Neurooculocardiogenitourinary Syndrome

Mendelian MONDO:0032850 Pathograph 41 Show in embeddings browser Autosomal dominant syndromic intellectual disability

Neurooculocardiogenitourinary syndrome (NOCGUS, OMIM 618652) is an autosomal dominant multisystem developmental disorder caused by heterozygous, almost always de novo, variants in WDR37, which encodes a WD40-repeat protein of unknown function. It was delineated in 2019 by two independent groups. The original variants are missense changes clustered in a short conserved stretch upstream of the first WD40 repeat (p.Thr115 to p.Thr130); a second cluster in and between the second and third WD40 repeats and one intronic splice variant were reported later. Presentation is neonatal or infantile. The core is neurological (seizures, usually severe developmental delay and intellectual disability, often absent speech, cerebellar hypoplasia and other structural brain anomalies) together with structural eye anomalies (coloboma, microphthalmia, microcornea, Peters anomaly) and facial dysmorphism that has been compared with CHARGE syndrome. Congenital heart defects, genitourinary and renal anomalies, skeletal (mostly spinal) anomalies, sensorineural hearing loss, feeding difficulties and poor postnatal growth are variable; one individual in a founding series died in infancy, while a later series describes milder developmental delay. WDR37 binds the paralogous sorting proteins PACS1 and PACS2, whose own de novo missense disorders (Schuurs-Hoeijmakers syndrome and DEE66) overlap clinically with NOCGUS. How the variants act is not settled: a dominant-negative mechanism has been proposed from zebrafish and cell data and is ClinGen's reading, Orphanet annotates the association as loss of function, and the main functional study states that the mechanism has not been established.

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Inheritance

1
Autosomal Dominant HP:0000006
Heterozygous variants, de novo in every individual with a pathogenic or likely pathogenic call. One inherited variant, from an unaffected mother, was classified as of uncertain significance by the reporting group.
Autosomal dominant inheritance
Show evidence (2 references)
CGGV:assertion_f3eaff9e-978b-47a6-ad55-88edabc62064-2024-10-18T160000.000Z SUPPORT Other
"WDR37 was first reported in relation to autosomal dominant neurooculocardiogenitourinary syndrome (NOCGUS) in 2019"
ClinGen records the disorder as autosomal dominant.
PMID:34642815 SUPPORT Human clinical
"The de novo variants identified in individuals 1 and 2 meet ACMG/AMP criteria to be considered likely pathogenic, but the significance of the inherited variant identified in Individual 3 is uncertain."
The one inherited variant reported is of uncertain significance; the pathogenic calls are de novo.
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Mechanistic Hypotheses

1
WDR37 variants act through the WDR37-PACS1-PACS2 complex
pacs_complex_dysfunction EMERGING
Evidence balance 1 support
The clinical overlap with the PACS1 and PACS2 disorders and the mutual stabilisation of WDR37 and PACS1 suggest the variants act by disturbing the complex, possibly including its control of ER calcium release. Against a simple version of this, most tested WDR37 variants bind PACS1 and PACS2 normally. Edges that depend on this hypothesis carry hypothesis_groups: [pacs_complex_dysfunction].
Pathograph links
Abnormal WDR37 Protein Function -> Altered WDR37-PACS1-PACS2 Complex Function UNKNOWN Hypothesis. Most tested variants still bind PACS1 and PACS2 normally, so a defect at the level of the complex, if there is one, is not loss of binding.
Altered WDR37-PACS1-PACS2 Complex Function -> Impaired ER Calcium Release UNKNOWN Shown only for deletion of Pacs1 or Wdr37 in mouse lymphocytes, not for a NOCGUS variant or in neural cells.
Show evidence (1 reference)
PMID:34642815 SUPPORT Human clinical
"The strong degree of phenotypic overlap as well as consistent evidence of interaction between WDR37 and PACS1/2 suggests that WDR37 may also be involved in protein transport and that the identified missense variants in these proteins disrupt their function through a dominant negative mechanism."
The authors' proposal linking the WDR37 disorder to PACS-mediated transport.
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Discussions and Knowledge Gaps

2
Do NOCGUS variants act by a dominant-negative effect, by loss of function, or by some other route, and do the N-terminal and C-terminal clusters act the same way?
CONTROVERSY OPEN nocgus_variant_mechanism
Attached to
pathophysiology#Abnormal WDR37 Protein Function genetic#WDR37
The sources disagree. ClinGen reads the functional data as consistent with a dominant-negative mechanism, which rests on the zebrafish contrast between lethal heterozygous missense alleles and viable heterozygous frameshift alleles and on preserved dimerization of variant proteins. Orphanet annotates the gene association as loss of function, and the fly rescue experiment shows the patient alleles have lost function. The 2021 functional study states the mechanism has not been established. The two clusters also behave differently in cells: N-terminal variant proteins are expressed normally and C-terminal variant proteins at reduced levels. No truncating allele has been reported as causal.
Show evidence (3 references)
PMID:34642815 SUPPORT In vitro / ex vivo
"Although a dominant negative effect for the previously reported missense alleles has been suggested ( Kanca et al. 2019 ; Reis et al. 2019 ), the mechanism of action has not been established for either the previously reported or the novel variants reported here."
The primary functional study leaves the mechanism open.
CGGV:assertion_f3eaff9e-978b-47a6-ad55-88edabc62064-2024-10-18T160000.000Z SUPPORT Other
"Functional studies are consistent with a dominant-negative mechanism of disease predominantly due to missense variants."
ClinGen's reading of the functional data.
ORPHA:684305 SUPPORT Other
"WDR37 | WD repeat domain 37 | hgnc:31406 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet's gene-association qualifier, which differs from ClinGen's.
Does a NOCGUS variant disturb PACS1 or PACS2 function, ER calcium handling or protein trafficking in neural or developing ocular cells?
KNOWLEDGE GAP OPEN nocgus_pacs_axis_mechanism
Attached to
pathophysiology#Altered WDR37-PACS1-PACS2 Complex Function pathophysiology#Impaired ER Calcium Release
The WDR37-PACS1 complex and its role in ER calcium release are shown with null alleles, in mouse lymphocytes and in C. elegans. No experiment cited here has put a NOCGUS variant into neurons or eye tissue and measured these processes, and no vertebrate knock-in of a human variant has been characterised for the eye, brain and heart malformations. Until then the mechanism nodes between the variant and the malformations are inferred.
Show evidence (1 reference)
PMID:34642815 SUPPORT In vitro / ex vivo
"Further work is needed to determine the role of PACS binding in the normal function of WDR37 and the mechanism of action for various pathogenic variants in WDR37."
The functional study names this as the open question.
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Pathophysiology

