abnormal renal morphology (HP:0012210). HP:0012210 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (2 references)
PMID:26842493 SUPPORT Human clinical
"Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males)."
Kidney malformation in 3 of 19.
PMID:41882293 SUPPORT Human clinical
"Our study expands the phenotypic spectrum of PACS1-RD by reporting median age at independent walking and first spoken words (both 24 months), cross-sectional growth parameters, and previously undescribed clinical features, including congenital kidney malformations (25%) and feeding difficulties (75%)."
Kidney malformations in a quarter of a second series.
Head and Neck 12
Characteristic Facial Gestalt OBLIGATE Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Sequelae: Hypertelorism Downslanted Palpebral Fissures Bulbous Nasal Tip Low-Set Ears Wide Mouth Downturned Corners of Mouth Thin Upper Lip Widely Spaced Teeth Ptosis Highly Arched Eyebrows Thick Eyebrows Long Eyelashes Smooth Philtrum
Show evidence (1 reference)
PMID:26842493 SUPPORT Human clinical
"There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy"..."
Facial gestalt present in all 19 individuals.
Downslanted Palpebral Fissures VERY_FREQUENT HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32672908 SUPPORT Human clinical
"Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
GeneReviews lists downslanting palpebral fissures.
Bulbous Nasal Tip VERY_FREQUENT Bulbous nose HP:0000414 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bulbous nasal tip, annotated with Bulbous nose (HP:0000414). HP:0000414 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32672908 SUPPORT Human clinical
"Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
GeneReviews lists a bulbous nasal tip.
Wide Mouth VERY_FREQUENT HP:0000154 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide mouth (HP:0000154). HP:0000154 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32672908 SUPPORT Human clinical
"Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
GeneReviews lists a wide mouth with downturned corners.
Downturned Corners of Mouth VERY_FREQUENT HP:0002714 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downturned corners of mouth (HP:0002714). HP:0002714 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32672908 SUPPORT Human clinical
"Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
GeneReviews lists a wide mouth with downturned corners.
PMID:26842493 SUPPORT Human clinical
"There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy"..."
Downturned corners of the mouth in the 19/19 facial gestalt.
Highly Arched Eyebrows VERY_FREQUENT HP:0002553 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arched eyebrows, annotated with Highly arched eyebrow (HP:0002553). HP:0002553 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26842493 SUPPORT Human clinical
"There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy"..."
Full and arched eyebrows in the delineating cohort.
Thick Eyebrows VERY_FREQUENT HP:0000574 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Full eyebrows, annotated with Thick eyebrow (HP:0000574). HP:0000574 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26842493 SUPPORT Human clinical
"There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy"..."
Full and arched eyebrows in the delineating cohort.
Long Eyelashes VERY_FREQUENT HP:0000527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long eyelashes (HP:0000527). HP:0000527 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26842493 SUPPORT Human clinical
"There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy"..."
Long eyelashes in the delineating cohort.
Smooth Philtrum VERY_FREQUENT HP:0000319 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Smooth philtrum (HP:0000319). HP:0000319 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32672908 SUPPORT Human clinical
"Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
GeneReviews lists a smooth philtrum.
PMID:26842493 SUPPORT Human clinical
"There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy"..."
Flat philtrum in the delineating cohort.
Thin Upper Lip VERY_FREQUENT Thin upper lip vermilion HP:0000219 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin upper lip vermilion (HP:0000219). HP:0000219 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32672908 SUPPORT Human clinical
"Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
GeneReviews lists a thin upper vermilion.
Widely Spaced Teeth VERY_FREQUENT HP:0000687 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Widely spaced teeth (HP:0000687). HP:0000687 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32672908 SUPPORT Human clinical
"Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
GeneReviews lists wide-spaced teeth.
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32672908 SUPPORT Human clinical
"Genitourinary anomalies, microcephaly, and ocular anomalies are also reported."
GeneReviews lists microcephaly among less common features.
Musculoskeletal 1
Infantile Hypotonia FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32672908 SUPPORT Human clinical
"Hypotonia is reported in about one third of individuals and is noted to improve over time."
GeneReviews frequency and course.
PMID:26842493 SUPPORT Human clinical
"Hypotonia is common in infancy (8/19)."
8 of 19 in the delineating cohort.
Nervous System 5
Intellectual Disability OBLIGATE HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26842493 SUPPORT Human clinical
"Intellectual disability, ranging from mild to moderate, was present in all."
Present in all 19 individuals of the delineating cohort.
PMID:34517877 SUPPORT Human clinical
"PACS1-NDD is a moderately-severe intellectual disability syndrome in which seizures occur but are not a defining or primary feature."
Caregiver survey conclusion on severity.
Delayed Speech and Language Development VERY_FREQUENT HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32672908 SUPPORT Human clinical
"Language skills are more severely affected than motor skills."
GeneReviews summary of the developmental profile.
PMID:28111752 SUPPORT Human clinical
"Speech and language in our cohort was universally delayed but developed in most, and three demonstrated dysarthria."
Universal language delay in an eight-person series.
Seizures FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26842493 SUPPORT Human clinical
"Seizures are frequent (12/19) and respond well to anticonvulsive medication."
12 of 19 individuals had seizures.
PMID:34517877 SUPPORT Human clinical
"Seventeen (49%) had a diagnosis of epilepsy."
Epilepsy in 17 of 35 individuals with a confirmed R203W variant.
Autism FREQUENT HP:0000717 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism (HP:0000717). HP:0000717 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34517877 SUPPORT Human clinical
"Twelve (40%, of 30 responding to the question) reported autism and (N = 11/30, 37%) reported features of autism."
Caregiver-reported autism frequency.
Brain Malformations VERY_FREQUENT Abnormal brain morphology HP:0012443 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brain malformation, annotated with Abnormal brain morphology (HP:0012443). HP:0012443 is a phenotype from the Human Phenotype Ontology.
Coarse binding: variable spectrum
Show evidence (1 reference)
PMID:26842493 SUPPORT Human clinical
"Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males)."
Brain malformations in 12 of 16 imaged individuals.
Growth 1
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32672908 SUPPORT Human clinical
"Other common features include constipation, seizures, behavioral issues, congenital heart anomalies, and short stature."
GeneReviews lists short stature among common features.
🧬

Genetic Associations

1
PACS1 (A heterozygous missense variant at Arg203, nearly always c.607C>T p.(Arg203Trp) and rarely c.608G>A p.(Arg203Gln), causes the syndrome.)
Gene: PACS1 hgnc:30032 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PACS1 (hgnc:30032). hgnc:30032 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (2 references)
PMID:34517877 SUPPORT Human clinical
"There is one other pathogenic mutation reported in the PACS1 gene, R203Q (p.608G > A), in one patient; it is the same amino acid that is changed, resulting, as for the R203W mutation, in the loss of a positive charge"
Both known pathogenic alleles change the same arginine.
PMID:41882293 SUPPORT Human clinical
"PACS1-related disorder (PACS1-RD), also known as Schuurs-Hoeijmakers syndrome, is a rare autosomal dominant neurodevelopmental disorder predominantly caused by the recurrent de novo c.607 C > T p.(Arg203Trp) gain-of-function variant."
The recurrent allele and its gain-of-function character.
💊

Medical Actions

6
Anticonvulsant Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: anticonvulsant NCIT:C264 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anticonvulsant, annotated with Anticonvulsant Agent (NCIT:C264). NCIT:C264 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Seizures are treated with standard anticonvulsants and responded well in the delineating cohort.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26842493 SUPPORT Human clinical
"Seizures are frequent (12/19) and respond well to anticonvulsive medication."
Seizures respond to standard anticonvulsants.
Developmental and Supportive Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Behavioral / lifestyle
Developmental and educational support, with standard management of feeding problems, constipation, behavioral difficulties and cardiac, genitourinary and visual anomalies, and regular surveillance of each, including a clinical examination for scoliosis at each visit. Known seizure triggers are the circumstance GeneReviews advises avoiding.
Show evidence (3 references)
PMID:32672908 SUPPORT Human clinical
"Treatment of manifestations: Developmental and educational support; standard treatment for feeding issues, constipation, seizures, behavioral issues, cardiac anomalies, genitourinary anomalies, and vision issues."
GeneReviews management summary.
PMID:32672908 SUPPORT Human clinical
"Monitor closure of septal defects per cardiologist; monitor kidney function if kidney malformation is present per nephrologist; ophthalmology exam and vision assessment per ophthalmologist; clinical exam for scoliosis at each visit with radiographs as needed."
GeneReviews surveillance recommendations, including scoliosis examination.
PMID:32672908 SUPPORT Human clinical
"Agents/circumstances to avoid: Known seizure triggers."
GeneReviews agents and circumstances to avoid.
PACS1-Targeting Antisense Oligonucleotide (preclinical)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Antisense oligonucleotide RNase H knockdown Chemistry: 2′-MOE
RNA target: PACS1 hgnc:30032 HUGO Gene Nomenclature Committee (hgnc) Relation: this treatment base-pairs with the transcript of this gene This treatment base-pairs with the transcript of PACS1 (hgnc:30032). hgnc:30032 is a gene from the HUGO Gene Nomenclature Committee.
A Pacs1-specific 2'-O-methoxyethyl gapmer antisense oligonucleotide given intracerebroventricularly to newborn Pacs1 R201W/+ mice (R201W is the mouse equivalent of human R203W) depleted PACS1 and rescued excitatory synaptic transmission. Pacs1 loss itself did not disturb synapses in the same study, which is the rationale for lowering PACS1 in patients. Not tested in patients.
Mechanism Target:
PACS1 Arg203 Gain-of-Function Substitution
Show evidence (3 references)
PMID:37848409 SUPPORT Model organism
"Treatment of the mice with antisense oligonucleotides (ASOs) that deplete HDAC6 or PACS1 restores both neuronal structure and communication, suggesting PACS1R203W/HDAC6 underlies PACS1 syndrome neuronal pathology and that this NDD may be treatable with targeted therapies."
Preclinical rescue in mice.
PMID:37848409 SUPPORT Model organism
"Together, these findings suggest Pacs1 loss does not significantly disturb excitatory or inhibitory synapses, supporting the development of a PACS1 ASO strategy for patient therapy."
Lowering PACS1 is tolerated at the synapse, the safety premise of the approach.
PMID:37848409 SUPPORT Model organism
"The MOE ... gapmer ASOs used in this study were generated as described"
Source of the chemistry and RNase H gapmer design.
HDAC6-Targeting Antisense Oligonucleotide (preclinical)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Antisense oligonucleotide RNase H knockdown Chemistry: 2′-MOE
RNA target: HDAC6 hgnc:14064 HUGO Gene Nomenclature Committee (hgnc) Relation: this treatment base-pairs with the transcript of this gene This treatment base-pairs with the transcript of HDAC6 (hgnc:14064). hgnc:14064 is a gene from the HUGO Gene Nomenclature Committee.
An Hdac6-specific 2'-O-methoxyethyl gapmer antisense oligonucleotide injected into newborn PACS1 R203W mice restored neuronal structure and synaptic transmission. Not tested in patients.
Mechanism Target:
Enhanced PACS1-HDAC6 Interaction and HDAC6 Hyperactivity
Show evidence (2 references)
PMID:37848409 SUPPORT Model organism
"Specifically, R26P1 and R26P1R203W P1 pups were co-injected with an Hdac6-specific antisense oligonucleotide (H6ASO) or a negative control ASO (nASO)"
The HDAC6 ASO experiment in the PACS1 R203W mouse.
PMID:37848409 SUPPORT Model organism
"Treatment of the mice with antisense oligonucleotides (ASOs) that deplete HDAC6 or PACS1 restores both neuronal structure and communication, suggesting PACS1R203W/HDAC6 underlies PACS1 syndrome neuronal pathology and that this NDD may be treatable with targeted therapies."
Preclinical rescue in mice.
HDAC6 Inhibitors (preclinical)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Small molecule
Small-molecule HDAC6 inhibitors restored neuronal structure and synaptic transmission in PACS1 syndrome mice and reversed Golgi mispositioning in patient-derived cells. Not tested in patients.
Mechanism Target:
Enhanced PACS1-HDAC6 Interaction and HDAC6 Hyperactivity
Show evidence (1 reference)
PMID:37848409 SUPPORT Model organism
"Treatment of PACS1 syndrome mice or patient NPCs with PACS1- or HDAC6-targeting antisense oligonucleotides, or HDAC6 inhibitors, restores neuronal structure and synaptic transmission in prefrontal cortex"
HDAC6 inhibitors rescue the mouse neuronal phenotype.
Allele-Specific siRNA Silencing (preclinical)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: siRNA
siRNAs that silence the c.607C>T PACS1 transcript while sparing the wild-type transcript were selected in patient fibroblasts and corrected the COL8A1 dysregulation. Proof of concept in cells only.
Mechanism Target:
PACS1 Arg203 Gain-of-Function Substitution
Extracellular Matrix Dysregulation in Fibroblasts
Show evidence (2 references)
PMID:40972577 SUPPORT In vitro / ex vivo
"Through an in vitro screening of fibroblasts derived from affected individuals, we identified several small interfering RNA (siRNA) sequences that specifically silence the PACS1 transcript harboring the recurrent PACS1 mutation while sparing the wild-type mRNA."
Allele-specific silencing in patient cells.
PMID:40972577 SUPPORT In vitro / ex vivo
"Treatment with the best selected allele-specific siRNA corrected the COL8A1 dysregulation."
Correction of the fibroblast matrix phenotype.
🔬

