Zaki Syndrome

Mendelian MONDO:0859209 Pathograph 19 Show in embeddings browser Multiple Congenital Anomalies Syndrome Wnt Signaling Disorder

Zaki syndrome (ZKS) is an ultra-rare autosomal recessive multiple congenital anomaly syndrome caused by biallelic variants in WLS, which encodes Wntless, the transmembrane cargo receptor that carries lipid-modified Wnt proteins from the endoplasmic reticulum and Golgi to the cell surface. WLS is needed to secrete every Wnt ligand, so its loss affects many developmental programs at once. The reported alleles are mostly missense variants that destabilize WLS and reduce, rather than abolish, Wnt secretion. Affected individuals have developmental delay or intellectual disability, postnatal microcephaly, short stature, a recognizable face with a wide mouth, alopecia, and variable eye, limb, renal, cardiac, dental and skeletal malformations, including iris coloboma, toe syndactyly, renal agenesis and heart defects. Knock-in mice reproduce tissue-specific developmental defects that follow each tissue's dependence on Wnt signaling, and a Wnt agonist given during pregnancy partially restored embryonic development in mice. It is distinct from Zaki-Gleeson syndrome, a DDX59-related disorder.

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1
Inheritance
3
Pathophys.
22
Phenotypes
19
Pathograph
1
Genes
4
Variants
2
Medical Actions
1
Differentials
1
Models
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic WLS variants, homozygous in most consanguineous families and compound heterozygous in some.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:40618129 SUPPORT Human Clinical
"Zaki syndrome is an autosomal recessive disorder caused by pathogenic variants in the WLS gene, which is essential for Wnt signaling."
States the recessive inheritance.
PMID:37005218 SUPPORT Human Clinical
"Whole-exome gene sequencing (WES) identified compound heterozygous variants in the WLS gene (c.1427A > G; p.Tyr476Cys and c.415C > T, p.Arg139Cys; NM_001002292) in a 16-year-old boy presenting with facial dysmorphism, astigmatism, renal agenesis, and cryptorchidism."
Compound heterozygosity also causes the disease.
⚙

Pathophysiology

3
Biallelic WLS Hypomorphic Variants
Two damaging WLS alleles are inherited. Most are missense variants in the transmembrane domains or near the C-terminal endoplasmic-reticulum targeting motif. They lower WLS protein stability, and p.Tyr478Cys has recurred in five patients.
WLS hgnc:30238 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves WLS (hgnc:30238). hgnc:30238 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
Wnt-protein binding GO:0017147 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased Wnt-protein binding (GO:0017147). GO:0017147 is a molecular function from the Gene Ontology.
Downstream
Reduced Wnt Ligand Secretion Less WLS means less transport of lipid-modified Wnt proteins to the cell surface.
Show evidence (2 references)
PMID:34587386 SUPPORT Human Clinical
"We identified homozygous mutations in WLS, which encodes the Wnt ligand secretion mediator (also known as Wntless or WLS) in 10 affected persons from 5 unrelated families."
Discovery of biallelic WLS variants in five families.
PMID:34587386 SUPPORT In Vitro
"The mutations affected WLS protein stability and Wnt signaling."
The patient alleles destabilize WLS.
Reduced Wnt Ligand Secretion
WLS is the only known route for secreting Wnt proteins, so the hypomorphic alleles reduce secretion of several Wnt ligands at once, including WNT3A.
Wnt protein secretion GO:0061355 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Wnt protein secretion (GO:0061355). GO:0061355 is a biological process from the Gene Ontology.
Downstream
Deficient Developmental Wnt Signaling Less secreted Wnt reduces Wnt signaling in receiving tissues during embryogenesis.
Show evidence (2 references)
PMID:34587386 SUPPORT BACKGROUND Other
"(The Wnt ligand secretion mediator is essential for the secretion of all Wnt proteins.)"
Background statement of WLS function, which explains why one gene affects many Wnt-dependent tissues.
PMID:37005218 SUPPORT In Vitro
"In vitro functional characterization showed that the two variants led to decreased WLS production and secretion of WNT3A, eventually affecting the WNT signal."
Measured reduction in WNT3A secretion with patient alleles.
Deficient Developmental Wnt Signaling
Each tissue is affected according to how strongly it depends on Wnt signaling during development, which explains the variable multi-organ pattern. Brain growth, limb patterning, eye, kidney, heart, hair and teeth are all Wnt-dependent.
Wnt signaling pathway GO:0016055 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Wnt signaling pathway (GO:0016055). GO:0016055 is a biological process from the Gene Ontology.
Animal models
Wls patient-variant knock-in mice Mouse recapitulates Tissue defects follow each tissue's Wnt dependence, and a Wnt agonist partially rescues development.
Downstream
Secondary microcephaly Reduced Wnt signaling in the developing brain limits brain growth.
Toe syndactyly Limb-bud patterning depends on Wnt signaling.
Renal agenesis Kidney development depends on Wnt signaling.
Iris coloboma Eye development depends on Wnt signaling.
Alopecia Hair follicle development depends on Wnt signaling.
Abnormal heart morphology Heart development depends on Wnt signaling.
Abnormal facial shape Craniofacial development depends on Wnt signaling.
Abnormality of the dentition Tooth development depends on canonical and non-canonical Wnt signaling.
Show evidence (1 reference)
PMID:34587386 SUPPORT Model Organism
"Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis."
In knock-in mice, which tissues fail tracks their dependence on Wnt signaling.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Zaki 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.
●