8
De Novo Heterozygous WDR37 Variant
The initiating lesion is a heterozygous WDR37 variant, arising de novo in every individual reported with a pathogenic or likely pathogenic call. The founding missense variants (p.Thr115Ile, p.Ser119Phe, p.Ser119Tyr, p.Thr125Ile, p.Ser129Cys, p.Thr130Ile) cluster upstream of the first WD40 repeat. A second cluster lies in or just after the second WD40 repeat (p.Asp220Gly and p.Asp260Asn de novo; p.Pro257His inherited from an unaffected mother and of uncertain significance). One de novo intronic deletion (c.727-27_727-24del) causes retention of 63 intronic bases and an in-frame insertion of 21 amino acids. No truncating variant has been reported as causal.
WDR37 hgnc:31406 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves WDR37 (hgnc:31406). hgnc:31406 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: DE_NOVO zygosity: HETEROZYGOUS
Downstream
Abnormal WDR37 Protein Function The variant protein is made and correctly localized but fails to perform the function the wild-type protein provides in the fly rescue assay.
Show evidence (5 references)
PMID:31327510 SUPPORT Human clinical
"we have discovered four de novo missense variants predicted to affect the N-terminal region of WDR37-p.Ser119Phe, p.Thr125Ile, p.Ser129Cys, and p.Thr130Ile-in unrelated individuals with a previously unrecognized syndrome"
Founding report of the clustered N-terminal de novo missense variants.
PMID:31327508 SUPPORT Human clinical
"Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats."
Independent founding cohort with de novo variants clustered outside the WD40 repeats.
PMID:32530092 SUPPORT Human clinical
"The variants fall within a highly conserved region upstream of the WD-repeat domains, within an apparent mutation cluster."
Two further de novo variants in the same N-terminal cluster.
+ 2 more references
Abnormal WDR37 Protein Function
The variant proteins reach the cytoplasm and still dimerize with wild-type WDR37. The N-terminal variants are expressed at levels similar to wild type, while the C-terminal variants are expressed at lower levels. Two human variants fail to rescue the Drosophila wdr37 null, so they impair function. In zebrafish, heterozygous missense alleles were lethal to larvae while heterozygous frameshift alleles were not, which suggested a dominant negative effect. Whether that is the mechanism in patients is open (see the discussion on variant mechanism). The only molecular activities shown for WDR37 are homodimerization and binding to PACS1 and PACS2; the homodimerization term is bound without a modifier because variant proteins still dimerize with wild type, so it names the activity, not a defect in it.
WDR37 variants act through the WDR37-PACS1-PACS2 complex
WDR37 hgnc:31406 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves WDR37 (hgnc:31406). hgnc:31406 is a gene from the HUGO Gene Nomenclature Committee.
WDR37 homodimerization GO:0042803 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves WDR37 homodimerization, annotated with protein homodimerization activity (GO:0042803). GO:0042803 is a molecular function from the Gene Ontology.
Downstream
Impaired Ocular Morphogenesis Inferred. WDR37 variants and the variants of its PACS partners share coloboma, which has been read as a role for the axis in eye development; no study has followed a WDR37 variant into a developing eye.
Impaired Embryonic Development of Multiple Organs Heterozygous missense wdr37 alleles impair growth and survival of zebrafish larvae; the organ-level steps between the protein defect and the human malformations are not known.
Neuronal Dysfunction Loss of the single fly ortholog causes a seizure-associated phenotype that human WDR37 rescues and the patient alleles do not.
Upregulated Cholesterol Biosynthesis Gene Expression Transcriptomic finding in zebrafish embryos carrying a missense allele; its relation to the human phenotype is unknown.
Altered WDR37-PACS1-PACS2 Complex Function Hypothesis. Most tested variants still bind PACS1 and PACS2 normally, so a defect at the level of the complex, if there is one, is not loss of binding. WDR37 variants act through the WDR37-PACS1-PACS2 complex
Show evidence (5 references)
PMID:31327508 SUPPORT Model organism
"The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein."
Patient alleles fail to complement the fly null, showing the variant proteins are functionally impaired.
PMID:31327510 SUPPORT In vitro / ex vivo
"Immunocytochemistry and western blot studies showed that wild-type WDR37 is localized predominantly in the cytoplasm and mutant proteins demonstrate similar protein levels and localization."
The N-terminal variant proteins are stable and correctly localized, so the defect is not simple loss of the protein.
PMID:34642815 SUPPORT In vitro / ex vivo
"The three novel mutants showed normal cellular localization but lower expression levels in comparison to wild-type WDR37."
The C-terminal variant proteins localize normally but are expressed at lower levels.
+ 2 more references
Altered WDR37-PACS1-PACS2 Complex Function
Hypothesis node. WDR37's main binding partners are the phosphofurin acidic cluster sorting proteins PACS1 and PACS2, and WDR37 and PACS1 depend on each other for stable expression in cultured cells and in C. elegans. Of the seven WDR37 variants tested for binding, only p.Asp220Gly lost binding to PACS1 and PACS2. So the shared biology of the three disorders points at this complex, but no study has shown that a NOCGUS variant impairs complex function.
WDR37 variants act through the WDR37-PACS1-PACS2 complex
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. PACS2 hgnc:23794 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PACS2 (hgnc:23794). hgnc:23794 is a gene from the HUGO Gene Nomenclature Committee.
intracellular protein transport GO:0006886 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal intracellular protein transport (GO:0006886). GO:0006886 is a biological process from the Gene Ontology.
Downstream
Impaired ER Calcium Release Shown only for deletion of Pacs1 or Wdr37 in mouse lymphocytes, not for a NOCGUS variant or in neural cells. WDR37 variants act through the WDR37-PACS1-PACS2 complex
Show evidence (4 references)
PMID:34642815 SUPPORT In vitro / ex vivo
"This revealed the ability of WDR37 to form homodimers and to strongly bind PACS1 and PACS2 phosphofurin acidic cluster sorting proteins; immunocytochemistry confirmed colocalization of WDR37 with PACS1 and PACS2 in human cells."
Establishes PACS1 and PACS2 as the major binding partners of WDR37.
PMID:34642815 REFUTE In vitro / ex vivo
"Interaction with wild-type WDR37 was not affected for any variant; however, one novel mutant, p.(Asp220Gly), lost its ability to bind PACS1 and PACS2."
Cuts against loss of PACS binding as a general mechanism: the other variants tested, including all four founding N-terminal variants, bound PACS1 and PACS2 normally.
PMID:41279321 SUPPORT In vitro / ex vivo
"This interaction stabilizes Wdr37 and is critical for the expression of both proteins."
Cryo-EM and biochemical study (a bioRxiv preprint indexed in PubMed) showing that the Pacs1-Wdr37 interaction is needed for both proteins' expression.
+ 1 more reference
Impaired ER Calcium Release
Mouse finding. In lymphocytes, Pacs1 and Wdr37 are needed for normal release of calcium from the endoplasmic reticulum after antigen receptor stimulation. No immune phenotype has been reported in NOCGUS, and ER calcium handling has not been measured in patient cells or in neurons carrying a NOCGUS variant, so this node is a lead for the mechanism, not part of the established chain.
lymphocyte CL:0000542 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves lymphocyte (CL:0000542). CL:0000542 is a cell type from the Cell Ontology.
endoplasmic reticulum calcium ion homeostasis GO:0032469 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal endoplasmic reticulum calcium ion homeostasis (GO:0032469). GO:0032469 is a biological process from the Gene Ontology.
Animal models
Mouse Wdr37 or Pacs1 deletion Mouse perturbs Shows that the Pacs1-Wdr37 complex is needed for ER calcium handling in lymphocytes.
Show evidence (1 reference)
PMID:33630350 SUPPORT Model organism
"Through forward genetic screening in mice, we identified two members of a new complex, Pacs1 and Wdr37, which are required for normal ER Ca2+ handling in lymphocytes."
Mouse genetics showing that the Pacs1-Wdr37 complex is required for ER calcium handling in lymphocytes.
Upregulated Cholesterol Biosynthesis Gene Expression
RNA-seq of zebrafish embryos carrying a heterozygous wdr37 missense allele showed upregulation of cholesterol biosynthesis pathways. It has not been examined in patients and its place in the mechanism is unknown.
cholesterol biosynthetic process GO:0006695 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cholesterol biosynthetic process (GO:0006695). GO:0006695 is a biological process from the Gene Ontology.
Animal models
Zebrafish wdr37 CRISPR missense and frameshift alleles Zebrafish measures RNA-seq of missense embryos.
Show evidence (1 reference)
PMID:31327510 SUPPORT Model organism
"RNA-seq analysis of zebrafish embryos carrying a missense variant detected significant upregulation of cholesterol biosynthesis pathways."
Transcriptomic finding in the zebrafish missense model.
Impaired Ocular Morphogenesis
Structural eye anomalies are the most consistent malformations: coloboma of the iris and retina, microphthalmia, microcornea, Peters anomaly and other anterior segment dysgenesis, and optic nerve hypoplasia, present from birth. The developmental step that WDR37 variants disturb has not been studied; the link is drawn from the congenital nature of the findings and the shared ocular phenotype of the WDR37, PACS1 and PACS2 disorders.
camera-type eye development GO:0043010 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal camera-type eye development (GO:0043010). GO:0043010 is a biological process from the Gene Ontology.
Downstream
Coloboma
Microphthalmia
Microcornea
Peters Anomaly
Ocular Anterior Segment Dysgenesis
Optic Nerve Hypoplasia
Cataract
Show evidence (2 references)
PMID:37064331 SUPPORT Human clinical
"This supports the previous statement that the so-called WDR37-PACS1-PACS2 axis might have an important role in ocular development"
Review of ocular findings across the three disorders, concluding the axis acts in eye development.
PMID:42546896 SUPPORT Human clinical
"Ocular findings identified at birth included bilateral microphthalmia, microcornea, corneal edema, marked anterior segment dysgenesis, and bilateral colobomatous posterior pole abnormalities."
The ocular malformations are present at birth, consistent with a defect of eye development.
Impaired Embryonic Development of Multiple Organs
The non-ocular malformations (cerebellar and other brain anomalies, septal and complex heart defects, renal dysplasia and cystic kidneys, other genitourinary anomalies, anal atresia, spinal anomalies, dysmorphic facial features) are congenital, and heterozygous missense wdr37 alleles impair growth and survival of zebrafish larvae. This node records that the variants disturb embryonic development; the organ-specific mechanisms are not known, and the edges from it to the individual malformations are inferred from their congenital nature rather than demonstrated.
embryo development GO:0009790 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal embryo development (GO:0009790). GO:0009790 is a biological process from the Gene Ontology.
Animal models
Zebrafish wdr37 CRISPR missense and frameshift alleles Zebrafish partially recapitulates Heterozygous missense alleles, as in patients, disturb vertebrate development where frameshift alleles do not.
Downstream
Cerebellar Hypoplasia
Cerebellar Vermis Anomaly
Microcephaly
Congenital Heart Defect
Renal Dysplasia
Polycystic Kidney Dysplasia
Genitourinary Anomalies
Anal Atresia
Scoliosis
Facial Dysmorphism
Tapered Fingers
Postnatal Growth Retardation
Short Stature
Corpus Callosum Anomaly
Atrial Septal Defect
Ventricular Septal Defect
Single Transverse Palmar Crease
Show evidence (2 references)
PMID:31327510 SUPPORT Model organism
"This study identifies variants in WDR37 associated with human disease and provides insight into its essential role in vertebrate development and possible molecular functions."
The zebrafish work places WDR37 in vertebrate development.
PMID:42546896 SUPPORT Human clinical
"The patient also had multiple systemic anomalies, including complex congenital heart disease, renal dysplasia, skeletal abnormalities, and cerebellar malformation."
Multiple congenital organ malformations in a neonate with a de novo WDR37 variant.
Neuronal Dysfunction
Seizures, developmental delay, intellectual disability and absent speech point to a defect of neuronal function in addition to the structural brain anomalies. The direct evidence is from Drosophila: the wdr37 null is bang-sensitive, a seizure-associated phenotype, and loses grip strength; human WDR37 rescues these phenotypes and two patient alleles do not. The neuronal process involved has not been identified.
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.
Animal models
Drosophila wdr37 (CG12333) null Fruit fly partially recapitulates A seizure-associated behavioural phenotype that patient alleles fail to rescue, linking the human variants to loss of a conserved neuronal function.
Downstream
Seizures
Intellectual Disability
Global Developmental Delay
Absent Speech
Show evidence (1 reference)
PMID:31327508 SUPPORT Model organism
"These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA."
Human WDR37 restores the neurological fly phenotypes, so they reflect loss of conserved WDR37 function.
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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 Neurooculocardiogenitourinary 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 Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart defect, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:32530092 SUPPORT Human clinical
"Consistent with the literature, intellectual disability, structural eye disorders, epilepsy, congenital heart disease, genitorenal anomalies and dysmorphic facial features were observed."
Congenital heart disease is part of the recognised spectrum.
PMID:34642815 SUPPORT Human clinical
"Individual 2 is a 15-year-old White (US) female born at term with multiple congenital anomalies including Dandy–Walker anomaly, thinning of the corpus callosum, atrial and ventricular septal defects, dysplastic right kidney"
Atrial and ventricular septal defects in an individual with a de novo variant.
PMID:42546896 SUPPORT Human clinical
"The patient also had multiple systemic anomalies, including complex congenital heart disease, renal dysplasia, skeletal abnormalities, and cerebellar malformation."
Complex congenital heart disease in a severely affected neonate.
Atrial Septal Defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34642815 SUPPORT Human clinical
"Individual 2 is a 15-year-old White (US) female born at term with multiple congenital anomalies including Dandy–Walker anomaly, thinning of the corpus callosum, atrial and ventricular septal defects, dysplastic right kidney"
Atrial septal defect in an individual with a de novo variant.
Ventricular Septal Defect HP:0001629 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular septal defect (HP:0001629). HP:0001629 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34642815 SUPPORT Human clinical
"Individual 2 is a 15-year-old White (US) female born at term with multiple congenital anomalies including Dandy–Walker anomaly, thinning of the corpus callosum, atrial and ventricular septal defects, dysplastic right kidney"
Ventricular septal defect in an individual with a de novo variant.
Digestive 2
Anal Atresia HP:0002023 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anal atresia (HP:0002023). HP:0002023 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38044197 SUPPORT Human clinical
"The patient had novel phenotypes, anal atresia, and polycystic kidney, in addition to intellectual disability, seizures, cerebellar vermian anomaly, and coloboma, which are typical in NOCGUS."
Anal atresia in the splice-variant case.
Feeding Difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor feeding, annotated with Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31327510 SUPPORT Human clinical
"significant neurological impairment with structural brain defects and seizures; poor feeding; poor post-natal growth"
Poor feeding in the founding series.
Ear 1
Sensorineural Hearing Impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34642815 SUPPORT Human clinical
"She has severe congenital sensorineural hearing loss of the left ear and auditory neuropathy spectrum disorder in the right ear."
Congenital sensorineural hearing loss in an individual with a de novo variant.
Eye 8
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 (3 references)
PMID:32530092 SUPPORT Human clinical
"All had a clinical phenotype consisting of bilateral iris and retinal coloboma, developmental delay and additional, variable multisystem features."
Bilateral iris and retinal coloboma in all three individuals of this series.
PMID:31327508 SUPPORT Human clinical
"The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia."
Colobomas are a shared feature of the founding cohort.
PMID:34642815 SUPPORT Human clinical
"Overall, the ocular anomalies are milder in this cohort (no coloboma or microphthalmia)"
Coloboma was not seen with the C-terminal cluster variants, so it is not universal.
Microphthalmia HP:0000568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microphthalmia (HP:0000568). HP:0000568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42546896 SUPPORT Human clinical
"Ocular findings identified at birth included bilateral microphthalmia, microcornea, corneal edema, marked anterior segment dysgenesis, and bilateral colobomatous posterior pole abnormalities."
Bilateral microphthalmia identified at birth.
Microcornea HP:0000482 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcornea (HP:0000482). HP:0000482 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31327510 SUPPORT Human clinical
"ocular anomalies such as corneal opacity/Peters anomaly, coloboma, and microcornea"
Microcornea is among the ocular anomalies of the founding series.
Peters Anomaly HP:0000659 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peters anomaly (HP:0000659). HP:0000659 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31327510 SUPPORT Human clinical
"ocular anomalies such as corneal opacity/Peters anomaly, coloboma, and microcornea"
Corneal opacity/Peters anomaly in the founding series.
PMID:37064331 SUPPORT Human clinical
"microphthalmia, microcornea, and Peters anomaly are found only among individuals with PACS1-related NDD and WDR37 syndrome, being more severe in the latter"
Review across the three related disorders; these anterior segment findings are more severe in WDR37 syndrome.
Ocular Anterior Segment Dysgenesis HP:0007700 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ocular anterior segment dysgenesis (HP:0007700). HP:0007700 is a phenotype from the Human Phenotype Ontology.
Sequelae: Glaucoma
Show evidence (2 references)
PMID:42546896 SUPPORT Human clinical
"Ocular findings identified at birth included bilateral microphthalmia, microcornea, corneal edema, marked anterior segment dysgenesis, and bilateral colobomatous posterior pole abnormalities."
Marked anterior segment dysgenesis identified at birth.
PMID:38044197 SUPPORT Human clinical
"left anterior segment dysgenesis (Peters’ anomaly and sclerocornea) with secondary glaucoma"
Unilateral anterior segment dysgenesis in the splice-variant case.
Glaucoma HP:0000501 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Glaucoma (HP:0000501). HP:0000501 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:38044197 SUPPORT Human clinical
"left anterior segment dysgenesis (Peters’ anomaly and sclerocornea) with secondary glaucoma"
Secondary glaucoma in the splice-variant case.
PMID:34642815 SUPPORT Human clinical
"PA, COL, MI, GL, CAT | PA, MI, COL, RET, ONH"
Ocular-features row of Table 1. The first cell is Reis 1 (de novo p.Ser119Phe), whose findings include GL (glaucoma) and CAT (cataract).
PMID:34642815 SUPPORT Human clinical
"COL, CAT | CO, MI, GL, ONH aphakia"
Ocular-features row of Table 1. The second cell is Kanca 5 (de novo p.Thr130Ile), whose findings include GL (glaucoma).
+ 1 more reference
Cataract HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:34642815 SUPPORT Human clinical
"PA, COL, MI, GL, CAT | PA, MI, COL, RET, ONH"
Ocular-features row of Table 1. The first cell is Reis 1 (de novo p.Ser119Phe), whose findings include CAT (cataract).
PMID:34642815 SUPPORT Human clinical
"COL, CAT | CO, MI, GL, ONH aphakia"
Ocular-features row of Table 1. The first cell is Kanca 4 (de novo p.Ser129Cys), whose findings include CAT (cataract).
PMID:34642815 SUPPORT Human clinical
"U unknown, CAT cataract, COL coloboma, GL glaucoma"
Table 1 legend defining the CAT abbreviation.
Optic Nerve Hypoplasia HP:0000609 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic nerve hypoplasia (HP:0000609). HP:0000609 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34642815 SUPPORT Human clinical
"his microcephaly, optic nerve hypoplasia, mildly short stature, and feeding disorder are consistent with WDR37 syndrome"
Optic nerve hypoplasia listed among features consistent with the syndrome.
Genitourinary 3
Renal Dysplasia HP:0000110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal dysplasia (HP:0000110). HP:0000110 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42546896 SUPPORT Human clinical
"The patient also had multiple systemic anomalies, including complex congenital heart disease, renal dysplasia, skeletal abnormalities, and cerebellar malformation."
Renal dysplasia in a neonate with a de novo WDR37 variant.
PMID:34642815 SUPPORT Human clinical
"Individual 2 is a 15-year-old White (US) female born at term with multiple congenital anomalies including Dandy–Walker anomaly, thinning of the corpus callosum, atrial and ventricular septal defects, dysplastic right kidney"
Dysplastic kidney in an individual with a de novo C-terminal variant.
Polycystic Kidney Dysplasia HP:0000113 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polycystic kidney, annotated with Polycystic kidney dysplasia (HP:0000113). HP:0000113 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38044197 SUPPORT Human clinical
"The patient had novel phenotypes, anal atresia, and polycystic kidney, in addition to intellectual disability, seizures, cerebellar vermian anomaly, and coloboma, which are typical in NOCGUS."
Polycystic kidney in the splice-variant case.
PMID:38044197 SUPPORT Human clinical
"At 31 weeks of gestation, ultrasonography had revealed a polycystic kidney and enlarged lateral ventricles of the brain."
Prenatal detection of the kidney anomaly.
Genitourinary Anomalies Abnormality of the genitourinary system HP:0000119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Genitourinary anomaly, annotated with Abnormality of the genitourinary system (HP:0000119). HP:0000119 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (2 references)
PMID:31327510 SUPPORT Human clinical
"poor post-natal growth; variable skeletal, cardiac, and genitourinary defects; and death in infancy in one individual"
Genitourinary defects in the founding series, not further specified.
PMID:32530092 SUPPORT Human clinical
"Consistent with the literature, intellectual disability, structural eye disorders, epilepsy, congenital heart disease, genitorenal anomalies and dysmorphic facial features were observed."
Genitorenal anomalies in a later series.
Head and Neck 2
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:34642815 SUPPORT Human clinical
"his microcephaly, optic nerve hypoplasia, mildly short stature, and feeding disorder are consistent with WDR37 syndrome"
The authors list microcephaly among the features consistent with the syndrome.
Facial Dysmorphism Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Facial dysmorphism, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31327508 SUPPORT Human clinical
"The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia."
Facial dysmorphology reminiscent of CHARGE syndrome in the founding cohort.
PMID:31327510 SUPPORT Human clinical
"Features of WDR37 syndrome include the following: ocular anomalies such as corneal opacity/Peters anomaly, coloboma, and microcornea; dysmorphic facial features"
Dysmorphic facial features in the second founding series.
Integument 1
Single Transverse Palmar Crease HP:0000954 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Single transverse palmar crease (HP:0000954). HP:0000954 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34642815 SUPPORT Human clinical
"prominent clinodactyly of the fifth digits, and a single transverse crease on both hands"
Bilateral single transverse palmar creases in an individual with a de novo variant.
Limbs 1
Tapered Fingers HP:0001182 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tapered finger (HP:0001182). HP:0001182 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34642815 SUPPORT Human clinical
"they show stronger phenotypic overlap with the previously reported cases including seizures, hearing loss, scoliosis, heart defects, tapered fingers, and feeding disorder"
Tapered fingers are listed among the features shared with earlier cases.
Musculoskeletal 1
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34642815 SUPPORT Human clinical
"Her height and weight percentiles have varied over time, but have typically been on the low end of normal and she has scoliosis."
Scoliosis in an individual with a de novo C-terminal variant.
CGGV:assertion_f3eaff9e-978b-47a6-ad55-88edabc62064-2024-10-18T160000.000Z SUPPORT Other
"as well as skeletal (mostly spinal), genitourinary, and gastrointestinal anomalies, with feeding issues and poor growth"
ClinGen's summary describes the skeletal involvement as mostly spinal.
Nervous System 7
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:31327508 SUPPORT Human clinical
"The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia."
Epilepsy is a shared feature of the founding cohort.
PMID:31327510 SUPPORT Human clinical
"significant neurological impairment with structural brain defects and seizures"
Seizures are part of the neurological phenotype in the second founding series.
PMID:34642815 SUPPORT Human clinical
"She is treated for a seizure disorder (onset at 6 years old)."
Childhood-onset seizures in an individual with a de novo C-terminal variant.
Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31327508 SUPPORT Human clinical
"The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia."
Intellectual disability is a shared feature of the founding cohort.
PMID:32530092 SUPPORT Human clinical
"Consistent with the literature, intellectual disability, structural eye disorders, epilepsy, congenital heart disease, genitorenal anomalies and dysmorphic facial features were observed."
Intellectual disability in a later independent series.
Global Developmental Delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32530092 SUPPORT Human clinical
"We further expand the phenotypic spectrum of WDR37-related disorders to include those with milder developmental delay"
Establishes that delay can be milder than in the founding reports.
PMID:34642815 SUPPORT Human clinical
"Similar to previous cases, all three individuals have severe developmental delay/cognitive impairment with limited to no ambulation and all are non-verbal."
Severe delay with limited or no ambulation in the C-terminal cluster series.
Absent Speech HP:0001344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent speech (HP:0001344). HP:0001344 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34642815 SUPPORT Human clinical
"Similar to previous cases, all three individuals have severe developmental delay/cognitive impairment with limited to no ambulation and all are non-verbal."
All three individuals in this series are non-verbal, as were earlier cases.
Cerebellar Hypoplasia HP:0001321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar hypoplasia (HP:0001321). HP:0001321 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31327508 SUPPORT Human clinical
"The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia."
Cerebellar hypoplasia is a shared feature of the founding cohort.
Cerebellar Vermis Anomaly Abnormal cerebellar vermis morphology HP:0002334 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal cerebellar vermis morphology (HP:0002334). HP:0002334 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38044197 SUPPORT Human clinical
"The patient had novel phenotypes, anal atresia, and polycystic kidney, in addition to intellectual disability, seizures, cerebellar vermian anomaly, and coloboma, which are typical in NOCGUS."
Cerebellar vermian anomaly, described as typical of the disorder.
PMID:34642815 SUPPORT Human clinical
"Individual 2 is a 15-year-old White (US) female born at term with multiple congenital anomalies including Dandy–Walker anomaly, thinning of the corpus callosum, atrial and ventricular septal defects, dysplastic right kidney"
Dandy-Walker anomaly in an individual with a de novo C-terminal variant.
Corpus Callosum Anomaly Abnormal corpus callosum morphology HP:0001273 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Corpus callosum anomaly, annotated with Abnormal corpus callosum morphology (HP:0001273). HP:0001273 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:34642815 SUPPORT Human clinical
"Individual 2 is a 15-year-old White (US) female born at term with multiple congenital anomalies including Dandy–Walker anomaly, thinning of the corpus callosum, atrial and ventricular septal defects, dysplastic right kidney"
Thinning of the corpus callosum in an individual with a de novo variant.
PMID:38044197 SUPPORT Human clinical
"shows thinning of the corpus callosum, mildly posteriorly malrotated hypoplastic cerebellar"
Thinning of the corpus callosum on MRI in the splice-variant case (figure legend).
PMID:34642815 SUPPORT Human clinical
"DW, PV, CCA, GRY, MYA | DW, CCA, PV, GYR, MYA | CCA, CBA, GYR | CCA, CBA | CCA, CBA, GRY | CCA, CBA, GYR"
Brain-anomalies row of Table 1 for Reis 2, Reis 3 and Kanca 2 to Kanca 5, all de novo; CCA appears in every one of these cells.
+ 1 more reference
Growth 2
Postnatal Growth Retardation HP:0008897 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor postnatal growth, annotated with Postnatal growth retardation (HP:0008897). HP:0008897 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31327510 SUPPORT Human clinical
"significant neurological impairment with structural brain defects and seizures; poor feeding; poor post-natal growth"
Poor postnatal growth in the founding series.
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:34642815 SUPPORT Human clinical
"his microcephaly, optic nerve hypoplasia, mildly short stature, and feeding disorder are consistent with WDR37 syndrome"
Mildly short stature in an individual with a de novo variant, which the authors count as consistent with the syndrome.
🧬