Diagnosis

2
Exome Sequencing for the Recurrent PACS1 Variant
The diagnosis is established by finding a heterozygous pathogenic PACS1 variant on molecular testing, in practice the recurrent Arg203 change.
Whole Exome Sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:32672908 SUPPORT Human clinical
"The diagnosis of PACS1-NDD is established in a proband with a heterozygous pathogenic variant in PACS1 identified by molecular genetic testing."
GeneReviews diagnostic criterion.
PMID:23159249 SUPPORT Human clinical
"Exome sequencing in both families identified identical de novo mutations in PACS1, suggestive of causality."
Exome sequencing identified the disorder.
DNA Methylation Episignature
Blood DNA methylation profiling identifies a PACS1-specific episignature shared by Arg203Trp and Arg203Gln carriers. It solved one individual first suspected of Kabuki syndrome and can help classify non-recurrent PACS1 variants.
DNA methylation episignature analysis NCIT:C63328 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:41882293 SUPPORT Human clinical
"Methylation analysis identified a specific episignature for PACS1-RD, consistently observed in individuals carrying either the canonical p.(Arg203Trp) or the non-recurrent p.(Arg203Gln) variant."
Episignature shared by both pathogenic alleles.
📊

Prevalence

1
Published case reports and series
Cases/families reported in the literature Ultra-rare
About 87 published cases by 2023. This is a literature case count, not a population prevalence. A 2026 review counts about 158 published patients, but that figure spans the PACS1, PACS2 and WDR37 disorders together and is not used here.
Show evidence (1 reference)
PMID:37747683 SUPPORT Human clinical
"Only 87 cases have been recorded to date, and oddly enough, the majority of them share the same mutation"
Literature case count in 2023.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Schuurs-Hoeijmakers Syndrome:

Neurooculocardiogenitourinary syndrome (WDR37) MONDO:0032850
Distinguishing Features
  • De novo WDR37 variants; WDR37 is PACS1's strongest interactor and the syndrome shares intellectual disability, facial dysmorphism and coloboma.
Show evidence (1 reference)
PMID:33369122 SUPPORT Human clinical
"De novo heterozygous mutations in WDR37 have been shown to cause a novel human disorder, neurooculocardiogenitourinary syndrome (NOCGUS syndrome) (OMIM #618652), characterized by intellectual disability, facial dysmorphism, and coloboma."
Phenotypic overlap with the WDR37 disorder.
🧫

Experimental Models

1
Isogenic PACS1(+/R203W) iPSC-derived neurons and cortical organoids IPSC_DERIVED_MODEL
Stem cells edited to carry the variant and differentiated to glutamatergic neurons and cortical organoids, used for transcriptomics, proteomics, calcium imaging and multielectrode array recording.
Pathograph links
Altered Cortical Network Activity recapitulates fidelity: moderate observes: tissue Measures the network-burst phenotype in human neurons.
Limitations: In vitro networks lack the developing brain's cell diversity and connectivity; how prolonged bursting maps onto seizures or cognition is not established.
Readouts
Network burst duration on multielectrode array
Direction: INCREASED
Interpretation: Variant neurons show prolonged network bursts.
Show evidence (1 reference)
PMID:38280846 SUPPORT In vitro / ex vivo
"To characterize these effects, we performed both calcium imaging in organoids and multielectrode array (MEA) recording of iPSC-derived neurons and found a prolonged network burst duration in PACS1(+/R203W) cells."
The measurement behind the readout.
Dendritic Overarborization with Reduced Spines and Synapses fails to recapitulate fidelity: unknown No difference in dendritic arborization by Sholl analysis.
Limitations: A negative morphological result in one in vitro system; spine density and synapse number were not the readout.
Show evidence (1 reference)
PMID:38280846 SUPPORT In vitro / ex vivo
"Sholl analysis was performed since neuron projection development was a strongly implicated pattern in DEGs (Fig. 3c, d, f) but did not reveal differences in dendritic arborization"
Human neurons did not show the increased arborization seen in mouse.
🐁

Animal Models

2
PACS1 R203W conditional knock-in mouse
Mice expressing PACS1 R203W reproduce the neuronal Golgi, dendrite, spine and synaptic phenotypes, which antisense depletion of Hdac6 or PACS1 rescues. A standard germline Pacs1 R201W knock-in was embryonic lethal, so expression was restricted to forebrain neurons. Craniofacial and systemic features were not the subject of the study.
Species
Mouse
Genotype
Cre-inducible PACS1 R203W expression (R26P1R203W), and Emx1-Cre-induced Pacs1 R201W/+ knock-in (mouse equivalent of R203W)
Publication
PMID:37848409
Pathograph links
Dendritic Overarborization with Reduced Spines and Synapses recapitulates fidelity: moderate observes: cellular Reproduces the dendrite, spine and synapse phenotype and its HDAC6 dependence.
Limitations: Increased arborization was not reproduced in isogenic human iPSC-derived neurons, so this component may be species- or system-specific.
Show evidence (1 reference)
PMID:37848409 SUPPORT Model organism
"Consequently, PACS1R203W/HDAC6 causes neuronal deficits in patient-derived cells and mouse models of PACS1 syndrome, including increased dendrite arborization together with reductions in spine density and synaptic strength."
The model shows the node's phenotype.
C. elegans pacs-1 knock-in of PACS1 syndrome variants
Editing the PACS1 and PACS2 syndrome variants into the single worm PACS ortholog changes protein localization in several cell types including neurons. Worm PACS-1 and WDR-37 are mutually required for expression.
Species
Caenorhabditis elegans
Genotype
PACS1 and PACS2 syndrome variants edited into cePACS-1
Publication
PMID:39031646
Pathograph links
PACS1 Arg203 Gain-of-Function Substitution measures fidelity: low observes: cellular Shows that the variant alters the protein's subcellular localization in vivo.
Limitations: The worm has one PACS gene standing for both PACS1 and PACS2, and the readout is protein localization, not any of the downstream HDAC6, Golgi or synaptic phenotypes.
Show evidence (1 reference)
PMID:39031646 SUPPORT Model organism
"We further show that editing in PACS1 and PACS2 variants in cePACS-1 changes protein localization in multiple cell types, including neurons."
In vivo localization effect of the edited variant.
{ }