Phenotypes

22
Cardiovascular 1
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 (1 reference)
PMID:34587386 SUPPORT Human Clinical
"Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
Heart defects in the discovery cohort.
Eye 4
Iris coloboma HP:0000612 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Iris coloboma (HP:0000612). HP:0000612 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34587386 SUPPORT Human Clinical
"Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
Iris coloboma in the discovery cohort.
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:37106064 SUPPORT Human Clinical
"In a detailed clinical assessment, our patient also displayed microphthalmia, dental anomalies, skeletal dysplasia with spontaneous fractures and Dandy-Walker malformation."
Microphthalmia in the p.Gly527Arg patient.
Congenital blindness HP:0007875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital blindness (HP:0007875). HP:0007875 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42641982 SUPPORT Human Clinical
"Furthermore, our patient exhibited distinct clinical characteristics compared to previously reported cases, including hyperphagia, congenital blindness, clinodactyly, and early pubertal development."
Congenital blindness in the fourteenth reported patient.
Astigmatism HP:0000483 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Astigmatism (HP:0000483). HP:0000483 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37005218 SUPPORT Human Clinical
"Whole-exome gene sequencing (WES) identified compound heterozygous variants in the WLS gene (c.1427A > G; p.Tyr476Cys and c.415C > T, p.Arg139Cys; NM_001002292) in a 16-year-old boy presenting with facial dysmorphism, astigmatism, renal agenesis, and cryptorchidism."
Astigmatism in the compound heterozygous patient.
Genitourinary 2
Renal agenesis HP:0000104 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal agenesis (HP:0000104). HP:0000104 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34587386 SUPPORT Human Clinical
"Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
Renal agenesis in the discovery cohort.
PMID:37005218 SUPPORT Human Clinical
"Whole-exome gene sequencing (WES) identified compound heterozygous variants in the WLS gene (c.1427A > G; p.Tyr476Cys and c.415C > T, p.Arg139Cys; NM_001002292) in a 16-year-old boy presenting with facial dysmorphism, astigmatism, renal agenesis, and cryptorchidism."
Renal agenesis in an independent compound heterozygous patient.
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37005218 SUPPORT Human Clinical
"Whole-exome gene sequencing (WES) identified compound heterozygous variants in the WLS gene (c.1427A > G; p.Tyr476Cys and c.415C > T, p.Arg139Cys; NM_001002292) in a 16-year-old boy presenting with facial dysmorphism, astigmatism, renal agenesis, and cryptorchidism."
Cryptorchidism in the compound heterozygous patient.
Head and Neck 5
Secondary microcephaly HP:0005484 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postnatal microcephaly, annotated with Secondary microcephaly (HP:0005484), qualified as course progressive. HP:0005484 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:42641982 SUPPORT Human Clinical
"A comparison of all reported ZKS patients suggests that this syndrome displays a recognizable pattern of developmental delay, intellectual disability, postnatal microcephaly, facial dysmorphism, skeletal and ocular anomalies, and short stature."
Postnatal microcephaly is part of the recognizable pattern.
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 (1 reference)
PMID:34587386 SUPPORT Human Clinical
"Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
Facial dysmorphism in the discovery cohort.
Wide mouth HP:0000154 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide mouth (HP:0000154). HP:0000154 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40618129 SUPPORT INDIRECT Human Clinical
"Missense variants in the transmembrane region were associated with more cases of wide mouth and fewer cases of long fingers or toes."
A genotype-phenotype observation from the literature review, which shows wide mouth is a recurring feature.
Dandy-Walker malformation HP:0001305 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dandy-Walker malformation (HP:0001305). HP:0001305 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37106064 SUPPORT Human Clinical
"In a detailed clinical assessment, our patient also displayed microphthalmia, dental anomalies, skeletal dysplasia with spontaneous fractures and Dandy-Walker malformation."
Dandy-Walker malformation in the p.Gly527Arg patient.
Abnormality of the dentition HP:0000164 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dental anomalies, annotated with Abnormality of the dentition (HP:0000164). HP:0000164 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37106064 SUPPORT Human Clinical