Genetic Associations

1
WDR37 (Heterozygous de novo WDR37 variants: missense changes in an N-terminal cluster upstream of the first WD40 repeat (p.Thr115 to p.Thr130), missense changes in a second cluster in and between WD40 repeats 2 and 3, and one in-frame splice variant.)
Gene: WDR37 hgnc:31406 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is WDR37 (hgnc:31406). hgnc:31406 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (2 references)
CGGV:assertion_f3eaff9e-978b-47a6-ad55-88edabc62064-2024-10-18T160000.000Z SUPPORT Other
"At least 9 unique pathogenic/likely pathogenic variants (8 missense, 1 intronic deletion/splice) have been reported in 13 unrelated probands in five publications"
ClinGen summary of the variant and proband count behind the Definitive classification.
ORPHA:684305 SUPPORT Other
"WDR37 | WD repeat domain 37 | hgnc:31406 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet records WDR37 as the disease-causing gene. Its loss-of-function qualifier differs from ClinGen's dominant-negative reading; see the discussion on variant mechanism.
🔬

Diagnosis

3
Exome Sequencing
The diagnosis is made by finding a heterozygous de novo WDR37 variant, in reported cases by trio or clinical exome sequencing. WDR37 has been recommended for intellectual disability, epilepsy and structural eye disorder gene panels.
Whole Exome Sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:42546896 SUPPORT Human clinical
"Clinical exome sequencing identified a de novo pathogenic variant in the WDR37 gene, confirming the diagnosis."
Clinical exome sequencing established the diagnosis.
PMID:32530092 SUPPORT Human clinical
"We promote the inclusion of WDR37 on gene panels for intellectual disability, epilepsy and structural eye disorders."
Recommendation to include WDR37 on diagnostic gene panels.
RNA Analysis of Candidate Splice Variants
An intronic WDR37 deletion outside the canonical splice sites was confirmed by RT-PCR to cause intron retention, so intronic variants near exon boundaries can be pathogenic.
Show evidence (1 reference)
PMID:38044197 SUPPORT Human clinical
"Reverse transcription polymerase chain reaction (RT-PCR) revealed intron retention of 63 base pairs before exon 10 in messenger RNA, which was predicted to insert 21 additional aberrant amino acids"
RT-PCR confirmed the splicing effect of an intronic variant.
Ophthalmologic Examination
Early eye examination in a neonate with multiple congenital anomalies can point to the diagnosis.
Eye Examination NCIT:C38060 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:42546896 SUPPORT Human clinical
"Early ophthalmologic evaluation in neonates with multisystem congenital anomalies may provide important diagnostic clues to rare genetic syndromes."
The authors recommend early ophthalmologic evaluation as a diagnostic clue.
📈

Progression

2
Congenital and neonatal presentation
The structural anomalies of eye, brain, heart and kidney are present at birth, and severe ocular involvement can be recognised in the neonatal period. Orphanet records onset as neonatal or in infancy. One individual in a founding series died in infancy.
Show evidence (3 references)
PMID:42546896 SUPPORT Human clinical
"This case is notable for the severity and very early neonatal presentation of ocular involvement and further illustrates the phenotypic variability of WDR37-associated disease."
Neonatal presentation of the ocular malformations.
ORPHA:684305 SUPPORT Other
"Age of onset: Neonatal"
Orphanet age-of-onset field.
PMID:31327510 SUPPORT Human clinical
"poor post-natal growth; variable skeletal, cardiac, and genitourinary defects; and death in infancy in one individual"
Infant death in one individual of the founding series.
Childhood course
Developmental delay, intellectual disability and seizures dominate childhood. Loss of acquired skills is not a recurrent feature: one possible case of skill loss is known among reported individuals with WDR37 variants, and the reviewers do not regard the PACS1-PACS2-WDR37 disorders as primarily regressive, but recommend longitudinal surveillance.
Show evidence (2 references)
PMID:42794636 SUPPORT REVIEW SYNTHESIS Human clinical
"The remaining published literature on WDR37-associated disorder has not identified developmental regression as a recurrent clinical feature"
Systematic review finding that regression is not a recurrent feature.
PMID:42794636 SUPPORT REVIEW SYNTHESIS Human clinical
"The available evidence does not support classifying these syndromes as primarily regressive disorders. However, the documented cases justify active surveillance and standardized longitudinal phenotypic characterization."
The review's conclusion and surveillance recommendation for the PACS1-PACS2-WDR37 disorders.
📊

Prevalence

2
Worldwide
Cases/families reported in the literature Ultra-rare
ClinGen counted 13 unrelated probands in five publications as of its 2024 curation, and a 2026 review counts 13 reported individuals with WDR37 variants. Later single case reports are not in either count. No population-based estimate exists, so no rate is given.
Show evidence (2 references)
CGGV:assertion_f3eaff9e-978b-47a6-ad55-88edabc62064-2024-10-18T160000.000Z SUPPORT Other
"At least 9 unique pathogenic/likely pathogenic variants (8 missense, 1 intronic deletion/splice) have been reported in 13 unrelated probands in five publications"
Proband count in the published literature as of the ClinGen curation.
PMID:42794636 SUPPORT REVIEW SYNTHESIS Human clinical
"To date, at least 113 patients with PACS1-associated syndrome (or Schuurs-Hoeijmakers syndrome), 32 with PACS2 and 13 with WDR37 have been reported"
Literature count from a 2026 review.
Worldwide
Point prevalence <1 in 1,000,000
Orphanet worldwide point-prevalence class <1 / 1,000,000, sourced to the two founding papers.
Show evidence (1 reference)
ORPHA:684305 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:31327508,PMID:31327510"
Orphanet epidemiology row.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Neurooculocardiogenitourinary Syndrome:

CHARGE syndrome MONDO:0008965
Distinguishing Features
  • Coloboma and the facial appearance overlap; the distinction is molecular.
Show evidence (1 reference)
PMID:31327508 SUPPORT Human clinical
"The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia."
The founding cohort's facial features were reminiscent of CHARGE syndrome.
Schuurs-Hoeijmakers syndrome (PACS1) MONDO:0014006
Distinguishing Features
  • Caused by a recurrent de novo PACS1 variant in WDR37's main binding partner. Shares intellectual disability, facial features, coloboma, heart and genitourinary anomalies, but coloboma, heart defects, poor growth and genitourinary anomalies are more penetrant in NOCGUS, and microphthalmia, microcornea and Peters anomaly are more severe in NOCGUS.
Show evidence (2 references)
PMID:34642815 SUPPORT Human clinical
"while ocular coloboma, heart defects, poor growth, and genitourinary anomalies are noted in all three conditions, they are much more penetrant in WDR37 syndrome"
Compares penetrance of shared malformations across the WDR37, PACS1 and PACS2 disorders.
PMID:37064331 SUPPORT Human clinical
"microphthalmia, microcornea, and Peters anomaly are found only among individuals with PACS1-related NDD and WDR37 syndrome, being more severe in the latter"
Ocular findings that separate the PACS1 and WDR37 disorders by severity.
🐁

Animal Models

3
Drosophila wdr37 (CG12333) null
Homozygous null flies are viable but bang-sensitive, have reduced grip strength and lose grip during copulation. Human reference WDR37 rescues these phenotypes; two patient alleles do not.
Species
Fruit fly
Genotype
CG12333/wdr37 coding region replaced with GAL4, homozygous
Publication
PMID:31327508
Pathograph links
Neuronal Dysfunction partially recapitulates fidelity: low observes: organism A seizure-associated behavioural phenotype that patient alleles fail to rescue, linking the human variants to loss of a conserved neuronal function.
Limitations: The model is a homozygous null in an invertebrate, whereas patients are heterozygous for missense or in-frame variants; it cannot test a dominant negative effect and has no counterpart of the eye, heart or kidney malformations.
Show evidence (1 reference)
PMID:31327508 SUPPORT Model organism
"These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies."
The fly null phenotype that the model contributes.
Zebrafish wdr37 CRISPR missense and frameshift alleles
Heterozygous missense alleles, including one matching the human p.Ser129Cys, caused poor growth and larval lethality, while heterozygous frameshift carriers survived to adulthood. Missense embryos upregulated cholesterol biosynthesis genes.
Species
Zebrafish
Genotype
Heterozygous wdr37 missense (p.Ser129Phe, p.Ser129Cys, p.Ser129Tyr) or frameshift (p.Lys127Cysfs, p.Gln95Argfs) alleles
Publication
PMID:31327510
Pathograph links
Impaired Embryonic Development of Multiple Organs partially recapitulates fidelity: moderate observes: organism Heterozygous missense alleles, as in patients, disturb vertebrate development where frameshift alleles do not.
Limitations: The published abstract reports growth and survival, not the specific eye, brain, heart or kidney malformations of the human disorder.
Show evidence (1 reference)
PMID:31327510 SUPPORT Model organism
"Zebrafish carrying heterozygous missense variants demonstrated poor growth and larval lethality, while heterozygotes with frameshift alleles survived to adulthood"
Allele-specific developmental effect in zebrafish.
Upregulated Cholesterol Biosynthesis Gene Expression measures observes: molecular RNA-seq of missense embryos.
Show evidence (1 reference)
PMID:31327510 SUPPORT Model organism
"RNA-seq analysis of zebrafish embryos carrying a missense variant detected significant upregulation of cholesterol biosynthesis pathways."
Transcriptomic readout in the missense model.
Mouse Wdr37 or Pacs1 deletion
Deletion of either gene causes peripheral lymphopenia with blunted ER calcium release after antigen receptor stimulation. The abstract reports no developmental, eye or neurological phenotype.
Species
Mouse
Genotype
Wdr37 or Pacs1 deletion identified by forward genetic screening
Publication
PMID:33630350
Pathograph links
Impaired ER Calcium Release perturbs fidelity: unknown observes: cellular Shows that the Pacs1-Wdr37 complex is needed for ER calcium handling in lymphocytes.
Limitations: A null allele studied in lymphocytes, not a NOCGUS variant in neural or developing tissue; no immune phenotype is reported in NOCGUS.
Show evidence (1 reference)
PMID:33630350 SUPPORT Model organism
"Deletion of Pacs1 or Wdr37 caused peripheral lymphopenia that was linked to blunted Ca2+ release from the ER after antigen receptor stimulation."
The lymphocyte calcium finding the model contributes.
{ }