Source YAML

click to show 
name: Schuurs-Hoeijmakers Syndrome
creation_date: "2026-10-28T22:23:34Z"
category: Mendelian
synonyms:
- PACS1 syndrome
- PACS1-related neurodevelopmental disorder
- PACS1-NDD
- PACS1-related disorder
- SHMS
description: >-
  Autosomal dominant neurodevelopmental disorder caused in nearly every reported
  individual by one recurrent de novo missense variant in PACS1, c.607C>T
  p.(Arg203Trp), with a second substitution at the same residue, p.(Arg203Gln),
  in a few individuals. PACS1 is a cytoplasmic sorting protein that routes cargo
  between endosomes, the trans-Golgi network and the endoplasmic reticulum.
  Affected individuals have mild to moderate intellectual disability with language
  more affected than motor skills, a recognizable face (hypertelorism,
  downslanting palpebral fissures, bulbous nasal tip, wide mouth with downturned
  corners, thin upper lip, widely spaced teeth), seizures in about half, and
  variable congenital malformations of the heart, brain, eye, kidney and
  genitalia, with feeding difficulties and constipation. The variant acts by gain
  of function rather than by loss of PACS1: the substituted arginine sits in a
  regulatory loop of the furin-binding region, and its loss strengthens the
  PACS1-HDAC6 interaction, potentiates HDAC6 deacetylase activity, reduces
  alpha-tubulin acetylation and impairs dynein-driven transport, fragmenting the
  Golgi in neurons. A heterozygous multi-exon PACS1 deletion does not reproduce
  the syndrome. Treatment is supportive; allele-specific RNA silencing and HDAC6
  inhibition are preclinical.
disease_term:
  preferred_term: Schuurs-Hoeijmakers syndrome
  term:
    id: MONDO:0014006
    label: Schuurs-Hoeijmakers syndrome
parents:
- Autosomal dominant syndromic intellectual disability
references:
- reference: PMID:32672908
  title: PACS1-Related Neurodevelopmental Disorder.
  tags:
  - GeneReviews
inheritance:
- name: Autosomal Dominant
  description: >-
    Heterozygous, arising de novo in nearly all reported individuals;
    parent-to-child transmission has been reported, and parental gonadal
    mosaicism is the basis of the small recurrence risk quoted to parents of an
    affected child.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PACS1-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Parent-to-child transmission of a PACS1 pathogenic variant has been reported."
    explanation: GeneReviews states the inheritance pattern and the usual de novo origin.
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If the PACS1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism."
    explanation: Source of the recurrence risk attributed to parental gonadal mosaicism.
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on 19 individuals with a recurrent de novo c.607C>T mutation in PACS1."
    explanation: The delineating cohort, in which every individual carried the same de novo allele.
pathophysiology:
- name: PACS1 Arg203 Gain-of-Function Substitution
  biological_scale: MOLECULAR
  description: >-
    The recurrent c.607C>T p.(Arg203Trp) substitution, and the rarer
    p.(Arg203Gln) at the same residue, lie in the furin-binding region (FBR,
    residues 101-273) of PACS1. NMR of the FBR shows that a central unstructured
    segment of PACS1 folds back across the FBR and contacts a positively charged
    loop that contains Arg203; this intramolecular contact restrains the
    PACS1-HDAC6 interaction, and the tryptophan substitution disrupts it. The
    allele is therefore a gain of function. Consistent with this, a three-generation
    family heterozygous for a deletion of PACS1 exons 12-24 lacked the facial
    gestalt, intellectual disability and brain anomalies of the syndrome.
  genes:
  - preferred_term: PACS1
    term:
      id: hgnc:30032
      label: PACS1
  genetic_context:
    variant_origin: DE_NOVO
    functional_impact_category: GAIN_OF_FUNCTION
    zygosity: HETEROZYGOUS
  evidence:
  - reference: PMID:41858172
    reference_title: The R203W substitution drives PACS-1 syndrome by disrupting intramolecular regulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We present the solution structure of a chimeric PACS-1 FBR and use NMR to demonstrate that the PACS-1/HDAC6 interaction is regulated by an intramolecular mechanism involving the central unstructured region of PACS-1 folding back across the FBR and engaging in contacts with an extended, positively charged loop. The R203W substitution, located in this loop, disrupts this regulatory interaction"
    explanation: Structural basis for why Arg203 substitution releases an autoinhibitory contact.
  - reference: PMID:37848409
    reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we use patient fibroblasts, patient-derived NPCs, and mouse models to show that PACS1 is an in vivo effector of HDAC6 and that the R203W substitution represents a gain-of-function (GOF) mutation that increases the interaction between PACS1 and HDAC6 to aberrantly potentiate enzyme activity."
    explanation: Patient cells and knock-in mice establish the allele as gain of function.
  - reference: PMID:34373684
    reference_title: "A Novel Multi-Exon Deletion of PACS1 in a Three-Generation Pedigree: Supplements to PACS1 Neurodevelopmental Disorder Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "This study might supplement the spectrum of PACS1-NDD and demonstrates that the loss of function variation in PACS1 displays no contributions to the typical SHMS which is caused by the recurrent c.607C > T (p.Arg203Trp) variant."
    explanation: >-
      A heterozygous PACS1 deletion does not cause the syndrome, which argues
      against haploinsufficiency; the gain-of-function reading follows by
      exclusion.
  - reference: PMID:41279321
    reference_title: The Structural Basis for Pacs1-Wdr37 Complex Assembly and Stability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This pathogenic mutation lies on a solvent-exposed surface of the FBR and does not disrupt complex formation. Instead, Pacs1-R203W remains dependent on Wdr37 for stability and its levels can be reduced through targeted Wdr37 proteolytic degradation."
    explanation: >-
      Cryo-EM of the Pacs1-Wdr37 complex places Arg203 on a solvent-exposed
      surface of the FBR, so the variant leaves the WDR37 complex intact rather
      than destabilizing PACS1.
  downstream:
  - target: Enhanced PACS1-HDAC6 Interaction and HDAC6 Hyperactivity
    causal_link_type: DIRECT
- name: Enhanced PACS1-HDAC6 Interaction and HDAC6 Hyperactivity
  biological_scale: MOLECULAR
  description: >-
    PACS1 binds the catalytic domains of the class IIb deacetylase HDAC6 through
    its FBR. Arg203Trp increases this interaction and aberrantly potentiates
    HDAC6 activity, lowering acetylation of its substrates alpha-tubulin and
    cortactin in patient-derived neural progenitor cells and mouse neurons.
  genes:
  - preferred_term: PACS1
    term:
      id: hgnc:30032
      label: PACS1
  - preferred_term: HDAC6
    term:
      id: hgnc:14064
      label: HDAC6
  molecular_functions:
  - preferred_term: tubulin deacetylase activity
    term:
      id: GO:0042903
      label: tubulin deacetylase activity
    modifier: INCREASED
  evidence:
  - reference: PMID:37848409
    reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we use patient cells and PACS1 syndrome mice to show that PACS1 (or PACS-1) is an HDAC6 effector and that the R203W substitution increases the PACS1/HDAC6 interaction, aberrantly potentiating deacetylase activity."
    explanation: Direct measurement of the increased interaction and deacetylase activity.
  - reference: PMID:41858172
    reference_title: The R203W substitution drives PACS-1 syndrome by disrupting intramolecular regulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "PACS-1 uses its Furin binding region (FBR: amino acids 101-273) to directly interact with the catalytic domains of HDAC6."
    explanation: Defines the binding interface the substitution acts on.
  downstream:
  - target: Alpha-Tubulin and Cortactin Hypoacetylation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37848409
      reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Consequently, PACS1R203W reduces acetylation of α-tubulin and cortactin, causing the Golgi ribbon in hippocampal neurons and patient-derived neural progenitor cells (NPCs) to fragment and overpopulate dendrites, increasing their arborization."
      explanation: HDAC6 hyperactivity lowers alpha-tubulin and cortactin acetylation.
  - target: Dynein-Mediated Transport Failure
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41888583
      reference_title: PACS1 syndrome mutation disrupts dynein-mediated cargo transport via HDAC6 and BICD2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We demonstrate that PACS1R203W-HDAC6 recruits the adaptor BICD2, forming a complex that disperses the Golgi and impairs dynein function."
      explanation: The PACS1 Arg203Trp-HDAC6 complex impairs dynein through BICD2.
- name: Alpha-Tubulin and Cortactin Hypoacetylation
  biological_scale: MOLECULAR
  description: >-
    The potentiated HDAC6 lowers acetylation of its substrates alpha-tubulin and
    cortactin in hippocampal neurons and patient-derived neural progenitor
    cells. A short exposure to the HDAC6 inhibitor tubacin restores Golgi
    positioning in patient cells, consistent with deacetylation being upstream
    of the Golgi defect.
  genes:
  - preferred_term: HDAC6
    term:
      id: hgnc:14064
      label: HDAC6
  biological_processes:
  - preferred_term: tubulin deacetylation
    term:
      id: GO:0090042
      label: tubulin deacetylation
    modifier: INCREASED
  evidence:
  - reference: PMID:37848409
    reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Consequently, PACS1R203W reduces acetylation of α-tubulin and cortactin, causing the Golgi ribbon in hippocampal neurons and patient-derived neural progenitor cells (NPCs) to fragment and overpopulate dendrites, increasing their arborization."
    explanation: Reduced acetylation of the two HDAC6 substrates.
  downstream:
  - target: Golgi Fragmentation and Dispersal into Dendrites
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37848409
      reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Consequently, PACS1R203W reduces acetylation of α-tubulin and cortactin, causing the Golgi ribbon in hippocampal neurons and patient-derived neural progenitor cells (NPCs) to fragment and overpopulate dendrites, increasing their arborization."
      explanation: The authors state that hypoacetylation causes the Golgi ribbon to fragment.
- name: Dynein-Mediated Transport Failure
  biological_scale: CELLULAR
  description: >-
    PACS1 binds cytoplasmic dynein-1 heavy chain and is needed to keep furin at
    the trans-Golgi network. The PACS1 Arg203Trp-HDAC6 complex recruits the dynein
    adaptor BICD2, and the result is a dynein loss-of-function phenotype: cargo
    motility assays show reduced dynein initiation frequency and velocity, which
    HDAC6 inhibition or the dynein regulator Lis1 rescues. This places the
    syndrome among microtubule trafficking disorders.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: microtubule-based transport
    term:
      id: GO:0099111
      label: microtubule-based transport
    modifier: DECREASED
  evidence:
  - reference: PMID:41888583
    reference_title: PACS1 syndrome mutation disrupts dynein-mediated cargo transport via HDAC6 and BICD2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrate that PACS1R203W-HDAC6 recruits the adaptor BICD2, forming a complex that disperses the Golgi and impairs dynein function. Cargo motility assays revealed that PACS1R203W reduces dynein initiation frequency and velocity, defects rescued by HDAC6 inhibition or by expressing the dynein regulator Lis1."
    explanation: Direct measurement of impaired dynein transport and its HDAC6 dependence.
  downstream:
  - target: Golgi Fragmentation and Dispersal into Dendrites
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41888583
      reference_title: PACS1 syndrome mutation disrupts dynein-mediated cargo transport via HDAC6 and BICD2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "PACS1R203W induces a dynein loss-of-function phenotype that disrupts furin trafficking and Golgi organization."
      explanation: Links the dynein defect to disrupted Golgi organization.
- name: Golgi Fragmentation and Dispersal into Dendrites
  biological_scale: CELLULAR
  description: >-
    In hippocampal neurons and patient-derived neural progenitor cells the Golgi
    ribbon fragments and Golgi elements overpopulate dendrites. A short exposure
    to the HDAC6 inhibitor tubacin restores paranuclear Golgi positioning in
    patient cells.
  cell_types:
  - preferred_term: hippocampal neuron
    term:
      id: CL:0002608
      label: hippocampal neuron
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: Golgi organization
    term:
      id: GO:0007030
      label: Golgi organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37848409
    reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Confocal analysis suggested PACS1R203W profoundly disturbed Golgi (Giantin) positioning and MT organization."
    explanation: Golgi positioning and microtubule organization are disturbed by the variant.
  - reference: PMID:37848409
    reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A 24-hr treatment with the HDAC6 inhibitor tubacin reversed this effect, restoring Golgi localization to the paranuclear region."
    explanation: Reversal by HDAC6 inhibition ties the Golgi phenotype to HDAC6 activity.
  downstream:
  - target: Dendritic Overarborization with Reduced Spines and Synapses
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37848409
      reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Consequently, PACS1R203W/HDAC6 causes neuronal deficits in patient-derived cells and mouse models of PACS1 syndrome, including increased dendrite arborization together with reductions in spine density and synaptic strength."
      explanation: Golgi outposts dispersed into dendrites accompany the dendritic phenotype.
- name: Dendritic Overarborization with Reduced Spines and Synapses
  biological_scale: CELLULAR
  description: >-
    In PACS1 syndrome mice, prefrontal cortical neurons carry more elaborate
    dendrites that are beaded with varicosities and have fewer spines and fewer
    functional synapses. Antisense oligonucleotides against PACS1 or HDAC6, or
    HDAC6 inhibitors, restore neuronal structure and synaptic transmission. The
    increased arborization was not seen in isogenic human iPSC-derived cortical
    neurons, whose deficit was in network activity instead, so the dendritic
    branching component is not settled across model systems.
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: dendritic spine development
    term:
      id: GO:0060996
      label: dendritic spine development
    modifier: DECREASED
  - preferred_term: dendrite morphogenesis
    term:
      id: GO:0048813
      label: dendrite morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37848409
    reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The dendrites, however, are beset with varicosities, diminished spine density, and fewer functional synapses, characteristic of NDDs."
    explanation: Mouse and patient-cell dendrite and synapse phenotype.
  - reference: PMID:38280846
    reference_title: iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Sholl analysis was performed since neuron projection development was a strongly implicated pattern in DEGs (Fig. 3c, d, f) but did not reveal differences in dendritic arborization"
    explanation: >-
      Isogenic human iPSC-derived neurons carrying the variant showed no
      difference in dendritic arborization, contradicting the increased
      branching reported in mouse.
  downstream:
  - target: Altered Cortical Network Activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37848409
      reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Treatment of PACS1 syndrome mice or patient NPCs with PACS1- or HDAC6-targeting antisense oligonucleotides, or HDAC6 inhibitors, restores neuronal structure and synaptic transmission in prefrontal cortex, suggesting that targeting PACS1R203W/HDAC6 may be an effective therapy for PACS1 syndrome."
      explanation: >-
        Structure and synaptic transmission are restored together by the same
        interventions, which ties the structural deficit to the transmission
        deficit.
- name: Altered Cortical Network Activity
  biological_scale: TISSUE
  description: >-
    Mature PACS1(+/R203W) glutamatergic neurons and cortical organoids
    differentiated from isogenic stem cells show reduced expression of synaptic
    signaling genes and prolonged network bursts with longer interspike
    intervals on multielectrode arrays and calcium imaging. Neural precursors
    show few changes, so the deficit appears with neuronal maturation. Organoid
    proteomics converge on the same developmental processes and on known
    neurodevelopmental disorder and autism risk genes. This node is the
    proposed substrate for intellectual disability, autism and seizures; no
    study has yet connected a specific circuit change to a specific clinical
    feature.
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38280846
    reference_title: iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "While few deleterious effects were detected in PACS1(+/R203W) neural precursors, mature PACS1(+/R203W) glutamatergic neurons exhibited impaired expression of genes involved in synaptic signaling processes."
    explanation: Synaptic gene expression is impaired in mature variant neurons.
  - reference: PMID:38280846
    reference_title: iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Subsequent characterization of neural activity using calcium imaging and multielectrode arrays revealed the p.R203W PACS1 variant leads to a prolonged neuronal network burst duration mediated by an increased interspike interval."
    explanation: Functional network phenotype in human neurons.
  - reference: PMID:42835086
    reference_title: PACS1 syndrome variant alters the proteomic landscape of developing cortical organoids.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Key dysregulated transcripts and proteins in PACS1(+/R203W) organoids were classified as NDD-causative and ASD-risk genes."
    explanation: Organoid proteome changes converge on neurodevelopmental disorder genes.
  downstream:
  - target: Intellectual Disability
  - target: Delayed Speech and Language Development
  - target: Seizures
  - target: Autism
- name: Aberrant Cranial Neural Crest Specification and Migration
  biological_scale: CELLULAR
  description: >-
    In zebrafish embryos, mRNA encoding the mutant PACS1 induces craniofacial
    cartilage defects, most likely in a dominant-negative fashion, through
    aberrant specification and migration of SOX10-positive cranial neural crest
    cells, while enteric neural crest is spared. In transfected cells the mutant
    protein forms cytoplasmic aggregates with increased stability. This is the
    proposed basis of the facial gestalt. The model is overexpression of human
    mRNA in fish, and the result predates the HDAC6 mechanism; how the two
    connect has not been tested.
  cell_types:
  - preferred_term: neural crest cell
    term:
      id: CL:0011012
      label: neural crest cell
  biological_processes:
  - preferred_term: neural crest cell migration
    term:
      id: GO:0001755
      label: neural crest cell migration
    modifier: ABNORMAL
  evidence:
  - reference: PMID:23159249
    reference_title: Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, consistent with the human pathology, expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion. This phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells."
    explanation: Zebrafish overexpression model of the craniofacial phenotype.
  - reference: PMID:23159249
    reference_title: Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Altered PACS1 forms cytoplasmic aggregates in vitro with concomitant increased protein stability"
    explanation: Mutant protein behavior in cultured cells.
  downstream:
  - target: Characteristic Facial Gestalt
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23159249
      reference_title: Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Our findings suggest that PACS1 is necessary for the formation of craniofacial structures and that perturbation of its functions results in a specific syndromic ID phenotype."
      explanation: The authors connect the neural crest defect to the human craniofacial phenotype.
- name: Extracellular Matrix Dysregulation in Fibroblasts
  biological_scale: CELLULAR
  description: >-
    Transcriptomes of patient fibroblasts show altered extracellular matrix
    organization, including raised COL8A1 expression and deposition, which an
    allele-specific siRNA against the c.607C>T transcript corrects. How this
    relates to the HDAC6 mechanism, and which clinical feature it contributes
    to, has not been established.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:40972577
    reference_title: Allele-specific RNAi therapy corrects an extracellular matrix defect in Schuurs-Hoeijmakers syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, transcriptomic analysis of SHMS fibroblasts revealed alterations in extracellular matrix organization in mutant cells, including elevated COL8A1 expression and extracellular deposition."
    explanation: Patient fibroblast transcriptomic and deposition finding.
phenotypes:
- category: Neurological
  name: Intellectual Disability
  description: >-
    Present in every reported individual, usually mild to moderate; the
    caregiver-reported series describes a moderately severe disorder overall.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual disability, ranging from mild to moderate, was present in all."
    explanation: Present in all 19 individuals of the delineating cohort.
  - reference: PMID:34517877
    reference_title: "PACS1-Neurodevelopmental disorder: clinical features and trial readiness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PACS1-NDD is a moderately-severe intellectual disability syndrome in which seizures occur but are not a defining or primary feature."
    explanation: Caregiver survey conclusion on severity.
- category: Neurological
  name: Delayed Speech and Language Development
  description: >-
    Language is more affected than motor development; independent walking and
    first words are both reached at a median of 24 months in one series.
  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:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Language skills are more severely affected than motor skills."
    explanation: GeneReviews summary of the developmental profile.
  - reference: PMID:28111752
    reference_title: Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Speech and language in our cohort was universally delayed but developed in most, and three demonstrated dysarthria."
    explanation: Universal language delay in an eight-person series.
- category: Neurological
  name: Seizures
  description: >-
    Seizures occur in about half of individuals, of several types, and in the
    delineating cohort responded well to anticonvulsants.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures are frequent (12/19) and respond well to anticonvulsive medication."
    explanation: 12 of 19 individuals had seizures.
  - reference: PMID:34517877
    reference_title: "PACS1-Neurodevelopmental disorder: clinical features and trial readiness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seventeen (49%) had a diagnosis of epilepsy."
    explanation: Epilepsy in 17 of 35 individuals with a confirmed R203W variant.
- category: Behavioral
  name: Autism
  description: >-
    Autism or autistic features are reported in a substantial minority, with
    other behavioral difficulties including obsessive-compulsive behavior,
    hyperactivity and self-injury.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:34517877
    reference_title: "PACS1-Neurodevelopmental disorder: clinical features and trial readiness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twelve (40%, of 30 responding to the question) reported autism and (N = 11/30, 37%) reported features of autism."
    explanation: Caregiver-reported autism frequency.
- category: Neurological
  name: Infantile Hypotonia
  description: Reported in about a third to a half of individuals, improving with age.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypotonia is reported in about one third of individuals and is noted to improve over time."
    explanation: GeneReviews frequency and course.
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypotonia is common in infancy (8/19)."
    explanation: 8 of 19 in the delineating cohort.
- category: Craniofacial
  name: Characteristic Facial Gestalt
  description: >-
    A recognizable face present in every reported individual. The individual
    features are recorded as separate phenotypes below.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual \"wavy\" profile, flat philtrum, and diastema of the teeth."
    explanation: Facial gestalt present in all 19 individuals.
  sequelae:
  - target: Hypertelorism
  - target: Downslanted Palpebral Fissures
  - target: Bulbous Nasal Tip
  - target: Low-Set Ears
  - target: Wide Mouth
  - target: Downturned Corners of Mouth
  - target: Thin Upper Lip
  - target: Widely Spaced Teeth
  - target: Ptosis
  - target: Highly Arched Eyebrows
  - target: Thick Eyebrows
  - target: Long Eyelashes
  - target: Smooth Philtrum
- category: Craniofacial
  name: Hypertelorism
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
    explanation: GeneReviews lists hypertelorism among the common facial features.
- category: Craniofacial
  name: Downslanted Palpebral Fissures
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
    explanation: GeneReviews lists downslanting palpebral fissures.
- category: Craniofacial
  name: Bulbous Nasal Tip
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Bulbous nasal tip
    term:
      id: HP:0000414
      label: Bulbous nose
  evidence:
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
    explanation: GeneReviews lists a bulbous nasal tip.
- category: Craniofacial
  name: Low-Set Ears
  description: Low-set and simple ears.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
    explanation: GeneReviews lists low-set and simple ears.
- category: Craniofacial
  name: Wide Mouth
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Wide mouth
    term:
      id: HP:0000154
      label: Wide mouth
  evidence:
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
    explanation: GeneReviews lists a wide mouth with downturned corners.
- category: Craniofacial
  name: Downturned Corners of Mouth
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Downturned corners of mouth
    term:
      id: HP:0002714
      label: Downturned corners of mouth
  evidence:
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
    explanation: GeneReviews lists a wide mouth with downturned corners.
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual \"wavy\" profile, flat philtrum, and diastema of the teeth."
    explanation: Downturned corners of the mouth in the 19/19 facial gestalt.
- category: Craniofacial
  name: Ptosis
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual \"wavy\" profile, flat philtrum, and diastema of the teeth."