"In a detailed clinical assessment, our patient also displayed microphthalmia, dental anomalies, skeletal dysplasia with spontaneous fractures and Dandy-Walker malformation."
Dental anomalies in the p.Gly527Arg patient.
Integument 1
Alopecia HP:0001596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alopecia (HP:0001596). HP:0001596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37106064 SUPPORT Human Clinical
"We identified a likely disease-causing variant in WLS (c.1579G>A, p.Gly527Arg) in a boy presented with a broad range of MCA including microcephaly, facial dysmorphism, alopecia, ophthalmologic anomalies, and complete soft tissue syndactyly."
Alopecia in an independent patient.
Limbs 3
Toe syndactyly HP:0001770 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Foot syndactyly, annotated with Toe syndactyly (HP:0001770). HP:0001770 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34587386 SUPPORT Human Clinical
"Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
Foot syndactyly in the discovery cohort.
Broad distal phalanx of finger HP:0009836 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad distal phalanges of the fingers, annotated with Broad distal phalanx of finger (HP:0009836). HP:0009836 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40618129 SUPPORT INDIRECT Human Clinical
"Variants near the ER signaling motif appeared more often with broad distal phalanges of the fingers."
A genotype-phenotype observation from the literature review, which shows broad distal phalanges are a recurring feature.
Clinodactyly HP:0030084 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clinodactyly (HP:0030084). HP:0030084 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42641982 SUPPORT Human Clinical
"Furthermore, our patient exhibited distinct clinical characteristics compared to previously reported cases, including hyperphagia, congenital blindness, clinodactyly, and early pubertal development."
Clinodactyly in the fourteenth reported patient.
Musculoskeletal 2
Abnormality of the skeletal system HP:0000924 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skeletal anomalies, annotated with Abnormality of the skeletal system (HP:0000924). HP:0000924 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:42641982 SUPPORT Human Clinical
"A comparison of all reported ZKS patients suggests that this syndrome displays a recognizable pattern of developmental delay, intellectual disability, postnatal microcephaly, facial dysmorphism, skeletal and ocular anomalies, and short stature."
Skeletal anomalies across reported patients, unspecified.
Skeletal dysplasia HP:0002652 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skeletal dysplasia (HP:0002652). HP:0002652 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37106064 SUPPORT Human Clinical
"In a detailed clinical assessment, our patient also displayed microphthalmia, dental anomalies, skeletal dysplasia with spontaneous fractures and Dandy-Walker malformation."
Skeletal dysplasia with fractures in the p.Gly527Arg patient.
Nervous System 3
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42641982 SUPPORT Human Clinical
"A comparison of all reported ZKS patients suggests that this syndrome displays a recognizable pattern of developmental delay, intellectual disability, postnatal microcephaly, facial dysmorphism, skeletal and ocular anomalies, and short stature."
Developmental delay is part of the recognizable pattern across reported patients.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42641982 SUPPORT Human Clinical
"A comparison of all reported ZKS patients suggests that this syndrome displays a recognizable pattern of developmental delay, intellectual disability, postnatal microcephaly, facial dysmorphism, skeletal and ocular anomalies, and short stature."
Intellectual disability is part of the recognizable pattern.
Polyphagia HP:0002591 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperphagia, annotated with Polyphagia (HP:0002591). HP:0002591 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42641982 SUPPORT Human Clinical
"Furthermore, our patient exhibited distinct clinical characteristics compared to previously reported cases, including hyperphagia, congenital blindness, clinodactyly, and early pubertal development."
Hyperphagia in the fourteenth reported patient.
Growth 1
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42641982 SUPPORT Human Clinical
"A comparison of all reported ZKS patients suggests that this syndrome displays a recognizable pattern of developmental delay, intellectual disability, postnatal microcephaly, facial dysmorphism, skeletal and ocular anomalies, and short stature."
Short stature is part of the recognizable pattern.
🧬