Source YAML

click to show 
name: Neurooculocardiogenitourinary Syndrome
creation_date: "2026-11-05T18:53:03Z"
category: Mendelian
disease_term:
  preferred_term: neurooculocardiogenitourinary syndrome
  term:
    id: MONDO:0032850
    label: neurooculocardiogenitourinary syndrome
description: >-
  Neurooculocardiogenitourinary syndrome (NOCGUS, OMIM 618652) is an autosomal
  dominant multisystem developmental disorder caused by heterozygous, almost
  always de novo, variants in WDR37, which encodes a WD40-repeat protein of
  unknown function. It was delineated in 2019 by two independent groups. The
  original variants are missense changes clustered in a short conserved stretch
  upstream of the first WD40 repeat (p.Thr115 to p.Thr130); a second cluster in
  and between the second and third WD40 repeats and one intronic splice variant
  were reported later. Presentation is neonatal or infantile. The core is
  neurological (seizures, usually severe developmental delay and intellectual
  disability, often absent speech, cerebellar hypoplasia and other structural
  brain anomalies) together with structural eye anomalies (coloboma,
  microphthalmia, microcornea, Peters anomaly) and facial dysmorphism that has
  been compared with CHARGE syndrome. Congenital heart defects, genitourinary
  and renal anomalies, skeletal (mostly spinal) anomalies, sensorineural hearing
  loss, feeding difficulties and poor postnatal growth are variable; one
  individual in a founding series died in infancy, while a later series
  describes milder developmental delay. WDR37 binds the paralogous sorting
  proteins PACS1 and PACS2, whose own de novo missense disorders
  (Schuurs-Hoeijmakers syndrome and DEE66) overlap clinically with NOCGUS. How
  the variants act is not settled: a dominant-negative mechanism has been
  proposed from zebrafish and cell data and is ClinGen's reading, Orphanet
  annotates the association as loss of function, and the main functional study
  states that the mechanism has not been established.
synonyms:
- NOCGUS
- Neuro-oculo-cardio-genito-urinary syndrome
- WDR37 syndrome
- WDR37-related disorder
parents:
- Autosomal dominant syndromic intellectual disability
pathophysiology:
- name: De Novo Heterozygous WDR37 Variant
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion is a heterozygous WDR37 variant, arising de novo in
    every individual reported with a pathogenic or likely pathogenic call. The
    founding missense variants (p.Thr115Ile, p.Ser119Phe, p.Ser119Tyr,
    p.Thr125Ile, p.Ser129Cys, p.Thr130Ile) cluster upstream of the first WD40
    repeat. A second cluster lies in or just after the second WD40 repeat
    (p.Asp220Gly and p.Asp260Asn de novo; p.Pro257His inherited from an
    unaffected mother and of uncertain significance). One de novo intronic
    deletion (c.727-27_727-24del) causes retention of 63 intronic bases and an
    in-frame insertion of 21 amino acids. No truncating variant has been
    reported as causal.
  genes:
  - preferred_term: WDR37
    term:
      id: hgnc:31406
      label: WDR37
  genetic_context:
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
  downstream:
  - target: Abnormal WDR37 Protein Function
    causal_link_type: DIRECT
    description: >-
      The variant protein is made and correctly localized but fails to perform
      the function the wild-type protein provides in the fly rescue assay.
  evidence:
  - reference: PMID:31327510
    reference_title: De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have discovered four de novo missense variants predicted to affect the N-terminal region of WDR37-p.Ser119Phe, p.Thr125Ile, p.Ser129Cys, and p.Thr130Ile-in unrelated individuals with a previously unrecognized syndrome"
    explanation: Founding report of the clustered N-terminal de novo missense variants.
  - reference: PMID:31327508
    reference_title: "De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats."
    explanation: Independent founding cohort with de novo variants clustered outside the WD40 repeats.
  - reference: PMID:32530092
    reference_title: Expanding the phenotypic spectrum consequent upon de novo WDR37 missense variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The variants fall within a highly conserved region upstream of the WD-repeat domains, within an apparent mutation cluster."
    explanation: Two further de novo variants in the same N-terminal cluster.
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The novel alleles are C-terminal to the prior variants and located either within the second WD40 motif (c.659A>G p.(Asp220Gly)) or in a disordered protein region connecting the second and third WD40 motifs (c.778G>A p.(Asp260Asn) and c.770C>A p.(Pro257His))."
    explanation: Second, C-terminal variant cluster in individuals with overlapping phenotypes.
  - reference: PMID:38044197
    reference_title: Splicing variant of WDR37 in a case of Neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reverse transcription polymerase chain reaction (RT-PCR) revealed intron retention of 63 base pairs before exon 10 in messenger RNA, which was predicted to insert 21 additional aberrant amino acids"
    explanation: The one reported non-missense variant is an in-frame splice change, not a truncating allele.
- name: Abnormal WDR37 Protein Function
  biological_scale: MOLECULAR
  description: >-
    The variant proteins reach the cytoplasm and still dimerize with wild-type
    WDR37. The N-terminal variants are expressed at levels similar to wild type,
    while the C-terminal variants are expressed at lower levels. Two human
    variants fail to rescue the Drosophila wdr37 null, so they impair function.
    In zebrafish, heterozygous missense alleles were lethal to larvae while
    heterozygous frameshift alleles were not, which suggested a dominant
    negative effect. Whether that is the mechanism in patients is open (see the
    discussion on variant mechanism). The only molecular activities shown for
    WDR37 are homodimerization and binding to PACS1 and PACS2; the
    homodimerization term is bound without a modifier because variant proteins
    still dimerize with wild type, so it names the activity, not a defect in it.
  genes:
  - preferred_term: WDR37
    term:
      id: hgnc:31406
      label: WDR37
  molecular_functions:
  - preferred_term: WDR37 homodimerization
    term:
      id: GO:0042803
      label: protein homodimerization activity
  downstream:
  - target: Impaired Ocular Morphogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred. WDR37 variants and the variants of its PACS partners share
      coloboma, which has been read as a role for the axis in eye development;
      no study has followed a WDR37 variant into a developing eye.
    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: "The present observation of coloboma as a shared feature among these three disorders suggests that this group of genes may be involved in ocular development."
      explanation: Clinical inference from shared coloboma that the WDR37-PACS1-PACS2 genes act in ocular development.
  - target: Impaired Embryonic Development of Multiple Organs
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Heterozygous missense wdr37 alleles impair growth and survival of zebrafish
      larvae; the organ-level steps between the protein defect and the human
      malformations are not known.
    evidence:
    - reference: PMID:31327510
      reference_title: De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Zebrafish carrying heterozygous missense variants demonstrated poor growth and larval lethality, while heterozygotes with frameshift alleles survived to adulthood"
      explanation: Heterozygous missense alleles disrupt vertebrate development in zebrafish.
  - target: Neuronal Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of the single fly ortholog causes a seizure-associated phenotype that
      human WDR37 rescues and the patient alleles do not.
    evidence:
    - reference: PMID:31327508
      reference_title: "De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies."
      explanation: Fly null phenotype linking WDR37 function to neuronal excitability.
  - target: Upregulated Cholesterol Biosynthesis Gene Expression
    causal_link_type: UNKNOWN
    description: >-
      Transcriptomic finding in zebrafish embryos carrying a missense allele; its
      relation to the human phenotype is unknown.
  - target: Altered WDR37-PACS1-PACS2 Complex Function
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - pacs_complex_dysfunction
    description: >-
      Hypothesis. Most tested variants still bind PACS1 and PACS2 normally, so
      a defect at the level of the complex, if there is one, is not loss of
      binding.
  evidence:
  - reference: PMID:31327508
    reference_title: "De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein."
    explanation: Patient alleles fail to complement the fly null, showing the variant proteins are functionally impaired.
  - reference: PMID:31327510
    reference_title: De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Immunocytochemistry and western blot studies showed that wild-type WDR37 is localized predominantly in the cytoplasm and mutant proteins demonstrate similar protein levels and localization."
    explanation: The N-terminal variant proteins are stable and correctly localized, so the defect is not simple loss of the protein.
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The three novel mutants showed normal cellular localization but lower expression levels in comparison to wild-type WDR37."
    explanation: The C-terminal variant proteins localize normally but are expressed at lower levels.
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "dimerization with wild-type WDR37 was not affected by any of the missense variants studied, supporting the possibility of a dominant negative effect"
    explanation: Variant proteins retain the ability to dimerize with wild type, which the authors read as compatible with a dominant negative effect.
  - reference: PMID:31327510
    reference_title: De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Zebrafish carrying heterozygous missense variants demonstrated poor growth and larval lethality, while heterozygotes with frameshift alleles survived to adulthood, suggesting a potential dominant-negative mechanism for the missense variants."
    explanation: Allele-type contrast in zebrafish that underlies the dominant-negative proposal.
- name: Altered WDR37-PACS1-PACS2 Complex Function
  biological_scale: MOLECULAR
  description: >-
    Hypothesis node. WDR37's main binding partners are the phosphofurin acidic
    cluster sorting proteins PACS1 and PACS2, and WDR37 and PACS1 depend on each
    other for stable expression in cultured cells and in C. elegans. Of the
    seven WDR37 variants tested for binding, only p.Asp220Gly lost binding to
    PACS1 and PACS2. So the shared biology of the three disorders points at this
    complex, but no study has shown that a NOCGUS variant impairs complex
    function.
  genes:
  - preferred_term: PACS1
    term:
      id: hgnc:30032
      label: PACS1
  - preferred_term: PACS2
    term:
      id: hgnc:23794
      label: PACS2
  biological_processes:
  - preferred_term: intracellular protein transport
    term:
      id: GO:0006886
      label: intracellular protein transport
    modifier: ABNORMAL
  downstream:
  - target: Impaired ER Calcium Release
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - pacs_complex_dysfunction
    description: >-
      Shown only for deletion of Pacs1 or Wdr37 in mouse lymphocytes, not for a
      NOCGUS variant or in neural cells.
    evidence:
    - reference: PMID:33630350
      reference_title: Calcium flux control by Pacs1-Wdr37 promotes lymphocyte quiescence and lymphoproliferative diseases.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Deletion of Pacs1 or Wdr37 caused peripheral lymphopenia that was linked to blunted Ca2+ release from the ER after antigen receptor stimulation."
      explanation: Loss of either complex member blunts ER calcium release in mouse lymphocytes.
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This revealed the ability of WDR37 to form homodimers and to strongly bind PACS1 and PACS2 phosphofurin acidic cluster sorting proteins; immunocytochemistry confirmed colocalization of WDR37 with PACS1 and PACS2 in human cells."
    explanation: Establishes PACS1 and PACS2 as the major binding partners of WDR37.
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Interaction with wild-type WDR37 was not affected for any variant; however, one novel mutant, p.(Asp220Gly), lost its ability to bind PACS1 and PACS2."
    explanation: >-
      Cuts against loss of PACS binding as a general mechanism: the other
      variants tested, including all four founding N-terminal variants, bound
      PACS1 and PACS2 normally.
  - reference: PMID:41279321
    reference_title: The Structural Basis for Pacs1-Wdr37 Complex Assembly and Stability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This interaction stabilizes Wdr37 and is critical for the expression of both proteins."
    explanation: >-
      Cryo-EM and biochemical study (a bioRxiv preprint indexed in PubMed)
      showing that the Pacs1-Wdr37 interaction is needed for both proteins'
      expression.
  - 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 show that cePACS-1 and ceWDR-37 colocalize to somatic cytoplasm of many types of cells and are mutually required for expression, supporting a conclusion that the intermolecular dependence of PACS1/PACS2/PACS-1 and WDR37/WDR-37 is evolutionarily conserved."
    explanation: The PACS-WDR37 mutual dependence is conserved in C. elegans.
- name: Impaired ER Calcium Release
  biological_scale: CELLULAR
  description: >-
    Mouse finding. In lymphocytes, Pacs1 and Wdr37 are needed for normal release
    of calcium from the endoplasmic reticulum after antigen receptor
    stimulation. No immune phenotype has been reported in NOCGUS, and ER calcium
    handling has not been measured in patient cells or in neurons carrying a
    NOCGUS variant, so this node is a lead for the mechanism, not part of the
    established chain.
  cell_types:
  - preferred_term: lymphocyte
    term:
      id: CL:0000542
      label: lymphocyte
  biological_processes:
  - preferred_term: endoplasmic reticulum calcium ion homeostasis
    term:
      id: GO:0032469
      label: endoplasmic reticulum calcium ion homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33630350
    reference_title: Calcium flux control by Pacs1-Wdr37 promotes lymphocyte quiescence and lymphoproliferative diseases.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Through forward genetic screening in mice, we identified two members of a new complex, Pacs1 and Wdr37, which are required for normal ER Ca2+ handling in lymphocytes."
    explanation: Mouse genetics showing that the Pacs1-Wdr37 complex is required for ER calcium handling in lymphocytes.
- name: Upregulated Cholesterol Biosynthesis Gene Expression
  biological_scale: MOLECULAR
  description: >-
    RNA-seq of zebrafish embryos carrying a heterozygous wdr37 missense allele
    showed upregulation of cholesterol biosynthesis pathways. It has not been
    examined in patients and its place in the mechanism is unknown.
  biological_processes:
  - preferred_term: cholesterol biosynthetic process
    term:
      id: GO:0006695
      label: cholesterol biosynthetic process
    modifier: INCREASED
  evidence:
  - reference: PMID:31327510
    reference_title: De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "RNA-seq analysis of zebrafish embryos carrying a missense variant detected significant upregulation of cholesterol biosynthesis pathways."
    explanation: Transcriptomic finding in the zebrafish missense model.
- name: Impaired Ocular Morphogenesis
  biological_scale: TISSUE
  description: >-
    Structural eye anomalies are the most consistent malformations: coloboma of
    the iris and retina, microphthalmia, microcornea, Peters anomaly and other
    anterior segment dysgenesis, and optic nerve hypoplasia, present from
    birth. The developmental step that WDR37 variants disturb has not been
    studied; the link is drawn from the congenital nature of the findings and
    the shared ocular phenotype of the WDR37, PACS1 and PACS2 disorders.
  biological_processes:
  - preferred_term: camera-type eye development
    term:
      id: GO:0043010
      label: camera-type eye development
    modifier: ABNORMAL
  downstream:
  - target: Coloboma
    causal_link_type: DIRECT
  - target: Microphthalmia
    causal_link_type: DIRECT
  - target: Microcornea
    causal_link_type: DIRECT
  - target: Peters Anomaly
    causal_link_type: DIRECT
  - target: Ocular Anterior Segment Dysgenesis
    causal_link_type: DIRECT
  - target: Optic Nerve Hypoplasia
    causal_link_type: DIRECT
  - target: Cataract
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:37064331
    reference_title: First Report of Mexican Patients with PACS1-Related Neurodevelopmental Disorder and Review of the PACS1-, PACS2-, and WDR37-Related Ophthalmological Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This supports the previous statement that the so-called WDR37-PACS1-PACS2 axis might have an important role in ocular development"
    explanation: Review of ocular findings across the three disorders, concluding the axis acts in eye development.
  - reference: PMID:42546896
    reference_title: Severe bilateral ocular coloboma and microphthalmia in a neonate with WDR37-associated neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular findings identified at birth included bilateral microphthalmia, microcornea, corneal edema, marked anterior segment dysgenesis, and bilateral colobomatous posterior pole abnormalities."
    explanation: The ocular malformations are present at birth, consistent with a defect of eye development.
- name: Impaired Embryonic Development of Multiple Organs
  biological_scale: TISSUE
  description: >-
    The non-ocular malformations (cerebellar and other brain anomalies, septal
    and complex heart defects, renal dysplasia and cystic kidneys, other
    genitourinary anomalies, anal atresia, spinal anomalies, dysmorphic facial
    features) are congenital, and heterozygous missense wdr37 alleles impair
    growth and survival of zebrafish larvae. This node records that the
    variants disturb embryonic development; the organ-specific mechanisms are
    not known, and the edges from it to the individual malformations are
    inferred from their congenital nature rather than demonstrated.
  biological_processes:
  - preferred_term: embryo development
    term:
      id: GO:0009790
      label: embryo development
    modifier: ABNORMAL
  downstream:
  - target: Cerebellar Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cerebellar Vermis Anomaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Congenital Heart Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Renal Dysplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Polycystic Kidney Dysplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Genitourinary Anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Anal Atresia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Facial Dysmorphism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Tapered Fingers
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Postnatal Growth Retardation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Short Stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Corpus Callosum Anomaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Atrial Septal Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ventricular Septal Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Single Transverse Palmar Crease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:31327510
    reference_title: De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This study identifies variants in WDR37 associated with human disease and provides insight into its essential role in vertebrate development and possible molecular functions."
    explanation: The zebrafish work places WDR37 in vertebrate development.
  - reference: PMID:42546896
    reference_title: Severe bilateral ocular coloboma and microphthalmia in a neonate with WDR37-associated neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient also had multiple systemic anomalies, including complex congenital heart disease, renal dysplasia, skeletal abnormalities, and cerebellar malformation."
    explanation: Multiple congenital organ malformations in a neonate with a de novo WDR37 variant.
- name: Neuronal Dysfunction
  biological_scale: CELLULAR
  description: >-
    Seizures, developmental delay, intellectual disability and absent speech
    point to a defect of neuronal function in addition to the structural brain
    anomalies. The direct evidence is from Drosophila: the wdr37 null is
    bang-sensitive, a seizure-associated phenotype, and loses grip strength;
    human WDR37 rescues these phenotypes and two patient alleles do not. The
    neuronal process involved has not been identified.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Absent Speech
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:31327508
    reference_title: "De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA."
    explanation: Human WDR37 restores the neurological fly phenotypes, so they reflect loss of conserved WDR37 function.
phenotypes:
- category: Neurological
  name: Seizures
  description: >-
    Seizures are present in most reported individuals and were a shared feature
    of one founding cohort. Onset is variable, from infancy to childhood (onset
    at 6 years in one individual).
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:31327508
    reference_title: "De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia."
    explanation: Epilepsy is a shared feature of the founding cohort.
  - reference: PMID:31327510
    reference_title: De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "significant neurological impairment with structural brain defects and seizures"
    explanation: Seizures are part of the neurological phenotype in the second founding series.
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She is treated for a seizure disorder (onset at 6 years old)."
    explanation: Childhood-onset seizures in an individual with a de novo C-terminal variant.
- category: Neurological
  name: Intellectual Disability
  description: >-
    Intellectual disability is usually severe; milder developmental delay has
    been reported in a later series.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:31327508
    reference_title: "De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia."
    explanation: Intellectual disability is a shared feature of the founding cohort.
  - reference: PMID:32530092
    reference_title: Expanding the phenotypic spectrum consequent upon de novo WDR37 missense variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistent with the literature, intellectual disability, structural eye disorders, epilepsy, congenital heart disease, genitorenal anomalies and dysmorphic facial features were observed."
    explanation: Intellectual disability in a later independent series.
- category: Neurological
  name: Global Developmental Delay
  description: >-
    Developmental delay is present in every reported individual. It is severe in
    most, but a later series extended the spectrum to milder delay.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:32530092
    reference_title: Expanding the phenotypic spectrum consequent upon de novo WDR37 missense variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We further expand the phenotypic spectrum of WDR37-related disorders to include those with milder developmental delay"
    explanation: Establishes that delay can be milder than in the founding reports.
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similar to previous cases, all three individuals have severe developmental delay/cognitive impairment with limited to no ambulation and all are non-verbal."
    explanation: Severe delay with limited or no ambulation in the C-terminal cluster series.
- category: Neurological
  name: Absent Speech
  description: >-
    Most reported individuals are non-verbal.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similar to previous cases, all three individuals have severe developmental delay/cognitive impairment with limited to no ambulation and all are non-verbal."
    explanation: All three individuals in this series are non-verbal, as were earlier cases.
- category: Neurological
  name: Cerebellar Hypoplasia
  description: >-
    Cerebellar hypoplasia is one of the shared features of a founding cohort and
    part of a wider set of structural brain anomalies.
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  evidence:
  - reference: PMID:31327508
    reference_title: "De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia."
    explanation: Cerebellar hypoplasia is a shared feature of the founding cohort.
- category: Neurological
  name: Cerebellar Vermis Anomaly
  description: >-
    Anomalies of the cerebellar vermis, including Dandy-Walker anomaly, are
    reported with both missense and splice variants.
  phenotype_term:
    preferred_term: Abnormal cerebellar vermis morphology
    term:
      id: HP:0002334
      label: Abnormal cerebellar vermis morphology
  evidence:
  - reference: PMID:38044197
    reference_title: Splicing variant of WDR37 in a case of Neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient had novel phenotypes, anal atresia, and polycystic kidney, in addition to intellectual disability, seizures, cerebellar vermian anomaly, and coloboma, which are typical in NOCGUS."
    explanation: Cerebellar vermian anomaly, described as typical of the disorder.
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individual 2 is a 15-year-old White (US) female born at term with multiple congenital anomalies including Dandy–Walker anomaly, thinning of the corpus callosum, atrial and ventricular septal defects, dysplastic right kidney"
    explanation: Dandy-Walker anomaly in an individual with a de novo C-terminal variant.
- category: Neurological
  name: Corpus Callosum Anomaly
  description: >-
    Corpus callosum anomalies are the most often tabulated brain finding in the
    2021 case table, present in most of the individuals listed. Where the type is
    described in prose it is thinning, in an individual with a de novo
    C-terminal variant and in the splice-variant case. The table records only
    "corpus callosum anomaly", so the general term is bound.
  phenotype_term:
    preferred_term: Corpus callosum anomaly
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individual 2 is a 15-year-old White (US) female born at term with multiple congenital anomalies including Dandy–Walker anomaly, thinning of the corpus callosum, atrial and ventricular septal defects, dysplastic right kidney"
    explanation: Thinning of the corpus callosum in an individual with a de novo variant.
  - reference: PMID:38044197
    reference_title: Splicing variant of WDR37 in a case of Neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "shows thinning of the corpus callosum, mildly posteriorly malrotated hypoplastic cerebellar"
    explanation: Thinning of the corpus callosum on MRI in the splice-variant case (figure legend).
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DW, PV, CCA, GRY, MYA | DW, CCA, PV, GYR, MYA | CCA, CBA, GYR | CCA, CBA | CCA, CBA, GRY | CCA, CBA, GYR"
    explanation: >-
      Brain-anomalies row of Table 1 for Reis 2, Reis 3 and Kanca 2 to Kanca 5,
      all de novo; CCA appears in every one of these cells.
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DW Dandy–Walker anomaly/variant, CBA cerebellar anomaly, CCA corpus callosum anomaly"
    explanation: Table 1 legend defining CCA.
- category: Neurological
  name: Microcephaly
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "his microcephaly, optic nerve hypoplasia, mildly short stature, and feeding disorder are consistent with WDR37 syndrome"
    explanation: The authors list microcephaly among the features consistent with the syndrome.
- category: Ophthalmologic
  name: Coloboma
  description: >-
    Ocular coloboma (iris and retina, and posterior pole) is the hallmark eye
    finding and is often bilateral. It was absent in the three individuals of the
    C-terminal cluster series, whose ocular anomalies were milder.
  phenotype_term:
    preferred_term: Coloboma
    term:
      id: HP:0000589
      label: Coloboma
  diagnostic: true
  evidence:
  - reference: PMID:32530092
    reference_title: Expanding the phenotypic spectrum consequent upon de novo WDR37 missense variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All had a clinical phenotype consisting of bilateral iris and retinal coloboma, developmental delay and additional, variable multisystem features."
    explanation: Bilateral iris and retinal coloboma in all three individuals of this series.
  - reference: PMID:31327508
    reference_title: "De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia."
    explanation: Colobomas are a shared feature of the founding cohort.
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, the ocular anomalies are milder in this cohort (no coloboma or microphthalmia)"
    explanation: Coloboma was not seen with the C-terminal cluster variants, so it is not universal.
- category: Ophthalmologic
  name: Microphthalmia
  description: >-
    Microphthalmia can be severe and bilateral at birth.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: PMID:42546896
    reference_title: Severe bilateral ocular coloboma and microphthalmia in a neonate with WDR37-associated neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular findings identified at birth included bilateral microphthalmia, microcornea, corneal edema, marked anterior segment dysgenesis, and bilateral colobomatous posterior pole abnormalities."
    explanation: Bilateral microphthalmia identified at birth.
- category: Ophthalmologic
  name: Microcornea
  phenotype_term:
    preferred_term: Microcornea
    term:
      id: HP:0000482
      label: Microcornea
  evidence:
  - reference: PMID:31327510
    reference_title: De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ocular anomalies such as corneal opacity/Peters anomaly, coloboma, and microcornea"
    explanation: Microcornea is among the ocular anomalies of the founding series.
- category: Ophthalmologic
  name: Peters Anomaly
  description: >-
    Corneal opacity or Peters anomaly.
  phenotype_term:
    preferred_term: Peters anomaly
    term:
      id: HP:0000659
      label: Peters anomaly
  evidence:
  - reference: PMID:31327510
    reference_title: De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ocular anomalies such as corneal opacity/Peters anomaly, coloboma, and microcornea"
    explanation: Corneal opacity/Peters anomaly in the founding series.
  - reference: PMID:37064331
    reference_title: First Report of Mexican Patients with PACS1-Related Neurodevelopmental Disorder and Review of the PACS1-, PACS2-, and WDR37-Related Ophthalmological Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microphthalmia, microcornea, and Peters anomaly are found only among individuals with PACS1-related NDD and WDR37 syndrome, being more severe in the latter"
    explanation: Review across the three related disorders; these anterior segment findings are more severe in WDR37 syndrome.
- category: Ophthalmologic
  name: Ocular Anterior Segment Dysgenesis
  phenotype_term:
    preferred_term: Ocular anterior segment dysgenesis
    term:
      id: HP:0007700
      label: Ocular anterior segment dysgenesis
  evidence:
  - reference: PMID:42546896
    reference_title: Severe bilateral ocular coloboma and microphthalmia in a neonate with WDR37-associated neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular findings identified at birth included bilateral microphthalmia, microcornea, corneal edema, marked anterior segment dysgenesis, and bilateral colobomatous posterior pole abnormalities."
    explanation: Marked anterior segment dysgenesis identified at birth.
  - reference: PMID:38044197
    reference_title: Splicing variant of WDR37 in a case of Neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "left anterior segment dysgenesis (Peters’ anomaly and sclerocornea) with secondary glaucoma"
    explanation: Unilateral anterior segment dysgenesis in the splice-variant case.
  sequelae:
  - target: Glaucoma
    causal_link_type: DIRECT
    description: >-
      In the splice-variant case the glaucoma is described as secondary to the
      anterior segment dysgenesis.
    evidence:
    - reference: PMID:38044197
      reference_title: Splicing variant of WDR37 in a case of Neurooculocardiogenitourinary syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "left anterior segment dysgenesis (Peters’ anomaly and sclerocornea) with secondary glaucoma"
      explanation: The source calls the glaucoma secondary to the anterior segment anomaly.
- category: Ophthalmologic
  name: Glaucoma
  description: >-
    Glaucoma is recorded in two of the de novo individuals in the 2021 case
    table (Reis 1 and Kanca 5) and, as secondary glaucoma with anterior segment
    dysgenesis, in the splice-variant case.
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  evidence:
  - reference: PMID:38044197
    reference_title: Splicing variant of WDR37 in a case of Neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "left anterior segment dysgenesis (Peters’ anomaly and sclerocornea) with secondary glaucoma"
    explanation: Secondary glaucoma in the splice-variant case.
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PA, COL, MI, GL, CAT | PA, MI, COL, RET, ONH"
    explanation: >-
      Ocular-features row of Table 1. The first cell is Reis 1 (de novo
      p.Ser119Phe), whose findings include GL (glaucoma) and CAT (cataract).
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "COL, CAT | CO, MI, GL, ONH aphakia"