    explanation: Ptosis is part of the facial gestalt in the delineating cohort.
- category: Craniofacial
  name: Highly Arched Eyebrows
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Arched eyebrows
    term:
      id: HP:0002553
      label: Highly arched eyebrow
  evidence:
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual \"wavy\" profile, flat philtrum, and diastema of the teeth."
    explanation: Full and arched eyebrows in the delineating cohort.
- category: Craniofacial
  name: Thick Eyebrows
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Full eyebrows
    term:
      id: HP:0000574
      label: Thick eyebrow
  evidence:
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual \"wavy\" profile, flat philtrum, and diastema of the teeth."
    explanation: Full and arched eyebrows in the delineating cohort.
- category: Craniofacial
  name: Long Eyelashes
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Long eyelashes
    term:
      id: HP:0000527
      label: Long eyelashes
  evidence:
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual \"wavy\" profile, flat philtrum, and diastema of the teeth."
    explanation: Long eyelashes in the delineating cohort.
- category: Craniofacial
  name: Smooth Philtrum
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Smooth philtrum
    term:
      id: HP:0000319
      label: Smooth philtrum
  evidence:
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
    explanation: GeneReviews lists a smooth philtrum.
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual \"wavy\" profile, flat philtrum, and diastema of the teeth."
    explanation: Flat philtrum in the delineating cohort.
- category: Craniofacial
  name: Thin Upper Lip
  description: Thin upper lip with an unusual wavy profile.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
    explanation: GeneReviews lists a thin upper vermilion.
- category: Craniofacial
  name: Widely Spaced Teeth
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Widely spaced teeth
    term:
      id: HP:0000687
      label: Widely spaced teeth
  evidence:
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth."
    explanation: GeneReviews lists wide-spaced teeth.
- category: Neurological
  name: Brain Malformations
  description: >-
    Structural brain anomalies are found in most individuals who have been
    imaged (12 of 16 in the delineating cohort), but they differ between
    individuals, so the phenotype is bound to the general term.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Brain malformation
    term:
      id: HP:0012443
      label: Abnormal brain morphology
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males)."
    explanation: Brain malformations in 12 of 16 imaged individuals.
- category: Neurological
  name: Microcephaly
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genitourinary anomalies, microcephaly, and ocular anomalies are also reported."
    explanation: GeneReviews lists microcephaly among less common features.
- category: Cardiovascular
  name: Congenital Heart Defect
  description: >-
    Present in roughly 40 to 50 percent; septal defects are most common,
    followed by patent ductus arteriosus. Ascending aortic dilatation and mitral
    valve prolapse have also been reported, and echocardiographic cardiac
    function was normal in one cohort.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males)."
    explanation: Heart malformation in 10 of 19.
  - reference: PMID:37373745
    reference_title: Heart Disease Characterization and Myocardial Strain Analysis in Patients with PACS1 Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the literature review, almost 42% (42/100) of individuals with PACS1-NDD reportedly experienced HD. Septal defects were the most common malformation, followed by patent ductus arteriosus."
    explanation: Pooled literature frequency and spectrum of heart disease.
  sequelae:
  - target: Atrial Septal Defect
  - target: Ventricular Septal Defect
- category: Cardiovascular
  name: Atrial Septal Defect
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:28111752
    reference_title: Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac defects were noted in four individuals, including two individuals with atrial septal defects, three with ventricular septal defects, and one individual with a dilated pulmonary artery."
    explanation: Atrial septal defects in two of eight individuals.
- category: Cardiovascular
  name: Ventricular Septal Defect
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:28111752
    reference_title: Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac defects were noted in four individuals, including two individuals with atrial septal defects, three with ventricular septal defects, and one individual with a dilated pulmonary artery."
    explanation: Ventricular septal defects in three of eight individuals.
- category: Ophthalmological
  name: Coloboma
  description: >-
    Ocular anomalies are reported in about half of the delineating cohort;
    coloboma is shared with the WDR37 and PACS2 disorders.
  phenotype_term:
    preferred_term: Coloboma
    term:
      id: HP:0000589
      label: Coloboma
  evidence:
  - reference: PMID:33369122
    reference_title: Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, coloboma has been described as a feature in a WDR37-related disorder and a PACS1-related disorder (Schuurs-Hoeijmakers syndrome), but not in a PACS2-related disorder."
    explanation: Coloboma is a recognized feature of the PACS1 disorder.
- category: Genitourinary
  name: Cryptorchidism
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males)."
    explanation: Cryptorchidism in 6 of 12 males.
  - reference: PMID:41882293
    reference_title: DNA methylation signature and clinical delineation of PACS1-related disorder in 24 unreported individuals.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with the literature, our series showed a higher prevalence of cryptorchidism (77.8%), congenital heart defect (45.8%), and hypotonia (75%)."
    explanation: Higher frequency in a second series of 24.
- category: Genitourinary
  name: Congenital Kidney Malformation
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Congenital kidney malformation
    term:
      id: HP:0012210
      label: Abnormal renal morphology
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males)."
    explanation: Kidney malformation in 3 of 19.
  - reference: PMID:41882293
    reference_title: DNA methylation signature and clinical delineation of PACS1-related disorder in 24 unreported individuals.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study expands the phenotypic spectrum of PACS1-RD by reporting median age at independent walking and first spoken words (both 24 months), cross-sectional growth parameters, and previously undescribed clinical features, including congenital kidney malformations (25%) and feeding difficulties (75%)."
    explanation: Kidney malformations in a quarter of a second series.
- category: Gastrointestinal
  name: Feeding Difficulties
  description: >-
    Feeding dysfunction presents in infancy with failure to thrive,
    gastroesophageal reflux and in some a gastrostomy tube; oral motor
    dysfunction persists.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:41882293
    reference_title: DNA methylation signature and clinical delineation of PACS1-related disorder in 24 unreported individuals.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study expands the phenotypic spectrum of PACS1-RD by reporting median age at independent walking and first spoken words (both 24 months), cross-sectional growth parameters, and previously undescribed clinical features, including congenital kidney malformations (25%) and feeding difficulties (75%)."
    explanation: Feeding difficulties in 75 percent.
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Feeding dysfunction is presenting in infancy with failure to thrive (5/19), gastroesophageal reflux (6/19), and gastrostomy tube placement (4/19)."
    explanation: Infant feeding dysfunction in the delineating cohort.
- category: Gastrointestinal
  name: Gastroesophageal Reflux
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Feeding dysfunction is presenting in infancy with failure to thrive (5/19), gastroesophageal reflux (6/19), and gastrostomy tube placement (4/19)."
    explanation: Reflux in 6 of 19.
- category: Gastrointestinal
  name: Constipation
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:28111752
    reference_title: Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of individuals in our series had gastroesophageal reflux, and constipation was common."
    explanation: Constipation common in an eight-person series.
- category: Growth
  name: Short Stature
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other common features include constipation, seizures, behavioral issues, congenital heart anomalies, and short stature."
    explanation: GeneReviews lists short stature among common features.
prevalence:
- population: Published case reports and series
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    About 87 published cases by 2023. This is a literature case count, not a
    population prevalence. A 2026 review counts about 158 published patients,
    but that figure spans the PACS1, PACS2 and WDR37 disorders together and is
    not used here.
  evidence:
  - reference: PMID:37747683
    reference_title: Genetic characterization of Schuurs-Hoeijmakers syndrome in a moroccan individual with heterozygote PACS1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 87 cases have been recorded to date, and oddly enough, the majority of them share the same mutation"
    explanation: Literature case count in 2023.
genetic:
- name: PACS1
  gene_term:
    preferred_term: PACS1
    term:
      id: hgnc:30032
      label: PACS1
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  association: >-
    A heterozygous missense variant at Arg203, nearly always c.607C>T
    p.(Arg203Trp) and rarely c.608G>A p.(Arg203Gln), causes the syndrome.
  evidence:
  - reference: PMID:34517877
    reference_title: "PACS1-Neurodevelopmental disorder: clinical features and trial readiness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is one other pathogenic mutation reported in the PACS1 gene, R203Q (p.608G > A), in one patient; it is the same amino acid that is changed, resulting, as for the R203W mutation, in the loss of a positive charge"
    explanation: Both known pathogenic alleles change the same arginine.
  - reference: PMID:41882293
    reference_title: DNA methylation signature and clinical delineation of PACS1-related disorder in 24 unreported individuals.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PACS1-related disorder (PACS1-RD), also known as Schuurs-Hoeijmakers syndrome, is a rare autosomal dominant neurodevelopmental disorder predominantly caused by the recurrent de novo c.607 C > T p.(Arg203Trp) gain-of-function variant."
    explanation: The recurrent allele and its gain-of-function character.
  notes: >-
    Intragenic PACS1 deletions are not an established cause: a heterozygous
    deletion of exons 12-24 segregated in a three-generation family without the
    syndrome's face, intellectual disability or brain anomalies.
diagnosis:
- name: Exome Sequencing for the Recurrent PACS1 Variant
  description: >-
    The diagnosis is established by finding a heterozygous pathogenic PACS1
    variant on molecular testing, in practice the recurrent Arg203 change.
  diagnosis_term:
    preferred_term: Whole Exome Sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of PACS1-NDD is established in a proband with a heterozygous pathogenic variant in PACS1 identified by molecular genetic testing."
    explanation: GeneReviews diagnostic criterion.
  - reference: PMID:23159249
    reference_title: Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing in both families identified identical de novo mutations in PACS1, suggestive of causality."
    explanation: Exome sequencing identified the disorder.
- name: DNA Methylation Episignature
  description: >-
    Blood DNA methylation profiling identifies a PACS1-specific episignature
    shared by Arg203Trp and Arg203Gln carriers. It solved one individual first
    suspected of Kabuki syndrome and can help classify non-recurrent PACS1
    variants.
  diagnosis_term:
    preferred_term: DNA methylation episignature analysis
    term:
      id: NCIT:C63328
      label: DNA Methylation Analysis
  evidence:
  - reference: PMID:41882293
    reference_title: DNA methylation signature and clinical delineation of PACS1-related disorder in 24 unreported individuals.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Methylation analysis identified a specific episignature for PACS1-RD, consistently observed in individuals carrying either the canonical p.(Arg203Trp) or the non-recurrent p.(Arg203Gln) variant."
    explanation: Episignature shared by both pathogenic alleles.
treatments:
- name: Anticonvulsant Therapy
  description: >-
    Seizures are treated with standard anticonvulsants and responded well in
    the delineating cohort.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticonvulsant
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:26842493
    reference_title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures are frequent (12/19) and respond well to anticonvulsive medication."
    explanation: Seizures respond to standard anticonvulsants.
- name: Developmental and Supportive Care
  description: >-
    Developmental and educational support, with standard management of feeding
    problems, constipation, behavioral difficulties and cardiac, genitourinary
    and visual anomalies, and regular surveillance of each, including a
    clinical examination for scoliosis at each visit. Known seizure triggers
    are the circumstance GeneReviews advises avoiding.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of manifestations: Developmental and educational support; standard treatment for feeding issues, constipation, seizures, behavioral issues, cardiac anomalies, genitourinary anomalies, and vision issues."
    explanation: GeneReviews management summary.
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Monitor closure of septal defects per cardiologist; monitor kidney function if kidney malformation is present per nephrologist; ophthalmology exam and vision assessment per ophthalmologist; clinical exam for scoliosis at each visit with radiographs as needed."
    explanation: GeneReviews surveillance recommendations, including scoliosis examination.
  - reference: PMID:32672908
    reference_title: PACS1-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Agents/circumstances to avoid: Known seizure triggers."
    explanation: GeneReviews agents and circumstances to avoid.
- name: PACS1-Targeting Antisense Oligonucleotide (preclinical)
  description: >-
    A Pacs1-specific 2'-O-methoxyethyl gapmer antisense oligonucleotide given
    intracerebroventricularly to newborn Pacs1 R201W/+ mice (R201W is the mouse
    equivalent of human R203W) depleted PACS1 and rescued excitatory synaptic
    transmission. Pacs1 loss itself did not disturb synapses in the same study,
    which is the rationale for lowering PACS1 in patients. Not tested in
    patients.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  oligonucleotide_details:
    oligonucleotide_mechanism: RNASE_H_KNOCKDOWN
    target_gene:
      preferred_term: PACS1
      term:
        id: hgnc:30032
        label: PACS1
    oligonucleotide_chemistry: TWO_PRIME_O_METHOXYETHYL
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: PACS1 Arg203 Gain-of-Function Substitution
  evidence:
  - reference: PMID:37848409
    reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Treatment of the mice with antisense oligonucleotides (ASOs) that deplete HDAC6 or PACS1 restores both neuronal structure and communication, suggesting PACS1R203W/HDAC6 underlies PACS1 syndrome neuronal pathology and that this NDD may be treatable with targeted therapies."
    explanation: Preclinical rescue in mice.
  - reference: PMID:37848409
    reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Together, these findings suggest Pacs1 loss does not significantly disturb excitatory or inhibitory synapses, supporting the development of a PACS1 ASO strategy for patient therapy."
    explanation: Lowering PACS1 is tolerated at the synapse, the safety premise of the approach.
  - reference: PMID:37848409
    reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The MOE ... gapmer ASOs used in this study were generated as described"
    explanation: Source of the chemistry and RNase H gapmer design.
- name: HDAC6-Targeting Antisense Oligonucleotide (preclinical)
  description: >-
    An Hdac6-specific 2'-O-methoxyethyl gapmer antisense oligonucleotide
    injected into newborn PACS1 R203W mice restored neuronal structure and
    synaptic transmission. Not tested in patients.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  oligonucleotide_details:
    oligonucleotide_mechanism: RNASE_H_KNOCKDOWN
    target_gene:
      preferred_term: HDAC6
      term:
        id: hgnc:14064
        label: HDAC6
    oligonucleotide_chemistry: TWO_PRIME_O_METHOXYETHYL
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Enhanced PACS1-HDAC6 Interaction and HDAC6 Hyperactivity
  evidence:
  - reference: PMID:37848409
    reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Specifically, R26P1 and R26P1R203W P1 pups were co-injected with an Hdac6-specific antisense oligonucleotide (H6ASO) or a negative control ASO (nASO)"
    explanation: The HDAC6 ASO experiment in the PACS1 R203W mouse.
  - reference: PMID:37848409
    reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Treatment of the mice with antisense oligonucleotides (ASOs) that deplete HDAC6 or PACS1 restores both neuronal structure and communication, suggesting PACS1R203W/HDAC6 underlies PACS1 syndrome neuronal pathology and that this NDD may be treatable with targeted therapies."
    explanation: Preclinical rescue in mice.
- name: HDAC6 Inhibitors (preclinical)
  description: >-
    Small-molecule HDAC6 inhibitors restored neuronal structure and synaptic
    transmission in PACS1 syndrome mice and reversed Golgi mispositioning in
    patient-derived cells. Not tested in patients.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Enhanced PACS1-HDAC6 Interaction and HDAC6 Hyperactivity
  evidence:
  - reference: PMID:37848409
    reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Treatment of PACS1 syndrome mice or patient NPCs with PACS1- or HDAC6-targeting antisense oligonucleotides, or HDAC6 inhibitors, restores neuronal structure and synaptic transmission in prefrontal cortex"
    explanation: HDAC6 inhibitors rescue the mouse neuronal phenotype.
- name: Allele-Specific siRNA Silencing (preclinical)
  description: >-
    siRNAs that silence the c.607C>T PACS1 transcript while sparing the
    wild-type transcript were selected in patient fibroblasts and corrected the
    COL8A1 dysregulation. Proof of concept in cells only.
  therapeutic_modality: SIRNA
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: PACS1 Arg203 Gain-of-Function Substitution
  - target: Extracellular Matrix Dysregulation in Fibroblasts
  evidence:
  - reference: PMID:40972577
    reference_title: Allele-specific RNAi therapy corrects an extracellular matrix defect in Schuurs-Hoeijmakers syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Through an in vitro screening of fibroblasts derived from affected individuals, we identified several small interfering RNA (siRNA) sequences that specifically silence the PACS1 transcript harboring the recurrent PACS1 mutation while sparing the wild-type mRNA."
    explanation: Allele-specific silencing in patient cells.
  - reference: PMID:40972577
    reference_title: Allele-specific RNAi therapy corrects an extracellular matrix defect in Schuurs-Hoeijmakers syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Treatment with the best selected allele-specific siRNA corrected the COL8A1 dysregulation."
    explanation: Correction of the fibroblast matrix phenotype.
animal_models:
- name: PACS1 R203W conditional knock-in mouse
  species: Mouse
  genotype: Cre-inducible PACS1 R203W expression (R26P1R203W), and Emx1-Cre-induced Pacs1 R201W/+ knock-in (mouse equivalent of R203W)
  publication: PMID:37848409
  description: >-
    Mice expressing PACS1 R203W reproduce the neuronal Golgi, dendrite, spine
    and synaptic phenotypes, which antisense depletion of Hdac6 or PACS1
    rescues. A standard germline Pacs1 R201W knock-in was embryonic lethal, so
    expression was restricted to forebrain neurons. Craniofacial and systemic
    features were not the subject of the study.
  modeled_mechanisms:
  - target: Dendritic Overarborization with Reduced Spines and Synapses
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Reproduces the dendrite, spine and synapse phenotype and its HDAC6 dependence.
    limitations: >-
      Increased arborization was not reproduced in isogenic human iPSC-derived
      neurons, so this component may be species- or system-specific.
    evidence:
    - reference: PMID:37848409
      reference_title: Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Consequently, PACS1R203W/HDAC6 causes neuronal deficits in patient-derived cells and mouse models of PACS1 syndrome, including increased dendrite arborization together with reductions in spine density and synaptic strength."
      explanation: The model shows the node's phenotype.
- name: C. elegans pacs-1 knock-in of PACS1 syndrome variants
  species: Caenorhabditis elegans
  genotype: PACS1 and PACS2 syndrome variants edited into cePACS-1
  publication: PMID:39031646
  description: >-
    Editing the PACS1 and PACS2 syndrome variants into the single worm PACS
    ortholog changes protein localization in several cell types including
    neurons. Worm PACS-1 and WDR-37 are mutually required for expression.
  modeled_mechanisms:
  - target: PACS1 Arg203 Gain-of-Function Substitution
    relationship: MEASURES
    fidelity: LOW
    model_scale: CELLULAR
    description: Shows that the variant alters the protein's subcellular localization in vivo.
    limitations: >-
      The worm has one PACS gene standing for both PACS1 and PACS2, and the
      readout is protein localization, not any of the downstream HDAC6, Golgi
      or synaptic phenotypes.
    evidence:
    - reference: PMID:39031646
      reference_title: PACS-1 variant protein is aberrantly localized in Caenorhabditis elegans model of PACS1/PACS2 syndromes.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We further show that editing in PACS1 and PACS2 variants in cePACS-1 changes protein localization in multiple cell types, including neurons."
      explanation: In vivo localization effect of the edited variant.
experimental_models:
- name: Isogenic PACS1(+/R203W) iPSC-derived neurons and cortical organoids
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Stem cells edited to carry the variant and differentiated to glutamatergic
    neurons and cortical organoids, used for transcriptomics, proteomics,
    calcium imaging and multielectrode array recording.
  modeled_mechanisms:
  - target: Altered Cortical Network Activity
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Measures the network-burst phenotype in human neurons.
    limitations: >-
      In vitro networks lack the developing brain's cell diversity and
      connectivity; how prolonged bursting maps onto seizures or cognition is
      not established.
    readouts:
    - name: Network burst duration on multielectrode array
      target: Altered Cortical Network Activity
      direction: INCREASED
      interpretation: Variant neurons show prolonged network bursts.
      evidence:
      - reference: PMID:38280846
        reference_title: iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "To characterize these effects, we performed both calcium imaging in organoids and multielectrode array (MEA) recording of iPSC-derived neurons and found a prolonged network burst duration in PACS1(+/R203W) cells."
        explanation: The measurement behind the readout.
  - target: Dendritic Overarborization with Reduced Spines and Synapses
    relationship: FAILS_TO_RECAPITULATE
    fidelity: UNKNOWN
    description: No difference in dendritic arborization by Sholl analysis.
    limitations: >-
      A negative morphological result in one in vitro system; spine density and
      synapse number were not the readout.
    evidence:
    - reference: PMID:38280846
      reference_title: iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Sholl analysis was performed since neuron projection development was a strongly implicated pattern in DEGs (Fig. 3c, d, f) but did not reveal differences in dendritic arborization"
      explanation: Human neurons did not show the increased arborization seen in mouse.
differential_diagnoses:
- name: PACS2-related developmental and epileptic encephalopathy (DEE66)
  disease_term:
    preferred_term: developmental and epileptic encephalopathy, 66
    term:
      id: MONDO:0054845
      label: developmental and epileptic encephalopathy, 66
  distinguishing_features:
  - >-
    Caused by a recurrent de novo PACS2 variant in the paralog; neonatal-onset
    epileptic encephalopathy with cerebellar dysgenesis, where seizures in
    PACS1 syndrome are milder and not a defining feature. The facial features
    overlap.
  evidence:
  - reference: PMID:33369122
    reference_title: Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our review of the phenotypes of three human disorders caused by WDR37, PACS1, and PACS2 mutations showed a significant overlap of epilepsy, intellectual disability, cerebellar atrophy, and facial features."
    explanation: Overlap among the three disorders of the WDR37-PACS1-PACS2 axis.
  - reference: PMID:40869285
    reference_title: "AI-Based Facial Phenotyping Supports a Shared Molecular Axis in PACS1-, PACS2-, and WDR37-Related Syndromes."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "In addition to consistently recognizing SHMS as a distinct clinical entity, the algorithms frequently matched DEE66 and NOCGUS, suggesting a shared facial gestalt."
    explanation: Facial analysis distinguishes SHMS but often matches it to DEE66 and NOCGUS.
- name: Neurooculocardiogenitourinary syndrome (WDR37)
  disease_term:
    preferred_term: neurooculocardiogenitourinary syndrome
    term:
      id: MONDO:0032850
      label: neurooculocardiogenitourinary syndrome
  distinguishing_features:
  - >-
    De novo WDR37 variants; WDR37 is PACS1's strongest interactor and the
    syndrome shares intellectual disability, facial dysmorphism and coloboma.
  evidence:
  - reference: PMID:33369122
    reference_title: Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "De novo heterozygous mutations in WDR37 have been shown to cause a novel human disorder, neurooculocardiogenitourinary syndrome (NOCGUS syndrome) (OMIM #618652), characterized by intellectual disability, facial dysmorphism, and coloboma."
    explanation: Phenotypic overlap with the WDR37 disorder.
notes: >-
  A GeneReviews chapter exists (PACS1-Related Neurodevelopmental Disorder,
  PMID:32672908) and its abstract is the phenotype baseline here. Brain
  malformations are reported in most individuals imaged in the delineating
  cohort (12 of 16) but differ between individuals, so they are recorded under
  one general brain-morphology phenotype rather than as specific anomalies.
📚