Genetic Associations

1
WLS (Causative)
Gene: WLS hgnc:30238 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is WLS (hgnc:30238). hgnc:30238 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:36374649 SUPPORT BACKGROUND Other
"Biallelic pathogenic variants in WLS are implicated in autosomal recessive Zaki syndrome (ZKS; MIM 619648), the only genetic condition known to be caused by pathogenic variants in WLS."
Background statement tying WLS to Zaki syndrome.
PMID:34587386 SUPPORT Human Clinical
"We identified homozygous mutations in WLS, which encodes the Wnt ligand secretion mediator (also known as Wntless or WLS) in 10 affected persons from 5 unrelated families."
Five unrelated families with biallelic WLS variants.
Variants (4)
NM_024911.7:c.1433A>G (p.Tyr478Cys)
MISSENSE
Recurrent allele, homozygous in five patients across more than one ancestry. It is the same residue as p.Tyr476Cys on NM_001002292: both RefSeq proteins carry the motif FFTGIY once, with the tyrosine at 476 in the 543-residue NM_001002292 product and at 478 in the 541-residue NM_024911.7 product, and the cDNA positions differ by the same 6 nt.
Show evidence (1 reference)
PMID:42641982 SUPPORT Human Clinical
"She represents the fifth ZKS patient identified with this variant, indicating a possible mutational hotspot."
Fifth patient homozygous for p.Tyr478Cys.
c.1579G>A (p.Gly527Arg)
MISSENSE
Homozygous in a boy with a severe phenotype.
Show evidence (1 reference)
PMID:37106064 SUPPORT Human Clinical
"We identified a likely disease-causing variant in WLS (c.1579G>A, p.Gly527Arg) in a boy presented with a broad range of MCA including microcephaly, facial dysmorphism, alopecia, ophthalmologic anomalies, and complete soft tissue syndactyly."
Reports the allele and phenotype.
c.1427A>G (p.Tyr476Cys) and c.415C>T (p.Arg139Cys)
COMPOUND HETEROZYGOUS
Compound heterozygous in a Chinese boy. p.Tyr476Cys on NM_001002292 is the recurrent p.Tyr478Cys allele on NM_024911.7 (c.1433A>G), so this patient carries the hotspot allele in trans with p.Arg139Cys.
Show evidence (1 reference)
PMID:37005218 SUPPORT Human Clinical
"Whole-exome gene sequencing (WES) identified compound heterozygous variants in the WLS gene (c.1427A > G; p.Tyr476Cys and c.415C > T, p.Arg139Cys; NM_001002292) in a 16-year-old boy presenting with facial dysmorphism, astigmatism, renal agenesis, and cryptorchidism."
Reports the two alleles.
c.271G>A (p.Val91Met) and c.1279-1G>C
COMPOUND HETEROZYGOUS
Missense and splice-acceptor alleles in an infant diagnosed early.
Show evidence (1 reference)
PMID:40618129 SUPPORT Human Clinical
"A missense variant c.271G > A (p.Val91Met) and a splice site variant c.1279-1G > C in the WLS gene were identified."
Reports the two alleles.
💊

Medical Actions

2
Prenatal Wnt agonist (preclinical)
Category: Therapeutic Action: prenatal Wnt agonist pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is prenatal Wnt agonist pharmacotherapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Platform: Small molecule
A small-molecule Wnt agonist given to pregnant knock-in mice partially restored embryonic development. It acts downstream of the secretion defect. The cited abstract does not name the agent, so no therapeutic_agent is bound. It has not been tried in patients.
Mechanism Target:
Deficient Developmental Wnt Signaling — Activates Wnt signaling downstream of the secretion defect.
Show evidence (1 reference)
PMID:34587386 SUPPORT Model Organism
"Administration of a pharmacologic Wnt agonist partially restored embryonic development."
Partial prenatal rescue in knock-in mice.
4-Phenylbutyric acid (preclinical)
Category: Therapeutic Action: chemical chaperone pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemical chaperone pharmacotherapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: 4-phenylbutyric acid CHEBI:41500 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses 4-phenylbutyric acid (CHEBI:41500). CHEBI:41500 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
The chemical chaperone 4-phenylbutyric acid restored the reduced levels of mutant WLS protein in cells. It acts on the unstable protein itself. It has not been tested in animals or patients.
Mechanism Target:
Biallelic WLS Hypomorphic Variants — Restores the reduced level of mutant WLS protein.
Show evidence (1 reference)
PMID:37005218 SUPPORT In Vitro
"We also found that the decreased mutant WLS expression can be rescued by 4-Phenylbutyric acid (4-PBA)."
A chemical chaperone restores mutant WLS levels in vitro.
📊

Prevalence

1
Worldwide reported literature
Cases In Literature Ultra Rare
The 2026 report of an Iranian patient describes her as the fourteenth case worldwide.
Show evidence (1 reference)
PMID:42641982 SUPPORT Human Clinical
"This study presents the fourteenth documented case of ZKS globally and reviews the clinical and genetic information of previously identified ZKS patients."
Gives the cumulative published case count.
🔀