    explanation: >-
      Ocular-features row of Table 1. The second cell is Kanca 5 (de novo
      p.Thr130Ile), whose findings include GL (glaucoma).
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "U unknown, CAT cataract, COL coloboma, GL glaucoma"
    explanation: Table 1 legend defining the GL and CAT abbreviations.
- category: Ophthalmologic
  name: Cataract
  description: >-
    Cataract is recorded in two de novo individuals in the 2021 case table
    (Reis 1 and Kanca 4). A third, surgically removed unilateral cataract was in
    the individual whose variant was inherited and of uncertain significance,
    and is not used as evidence here.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PA, COL, MI, GL, CAT | PA, MI, COL, RET, ONH"
    explanation: >-
      Ocular-features row of Table 1. The first cell is Reis 1 (de novo
      p.Ser119Phe), whose findings include CAT (cataract).
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "COL, CAT | CO, MI, GL, ONH aphakia"
    explanation: >-
      Ocular-features row of Table 1. The first cell is Kanca 4 (de novo
      p.Ser129Cys), whose findings include CAT (cataract).
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "U unknown, CAT cataract, COL coloboma, GL glaucoma"
    explanation: Table 1 legend defining the CAT abbreviation.
- category: Ophthalmologic
  name: Optic Nerve Hypoplasia
  phenotype_term:
    preferred_term: Optic nerve hypoplasia
    term:
      id: HP:0000609
      label: Optic nerve hypoplasia
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "his microcephaly, optic nerve hypoplasia, mildly short stature, and feeding disorder are consistent with WDR37 syndrome"
    explanation: Optic nerve hypoplasia listed among features consistent with the syndrome.
- category: Craniofacial
  name: Facial Dysmorphism
  description: >-
    Dysmorphic facial features, compared in one founding cohort with CHARGE
    syndrome and overlapping with the facial gestalt of the PACS1 and PACS2
    disorders. The founding abstracts do not itemise a consistent set of
    features, so the binding is to the general term.
  phenotype_term:
    preferred_term: Facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:31327508
    reference_title: "De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia."
    explanation: Facial dysmorphology reminiscent of CHARGE syndrome in the founding cohort.
  - reference: PMID:31327510
    reference_title: De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Features of WDR37 syndrome include the following: ocular anomalies such as corneal opacity/Peters anomaly, coloboma, and microcornea; dysmorphic facial features"
    explanation: Dysmorphic facial features in the second founding series.
- category: Cardiovascular
  name: Congenital Heart Defect
  description: >-
    Congenital heart defects are variable, from atrial and ventricular septal
    defects to complex congenital heart disease in a severely affected neonate.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:32530092
    reference_title: Expanding the phenotypic spectrum consequent upon de novo WDR37 missense variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistent with the literature, intellectual disability, structural eye disorders, epilepsy, congenital heart disease, genitorenal anomalies and dysmorphic facial features were observed."
    explanation: Congenital heart disease is part of the recognised spectrum.
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individual 2 is a 15-year-old White (US) female born at term with multiple congenital anomalies including Dandy–Walker anomaly, thinning of the corpus callosum, atrial and ventricular septal defects, dysplastic right kidney"
    explanation: Atrial and ventricular septal defects in an individual with a de novo variant.
  - reference: PMID:42546896
    reference_title: Severe bilateral ocular coloboma and microphthalmia in a neonate with WDR37-associated neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient also had multiple systemic anomalies, including complex congenital heart disease, renal dysplasia, skeletal abnormalities, and cerebellar malformation."
    explanation: Complex congenital heart disease in a severely affected neonate.
- category: Cardiovascular
  name: Atrial Septal Defect
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individual 2 is a 15-year-old White (US) female born at term with multiple congenital anomalies including Dandy–Walker anomaly, thinning of the corpus callosum, atrial and ventricular septal defects, dysplastic right kidney"
    explanation: Atrial septal defect in an individual with a de novo variant.
- category: Cardiovascular
  name: Ventricular Septal Defect
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individual 2 is a 15-year-old White (US) female born at term with multiple congenital anomalies including Dandy–Walker anomaly, thinning of the corpus callosum, atrial and ventricular septal defects, dysplastic right kidney"
    explanation: Ventricular septal defect in an individual with a de novo variant.
- category: Renal
  name: Renal Dysplasia
  phenotype_term:
    preferred_term: Renal dysplasia
    term:
      id: HP:0000110
      label: Renal dysplasia
  evidence:
  - reference: PMID:42546896
    reference_title: Severe bilateral ocular coloboma and microphthalmia in a neonate with WDR37-associated neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient also had multiple systemic anomalies, including complex congenital heart disease, renal dysplasia, skeletal abnormalities, and cerebellar malformation."
    explanation: Renal dysplasia in a neonate with a de novo WDR37 variant.
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individual 2 is a 15-year-old White (US) female born at term with multiple congenital anomalies including Dandy–Walker anomaly, thinning of the corpus callosum, atrial and ventricular septal defects, dysplastic right kidney"
    explanation: Dysplastic kidney in an individual with a de novo C-terminal variant.
- category: Renal
  name: Polycystic Kidney Dysplasia
  description: >-
    Reported in the individual with the splice variant, where the authors
    described it as a novel feature. It was left-sided and was seen on prenatal
    ultrasound at 31 weeks of gestation. The source says only "polycystic
    kidney"; it does not describe the cysts further.
  phenotype_term:
    preferred_term: Polycystic kidney
    term:
      id: HP:0000113
      label: Polycystic kidney dysplasia
  evidence:
  - reference: PMID:38044197
    reference_title: Splicing variant of WDR37 in a case of Neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient had novel phenotypes, anal atresia, and polycystic kidney, in addition to intellectual disability, seizures, cerebellar vermian anomaly, and coloboma, which are typical in NOCGUS."
    explanation: Polycystic kidney in the splice-variant case.
  - reference: PMID:38044197
    reference_title: Splicing variant of WDR37 in a case of Neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 31 weeks of gestation, ultrasonography had revealed a polycystic kidney and enlarged lateral ventricles of the brain."
    explanation: Prenatal detection of the kidney anomaly.
- category: Genitourinary
  name: Genitourinary Anomalies
  description: >-
    Genitourinary and genitorenal anomalies are part of the defining spectrum,
    but the founding abstracts do not specify them.
  phenotype_term:
    preferred_term: Genitourinary anomaly
    term:
      id: HP:0000119
      label: Abnormality of the genitourinary system
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:31327510
    reference_title: De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "poor post-natal growth; variable skeletal, cardiac, and genitourinary defects; and death in infancy in one individual"
    explanation: Genitourinary defects in the founding series, not further specified.
  - reference: PMID:32530092
    reference_title: Expanding the phenotypic spectrum consequent upon de novo WDR37 missense variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistent with the literature, intellectual disability, structural eye disorders, epilepsy, congenital heart disease, genitorenal anomalies and dysmorphic facial features were observed."
    explanation: Genitorenal anomalies in a later series.
- category: Gastrointestinal
  name: Anal Atresia
  description: >-
    Reported once, in the individual with the splice variant.
  phenotype_term:
    preferred_term: Anal atresia
    term:
      id: HP:0002023
      label: Anal atresia
  evidence:
  - reference: PMID:38044197
    reference_title: Splicing variant of WDR37 in a case of Neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient had novel phenotypes, anal atresia, and polycystic kidney, in addition to intellectual disability, seizures, cerebellar vermian anomaly, and coloboma, which are typical in NOCGUS."
    explanation: Anal atresia in the splice-variant case.
- category: Skeletal
  name: Scoliosis
  description: >-
    Skeletal involvement is mostly spinal; scoliosis is reported, and a more
    specific musculoskeletal phenotype was described with p.Thr115Ile.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her height and weight percentiles have varied over time, but have typically been on the low end of normal and she has scoliosis."
    explanation: Scoliosis in an individual with a de novo C-terminal variant.
  - reference: CGGV:assertion_f3eaff9e-978b-47a6-ad55-88edabc62064-2024-10-18T160000.000Z
    reference_title: "WDR37 / neurooculocardiogenitourinary syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "as well as skeletal (mostly spinal), genitourinary, and gastrointestinal anomalies, with feeding issues and poor growth"
    explanation: ClinGen's summary describes the skeletal involvement as mostly spinal.
- category: Skeletal
  name: Tapered Fingers
  phenotype_term:
    preferred_term: Tapered finger
    term:
      id: HP:0001182
      label: Tapered finger
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "they show stronger phenotypic overlap with the previously reported cases including seizures, hearing loss, scoliosis, heart defects, tapered fingers, and feeding disorder"
    explanation: Tapered fingers are listed among the features shared with earlier cases.
- category: Skeletal
  name: Single Transverse Palmar Crease
  phenotype_term:
    preferred_term: Single transverse palmar crease
    term:
      id: HP:0000954
      label: Single transverse palmar crease
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prominent clinodactyly of the fifth digits, and a single transverse crease on both hands"
    explanation: Bilateral single transverse palmar creases in an individual with a de novo variant.
- category: Auditory
  name: Sensorineural Hearing Impairment
  description: >-
    Sensorineural hearing loss, which can be congenital and severe, is reported
    in some individuals.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She has severe congenital sensorineural hearing loss of the left ear and auditory neuropathy spectrum disorder in the right ear."
    explanation: Congenital sensorineural hearing loss in an individual with a de novo variant.
- category: Gastrointestinal
  name: Feeding Difficulties
  phenotype_term:
    preferred_term: Poor feeding
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:31327510
    reference_title: De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "significant neurological impairment with structural brain defects and seizures; poor feeding; poor post-natal growth"
    explanation: Poor feeding in the founding series.
- category: Growth
  name: Postnatal Growth Retardation
  phenotype_term:
    preferred_term: Poor postnatal growth
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  evidence:
  - reference: PMID:31327510
    reference_title: De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "significant neurological impairment with structural brain defects and seizures; poor feeding; poor post-natal growth"
    explanation: Poor postnatal growth in the founding series.
- category: Growth
  name: Short Stature
  description: >-
    Recorded as its own row, separate from poor postnatal growth, in the 2021
    case table; mildly short stature is listed among the features consistent
    with the syndrome in the individual with p.Asp220Gly.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "his microcephaly, optic nerve hypoplasia, mildly short stature, and feeding disorder are consistent with WDR37 syndrome"
    explanation: Mildly short stature in an individual with a de novo variant, which the authors count as consistent with the syndrome.
genetic:
- name: WDR37
  gene_term:
    preferred_term: WDR37
    term:
      id: hgnc:31406
      label: WDR37
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  association: >-
    Heterozygous de novo WDR37 variants: missense changes in an N-terminal
    cluster upstream of the first WD40 repeat (p.Thr115 to p.Thr130), missense
    changes in a second cluster in and between WD40 repeats 2 and 3, and one
    in-frame splice variant.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_f3eaff9e-978b-47a6-ad55-88edabc62064-2024-10-18T160000.000Z
    evidence:
    - reference: CGGV:assertion_f3eaff9e-978b-47a6-ad55-88edabc62064-2024-10-18T160000.000Z
      reference_title: "WDR37 / neurooculocardiogenitourinary syndrome (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "WDR37 | HGNC:31406 | neurooculocardiogenitourinary syndrome | MONDO:0032850 | AD | Definitive"
      explanation: ClinGen Syndromic Disorders GCEP classifies the WDR37-NOCGUS relationship as Definitive (AD).
  evidence:
  - reference: CGGV:assertion_f3eaff9e-978b-47a6-ad55-88edabc62064-2024-10-18T160000.000Z
    reference_title: "WDR37 / neurooculocardiogenitourinary syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "At least 9 unique pathogenic/likely pathogenic variants (8 missense, 1 intronic deletion/splice) have been reported in 13 unrelated probands in five publications"
    explanation: ClinGen summary of the variant and proband count behind the Definitive classification.
  - reference: ORPHA:684305
    reference_title: Neurooculocardiogenitourinary syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "WDR37 | WD repeat domain 37 | hgnc:31406 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: >-
      Orphanet records WDR37 as the disease-causing gene. Its loss-of-function
      qualifier differs from ClinGen's dominant-negative reading; see the
      discussion on variant mechanism.
  notes: >-
    ClinGen's curation states that functional studies are consistent with a
    dominant-negative mechanism, Orphanet annotates the association as loss of
    function, and the 2021 functional study says the mechanism has not been
    established. functional_impact_category is therefore left unset.
inheritance:
- name: Autosomal Dominant
  description: >-
    Heterozygous variants, de novo in every individual with a pathogenic or
    likely pathogenic call. One inherited variant, from an unaffected mother, was
    classified as of uncertain significance by the reporting group.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: CGGV:assertion_f3eaff9e-978b-47a6-ad55-88edabc62064-2024-10-18T160000.000Z
    reference_title: "WDR37 / neurooculocardiogenitourinary syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "WDR37 was first reported in relation to autosomal dominant neurooculocardiogenitourinary syndrome (NOCGUS) in 2019"
    explanation: ClinGen records the disorder as autosomal dominant.
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The de novo variants identified in individuals 1 and 2 meet ACMG/AMP criteria to be considered likely pathogenic, but the significance of the inherited variant identified in Individual 3 is uncertain."
    explanation: The one inherited variant reported is of uncertain significance; the pathogenic calls are de novo.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    ClinGen counted 13 unrelated probands in five publications as of its 2024
    curation, and a 2026 review counts 13 reported individuals with WDR37
    variants. Later single case reports are not in either count. No
    population-based estimate exists, so no rate is given.
  evidence:
  - reference: CGGV:assertion_f3eaff9e-978b-47a6-ad55-88edabc62064-2024-10-18T160000.000Z
    reference_title: "WDR37 / neurooculocardiogenitourinary syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "At least 9 unique pathogenic/likely pathogenic variants (8 missense, 1 intronic deletion/splice) have been reported in 13 unrelated probands in five publications"
    explanation: Proband count in the published literature as of the ClinGen curation.
  - reference: PMID:42794636
    reference_title: "Is the Loss of Previously Acquired Skills a Feature of PACS1-, PACS2- and WDR37-Related Syndromes? A Systematized Narrative Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "To date, at least 113 patients with PACS1-associated syndrome (or Schuurs-Hoeijmakers syndrome), 32 with PACS2 and 13 with WDR37 have been reported"
    explanation: Literature count from a 2026 review.
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Orphanet worldwide point-prevalence class <1 / 1,000,000, sourced to the two
    founding papers.
  evidence:
  - reference: ORPHA:684305
    reference_title: Neurooculocardiogenitourinary syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:31327508,PMID:31327510"
    explanation: Orphanet epidemiology row.
progression:
- phase: Congenital and neonatal presentation
  notes: >-
    The structural anomalies of eye, brain, heart and kidney are present at
    birth, and severe ocular involvement can be recognised in the neonatal
    period. Orphanet records onset as neonatal or in infancy. One individual in
    a founding series died in infancy.
  evidence:
  - reference: PMID:42546896
    reference_title: Severe bilateral ocular coloboma and microphthalmia in a neonate with WDR37-associated neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case is notable for the severity and very early neonatal presentation of ocular involvement and further illustrates the phenotypic variability of WDR37-associated disease."
    explanation: Neonatal presentation of the ocular malformations.
  - reference: ORPHA:684305
    reference_title: Neurooculocardiogenitourinary syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Neonatal"
    explanation: Orphanet age-of-onset field.
  - reference: PMID:31327510
    reference_title: De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "poor post-natal growth; variable skeletal, cardiac, and genitourinary defects; and death in infancy in one individual"
    explanation: Infant death in one individual of the founding series.
- phase: Childhood course
  notes: >-
    Developmental delay, intellectual disability and seizures dominate
    childhood. Loss of acquired skills is not a recurrent feature: one possible
    case of skill loss is known among reported individuals with WDR37 variants,
    and the reviewers do not regard the PACS1-PACS2-WDR37 disorders as primarily
    regressive, but recommend longitudinal surveillance.
  evidence:
  - reference: PMID:42794636
    reference_title: "Is the Loss of Previously Acquired Skills a Feature of PACS1-, PACS2- and WDR37-Related Syndromes? A Systematized Narrative Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The remaining published literature on WDR37-associated disorder has not identified developmental regression as a recurrent clinical feature"
    explanation: Systematic review finding that regression is not a recurrent feature.
  - reference: PMID:42794636
    reference_title: "Is the Loss of Previously Acquired Skills a Feature of PACS1-, PACS2- and WDR37-Related Syndromes? A Systematized Narrative Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The available evidence does not support classifying these syndromes as primarily regressive disorders. However, the documented cases justify active surveillance and standardized longitudinal phenotypic characterization."
    explanation: The review's conclusion and surveillance recommendation for the PACS1-PACS2-WDR37 disorders.
diagnosis:
- name: Exome Sequencing
  description: >-
    The diagnosis is made by finding a heterozygous de novo WDR37 variant, in
    reported cases by trio or clinical exome sequencing. WDR37 has been
    recommended for intellectual disability, epilepsy and structural eye
    disorder gene panels.
  diagnosis_term:
    preferred_term: Whole Exome Sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:42546896
    reference_title: Severe bilateral ocular coloboma and microphthalmia in a neonate with WDR37-associated neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical exome sequencing identified a de novo pathogenic variant in the WDR37 gene, confirming the diagnosis."
    explanation: Clinical exome sequencing established the diagnosis.
  - reference: PMID:32530092
    reference_title: Expanding the phenotypic spectrum consequent upon de novo WDR37 missense variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We promote the inclusion of WDR37 on gene panels for intellectual disability, epilepsy and structural eye disorders."
    explanation: Recommendation to include WDR37 on diagnostic gene panels.
- name: RNA Analysis of Candidate Splice Variants
  description: >-
    An intronic WDR37 deletion outside the canonical splice sites was confirmed
    by RT-PCR to cause intron retention, so intronic variants near exon
    boundaries can be pathogenic.
  evidence:
  - reference: PMID:38044197
    reference_title: Splicing variant of WDR37 in a case of Neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reverse transcription polymerase chain reaction (RT-PCR) revealed intron retention of 63 base pairs before exon 10 in messenger RNA, which was predicted to insert 21 additional aberrant amino acids"
    explanation: RT-PCR confirmed the splicing effect of an intronic variant.
- name: Ophthalmologic Examination
  description: >-
    Early eye examination in a neonate with multiple congenital anomalies can
    point to the diagnosis.
  diagnosis_term:
    preferred_term: Eye Examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  evidence:
  - reference: PMID:42546896
    reference_title: Severe bilateral ocular coloboma and microphthalmia in a neonate with WDR37-associated neurooculocardiogenitourinary syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early ophthalmologic evaluation in neonates with multisystem congenital anomalies may provide important diagnostic clues to rare genetic syndromes."
    explanation: The authors recommend early ophthalmologic evaluation as a diagnostic clue.
differential_diagnoses:
- name: CHARGE syndrome
  disease_term:
    preferred_term: CHARGE syndrome
    term:
      id: MONDO:0008965
      label: CHARGE syndrome
  distinguishing_features:
  - >-
    Coloboma and the facial appearance overlap; the distinction is molecular.
  evidence:
  - reference: PMID:31327508
    reference_title: "De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia."
    explanation: The founding cohort's facial features were reminiscent of CHARGE syndrome.
- name: Schuurs-Hoeijmakers syndrome (PACS1)
  disease_term:
    preferred_term: Schuurs-Hoeijmakers syndrome
    term:
      id: MONDO:0014006
      label: Schuurs-Hoeijmakers syndrome
  distinguishing_features:
  - >-
    Caused by a recurrent de novo PACS1 variant in WDR37's main binding partner.
    Shares intellectual disability, facial features, coloboma, heart and
    genitourinary anomalies, but coloboma, heart defects, poor growth and
    genitourinary anomalies are more penetrant in NOCGUS, and microphthalmia,
    microcornea and Peters anomaly are more severe in NOCGUS.
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "while ocular coloboma, heart defects, poor growth, and genitourinary anomalies are noted in all three conditions, they are much more penetrant in WDR37 syndrome"
    explanation: Compares penetrance of shared malformations across the WDR37, PACS1 and PACS2 disorders.
  - reference: PMID:37064331
    reference_title: First Report of Mexican Patients with PACS1-Related Neurodevelopmental Disorder and Review of the PACS1-, PACS2-, and WDR37-Related Ophthalmological Manifestations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microphthalmia, microcornea, and Peters anomaly are found only among individuals with PACS1-related NDD and WDR37 syndrome, being more severe in the latter"
    explanation: Ocular findings that separate the PACS1 and WDR37 disorders by severity.
- 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 WDR37's other binding
    partner; shares epilepsy, intellectual disability, cerebellar anomalies and
    facial features.
  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 algorithms often match DEE66 and NOCGUS, so facial gestalt alone does not separate them.
animal_models:
- name: Drosophila wdr37 (CG12333) null
  species: Fruit fly
  genotype: CG12333/wdr37 coding region replaced with GAL4, homozygous
  publication: PMID:31327508
  description: >-
    Homozygous null flies are viable but bang-sensitive, have reduced grip
    strength and lose grip during copulation. Human reference WDR37 rescues
    these phenotypes; two patient alleles do not.
  modeled_mechanisms:
  - target: Neuronal Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      A seizure-associated behavioural phenotype that patient alleles fail to
      rescue, linking the human variants to loss of a conserved neuronal
      function.
    limitations: >-
      The model is a homozygous null in an invertebrate, whereas patients are
      heterozygous for missense or in-frame variants; it cannot test a dominant
      negative effect and has no counterpart of the eye, heart or kidney
      malformations.
    evidence:
    - reference: PMID:31327508
      reference_title: "De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies."
      explanation: The fly null phenotype that the model contributes.
- name: Zebrafish wdr37 CRISPR missense and frameshift alleles
  species: Zebrafish
  genotype: Heterozygous wdr37 missense (p.Ser129Phe, p.Ser129Cys, p.Ser129Tyr) or frameshift (p.Lys127Cysfs, p.Gln95Argfs) alleles
  publication: PMID:31327510
  description: >-
    Heterozygous missense alleles, including one matching the human
    p.Ser129Cys, caused poor growth and larval lethality, while heterozygous
    frameshift carriers survived to adulthood. Missense embryos upregulated
    cholesterol biosynthesis genes.
  modeled_mechanisms:
  - target: Impaired Embryonic Development of Multiple Organs
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Heterozygous missense alleles, as in patients, disturb vertebrate
      development where frameshift alleles do not.
    limitations: >-
      The published abstract reports growth and survival, not the specific eye,
      brain, heart or kidney malformations of the human disorder.
    evidence:
    - reference: PMID:31327510
      reference_title: De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Zebrafish carrying heterozygous missense variants demonstrated poor growth and larval lethality, while heterozygotes with frameshift alleles survived to adulthood"
      explanation: Allele-specific developmental effect in zebrafish.
  - target: Upregulated Cholesterol Biosynthesis Gene Expression
    relationship: MEASURES
    model_scale: MOLECULAR
    description: RNA-seq of missense embryos.
    evidence:
    - reference: PMID:31327510
      reference_title: De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "RNA-seq analysis of zebrafish embryos carrying a missense variant detected significant upregulation of cholesterol biosynthesis pathways."
      explanation: Transcriptomic readout in the missense model.
- name: Mouse Wdr37 or Pacs1 deletion
  species: Mouse
  genotype: Wdr37 or Pacs1 deletion identified by forward genetic screening
  publication: PMID:33630350
  description: >-
    Deletion of either gene causes peripheral lymphopenia with blunted ER
    calcium release after antigen receptor stimulation. The abstract reports no
    developmental, eye or neurological phenotype.
  modeled_mechanisms:
  - target: Impaired ER Calcium Release
    relationship: PERTURBS
    fidelity: UNKNOWN
    model_scale: CELLULAR
    description: >-
      Shows that the Pacs1-Wdr37 complex is needed for ER calcium handling in
      lymphocytes.
    limitations: >-
      A null allele studied in lymphocytes, not a NOCGUS variant in neural or
      developing tissue; no immune phenotype is reported in NOCGUS.
    evidence:
    - reference: PMID:33630350
      reference_title: Calcium flux control by Pacs1-Wdr37 promotes lymphocyte quiescence and lymphoproliferative diseases.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Deletion of Pacs1 or Wdr37 caused peripheral lymphopenia that was linked to blunted Ca2+ release from the ER after antigen receptor stimulation."
      explanation: The lymphocyte calcium finding the model contributes.
mechanistic_hypotheses:
- hypothesis_group_id: pacs_complex_dysfunction
  hypothesis_label: >-
    WDR37 variants act through the WDR37-PACS1-PACS2 complex
  status: EMERGING
  description: >-
    The clinical overlap with the PACS1 and PACS2 disorders and the mutual
    stabilisation of WDR37 and PACS1 suggest the variants act by disturbing the
    complex, possibly including its control of ER calcium release. Against a
    simple version of this, most tested WDR37 variants bind PACS1 and PACS2
    normally. Edges that depend on this hypothesis carry
    hypothesis_groups: [pacs_complex_dysfunction].
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The strong degree of phenotypic overlap as well as consistent evidence of interaction between WDR37 and PACS1/2 suggests that WDR37 may also be involved in protein transport and that the identified missense variants in these proteins disrupt their function through a dominant negative mechanism."
    explanation: The authors' proposal linking the WDR37 disorder to PACS-mediated transport.
discussions:
- discussion_id: nocgus_variant_mechanism
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Do NOCGUS variants act by a dominant-negative effect, by loss of function,
    or by some other route, and do the N-terminal and C-terminal clusters act
    the same way?
  attaches_to:
  - pathophysiology#Abnormal WDR37 Protein Function
  - genetic#WDR37
  rationale: >-
    The sources disagree. ClinGen reads the functional data as consistent with a
    dominant-negative mechanism, which rests on the zebrafish contrast between
    lethal heterozygous missense alleles and viable heterozygous frameshift
    alleles and on preserved dimerization of variant proteins. Orphanet
    annotates the gene association as loss of function, and the fly rescue
    experiment shows the patient alleles have lost function. The 2021
    functional study states the mechanism has not been established. The two
    clusters also behave differently in cells: N-terminal variant proteins are
    expressed normally and C-terminal variant proteins at reduced levels. No
    truncating allele has been reported as causal.
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Although a dominant negative effect for the previously reported missense alleles has been suggested ( Kanca et al. 2019 ; Reis et al. 2019 ), the mechanism of action has not been established for either the previously reported or the novel variants reported here."
    explanation: The primary functional study leaves the mechanism open.
  - reference: CGGV:assertion_f3eaff9e-978b-47a6-ad55-88edabc62064-2024-10-18T160000.000Z
    reference_title: "WDR37 / neurooculocardiogenitourinary syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Functional studies are consistent with a dominant-negative mechanism of disease predominantly due to missense variants."
    explanation: ClinGen's reading of the functional data.
  - reference: ORPHA:684305
    reference_title: Neurooculocardiogenitourinary syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "WDR37 | WD repeat domain 37 | hgnc:31406 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet's gene-association qualifier, which differs from ClinGen's.
- discussion_id: nocgus_pacs_axis_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does a NOCGUS variant disturb PACS1 or PACS2 function, ER calcium handling
    or protein trafficking in neural or developing ocular cells?
  attaches_to:
  - pathophysiology#Altered WDR37-PACS1-PACS2 Complex Function
  - pathophysiology#Impaired ER Calcium Release
  rationale: >-
    The WDR37-PACS1 complex and its role in ER calcium release are shown with
    null alleles, in mouse lymphocytes and in C. elegans. No experiment cited
    here has put a NOCGUS variant into neurons or eye tissue and measured these
    processes, and no vertebrate knock-in of a human variant has been
    characterised for the eye, brain and heart malformations. Until then the
    mechanism nodes between the variant and the malformations are inferred.
  evidence:
  - reference: PMID:34642815
    reference_title: "WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Further work is needed to determine the role of PACS binding in the normal function of WDR37 and the mechanism of action for various pathogenic variants in WDR37."
    explanation: The functional study names this as the open question.
notes: >-
  No GeneReviews chapter covers this disorder. No treatment study,
  natural-history study or management guideline was found, so the entry has no
  treatments section. The N-terminal and C-terminal variant clusters and the
  splice variant are curated as one disease rather than as subtypes: ClinGen
  includes all three in this disease, and the C-terminal series differs mainly
  in milder ocular involvement in three individuals, too few to establish a
  separate entity. Phenotype frequencies are not given because the published
  case table is small and no source states frequencies in prose.
📚