References & Deep Research

References

1
PMID:32672908
PACS1-Related Neurodevelopmental Disorder.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Schuurs-Hoeijmakers_Syndrome · 2026-10-28T23:11:13Z · View source

New entry for PACS1 syndrome (MONDO:0014006). Built from one OpenScientist deep-research report (26 of 26 references resolved, 23 on topic; the report is about PACS1 throughout) plus PubMed searches; the GeneReviews chapter PACS1-Related Neurodevelopmental Disorder (PMID:32672908) is the phenotype baseline and is tagged. Pathophysiology is a chain from the Arg203 gain-of-function substitution (NMR and cryo-EM structural work) through enhanced PACS1-HDAC6 interaction, microtubule hypoacetylation and dynein transport failure, Golgi fragmentation, dendrite and synapse changes, to altered cortical network activity, plus side branches for zebrafish cranial neural crest defects and fibroblast extracellular matrix changes. The mouse increase in dendritic arborization is recorded together with a REFUTE item from isogenic human iPSC neurons that showed none. A multi-exon PACS1 deletion family without the syndrome is cited against haploinsufficiency. Preprint versions (PMID:36747781, PMID:41497635) were set aside in favour of the published papers. just preflight-dr was not run to completion because the local MONDO build is absent; the entity check was done by reading. Validation: validate, validate-terms, count-verified-snippets, the whole-repo snippet and title gates, check-snippet-grading, entity-ref, causal-target, coarse-phenotype, logical-rule and enum checks, check-genereviews and validate-disorders.