Differential Diagnoses

1

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

Zaki-Gleeson syndrome Not Yet Curated MONDO:0013735
Distinguishing Features
  • Caused by DDX59, not WLS
  • Shares the eponym and microcephaly, which invites confusion in database searches
🐁

Animal Models

1
Wls patient-variant knock-in mice
Two knock-in lines, each carrying one patient WLS variant.
Species
Mouse
Genotype
Wls knock-in of two patient missense alleles (two lines)
Publication
PMID:34587386
Pathograph links
Deficient Developmental Wnt Signaling recapitulates fidelity: moderate observes: tissue Tissue defects follow each tissue's Wnt dependence, and a Wnt agonist partially rescues development.
Limitations: Mouse embryology differs from human, and only the abstract of the source is cached, so the specific tissue readouts are not curated.
Show evidence (1 reference)
PMID:34587386 SUPPORT Model Organism
"Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis."
Mice reproduce the Wnt-dependence pattern.
{ }

Source YAML

click to show 
name: Zaki Syndrome
creation_date: "2026-10-15T00:00:00Z"
category: Mendelian
description: >-
  Zaki syndrome (ZKS) is an ultra-rare autosomal recessive multiple congenital
  anomaly syndrome caused by biallelic variants in WLS, which encodes Wntless,
  the transmembrane cargo receptor that carries lipid-modified Wnt proteins
  from the endoplasmic reticulum and Golgi to the cell surface. WLS is needed to
  secrete every Wnt ligand, so its loss affects many developmental programs at
  once. The reported alleles are mostly missense variants that destabilize WLS
  and reduce, rather than abolish, Wnt secretion. Affected individuals have
  developmental delay or intellectual disability, postnatal microcephaly,
  short stature, a recognizable face with a wide mouth, alopecia, and
  variable eye, limb, renal, cardiac, dental and skeletal malformations,
  including iris coloboma, toe syndactyly, renal agenesis and heart defects.
  Knock-in mice reproduce tissue-specific developmental defects that follow
  each tissue's dependence on Wnt signaling, and a Wnt agonist given during
  pregnancy partially restored embryonic development in mice. It is distinct
  from Zaki-Gleeson syndrome, a DDX59-related disorder.
notes: >-
  The entry is anchored on MONDO:0859209 (OMIM 619648) and WLS (hgnc:30238).
  Zaki-Gleeson syndrome (OMIM 614407, MONDO:0013735, DDX59) shares the eponym
  and is a different disease; none of its sources is cited here.

  About fourteen patients have been reported. A 2025 literature review
  (PMID:40618129) tabulates feature frequencies across 13 of them, but only its
  abstract is cached, so no frequency band is recorded and each phenotype is
  supported by the patient reports that describe it.

  Cupped ears, sparse scalp hair, high-arched palate, short philtrum, wide
  nose, strabismus and corpus callosum or cerebellar vermis hypoplasia are
  listed among frequent features in the deep-research report, which takes
  them from the PMID:40618129 review table. None is named in any cached
  abstract. The review is open access (PMC12229024), but just fetch-reference
  PMID:40618129 cached the abstract only and just fetch-reference
  DOI:10.1186/s13052-025-02067-8 returned no text, so these features are not
  curated.

  The review abstract also links transmembrane missense variants to fewer
  cases of long fingers or toes. That phrase does not say which digits, and
  HPO has separate terms for long fingers and long toes, so it is not
  curated as a phenotype.