References & Deep Research

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Neurooculocardiogenitourinary Syndrome (NOCGUS) — Comprehensive Disease Report
openscientist-autonomous 15 citations 2026-11-05T18:32:27.590769

Neurooculocardiogenitourinary Syndrome (NOCGUS) — Comprehensive Disease Report

Disease: Neurooculocardiogenitourinary Syndrome (NOCGUS) Causal gene: WDR37 (WD repeat–containing protein 37; HGNC:31406; NCBIGene:22884; Ensembl ENSG00000047056; UniProt Q9Y2I8) OMIM: #618652 · MONDO: 0032850 · Orphanet: 684305 · DOID: 0111675 · GARD: 0027365 · UMLS: C5231443 · MedGen: 1684841

Summary

Neurooculocardiogenitourinary syndrome (NOCGUS) is a rare, severe, autosomal-dominant multisystem developmental disorder caused by de novo missense variants (and rare splice variants) that cluster in the conserved N-terminal region upstream of the WD40 repeat domain of the WDR37 gene (chromosome 10p13; protein UniProt Q9Y2I8, 494 amino acids with seven WD40 repeats). The disorder was defined simultaneously in 2019 by two independent cohorts — Reis et al. (American Journal of Human Genetics) and Kanca et al. — who reported unrelated probands with de novo variants in a narrow N-terminal mutational hotspot. The name "neurooculocardiogenitourinary" is an acronym for the four organ systems most consistently involved: the nervous system (epilepsy, intellectual disability, absent speech, cerebellar hypoplasia), the eye (coloboma, microphthalmia, Peters/anterior-segment anomalies), the heart (septal defects), and the genitourinary tract (cryptorchidism, renal dysplasia).