OpenScientist ▸
Schuurs-Hoeijmakers Syndrome (PACS1-Related Disorder): Comprehensive Disease Characteristics Report
openscientist-autonomous 26 citations 2026-10-28T23:06:42.480055

Schuurs-Hoeijmakers Syndrome (PACS1-Related Disorder): Comprehensive Disease Characteristics Report

Disease: Schuurs-Hoeijmakers Syndrome (SHMS) — also PACS1 neurodevelopmental disorder (PACS1-NDD), PACS1-related disorder (PACS1-RD), Intellectual Developmental Disorder, Autosomal Dominant 17 (MRD17) MONDO ID: MONDO:0014006 OMIM: #615009 Causal gene: PACS1 (Phosphofurin Acidic Cluster Sorting Protein 1), chromosome 11q13.1, HGNC:30032 Category: Mendelian, autosomal dominant (de novo)

Gene identity (read first): This disease is caused by the gene PACS1 on chromosome 11q13.1. It is distinct from the clinically overlapping but genetically separate PACS2-related disorder (EIEE66) and WDR37-related NOCGUS syndrome. All claims below refer to the PACS1 entity.

Summary

Schuurs-Hoeijmakers syndrome is an ultra-rare, autosomal dominant neurodevelopmental disorder caused by the gene PACS1. In the overwhelming majority of patients the disease is produced by a single, recurrent, de novo heterozygous missense variant, c.607C>T (p.Arg203Trp / R203W), located in the furin-binding region (FBR) of the PACS1 protein. A rarer alternative nucleotide change producing the same amino acid substitution (c.608G>A, p.Arg203Trp) and a non-recurrent p.Arg203Gln (R203Q) variant have also been reported. The recurrence of a single codon change across virtually all unrelated patients worldwide is one of the most striking features of this condition and points to a specific gain-of-function/dominant-negative mechanism rather than simple haploinsufficiency.

Clinically, SHMS produces a highly recognizable and essentially fully penetrant facial gestalt (full arched eyebrows, hypertelorism with downslanting palpebral fissures, long eyelashes, ptosis, bulbous nasal tip, wide mouth with downturned corners, thin "wavy" upper lip, flat philtrum, dental diastema), accompanied by mild-to-moderate intellectual disability, autistic traits, infantile hypotonia, and anticonvulsant-responsive seizures. Structural malformations of the heart, brain, eyes, kidneys, and genitalia (cryptorchidism) occur in a substantial minority, and feeding difficulties/failure to thrive are common in infancy. The condition is lifelong and managed symptomatically; mortality is not a defining feature and most patients survive into adulthood.

Mechanistically, the R203W substitution disrupts an intramolecular autoregulatory switch in PACS1: the central unstructured region normally folds back onto a positively charged loop containing Arg203 to autoinhibit the FBR. Loss of this regulation unlocks aberrant protein–protein interactions, including enhanced binding to the deacetylase HDAC6 and disruption of dynein/BICD2-mediated cargo transport, as well as perturbation of the PACS1–WDR37 complex. Downstream consequences demonstrated in disease models include defective cranial-neural-crest-cell migration (craniofacial anomalies), altered cortical neuronal activity in iPSC-derived organoids, and extracellular-matrix dysregulation (elevated COL8A1) in patient fibroblasts. A blood DNA-methylation episignature provides a functional diagnostic biomarker, and allele-specific RNAi that silences the mutant transcript while sparing wild-type PACS1 has corrected molecular defects in patient cells, offering proof-of-concept for precision therapy.

Key Findings

Finding 1 — PACS1 c.607C>T (p.Arg203Trp) is the recurrent de novo cause of SHMS

Schuurs-Hoeijmakers syndrome is defined molecularly by a recurrent de novo heterozygous missense variant in PACS1, c.607C>T, p.Arg203Trp. In the pivotal 2016 clinical delineation cohort, all 19/19 unrelated patients carried the identical variant (PMID: 26842493: "We report on 19 individuals with a recurrent de novo c.607C>T mutation in PACS1. This specific mutation gives rise to a recognizable intellectual disability syndrome."). The recurrence has been confirmed repeatedly across diverse populations (India, Morocco, Brazil, China), and a 2023 review noted that of ~87 recorded cases, "the majority of them share the same mutation (c.607 C > T; p.R203W)" (PMID: 37747683).

Rare molecular alternatives include c.608G>A (same p.Arg203Trp protein change; PMID: 30690871) and the non-recurrent p.Arg203Gln (R203Q) allele, which shares the PACS1-RD episignature (PMID: 41882293). A novel variant has also been reported (c.943C>T, p.Arg315Trp). The variant is classified pathogenic by ACMG criteria and is essentially absent from gnomAD population databases, consistent with a highly penetrant, de novo disease allele.

  • Evidence type: Human clinical/genetic.
  • Variant nomenclature: NM_018026.3:c.607C>T (p.Arg203Trp); chr11q13.1.
  • Ontology: MONDO:0014006; HGNC:30032 (PACS1).

Finding 2 — Core clinical phenotype: facial gestalt, intellectual disability, seizures, multi-organ malformations

The syndrome has a distinctive and essentially fully penetrant facial appearance present in 19/19 patients in the defining cohort (PMID: 26842493: "There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual 'wavy' profile, flat philtrum, and diastema of the teeth.").

Beyond the face, the phenotype includes intellectual disability (mild–moderate) in 19/19, infantile hypotonia (8/19), and frequent, treatment-responsive seizures (12/19). Structural malformations are common: "Seizures are frequent (12/19) and respond well to anticonvulsive medication. Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males)." (PMID: 26842493). Feeding dysfunction/failure to thrive (5/19) and GERD (6/19) are frequent in infancy.

A 2026 DNA-methylation cohort of 24 unreported individuals updated frequencies: feeding difficulties 75%, hypotonia 75%, cryptorchidism 77.8%, congenital heart defect 45.8%, congenital kidney malformation 25%, with median independent walking and first words both ~24 months (PMID: 41882293). Longitudinal multimodal study of five children confirmed global developmental delay, pronounced motor impairment, autistic traits with elevated restricted/repetitive behaviors, relatively preserved pragmatic skills, and globally reduced gray and white matter volumes on MRI (PMID: 42392841).

Phenotype table with suggested HPO terms:

Phenotype Frequency HPO term (suggested)
Intellectual disability, mild–moderate ~100% HP:0001249
Distinctive facial gestalt 19/19 (100%) HP:0001999
Hypertelorism common HP:0000316
Downslanting palpebral fissures common HP:0000494
Ptosis common HP:0000508
Seizures 12/19 (~63%) HP:0001250
Infantile hypotonia 8/19–75% HP:0008947 / HP:0001252
Autistic behavior frequent HP:0000729
Congenital heart defect 45.8–53% HP:0001627
Brain structural anomaly 12/16 (~75%) HP:0012443
Eye malformation / coloboma 10/19 (~53%) HP:0000589 (coloboma)
Renal malformation 25% HP:0000792
Cryptorchidism 6/12 males (~50–78%) HP:0000028
Feeding difficulties / FTT 26–75% HP:0011968 / HP:0001508
Gastroesophageal reflux 6/19 (~32%) HP:0002020
Dental diastema common HP:0000699
Cleft lip (rare) reported HP:0410030
  • Evidence type: Human clinical.

Finding 3 — Mechanism: disrupted protein sorting/trafficking with neuronal and ECM defects

PACS1 (phosphofurin acidic cluster sorting protein 1) is a multidomain cytosolic sorting adaptor that directs trans-Golgi-network/endosomal cargo trafficking and also has nuclear functions. Multiple disease models demonstrate that the R203W variant perturbs these functions:

  • Craniofacial / neural crest: In a zebrafish model, mutant pacs1 "significantly reduced cranial cartilaginous structures, inducing craniofacial alterations predominantly in a dominant-negative fashion" (PMID: 36415352).
  • Cortical neurons: iPSC-derived cortical organoids carrying p.R203W show transcriptional and functional deficits in neuron activity (PMID: 38280846), affecting neuronal firing without gross disruption of organoid architecture (PMID: 38521709). Proteomic analysis of organoids identified convergent dysregulated developmental processes and additional pathways not seen transcriptomically (PMID: 42835086).

  • Extracellular matrix: "transcriptomic analysis of SHMS fibroblasts revealed alterations in extracellular matrix organization in mutant cells, including elevated COL8A1 expression and extracellular deposition. Treatment with the best selected allele-specific siRNA corrected the COL8A1 dysregulation." (PMID: 40972577).

  • Evidence type: Model organism (zebrafish), in vitro (iPSC organoids, patient fibroblasts).

  • Suggested GO / CL: GO:0016192 (vesicle-mediated transport), GO:0030198 (extracellular matrix organization), neural-crest migration; CL:0000333 (migratory neural crest cell), CL:0000540 (neuron).

Finding 4 — Ultra-rare; symptomatic management; emerging allele-specific RNAi therapy

SHMS is ultra-rare: ~87 cases reported by 2023 (PMID: 37747683) and ~158 published patients by 2026 (PMID: 42794636). No disease-modifying therapy currently exists; management is supportive — anticonvulsants (which respond well), developmental/physical/speech therapy, and treatment of congenital malformations. The disorder is characterized as a "moderately-severe intellectual disability syndrome in which seizures occur but are not a defining or primary feature. Successful precision medicine clinical trials for this ultra-rare disorder must target important core features" (PMID: 34517877).

The leading precision-therapy candidate is allele-specific RNA interference: "we identified several small interfering RNA (siRNA) sequences that specifically silence the PACS1 transcript harboring the recurrent PACS1 mutation while sparing the wild-type mRNA" — these corrected the ECM/COL8A1 defect in patient fibroblasts (PMID: 40972577).

  • Evidence type: Human clinical / in vitro proof-of-concept.
  • Suggested NCIT: NCIT:C15688 (Pharmacotherapy), NCIT:C20151 (RNA interference), NCIT:C15277 (Rehabilitation Therapy), NCIT:C38148 (Anticonvulsant Agent).

Finding 5 — Structural mechanism: R203W disrupts PACS1 intramolecular autoregulation

A 2026 NMR solution-structure study provided the mechanistic framework. PACS1's furin-binding region (FBR; amino acids 101–273) is normally autoinhibited: the central unstructured region folds back onto a positively charged loop containing Arg203. "The R203W substitution, located in this loop, disrupts this regulatory interaction and, in vitro, displays the ability to promote aberrant protein-protein interactions." (PMID: 41858172). The FBR directly engages the deacetylase HDAC6: "PACS-1 uses its Furin binding region (FBR: amino acids 101-273) to directly interact with the catalytic domains of HDAC6." (PMID: 41858172). A companion commentary framed this as a single mutation that "disrupts intramolecular regulation to drive neurodevelopmental disease" (PMID: 42304662).

The downstream trafficking consequence is disruption of dynein-mediated cargo transport via HDAC6 and BICD2 (PMID: 41888583). Cryo-EM of the PACS1–WDR37 complex shows PACS1 binds and stabilizes WDR37 through a conserved FBR interface, and a gain-of-function mutation affects the complex (PMID: 41279321).

  • Evidence type: In vitro / structural (NMR, cryo-EM), computational.
  • Suggested GO: GO:0070840 (dynein complex binding), GO:0030286 (dynein complex), protein deacetylase binding (HDAC6 context).

Finding 6 — PACS1-RD has a diagnostic blood DNA-methylation episignature

Genome-wide methylation profiling (~860,000 CpG sites) of 24 unreported individuals identified a specific episignature for PACS1-RD. "Methylation analysis identified a specific episignature for PACS1-RD, consistently observed in individuals carrying either the canonical p.(Arg203Trp) or the non-recurrent p.(Arg203Gln) variant. This episignature further enabled PACS1-RD diagnosis in one unsolved individual initially suspected of Kabuki syndrome." (PMID: 41882293). This provides a functional classifier that can resolve variants of uncertain significance and distinguish SHMS from phenotypically overlapping conditions (e.g., Kabuki syndrome).

  • Evidence type: Human clinical / epigenomic.
  • Suggested terms: GO:0006306 (DNA methylation); diagnostic episignature biomarker.

Finding 7 — Invertebrate models recapitulate trafficking/seizure phenotypes; QoL reduced but above Cornelia de Lange

Conserved invertebrate models validate the PACS–WDR37 axis. In Drosophila, PACS deficiency "disrupts Golgi architecture and causes cytokinesis failures and seizure-like phenotype" (PMID: 39999877). In C. elegans, editing in PACS1/PACS2 variants aberrantly relocalizes the cePACS-1 protein across cell types including neurons, and "expression of human PACS1 can functionally complement C. elegans PACS-1 in neurons, demonstrating conserved functions of the PACS-WDR37 axis in an invertebrate model system" (PMID: 39031646; see also PMID: 38712144).

Quality of life was quantified in 21 individuals aged 4–21 using the caregiver-proxy KidsLife scale: "The mean QoLI was 48.1 ± 28.3, slightly below the median for individuals with intellectual disability, but higher than other neurodevelopmental disorders such as Cornelia de Lange Syndrome." with autonomy/self-determination most compromised (PMID: 41750059).

  • Evidence type: Model organism (Drosophila, C. elegans); human clinical (QoL).

Finding 8 — Founding 2012 discovery: PACS1 c.607C>T via defective cranial-neural-crest migration

The disease was first defined by Schuurs-Hoeijmakers et al. (2012, Am J Hum Genet 91:1122–1127; PMID: 23159249), who identified the recurrent de novo c.607C>T (p.Arg203Trp) PACS1 variant in two unrelated children with a shared ID phenotype and showed in zebrafish that mutant pacs1 mRNA produces craniofacial cartilage defects attributable to defective cranial-neural-crest-cell migration, consistent with a dominant-negative action. (Note: the founding paper was not retrievable through the PubMed interface in this session; the citation is supplied from domain knowledge and the abstract text was not re-verified here.)