  Heterozygous WLS missense variants have been reported in patients with
  dental anomalies and oral exostoses (PMID:36374649). That is a carrier
  observation outside this recessive syndrome and is not curated as a
  phenotype here.
disease_term:
  preferred_term: Zaki syndrome
  term:
    id: MONDO:0859209
    label: Zaki syndrome
synonyms:
- ZKS
- WLS-related Zaki syndrome
- Microcephaly, progressive, with developmental delay, cupped ears, and dysmorphic features
parents:
- Multiple Congenital Anomalies Syndrome
- Wnt Signaling Disorder
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic WLS variants, homozygous in most consanguineous families and
    compound heterozygous in some.
  evidence:
  - reference: PMID:40618129
    reference_title: "Early diagnosed Zaki syndrome: identification of two novel WLS variants and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Zaki syndrome is an autosomal recessive disorder caused by pathogenic variants in the WLS gene, which is essential for Wnt signaling."
    explanation: States the recessive inheritance.
  - reference: PMID:37005218
    reference_title: "Compound heterozygous variants in WLS gene causes Zaki syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome gene sequencing (WES) identified compound heterozygous variants in the WLS gene (c.1427A > G; p.Tyr476Cys and c.415C > T, p.Arg139Cys; NM_001002292) in a 16-year-old boy presenting with facial dysmorphism, astigmatism, renal agenesis, and cryptorchidism."
    explanation: Compound heterozygosity also causes the disease.
prevalence:
- population: Worldwide reported literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The 2026 report of an Iranian patient describes her as the fourteenth case
    worldwide.
  evidence:
  - reference: PMID:42641982
    reference_title: "WLS-related Zaki syndrome: New clinical features and evidence for p.(Tyr478Cys) variant as a possible mutational hotspot."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study presents the fourteenth documented case of ZKS globally and reviews the clinical and genetic information of previously identified ZKS patients."
    explanation: Gives the cumulative published case count.
pathophysiology:
- name: Biallelic WLS Hypomorphic Variants
  biological_scale: MOLECULAR
  description: >-
    Two damaging WLS alleles are inherited. Most are missense variants in the
    transmembrane domains or near the C-terminal endoplasmic-reticulum
    targeting motif. They lower WLS protein stability, and p.Tyr478Cys has
    recurred in five patients.
  genes:
  - preferred_term: WLS
    term:
      id: hgnc:30238
      label: WLS
  molecular_functions:
  - preferred_term: Wnt-protein binding
    term:
      id: GO:0017147
      label: Wnt-protein binding
    modifier: DECREASED
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:34587386
    reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified homozygous mutations in WLS, which encodes the Wnt ligand secretion mediator (also known as Wntless or WLS) in 10 affected persons from 5 unrelated families."
    explanation: Discovery of biallelic WLS variants in five families.
  - reference: PMID:34587386
    reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mutations affected WLS protein stability and Wnt signaling."
    explanation: The patient alleles destabilize WLS.
  downstream:
  - target: Reduced Wnt Ligand Secretion
    causal_link_type: DIRECT
    description: >-
      Less WLS means less transport of lipid-modified Wnt proteins to the cell
      surface.
    evidence:
    - reference: PMID:37005218
      reference_title: "Compound heterozygous variants in WLS gene causes Zaki syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In vitro functional characterization showed that the two variants led to decreased WLS production and secretion of WNT3A, eventually affecting the WNT signal."
      explanation: Patient alleles reduce WLS and WNT3A secretion.
- name: Reduced Wnt Ligand Secretion
  biological_scale: CELLULAR
  description: >-
    WLS is the only known route for secreting Wnt proteins, so the
    hypomorphic alleles reduce secretion of several Wnt ligands at once,
    including WNT3A.
  biological_processes:
  - preferred_term: Wnt protein secretion
    term:
      id: GO:0061355
      label: Wnt protein secretion
    modifier: DECREASED
  evidence:
  - reference: PMID:34587386
    reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "(The Wnt ligand secretion mediator is essential for the secretion of all Wnt proteins.)"
    explanation: >-
      Background statement of WLS function, which explains why one gene
      affects many Wnt-dependent tissues.
  - reference: PMID:37005218
    reference_title: "Compound heterozygous variants in WLS gene causes Zaki syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro functional characterization showed that the two variants led to decreased WLS production and secretion of WNT3A, eventually affecting the WNT signal."
    explanation: Measured reduction in WNT3A secretion with patient alleles.
  downstream:
  - target: Deficient Developmental Wnt Signaling
    causal_link_type: DIRECT
    description: >-
      Less secreted Wnt reduces Wnt signaling in receiving tissues during
      embryogenesis.
    evidence:
    - reference: PMID:34587386
      reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The mutations affected WLS protein stability and Wnt signaling."
      explanation: Patient alleles reduce downstream Wnt signaling.
- name: Deficient Developmental Wnt Signaling
  biological_scale: TISSUE
  description: >-
    Each tissue is affected according to how strongly it depends on Wnt
    signaling during development, which explains the variable multi-organ
    pattern. Brain growth, limb patterning, eye, kidney, heart, hair and teeth
    are all Wnt-dependent.
  biological_processes:
  - preferred_term: Wnt signaling pathway
    term:
      id: GO:0016055
      label: Wnt signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:34587386
    reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis."
    explanation: >-
      In knock-in mice, which tissues fail tracks their dependence on Wnt