The clinical picture is defined by near-universal epilepsy, global developmental delay/intellectual disability with absent speech, a recognizable facial gestalt reminiscent of CHARGE syndrome, and the hallmark ocular feature of coloboma. Severity is highly variable, ranging from infantile lethality with complex multisystem malformation at one extreme to milder developmental delay at the other. Mechanistically, WDR37 is a binding partner of the phosphofurin acidic cluster sorting proteins PACS1 and PACS2; the WDR37–PACS1–PACS2 axis governs intracellular protein trafficking and endoplasmic-reticulum (ER) calcium handling. NOCGUS, PACS1 (Schuurs-Hoeijmakers) syndrome, and PACS2 syndrome form an overlapping clinical-molecular spectrum sharing epilepsy, intellectual disability, cerebellar atrophy, distinctive facies, and coloboma.

Importantly, population constraint data and model-organism genetics argue that NOCGUS does not arise from simple haploinsufficiency. WDR37 is constrained against loss-of-function (gnomAD LOEUF 0.412, pLI 0.57), all pathogenic alleles are clustered de novo missense (not truncating), and a Drosophila wdr37 null is homozygous viable. Mutant WDR37 protein is correctly localized but expressed at reduced levels, favoring a gain-of-function or dominant-negative mechanism. There is currently no disease-modifying therapy; management is entirely supportive and multidisciplinary.

Section 1 — Disease Information

Overview. NOCGUS is a congenital, autosomal-dominant, multisystemic malformation/neurodevelopmental syndrome. The acronym reflects the organ systems named in the disorder: neuro (brain/seizures/cognition), oculo (eye), cardio (heart), and genitourinary (kidneys, genitalia). Kanca et al. summarized the neurodevelopmental core as "epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia" (PMID: 31327508).

Key identifiers.

Resource Identifier
OMIM #618652
MONDO MONDO:0032850
Orphanet 684305
Disease Ontology (DOID) 0111675
GARD 0027365
UMLS C5231443
MedGen 1684841
Causal gene WDR37 (HGNC:31406; NCBIGene:22884; Ensembl ENSG00000047056; UniProt Q9Y2I8)

Synonyms / alternative names. Official abbreviation NOCGUS; "WDR37 syndrome"; "WDR37-related disorder"; "WDR37-associated neurooculocardiogenitourinary syndrome." No synonyms were originally recorded in the source template; the above are established in the literature and MONDO cross-references.

Source of information. Information is derived from aggregated disease-level resources (OMIM, Orphanet, MONDO, HPO) and from individual-patient case reports/case series published in the primary literature (Reis 2019, Kanca 2019, Hay 2020, and subsequent single-case reports). This is an ultra-rare disorder with an estimated <60 published patients; all knowledge is case-based rather than from EHR-scale or registry cohorts.

Section 2 — Etiology

Disease causal factors. NOCGUS is a monogenic (Mendelian) disorder. The primary cause is a heterozygous, almost always de novo, pathogenic variant in WDR37. There is no known environmental, infectious, or multifactorial contribution. Reis et al. reported "four de novo missense variants predicted to affect the N-terminal region of WDR37—p.Ser119Phe, p.Thr125Ile, p.Ser129Cys, and p.Thr130Ile—in unrelated individuals with a previously unrecognized syndrome" (PMID: 31327510). Kanca et al. "identified five pediatric probands with de novo variants in WDR37" (PMID: 31327508).

Genetic risk factors. The sole known genetic cause is a de novo pathogenic WDR37 variant in the N-terminal mutational hotspot. No susceptibility loci or modifier genes have been formally established. Because variants are de novo, there are effectively no inherited risk alleles in the general population.

Environmental risk factors. None identified. Advanced paternal age is a theoretical contributor to de novo mutation burden generally, but has not been specifically studied in NOCGUS.

Protective factors. None identified (genetic or environmental). WDR37 is constrained against loss-of-function (see Section 4), but this reflects gene essentiality rather than a protective allele.

Gene–environment interactions. None described. As a fully penetrant de novo Mendelian malformation syndrome, NOCGUS has no documented GxE component.

Section 3 — Phenotypes

Phenotype frequencies below come from the official HPO annotation set for OMIM:618652 (frequencies derived primarily from the Kanca et al. cohort, PMID: 31327508), supplemented by Reis et al. and later case reports.

Neurological phenotypes (near-universal)

Phenotype HPO term Frequency Notes
Seizure / epilepsy HP:0001250 5/5 Often early infantile onset
Intellectual disability HP:0001249 4/4 Typically moderate–severe
Global developmental delay HP:0001263 4/4
Absent speech HP:0001344 4/4
Cerebellar hypoplasia / vermian anomaly HP:0001321 Frequent Structural brain malformation

Ocular phenotypes (hallmark)

Phenotype HPO term Frequency Notes
Coloboma HP:0000589 4/5 Iris, retinal, choroidal; the hallmark feature
Microphthalmia HP:0000568 3/5
Peters anomaly / anterior-segment dysgenesis HP:0000659 1/5 Corneal opacity
Microcornea HP:0000482 Variable

Craniofacial / dysmorphic (CHARGE-like)

Phenotype HPO term Frequency
Abnormal palmar crease HP:0010490 5/5
Prominent nasal bridge HP:0000426 5/5
Downturned corners of mouth HP:0002714 5/5
Smooth philtrum HP:0000319 4/4

Cardiac

Phenotype HPO term Frequency
Ventricular septal defect (most common CHD) HP:0001629 3/5
Atrial septal defect HP:0001631 2/5
Patent ductus arteriosus HP:0001643 2/5

Genitourinary

Phenotype HPO term Frequency
Bilateral cryptorchidism HP:0008689 2/2 (males)
Renal dysplasia / polycystic kidney HP:0000110 / HP:0000113 Reported in severe cases

Other

  • Sensorineural hearing impairment (HP:0000407) — 2/4
  • Poor feeding and poor postnatal growth — frequent (Reis 2019)
  • Anal atresia — reported in a splice-variant case (Samejima 2024, PMID: 38044197)

Phenotype characteristics. Onset is congenital/neonatal for malformations (coloboma, CHD, cerebellar anomaly) and infantile for epilepsy. Severity is highly variable — Reis et al. reported "death in infancy in one individual," whereas Hay et al. (2020) expanded the spectrum "to include those with milder developmental delay" (PMID: 32530092). The course is generally stable/non-progressive developmentally; a systematic review found that regression/skill loss is uncommon and the syndromes should not be classified as primarily regressive (PMID: 42794636).

Quality-of-life impact. Severe, lifelong. Combined intellectual disability, absent speech, epilepsy, and visual impairment produce profound dependence for daily functioning. No disease-specific QoL instrument data (EQ-5D/SF-36/PROMIS) exist for this ultra-rare disorder.

Section 4 — Genetic / Molecular Information

Causal gene. WDR37 (HGNC:31406; NCBIGene:22884; Ensembl ENSG00000047056; canonical transcript ENST00000358220). Genomic location chr10:1,095,478–1,178,237 (GRCh37), 10p13. Protein UniProt Q9Y2I8 (WDR37_HUMAN), 494 amino acids, with seven WD40 repeats and predominantly cytoplasmic localization.

Pathogenic variants. The founding variants were all de novo missense changes in a tight N-terminal cluster upstream of the WD40 domain:

Variant (protein) Source
p.Ser119Phe Reis 2019 (PMID: 31327510)
p.Thr125Ile Reis 2019
p.Ser129Cys Reis 2019
p.Thr130Ile Reis 2019
p.Thr115Ile Hay 2020 (PMID: 32530092)
p.Ser119Tyr Hay 2020
c.727-27_727-24del (intronic, aberrant splicing → p.S242_I243ins21aa) Samejima 2024 (PMID: 38044197)

Hay et al. noted the variants "fall within a highly conserved region upstream of the WD-repeat domains, within an apparent mutation cluster." Sorokina et al. (2021) identified a distinct new cluster of disease-associated variants and performed functional analyses of mutant proteins (PMID: 34642815).

  • Variant classification (ACMG/AMP): Pathogenic / Likely pathogenic (de novo occurrence + hotspot clustering + absence from population databases). ClinVar (queried Nov 2026) contains ~228 WDR37 records, dozens classified Pathogenic/Likely pathogenic.
  • Variant type/class: predominantly missense; one intronic splice variant.
  • Allele frequency: pathogenic alleles are absent from gnomAD (de novo).
  • Somatic vs germline: germline de novo.
  • Functional consequence: mutant protein is correctly localized but expressed at reduced levels — consistent with gain-of-function or dominant-negative rather than haploinsufficiency.

Non-haploinsufficiency mechanism (Finding F004). WDR37 is constrained against loss-of-function: gnomAD v2.1.1 reports observed/expected LoF = 0.209 (90% CI 0.113–0.412; LOEUF 0.412), LoF Z = 3.93, pLI = 0.57; missense o/e = 0.637 (Z = 2.31). Critically, all known pathogenic alleles are de novo missense (or one splice) clustered in the N-terminal/WD40 region, not truncating. Kanca et al. showed a Drosophila wdr37 null "are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies" (PMID: 31327508) — a homozygous-viable null supports that loss-of-function alone is not the human disease mechanism.

Modifier genes. None established. Given the WDR37–PACS1–PACS2 interaction, PACS1/PACS2 are candidate biological modulators but have not been shown to modify NOCGUS severity.

Epigenetic information. No disease-specific methylation/histone signature has been reported for NOCGUS.

Chromosomal abnormalities. None; NOCGUS is caused by point/small variants, not by large CNVs.

Section 5 — Environmental Information

No environmental, lifestyle, or infectious factors contribute to NOCGUS. It is a fully penetrant monogenic de novo disorder. This section is not applicable.

Section 6 — Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation)

  1. A de novo missense variant arises in the conserved N-terminal region (hotspot ~aa 115–130) of WDR37 → leads to an amino-acid substitution in the WDR37 protein near its WD40 β-propeller platform.
  2. The variant protein is correctly localized to the cytoplasm but expressed at reduced levels → results in altered WDR37 dosage/activity (not complete loss). [Inferred from functional studies; Sorokina 2021]
  3. Because WDR37 binds PACS1 and PACS2 and the two proteins are mutually required for stable expression, perturbed WDR37 → destabilizes the WDR37–PACS1–PACS2 complex that recognizes cargo and controls sorting. [Demonstrated: co-IP, cryo-EM]
  4. Disruption of this complex → impairs intracellular protein trafficking and ER calcium flux normally controlled by Pacs1–Wdr37. [Demonstrated in mouse: Nair-Gill 2021]
  5. Branch A (development): dysregulated trafficking/calcium signaling during organogenesis → impairs development of neural crest– and neuroectoderm-derived structures → coloboma, anterior-segment dysgenesis, cerebellar hypoplasia, CHARGE-like facies, cardiac septal and genitourinary malformations. [Inferred from phenotype convergence across the WDR37–PACS1–PACS2 axis]
  6. Branch B (neuronal excitability): altered ER calcium handling and neuronal function → lowers seizure threshold → epilepsy (paralleled by bang-sensitivity in the Drosophila null). [Model-organism supported]
  7. Combined developmental and functional CNS disruption → intellectual disability, developmental delay, absent speech — the clinical endpoint.

Molecular detail

  • Molecular pathways / protein interactions. Sorokina et al. showed "the ability of WDR37 to form homodimers and to strongly bind PACS1 and PACS2 phosphofurin acidic cluster sorting proteins; immunocytochemistry confirmed colocalization of WDR37 with PACS1 and PACS2 in human cells" (PMID: 34642815). Xiao et al. solved the cryo-EM structure: "Pacs1 binds Wdr37 through a conserved interface within its furin-binding region (FBR)… This interaction stabilizes Wdr37 and is critical for the expression of both proteins" (PMID: 41279321).
  • Cellular processes. ER calcium homeostasis; protein cargo sorting/trafficking; lymphocyte quiescence. Nair-Gill et al. demonstrated "Calcium flux control by Pacs1-Wdr37 promotes lymphocyte quiescence" (PMID: 33630350).
  • Protein dysfunction. WD40 β-propeller scaffold protein; variant substitutions in the N-terminal FBR-interacting region reduce stability and likely perturb complex assembly (dominant-negative/gain-of-function).
  • Shared axis. Yamamoto et al. proposed that "dysregulation of the WDR37-PACS1-PACS2 axis results in a spectrum that is recognizable by intellectual disability, distinctive facial features, and coloboma," and that "this group of genes may be involved in ocular development" (PMID: 33369122).

Suggested ontology terms

  • GO biological process: protein targeting (GO:0006605); intracellular protein transport (GO:0006886); regulation of ER calcium ion concentration (GO:0032469); calcium ion transport (GO:0006816).
  • GO cellular component: cytoplasm (GO:0005737); endoplasmic reticulum (GO:0005783).
  • CL cell types: neuron (CL:0000540); neural crest cell (CL:0000333); cerebellar Purkinje cell (CL:0000121); lymphocyte (CL:0000542).

Section 7 — Anatomical Structures Affected

Organ level (primary). - Brain (UBERON:0000955) — cerebellum (UBERON:0002037), especially vermis; cerebral cortex. - Eye (UBERON:0000970) — iris, retina, choroid (coloboma), cornea/anterior segment, globe (microphthalmia). - Heart (UBERON:0000948) — interventricular/interatrial septa. - Kidney (UBERON:0002113) and male genitalia (testis, UBERON:0000473).

Secondary / body-system involvement. Nervous (CNS), visual, cardiovascular, genitourinary/renal, musculoskeletal (skeletal anomalies; Hay 2020), auditory (sensorineural hearing loss), and gastrointestinal (anal atresia in one case).

Tissue / cell level. Neuroectoderm- and neural crest–derived tissues are prominently affected, consistent with the coloboma + craniofacial + cardiac-outflow + enteric pattern (a "neurocristopathy-like" distribution). Cerebellar Purkinje/granule neurons implicated by cerebellar hypoplasia.

Subcellular level. Cytoplasm (GO:0005737); endoplasmic reticulum (GO:0005783) — site of PACS1–WDR37 calcium-flux control.

Localization / lateralization. Ocular and genitourinary findings are typically bilateral (e.g., bilateral microphthalmia/coloboma, bilateral cryptorchidism), though severity can be asymmetric.