Section-by-Section Report

1. Disease Information

Overview. Schuurs-Hoeijmakers syndrome (SHMS) is an ultra-rare autosomal dominant neurodevelopmental syndrome caused by the gene PACS1. It is characterized by a recognizable facial gestalt, mild-to-moderate intellectual disability, autistic features, seizures, and variable congenital malformations. It is a disease-level (aggregated) entity: information derives from published case series, cohort studies, and functional/model-organism research rather than a single EHR source.

Key identifiers. - MONDO: MONDO:0014006 - OMIM: #615009 (Intellectual developmental disorder, autosomal dominant 17; MRD17) - Orphanet: PACS1 syndrome / Schuurs-Hoeijmakers syndrome - MeSH: No dedicated legacy MeSH descriptor; indexed via PACS1 gene + Intellectual Disability - ICD-10: Q87.8 (other specified congenital malformation syndromes) — no specific code - ICD-11: within developmental anomaly syndromes — no dedicated code - Gene: PACS1, HGNC:30032, NCBI Gene 55690, UniProt Q6VY07, Ensembl ENSG00000175115, chr11q13.1

Synonyms / alternative names: PACS1 syndrome; PACS1 neurodevelopmental disorder (PACS1-NDD); PACS1-related disorder (PACS1-RD); Intellectual developmental disorder, autosomal dominant 17 (MRD17); Schuurs-Hoeijmakers syndrome.

2. Etiology

Primary cause — genetic. SHMS is a monogenic disorder caused by a de novo heterozygous gain-of-function/dominant-negative missense variant in PACS1, almost always c.607C>T (p.Arg203Trp). There is no environmental or infectious cause.

Genetic risk factors. The disease-causing allele is itself the sole established risk factor; there are no reported susceptibility loci or modifier genes. The mutation arises de novo (not inherited), so the principal "risk factor" is a sporadic germline mutational event. Advanced parental age is a plausible but unproven contributor to the de novo mutation rate (not specifically demonstrated for PACS1).

Environmental / lifestyle risk factors. None identified. The condition is not linked to toxins, diet, occupational exposure, smoking, or alcohol.

Protective factors. None identified (genetic or environmental). Given monogenic de novo causation, classical protective-allele concepts do not apply; however, allele-specific silencing of the mutant transcript functionally reverses cellular phenotypes (PMID: 40972577).

Gene–environment interactions. None established. Disease expression is driven by the single dominant variant; variable expressivity likely reflects stochastic/developmental factors and genetic background rather than defined G×E interactions.

3. Phenotypes

See the phenotype table in Finding 2 above for HPO-mapped features and frequencies. Key characteristics:

  • Age of onset: Congenital/neonatal for malformations and dysmorphism; infantile for hypotonia and feeding problems; childhood for developmental delay, seizures, and autistic traits. Median independent walking and first words ~24 months (PMID: 41882293).
  • Severity: Intellectual disability mild-to-moderate ("moderately-severe" per PMID: 34517877); variable malformation burden.
  • Progression: Predominantly stable/non-regressive. A systematic review of ~158 patients found skill loss in only 5 patients (2 PACS1), concluding the evidence "does not support classifying these syndromes as primarily regressive disorders" while justifying surveillance (PMID: 42794636).
  • Quality of life: Mean KidsLife QoL index 48.1 ± 28.3; autonomy/self-determination most affected (PMID: 41750059).

4. Genetic / Molecular Information

  • Causal gene: PACS1 (HGNC:30032; chr11q13.1).
  • Pathogenic variant: NM_018026.3:c.607C>T (p.Arg203Trp); recurrent de novo; ACMG pathogenic; essentially absent in gnomAD. Alternatives: c.608G>A (p.Arg203Trp), p.Arg203Gln (R203Q, shares episignature), and a reported c.943C>T (p.Arg315Trp). A multi-exon deletion of PACS1 has also been described (PMID: 34373684).
  • Variant type: Missense (single nucleotide substitution) at a CpG-containing hotspot codon (Arg203).
  • Origin: Germline, de novo.
  • Functional consequence: Gain-of-function / dominant-negative — disrupts intramolecular autoregulation and promotes aberrant interactions (PMID: 41858172); dominant-negative craniofacial effect in zebrafish (PMID: 36415352).
  • Modifier genes: None established; the WDR37–PACS1–PACS2 interaction axis modulates overlapping phenotypes (PMID: 33369122).
  • Epigenetic information: Robust, disease-specific DNA-methylation episignature across ~860,000 CpG sites (PMID: 41882293).
  • Chromosomal abnormalities: Not characteristic; rare structural (multi-exon deletion) events reported.

5. Environmental Information

Not applicable. No environmental factors, lifestyle factors, or infectious agents are implicated in SHMS. The condition is entirely genetic (de novo monogenic).

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. A de novo c.607C>T mutation in PACS1 results in the p.Arg203Trp substitution within the positively charged autoregulatory loop of the furin-binding region (FBR, aa 101–273). (demonstrated — PMID: 26842493, PMID: 41858172)
  2. R203W disrupts the intramolecular autoinhibitory interaction by which the central unstructured region folds onto the Arg203 loop, leading to a constitutively "unlocked" FBR. (demonstrated, in vitro/NMR — PMID: 41858172)
  3. The unlocked FBR promotes aberrant protein–protein interactions, notably enhanced binding to HDAC6 catalytic domains, which branches into: (demonstrated in vitro — PMID: 41858172)
  4. 3a. Disruption of dynein/BICD2-mediated cargo transport, impairing intracellular/axonal trafficking. (demonstrated — PMID: 41888583)
  5. 3b. Perturbation of the PACS1–WDR37 complex stability/assembly. (demonstrated, cryo-EM — PMID: 41279321)
  6. Altered sorting/trafficking during development leads to defective cranial-neural-crest-cell migration, resulting in craniofacial cartilage anomalies and the facial gestalt. (demonstrated, zebrafish — PMID: 36415352; founding 2012 study PMID: 23159249)
  7. In the developing cortex, the variant alters the transcriptomic and proteomic landscape and produces deficits in neuronal firing/activity, leading to intellectual disability, autistic traits, and seizure susceptibility. (demonstrated, iPSC organoids — PMID: 38280846, PMID: 42835086, PMID: 38521709)
  8. In connective tissue, the variant dysregulates extracellular-matrix organization (elevated COL8A1 deposition), contributing to structural/tissue phenotypes. (demonstrated, patient fibroblasts — PMID: 40972577)
  9. The combined developmental perturbations manifest as the multi-system clinical syndrome (facial, neurological, cardiac, renal, ocular, genital). (inferred synthesis)
PACS1 c.607C>T (p.R203W)
│
▼
 Loss of FBR autoinhibition (R203 loop)
│
▼
 Aberrant interactions (↑HDAC6 binding)
     ┌──────────────┴──────────────┐
     ▼                              ▼
 Disrupted dynein/BICD2      Perturbed PACS1–WDR37
 cargo transport             complex
     └──────────────┬──────────────┘
            ▼
   Altered protein sorting/trafficking in development
     ┌──────────────┼──────────────┐
     ▼              ▼              ▼
 Neural-crest    Cortical       ECM dysregulation
 migration ↓     neuron         (↑COL8A1)
     │           activity ↓         │
     ▼              ▼              ▼
 Craniofacial   ID / ASD /     Tissue/structural
 gestalt        seizures       phenotypes
     └──────────────┴──────────────┘
            ▼
     Multi-system Schuurs-Hoeijmakers syndrome

Molecular pathways / cellular processes: Vesicle-mediated protein sorting (TGN/endosome), dynein-based intracellular transport, protein (de)acetylation via HDAC6, extracellular-matrix organization. Suggested GO: GO:0016192 (vesicle-mediated transport), GO:0030198 (ECM organization), GO:0070840 (dynein complex binding), GO:0006306 (DNA methylation). Suggested CL: CL:0000333 (migratory neural crest cell), CL:0000540 (neuron), CL:0000057 (fibroblast). Suggested CHEBI (therapeutics context): CHEBI:35623 (anticonvulsant).

7. Anatomical Structures Affected

  • Primary organ/system: Central nervous system — cerebral cortex and white matter (globally reduced gray/white matter volumes, PMID: 42392841); cerebellum (atrophy reported in the WDR37–PACS1–PACS2 spectrum, PMID: 33369122). UBERON: UBERON:0000955 (brain), UBERON:0000956 (cerebral cortex), UBERON:0002037 (cerebellum).
  • Craniofacial: Neural-crest-derived facial skeleton/cartilage. UBERON: UBERON:0001456 (face), cranial skeletal system.
  • Secondary organ involvement: Heart (congenital defects; UBERON:0000948), kidney (malformations; UBERON:0002113), eyes (coloboma, ptosis; UBERON:0000970), male genitalia (cryptorchidism; UBERON:0000473 testis), GI tract (reflux, feeding difficulty; UBERON:0001555).
  • Tissue/cell level: Nervous tissue (neurons), neural crest cells, connective tissue/fibroblasts (ECM). CL: CL:0000333, CL:0000540, CL:0000057.
  • Subcellular compartments: Trans-Golgi network, endosomes, cytosol, nucleus; cytoskeletal (dynein) transport machinery. GO CC: GO:0005802 (trans-Golgi network), GO:0005768 (endosome), GO:0005634 (nucleus), GO:0030286 (dynein complex).
  • Lateralization: Bilateral/symmetric for CNS and facial features; malformations variable.

8. Temporal Development

  • Onset: Congenital (malformations, dysmorphism) to infantile (hypotonia, feeding); developmental delay evident in early childhood.
  • Progression: Chronic, lifelong, predominantly stable/non-progressive; regression is uncommon (~5/158 patients across the axis) (PMID: 42794636).
  • Course pattern: Static encephalopathy with developmental delay; seizures episodic but generally well-controlled.
  • Critical period: Embryonic/fetal neurodevelopment and neural-crest migration is the key window of vulnerability; postnatally, early developmental intervention and the neonatal period (feeding, cardiac) are critical care windows.
  • Duration: Chronic lifelong.

9. Inheritance and Population

  • Epidemiology: Ultra-rare; ~87 cases by 2023, ~158 by 2026. Prevalence/incidence not formally established (well below 1/1,000,000).
  • Inheritance: Autosomal dominant, essentially always de novo (sporadic). Penetrance: Complete for the recurrent variant (facial gestalt 19/19). Expressivity: Variable (malformation burden, seizure presence).
  • Genetic anticipation: Not applicable (not a repeat-expansion disorder).
  • Germline mosaicism: Theoretically possible and relevant to recurrence-risk counseling (parental gonadal mosaicism), though empirical recurrence is very low; prenatal diagnosis has been performed (PMID: 37906144).
  • Founder effects / consanguinity / carrier frequency: Not applicable (de novo dominant).
  • Population demographics: Pan-ethnic — reported across Europe, India (PMID: 30690871), Morocco (PMID: 37747683), Brazil/Indigenous (PMID: 36415352), China (PMID: 37906144). No geographic clustering. Sex ratio: approximately equal (autosomal). Age distribution: Diagnosed in childhood; patients survive to adulthood.

10. Diagnostics

  • Genetic testing (definitive): Targeted single-gene/variant testing for PACS1 c.607C>T; whole-exome sequencing (WES) and whole-genome sequencing (WGS) are highly effective and often the route to diagnosis, including in prenatal settings where CNV analysis is negative (PMID: 37906144). NDD/ID gene panels include PACS1. CMA/karyotype are generally normal (useful to exclude structural causes; rare PACS1 deletions detectable).
  • Epigenomic diagnostics: Blood DNA-methylation episignature confirms PACS1-RD and reclassifies VUS/uncertain cases (e.g., one case initially suspected Kabuki) (PMID: 41882293).
  • Supportive clinical evaluations: Brain MRI (structural anomalies, reduced gray/white matter), EEG (seizures), echocardiography (cardiac defects), renal ultrasound, ophthalmologic exam (coloboma, ptosis).
  • Clinical recognition: The facial gestalt is highly recognizable; AI-based facial phenotyping supports the shared molecular axis and aids recognition (PMID: 40869285).
  • Differential diagnosis: Kabuki syndrome, Cornelia de Lange syndrome, and the phenotypically overlapping PACS2- and WDR37-related disorders (distinguished by gene, methylation signature, and specific features such as coloboma pattern) (PMID: 33369122, PMID: 42794636).
  • Screening: No newborn/carrier screening (de novo). Prenatal/exome testing applicable when fetal malformations are detected.

11. Outcome / Prognosis

  • Survival/mortality: Not a lethal disorder; mortality is not a defining feature and most patients reach adulthood. No established reduction in life expectancy; formal survival statistics are lacking given rarity.
  • Morbidity/function: Lifelong intellectual disability and developmental disability are the principal morbidities; motor impairment is pronounced; autonomy is the most compromised QoL domain (KidsLife QoLI 48.1 ± 28.3) (PMID: 41750059).
  • Disease course: Generally stable; regression uncommon but warrants surveillance (PMID: 42794636).
  • Complications: Seizures, feeding difficulty/failure to thrive, GERD, consequences of congenital cardiac/renal malformations. A single report described PAX3/7-FOXO1 fusion-negative alveolar rhabdomyosarcoma in an SHS patient, raising a speculative, unproven link between PACS1 (apoptosis regulation) and oncogenesis — "no previous reports describing malignancy associated with SHS" (PMID: 34341476); this is anecdotal and not an established feature.
  • Prognostic factors: Severity of malformations, seizure control, degree of developmental delay. No validated molecular prognostic biomarkers.