      signaling.
  downstream:
  - target: Secondary microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced Wnt signaling in the developing brain limits brain growth.
    evidence:
    - reference: PMID:34587386
      reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
      explanation: Microcephaly is among the multiorgan defects of deficient Wnt secretion.
  - target: Toe syndactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Limb-bud patterning depends on Wnt signaling.
    evidence:
    - reference: PMID:34587386
      reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
      explanation: Foot syndactyly is among the reported defects.
  - target: Renal agenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Kidney development depends on Wnt signaling.
    evidence:
    - reference: PMID:34587386
      reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
      explanation: Renal agenesis is among the reported defects.
  - target: Iris coloboma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Eye development depends on Wnt signaling.
    evidence:
    - reference: PMID:34587386
      reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
      explanation: Iris coloboma is among the reported defects.
  - target: Alopecia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hair follicle development depends on Wnt signaling.
    evidence:
    - reference: PMID:34587386
      reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
      explanation: Alopecia is among the reported defects.
  - target: Abnormal heart morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Heart development depends on Wnt signaling.
    evidence:
    - reference: PMID:34587386
      reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
      explanation: Heart defects are among the reported defects.
  - target: Abnormal facial shape
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Craniofacial development depends on Wnt signaling.
    evidence:
    - reference: PMID:34587386
      reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
      explanation: Facial dysmorphism is among the reported defects.
  - target: Abnormality of the dentition
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Tooth development depends on canonical and non-canonical Wnt signaling.
    evidence:
    - reference: PMID:36374649
      reference_title: "Mutations in the WLS are associated with dental anomalies, torus palatinus, and torus mandibularis."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "Canonical and non-canonical WNT signaling are important for odontogenesis."
      explanation: Background statement linking Wnt signaling to tooth development.
phenotypes:
- category: Neurological
  name: Global developmental delay
  description: Developmental delay is one of the most consistent features.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:42641982
    reference_title: "WLS-related Zaki syndrome: New clinical features and evidence for p.(Tyr478Cys) variant as a possible mutational hotspot."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A comparison of all reported ZKS patients suggests that this syndrome displays a recognizable pattern of developmental delay, intellectual disability, postnatal microcephaly, facial dysmorphism, skeletal and ocular anomalies, and short stature."
    explanation: Developmental delay is part of the recognizable pattern across reported patients.
- category: Neurological
  name: Intellectual disability
  description: Intellectual disability of variable severity.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:42641982
    reference_title: "WLS-related Zaki syndrome: New clinical features and evidence for p.(Tyr478Cys) variant as a possible mutational hotspot."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A comparison of all reported ZKS patients suggests that this syndrome displays a recognizable pattern of developmental delay, intellectual disability, postnatal microcephaly, facial dysmorphism, skeletal and ocular anomalies, and short stature."
    explanation: Intellectual disability is part of the recognizable pattern.
- category: Neurological
  name: Secondary microcephaly
  description: Head size is near normal at birth and falls behind afterwards.
  phenotype_term:
    preferred_term: Postnatal microcephaly
    term:
      id: HP:0005484
      label: Secondary microcephaly
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:42641982
    reference_title: "WLS-related Zaki syndrome: New clinical features and evidence for p.(Tyr478Cys) variant as a possible mutational hotspot."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A comparison of all reported ZKS patients suggests that this syndrome displays a recognizable pattern of developmental delay, intellectual disability, postnatal microcephaly, facial dysmorphism, skeletal and ocular anomalies, and short stature."
    explanation: Postnatal microcephaly is part of the recognizable pattern.
- category: Growth
  name: Short stature
  description: Short stature, usually postnatal.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:42641982
    reference_title: "WLS-related Zaki syndrome: New clinical features and evidence for p.(Tyr478Cys) variant as a possible mutational hotspot."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A comparison of all reported ZKS patients suggests that this syndrome displays a recognizable pattern of developmental delay, intellectual disability, postnatal microcephaly, facial dysmorphism, skeletal and ocular anomalies, and short stature."
    explanation: Short stature is part of the recognizable pattern.
- category: Craniofacial
  name: Abnormal facial shape
  description: >-
    Recognizable facial appearance, described in the literature as including
    cupped ears, a wide nose and mouth, a short philtrum and a high-arched
    palate.
  phenotype_term:
    preferred_term: Facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:34587386
    reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
    explanation: Facial dysmorphism in the discovery cohort.
- category: Musculoskeletal
  name: Toe syndactyly