Section 8 — Temporal Development

  • Onset: Congenital (structural malformations present at birth; a neonatal case showed severe bilateral ocular abnormalities identified at birth — PMID: 42546896). Epilepsy is typically early infantile.
  • Onset pattern: congenital/insidious for developmental features; seizures may present acutely.
  • Progression: Developmentally stable/non-progressive in most patients; regression is uncommon and does not define the disorder (PMID: 42794636).
  • Disease course: chronic, lifelong. Severity spans infantile lethality (Reis 2019) to milder delay (Hay 2020).
  • Critical periods: organogenesis (first trimester) is the window during which the malformations (eye, heart, cerebellum, kidney) are established — making prenatal/early mechanisms the key vulnerability window.

Section 9 — Inheritance and Population

  • Inheritance: Autosomal dominant (HP:0000006), essentially always via de novo variants. Recurrence risk for unaffected parents is low (germline mosaicism not formally documented but theoretically possible).
  • Penetrance: Complete for the molecular/malformation phenotype among reported probands.
  • Expressivity: Highly variable (infantile lethal → mild DD).
  • Epidemiology: No prevalence/incidence estimate exists; ultra-rare, with <60 published patients worldwide as of 2026. Orphanet lists it without a prevalence class.
  • Founder effects / consanguinity: Not applicable (de novo).
  • Carrier frequency: Not applicable (de novo; constrained gene, no common pathogenic alleles).
  • Population demographics: Reported across diverse populations (Caucasian — Hay 2020; Mexican patients — PMID: 37064331; Japanese — Samejima 2024). No ethnic predilection.
  • Sex ratio: No established skew; genitourinary features (cryptorchidism) are male-specific.

Section 10 — Diagnostics

Genetic testing (definitive). Diagnosis rests on identifying a de novo pathogenic WDR37 variant. Recommended approaches: - Whole-exome sequencing (WES) — the primary diagnostic modality; most reported cases were ascertained by trio exome (e.g., "Clinical exome sequencing identified a de novo pathogenic variant in the WDR37 gene, confirming the diagnosis," PMID: 42546896). - Whole-genome sequencing (WGS) — useful to detect deep intronic/splice variants (as in the c.727-27_727-24del splice case, PMID: 38044197); RT-PCR confirmed aberrant splicing in that patient. - Multigene panels — WDR37 should be included on panels for intellectual disability, epilepsy, and structural eye disorders; Hay et al. explicitly "promote the inclusion of WDR37 on gene panels for intellectual disability, epilepsy and structural eye disorders." - Trio analysis confirms de novo status, strongly supporting pathogenicity (ACMG PS2). - CMA/karyotype/FISH are generally unrevealing (no CNV mechanism).

Clinical / imaging workup. Brain MRI (cerebellar hypoplasia/vermian anomaly); detailed ophthalmologic exam (coloboma, microphthalmia, anterior-segment dysgenesis); echocardiography (septal defects); renal ultrasound; hearing evaluation. "Early ophthalmologic evaluation in neonates with multisystem congenital anomalies may provide important diagnostic clues to rare genetic syndromes" (PMID: 42546896).

Biomarkers / omics. No validated biochemical biomarker or clinical omics test for NOCGUS.

Differential diagnosis. CHARGE syndrome (facial overlap), PACS1 (Schuurs-Hoeijmakers) syndrome, PACS2 syndrome, and other coloboma/anterior-segment-dysgenesis disorders. Coloboma is a shared feature across the WDR37–PACS1–PACS2 axis (PMID: 33369122).

Screening. No newborn or carrier screening (de novo, ultra-rare).

Section 11 — Outcome / Prognosis

  • Survival/mortality: Variable. At least one infant died in infancy (Reis 2019); severe neonatal presentations with complex CHD, renal dysplasia, and cerebellar malformation carry high early mortality. Milder cases survive into childhood/adulthood (an affected adult is reported in the axis-overlap literature).
  • Morbidity/function: Profound — lifelong intellectual disability, absent speech, refractory epilepsy risk, and visual impairment produce severe disability and full-care dependence.
  • Complications: Seizure-related morbidity, feeding difficulties/failure to thrive, visual loss, cardiac and renal complications.
  • Recovery: No recovery of the underlying developmental deficits; developmentally stable with supportive care.
  • Prognostic factors: Degree of structural malformation (especially CHD severity, renal involvement, cerebellar malformation) and seizure control drive outcome. No molecular prognostic biomarker beyond the general severity-by-variant correlations suggested within the hotspot.

Section 12 — Treatment

No disease-modifying therapy exists. Management is entirely supportive, symptomatic, and multidisciplinary:

  • Pharmacotherapy: Antiseizure medications for epilepsy (agent choice per seizure semiology; no NOCGUS-specific regimen). NCIT: Anticonvulsant Agent (C264).
  • Surgical/interventional: Repair of congenital heart defects (VSD/ASD/PDA); orchidopexy for cryptorchidism; management of anal atresia/urological anomalies; ophthalmologic surgery as indicated.
  • Supportive/rehabilitative: Early developmental intervention, physical/occupational/speech therapy (AAC given absent speech), feeding support (NG/gastrostomy for poor feeding), low-vision services, hearing aids/audiologic support.
  • Advanced therapeutics / pharmacogenomics / experimental trials: None reported; no NCT-registered trials specific to NOCGUS. Antisense-oligonucleotide and client-protein-targeting strategies have been proposed conceptually for the related PACS1 disorder (given its gain-of-function/dominant-negative mechanism, PMID: 36077045) and are a plausible future direction for WDR37, but remain theoretical.

NCIT suggestions: Supportive Care (C133453); Anticonvulsant Agent (C264); Physical Therapy (C15321); Occupational Therapy (C15317); Speech Therapy (C15349); Surgical Procedure (C15329).

Section 13 — Prevention

  • Primary prevention: Not possible (de novo mutation).
  • Secondary prevention: Early multisystem surveillance (cardiac, renal, ophthalmologic, audiologic, developmental) after diagnosis to detect and treat complications.
  • Tertiary prevention: Seizure control, feeding/nutrition optimization, vision/hearing support, and developmental therapies to limit secondary disability.
  • Genetic counseling: Essential. Recurrence risk for parents of an affected de novo child is low but non-zero (germline mosaicism cannot be excluded); affected individuals rarely reproduce. Prenatal/preimplantation testing is feasible once a familial variant is known.
  • Immunization / public-health / behavioral / environmental prevention: Not applicable.

Section 14 — Other Species / Natural Disease

  • Orthologous genes. Wdr37 exists in mouse (Mus musculus, NCBI Taxon 10090), fly (Drosophila melanogaster, Taxon 7227), and C. elegans (Taxon 6239, ortholog wdr-37). The PACS–WDR37 interaction is evolutionarily conserved: in C. elegans, "cePACS-1 and ceWDR-37 colocalize to somatic cytoplasm… and are mutually required for expression, supporting a conclusion that the intermolecular dependence… is evolutionarily conserved" (PMID: 39031646).
  • Natural disease / veterinary relevance. No naturally occurring NOCGUS-equivalent disease has been reported in companion animals or wildlife (not in OMIA). WDR37 appears as a candidate gene in livestock growth-trait GWAS (Korean native chickens PMID: 34440344; Dongliao black pigs PMID: 40665728), but these are unrelated QTL associations, not the human syndrome.
  • Zoonotic potential: None (genetic disorder).

Section 15 — Model Organisms

Model System Key finding Reference
Drosophila melanogaster wdr37 null Homozygous viable but severe bang sensitivity (seizure-associated phenotype) — supports non-haploinsufficiency and links WDR37 to neuronal excitability Kanca 2019 PMID: 31327508
Mus musculus Pacs1–Wdr37 Controls ER calcium flux to promote lymphocyte quiescence; loss predisposes to lymphoproliferative disease Nair-Gill 2021 PMID: 33630350
C. elegans wdr-37 / pacs-1 Conserved colocalization and mutual requirement for expression; human PACS1 complements worm PACS-1 in neurons; variant editing alters neuronal localization PMID: 39031646
In vitro (human cells) Overexpression / co-IP / ICC WDR37 homodimerizes, binds PACS1/PACS2, colocalizes; variant proteins analyzed functionally Sorokina 2021 PMID: 34642815
Cryo-EM (recombinant) Pacs1–Wdr37 complex Structural basis of assembly; Pacs1 FBR interface stabilizes Wdr37 Xiao 2025 PMID: 41279321

Phenotype recapitulation. No mouse knock-in of the human N-terminal hotspot variants has been reported; existing models capture molecular (complex assembly, calcium flux) and partial neuronal (seizure-like bang sensitivity) aspects rather than the full multisystem malformation syndrome. Model limitation: the developmental malformation spectrum (coloboma, CHD, cerebellar hypoplasia) has not been fully reproduced in a vertebrate genetic model of the specific human variants.

Mechanistic Model (synthesis)

 de novo WDR37 missense (hotspot aa ~115–130, N-terminal, upstream of WD40)
         │
         ▼
   Mutant WDR37 protein: correctly localized, REDUCED expression/stability
 (gain-of-function / dominant-negative — NOT haploinsufficiency)
         │
         ▼
   Destabilized WDR37–PACS1–PACS2 complex (Pacs1 FBR interface; cryo-EM)
         │
  ┌──────────────┴───────────────┐
  ▼                              ▼
  Impaired cargo trafficking     Dysregulated ER Ca²⁺ flux
  │                              │
  ▼                              ▼
  Faulty organogenesis of         Altered neuronal excitability
  neuroectoderm/neural-crest      → lowered seizure threshold
  derivatives                              │
  │                                ▼
  ▼                            EPILEPSY
  Coloboma, anterior-segment
  dysgenesis, cerebellar
  hypoplasia, CHARGE-like facies,
  septal CHD, GU anomalies
  │
  └────────────► Intellectual disability, absent speech,
         global developmental delay

The upstream, demonstrated steps are the physical WDR37–PACS1/2 interaction and the calcium-flux/lymphocyte function (in vitro and mouse). The downstream developmental branch (how trafficking/calcium dysregulation produces coloboma and the organ malformations) is inferred from phenotypic convergence across the WDR37–PACS1–PACS2 axis rather than directly demonstrated.

Evidence Base

PMID Title (abbrev.) Contribution
31327510 De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome Founding cohort; 4 de novo N-terminal missense variants; defines multisystem phenotype incl. infantile lethality
31327508 De Novo Variants in WDR37… Epilepsy, Colobomas… Cerebellar Hypoplasia Independent cohort (5 probands); Drosophila null (homozygous viable, bang-sensitive); HPO frequency source
34642815 WDR37 syndrome… functional analyses of mutant proteins Homodimerization; strong PACS1/PACS2 binding; new variant cluster
41279321 Structural Basis for Pacs1-Wdr37 Complex Assembly and Stability Cryo-EM; Pacs1 FBR interface stabilizes Wdr37; mutual expression dependence
33630350 Calcium flux control by Pacs1-Wdr37… Functional role in ER Ca²⁺ flux and lymphocyte quiescence (mouse)
33369122 Coloboma… WDR37-PACS1-PACS2 axis Establishes the shared clinical-molecular axis; coloboma as unifying feature
32530092 Expanding the phenotypic spectrum… de novo WDR37 Milder cases; p.Thr115Ile, p.Ser119Tyr; panel-inclusion recommendation
38044197 Splicing variant of WDR37… First splice variant; novel phenotypes (anal atresia, polycystic kidney)
42546896 Severe bilateral coloboma/microphthalmia in a neonate… Severe neonatal ocular/multisystem presentation; exome-confirmed
39031646 PACS-1 variant… C. elegans model Evolutionary conservation of PACS–WDR37 interaction
42794636 Loss of acquired skills in PACS1/PACS2/WDR37… Regression uncommon; not a primarily regressive disorder
36077045 Molecular basis of Schuurs-Hoeijmakers (PACS1)… Proposes gain-of-function/dominant-negative and ASO therapeutic concepts for the axis

Limitations and Knowledge Gaps

  1. Small N. All clinical knowledge derives from <60 published patients; frequency estimates (e.g., 5/5, 4/5) are from tiny cohorts and are statistically fragile.
  2. No prevalence/incidence data. Epidemiology is unquantified.
  3. Mechanism partly inferred. The link from WDR37–PACS1/2 complex disruption to the specific developmental malformations (coloboma, CHD) is based on phenotypic convergence, not direct experimental demonstration in a vertebrate model of the human variants.
  4. No knock-in animal model of the human N-terminal hotspot variants recapitulating the full syndrome.
  5. Genotype–phenotype correlations within the hotspot (why some variants are lethal and others mild) are unresolved.
  6. No biomarkers, no QoL data, no natural-history study, no therapy.

Proposed Follow-up Experiments / Actions

  1. Generate a knock-in mouse (or zebrafish) carrying a human hotspot variant (e.g., p.Ser119Phe) to test whether it reproduces coloboma, cerebellar hypoplasia, CHD, and seizures — directly testing the developmental branch of the model.
  2. Quantify the variant's effect on the WDR37–PACS1–PACS2 complex using the cryo-EM framework (Xiao 2025): measure complex stability, stoichiometry, and ER Ca²⁺ flux for each pathogenic variant to establish gain-of-function vs dominant-negative.
  3. Single-cell/spatial transcriptomics of developing eye and cerebellum in the model to define cell-type-specific consequences (Purkinje, neural crest, optic-fissure cells).
  4. Establish an international NOCGUS registry/natural-history study to obtain robust phenotype frequencies, survival, and genotype–phenotype correlations.
  5. Explore ASO / allele-selective knockdown of the mutant WDR37 allele (by analogy with PACS1 strategies, PMID: 36077045) as a proof-of-concept precision therapy if a dominant-negative/gain-of-function mechanism is confirmed.

Report compiled from OMIM, MONDO, HPO, gnomAD, UniProt, ClinVar, and primary literature. Evidence source types: human clinical case series/reports (Reis, Kanca, Hay, Samejima, neonate report, Mexican cohort); model organism (Drosophila, mouse, C. elegans); in vitro and structural (Sorokina, Xiao).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.5.1.

Outcome Count
References checked 15
Resolved 15
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 12
Quoted claims found in source 10
Quoted claims not found in source 2
References weighed for topical relevance 15
On topic 11
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

1 of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:41279321 (abstract only): "Pacs1 binds Wdr37 through a conserved interface within its furin-binding region (FBR)… This interaction stabilizes Wdr37 and is critical for the expression of both proteins"
  • closest text in source: "Pacs1 binds Wdr37 through a conserved interface within its furin-binding region (FBR), the domain previously linked to cargo recognition"
  • PMID:39031646: "cePACS-1 and ceWDR-37 colocalize to somatic cytoplasm… and are mutually required for expression, supporting a conclusion that the intermolecular dependence… is evolutionarily conserved"
  • closest text in source: "We show that cePACS-1 and ceWDR-37 colocalize to somatic cytoplasm of many types of cells and are mutually required for expression, supporting a conclusion that the intermolecular dependence of PACS1/PACS2/PACS-1 and WDR37/WDR-37 is evolutionarily conserved"

Term Validation

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

Outcome Count
Terms checked 41
Resolved 38
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 3
Terms whose name was checked 27
Terms named correctly 17
Terms named as a different term 3
Terms whose name is worth a second look 7

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:

  • MONDO:0032850 (1 mention) - the report calls it "MONDO"; MONDO calls it neurooculocardiogenitourinary syndrome
  • GO:0005737 (2 mentions) - the report calls it "GO cellular component: cytoplasm"; GO calls it cytoplasm**
  • CL:0000540 (1 mention) - the report calls it "CL cell types: neuron"; CL calls it neuron**

Terms whose name is worth a second look

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

  • HP:0001250 (1 mention) - the report calls it "Seizure / epilepsy"; HP calls it Seizure, and lists "Seizures" among its other names
  • HP:0001321 (1 mention) - the report calls it "Cerebellar hypoplasia / vermian anomaly"; HP calls it Cerebellar hypoplasia
  • HP:0000659 (1 mention) - the report calls it "Peters anomaly / anterior-segment dysgenesis"; HP calls it Peters anomaly
  • HP:0010490 (1 mention) - the report calls it "Abnormal palmar crease"; HP calls it Abnormal palmar crease morphology
  • HP:0001629 (1 mention) - the report calls it "Ventricular septal defect (most common CHD)"; HP calls it Ventricular septal defect, and lists "Ventricular septal defects" among its other names
  • GO:0006605 (1 mention) - the report calls it "GO biological process: protein targeting"; GO calls it protein targeting**
  • HP:0000006 (1 mention) - the report calls it "Autosomal dominant", "Inheritance: Autosomal dominant"; HP calls it Autosomal dominant inheritance, and lists "Autosomal dominant" among its other names

Terms named inconsistently

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

  • HP:0000006 - called "Autosomal dominant", "Inheritance: Autosomal dominant"

Prefixes with no resolver

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