12. Treatment

No disease-modifying therapy currently exists; management is symptomatic and multidisciplinary.

  • Pharmacotherapy: Anticonvulsants for seizures (respond well, PMID: 26842493); symptom-directed medications (e.g., for reflux). NCIT: NCIT:C38148 (Anticonvulsant Agent).
  • Supportive/rehabilitative: Developmental, physical, occupational, and speech therapy; feeding support; management of congenital malformations. NCIT: NCIT:C15277 (Rehabilitation Therapy), NCIT:C53543 (Speech Therapy).
  • Surgical/interventional: As needed for congenital heart defects, cryptorchidism (orchidopexy), ocular anomalies, cleft lip (PMID: 30690871).
  • Experimental / advanced therapeutics: Allele-specific siRNA/RNAi silencing the mutant PACS1 transcript while sparing wild-type — corrected ECM/COL8A1 defects in patient fibroblasts, a proof-of-concept precision therapy (PMID: 40972577). Aberrant neuronal electrophysiology has been proposed as an interventional target (PMID: 38521709). NCIT: NCIT:C20151 (RNA Interference). No approved gene/cell therapies; no PACS1-specific pharmacogenomics.
  • Personalized medicine: The singular recurrent variant makes SHMS an ideal candidate for an allele-specific therapeutic; trial-readiness work emphasizes targeting core features (PMID: 34517877).

13. Prevention

  • Primary prevention: Not possible (sporadic de novo mutation); no risk-factor modification applies.
  • Secondary prevention: Early diagnosis (WES/WGS, episignature) enables early developmental intervention, seizure control, and malformation management.
  • Genetic counseling: De novo dominant; recurrence risk for parents is low but non-zero due to possible gonadal mosaicism; affected individuals have 50% transmission risk (reproduction uncommon given ID). Prenatal diagnosis is available for at-risk pregnancies and for fetal malformation workups (PMID: 37906144); preimplantation genetic testing is theoretically applicable.
  • Immunization / public health / behavioral / environmental interventions: Not applicable.
  • Tertiary prevention: Surveillance for seizures, feeding/growth, cardiac/renal complications, and (per systematic review) monitoring for any skill loss (PMID: 42794636).

14. Other Species / Natural Disease

  • Orthologs: PACS1 is conserved across vertebrates and invertebrates. NCBI Gene (human): 55690. Orthologs: mouse Pacs1 (Mus musculus, NCBI:txid10090), zebrafish pacs1 (Danio rerio, NCBI:txid7955), Drosophila melanogaster PACS (NCBI:txid7227), C. elegans pacs-1/cePACS-1 (NCBI:txid6239).
  • Natural disease in other species: No naturally occurring SHMS-equivalent disease documented in companion animals or wildlife (no OMIA entry identified); the condition is human and model-induced.
  • Comparative biology / conservation: The PACS–WDR37 axis is functionally conserved — human PACS1 complements C. elegans PACS-1 in neurons (PMID: 39031646); Drosophila PACS deficiency reproduces Golgi/trafficking and seizure-like phenotypes (PMID: 39999877).
  • Zoonotic potential / cross-species transmission: Not applicable (genetic disorder).

15. Model Organisms

Model Type Key phenotype recapitulated Reference
Zebrafish (pacs1 mRNA, R203W) Vertebrate, in vivo Reduced cranial cartilage; craniofacial anomalies via neural-crest migration; dominant-negative PMID: 36415352; founding 2012 study
iPSC-derived cortical organoids (p.R203W) Human in vitro Transcriptomic + proteomic dysregulation; neuronal activity/firing deficits; NDD/ASD gene convergence PMID: 38280846, PMID: 42835086
Patient fibroblasts (R203W) Human in vitro ECM dysregulation (↑COL8A1); corrected by allele-specific siRNA PMID: 40972577
Drosophila (PACS deficiency) Invertebrate Golgi disruption, cytokinesis failure, seizure-like phenotype PMID: 39999877
C. elegans (cePACS-1 variant knock-in) Invertebrate Aberrant protein localization in neurons; human PACS1 complements PMID: 39031646, PMID: 38712144
  • Genetic model types available: Knock-in missense (R203W) in zebrafish, iPSC (patient-derived and gene-edited isogenic), C. elegans CRISPR knock-in; no widely reported germline mouse model of R203W to date (knowledge gap).
  • Phenotype recapitulation: Strong for craniofacial (zebrafish), neuronal activity (organoids), and trafficking/seizure (invertebrates); ECM defects captured in fibroblasts.
  • Limitations: Invertebrate models lack the full mammalian facial/organ phenotype; organoids lack whole-organism circuitry; no established mammalian in-vivo model recapitulating the complete syndrome.
  • Resources: ZFIN (zebrafish), WormBase/FlyBase (invertebrates), Cellosaurus/patient iPSC lines; Alliance of Genome Resources for orthology.

Mechanistic Model / Interpretation

The unifying model is that a single codon change converts PACS1 from a tightly autoregulated sorting adaptor into a dysregulated interaction hub. Arg203 sits in a positively charged loop that, in the wild-type protein, is kept autoinhibited by the central unstructured region. The R203W substitution breaks this intramolecular "lock," freeing the furin-binding region to engage partners it should not (prominently HDAC6) and to destabilize partners it should support (WDR37). Because PACS1 is a trafficking adaptor coupled to the dynein/BICD2 motor system, the net result is misdirected cargo transport and sorting at a cell-biological level.

This single lesion fans out across developmental contexts. In migrating cranial neural crest cells, it impairs the morphogenetic movements that build the facial skeleton — explaining the pathognomonic, fully penetrant gestalt. In developing cortical neurons, it reshapes the transcriptome and proteome and dampens neuronal firing — explaining intellectual disability, autistic traits, reduced brain volumes, and seizure propensity. In connective tissue/fibroblasts, it dysregulates extracellular-matrix genes such as COL8A1. The dominant-negative/gain-of-function nature (not haploinsufficiency) is supported by the extreme variant recurrence, the zebrafish dominant-negative craniofacial result, and the in-vitro demonstration of acquired aberrant interactions.

Two features make SHMS exceptionally tractable for precision medicine: (1) the disease is molecularly homogeneous (one variant explains nearly all cases), and (2) the mutant allele's product is the active toxic species. Allele-specific RNAi exploits both — knocking down only the mutant transcript reversed the ECM phenotype in patient cells, a rare "druggable" opportunity in a monogenic NDD. The blood methylation episignature adds a reliable, variant-agnostic diagnostic and potential pharmacodynamic biomarker.

Evidence Base

PMID Role in this report Evidence type
26842493 Defining 19-patient cohort; recurrent variant; facial gestalt and malformation frequencies Human clinical
23159249 Founding 2012 discovery; neural-crest-migration mechanism (not re-verified this session) Human + zebrafish
41858172 Structural basis: R203W disrupts intramolecular autoregulation; FBR–HDAC6 In vitro/NMR
42304662 Commentary framing the autoregulatory mechanism Review
41888583 Dynein/BICD2 cargo-transport disruption via HDAC6 In vitro
41279321 Cryo-EM PACS1–WDR37 complex; FBR interface Structural
38280846 iPSC organoids: neuronal activity/transcriptional deficits In vitro
42835086 Organoid proteomic landscape changes In vitro
38521709 Neuronal firing as interventional target Review/commentary
40972577 ECM/COL8A1 defect; allele-specific siRNA correction In vitro
36415352 Zebrafish dominant-negative craniofacial model Model organism
41882293 DNA-methylation episignature; updated phenotype frequencies Human/epigenomic
34517877 Severity characterization; trial readiness Human clinical
37747683 ~87 cases; majority share recurrent variant Human clinical
42794636 ~158 patients; skill-loss systematic review (non-regressive) Review
41750059 Quality-of-life quantification (KidsLife) Human clinical
39999877 Drosophila Golgi/seizure phenotype Model organism
39031646 / 38712144 C. elegans model; human PACS1 complementation Model organism
42392841 Longitudinal multimodal characterization; MRI volume loss; autistic traits Human clinical
33369122 WDR37–PACS1–PACS2 axis; coloboma; differential dx Human clinical/review
30690871 Indian patient; cleft lip; pan-ethnic occurrence Human clinical
37906144 Prenatal diagnosis via WES Human clinical
40869285 AI facial phenotyping; shared molecular axis Computational
34341476 Single rhabdomyosarcoma case (speculative oncogenesis link) Human case report
34373684 Multi-exon PACS1 deletion (rare structural variant) Human case report

Citation caveat: For PMID: 38280846 and PMID: 41888583, supporting text was drawn from the title/knowledge snippet (flagged as "mismatch" during verification), so quoted phrasing should be treated as paraphrase pending direct abstract confirmation. PMID: 23159249 (founding paper) was not retrievable through the PubMed interface in this session.

Limitations and Knowledge Gaps

  1. No germline mammalian (mouse) model of R203W is established in the reviewed literature, limiting in-vivo study of the full syndrome and preclinical therapeutic testing.
  2. Formal epidemiology is absent — prevalence/incidence are unknown; case counts (~158 by 2026) reflect ascertainment, not true frequency.
  3. Mechanistic completeness: The HDAC6/dynein/WDR37 and ECM findings are largely in vitro/single-model; how each contributes quantitatively to specific clinical features is not resolved, and the causal link to skill loss is explicitly unproven (PMID: 42794636).
  4. Genotype–phenotype for rare alleles (R203Q, R315W, deletions) is based on few patients; expressivity determinants are unknown.
  5. The malignancy association (rhabdomyosarcoma) rests on a single case and is not an established feature (PMID: 34341476).
  6. Therapy is pre-clinical: allele-specific siRNA is proof-of-concept in fibroblasts only — no in-vivo efficacy, delivery (especially CNS), or safety data yet.
  7. Two key citations (neuronal-activity iPSC paper, founding 2012 paper) were not fully re-verified against stored abstracts in this session.

Proposed Follow-up Experiments / Actions

  1. Generate a knock-in mouse model (Pacs1 R203W) to recapitulate craniofacial, neurological, cardiac, and renal phenotypes and to serve as a preclinical platform.
  2. Advance allele-specific RNAi/ASO toward the clinic: optimize mutant-selective sequences, test CNS-penetrant delivery (e.g., intrathecal), and establish efficacy and safety in iPSC-neurons and animal models; use the methylation episignature and ECM/neuronal-activity readouts as pharmacodynamic biomarkers.
  3. Build a prospective natural-history registry with standardized longitudinal phenotyping (development, behavior, MRI, seizures, growth) to define progression, QoL trajectories, and surveillance protocols — directly supporting trial readiness.
  4. Dissect mechanism contributions: use isogenic iPSC lines and targeted perturbation (HDAC6 inhibition, BICD2/dynein manipulation, WDR37 modulation) to apportion phenotype to each downstream branch; test HDAC6 inhibitors as a repurposing candidate.
  5. Deepen genotype–phenotype analysis of rare alleles (R203Q, structural variants) and define expressivity modifiers via multi-omics across larger cohorts.
  6. Validate the methylation episignature as a clinical diagnostic and a treatment-response biomarker across laboratories.
  7. Re-verify flagged citations (PMID 23159249, 38280846, 41888583) against primary abstracts before knowledge-base ingestion.

Report compiled from 8 confirmed findings and 29 reviewed papers across 5 investigation iterations. Evidence sources span human clinical cohorts, structural biology, iPSC/organoid and fibroblast in-vitro models, and zebrafish/Drosophila/C. elegans model organisms.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome Count
References checked 26
Resolved 26
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 26
On topic 23
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 47
Resolved 44
Unresolved (possible confabulation) 1
Obsolete 1
Unverifiable 1
Terms whose name was checked 28
Terms named correctly 15
Terms named as a different term 10
Terms whose name is worth a second look 3

Terms the report names something else

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

  • HP:0000316 (1 mention) - the report calls it "common"; HP calls it Hypertelorism
  • HP:0000494 (1 mention) - the report calls it "common"; HP calls it Downslanted palpebral fissures
  • HP:0000508 (1 mention) - the report calls it "common"; HP calls it Ptosis
  • HP:0000729 (1 mention) - the report calls it "frequent"; HP calls it Autistic behavior
  • HP:0000028 (1 mention) - the report calls it "6/12 males (~50–78%)"; HP calls it Cryptorchidism
  • HP:0000699 (1 mention) - the report calls it "common"; HP calls it Diastema
  • NCIT:C20151 (2 mentions) - the report calls it "RNA interference", "RNA Interference"; NCIT calls it Inflammatory Response
  • NCIT:C15277 (2 mentions) - the report calls it "Rehabilitation Therapy"; NCIT calls it Mastectomy
  • NCIT:C38148 (2 mentions) - the report calls it "Anticonvulsant Agent"; NCIT calls it Yes, No, or Unknown Response
  • NCIT:C53543 (1 mention) - the report calls it "Speech Therapy"; NCIT calls it Rare Non-Neoplastic Disorder

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0000792 (1 mention) - HP does not contain this term

Obsolete terms

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

  • GO:0006306 (obsolete DNA methylation) (2 mentions)

Terms whose name is worth a second look

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

  • GO:0030198 (2 mentions) - the report calls it "extracellular matrix organization", "ECM organization"; GO calls it extracellular matrix organization
  • NCIT:C15688 (1 mention) - the report calls it "Pharmacotherapy"; NCIT calls it Maintenance Therapy
  • GO:0006306 (2 mentions) - the report calls it "DNA methylation"; GO calls it obsolete DNA methylation

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • GO:0030198 - called "extracellular matrix organization", "ECM organization"
  • NCIT:C20151 - called "RNA interference", "RNA Interference"