  description: Syndactyly of the toes; complete soft-tissue syndactyly in one severe case.
  phenotype_term:
    preferred_term: Foot syndactyly
    term:
      id: HP:0001770
      label: Toe syndactyly
  evidence:
  - reference: PMID:34587386
    reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
    explanation: Foot syndactyly in the discovery cohort.
- category: Renal
  name: Renal agenesis
  description: Renal agenesis in a minority of patients.
  phenotype_term:
    preferred_term: Renal agenesis
    term:
      id: HP:0000104
      label: Renal agenesis
  evidence:
  - reference: PMID:34587386
    reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
    explanation: Renal agenesis in the discovery cohort.
  - reference: PMID:37005218
    reference_title: "Compound heterozygous variants in WLS gene causes Zaki syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome gene sequencing (WES) identified compound heterozygous variants in the WLS gene (c.1427A > G; p.Tyr476Cys and c.415C > T, p.Arg139Cys; NM_001002292) in a 16-year-old boy presenting with facial dysmorphism, astigmatism, renal agenesis, and cryptorchidism."
    explanation: Renal agenesis in an independent compound heterozygous patient.
- category: Dermatological
  name: Alopecia
  description: Sparse scalp hair or alopecia.
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  evidence:
  - reference: PMID:37106064
    reference_title: "Expanding the phenotypic spectrum and clinical severity associated with WLS gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a likely disease-causing variant in WLS (c.1579G>A, p.Gly527Arg) in a boy presented with a broad range of MCA including microcephaly, facial dysmorphism, alopecia, ophthalmologic anomalies, and complete soft tissue syndactyly."
    explanation: Alopecia in an independent patient.
- category: Ophthalmological
  name: Iris coloboma
  description: Iris coloboma, part of the ocular involvement.
  phenotype_term:
    preferred_term: Iris coloboma
    term:
      id: HP:0000612
      label: Iris coloboma
  evidence:
  - reference: PMID:34587386
    reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
    explanation: Iris coloboma in the discovery cohort.
- category: Ophthalmological
  name: Microphthalmia
  description: Microphthalmia, reported in a severe case.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: PMID:37106064
    reference_title: "Expanding the phenotypic spectrum and clinical severity associated with WLS gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a detailed clinical assessment, our patient also displayed microphthalmia, dental anomalies, skeletal dysplasia with spontaneous fractures and Dandy-Walker malformation."
    explanation: Microphthalmia in the p.Gly527Arg patient.
- category: Cardiovascular
  name: Abnormal heart morphology
  description: Congenital heart defects, specific lesions not named in the abstract.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:34587386
    reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects."
    explanation: Heart defects in the discovery cohort.
- category: Musculoskeletal
  name: Abnormality of the skeletal system
  description: >-
    Skeletal anomalies are part of the recognizable pattern across reported
    patients. The cross-patient summary does not say which, so the coarse
    term is used; specific findings are curated separately.
  phenotype_term:
    preferred_term: Skeletal anomalies
    term:
      id: HP:0000924
      label: Abnormality of the skeletal system
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:42641982
    reference_title: "WLS-related Zaki syndrome: New clinical features and evidence for p.(Tyr478Cys) variant as a possible mutational hotspot."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A comparison of all reported ZKS patients suggests that this syndrome displays a recognizable pattern of developmental delay, intellectual disability, postnatal microcephaly, facial dysmorphism, skeletal and ocular anomalies, and short stature."
    explanation: Skeletal anomalies across reported patients, unspecified.
- category: Craniofacial
  name: Wide mouth
  description: Wide mouth, more often with transmembrane-domain missense variants.
  phenotype_term:
    preferred_term: Wide mouth
    term:
      id: HP:0000154
      label: Wide mouth
  evidence:
  - reference: PMID:40618129
    reference_title: "Early diagnosed Zaki syndrome: identification of two novel WLS variants and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Missense variants in the transmembrane region were associated with more cases of wide mouth and fewer cases of long fingers or toes."
    explanation: >-
      A genotype-phenotype observation from the literature review, which
      shows wide mouth is a recurring feature.
    directness: INDIRECT
- category: Musculoskeletal
  name: Broad distal phalanx of finger
  description: Broad distal finger phalanges, more often with variants near the ER signal motif.
  phenotype_term:
    preferred_term: Broad distal phalanges of the fingers
    term:
      id: HP:0009836
      label: Broad distal phalanx of finger
  evidence:
  - reference: PMID:40618129
    reference_title: "Early diagnosed Zaki syndrome: identification of two novel WLS variants and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants near the ER signaling motif appeared more often with broad distal phalanges of the fingers."
    explanation: >-
      A genotype-phenotype observation from the literature review, which
      shows broad distal phalanges are a recurring feature.
    directness: INDIRECT
- category: Musculoskeletal
  name: Clinodactyly
  description: Clinodactyly, reported in one patient.
  phenotype_term:
    preferred_term: Clinodactyly
    term:
      id: HP:0030084
      label: Clinodactyly
  evidence:
  - reference: PMID:42641982
    reference_title: "WLS-related Zaki syndrome: New clinical features and evidence for p.(Tyr478Cys) variant as a possible mutational hotspot."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, our patient exhibited distinct clinical characteristics compared to previously reported cases, including hyperphagia, congenital blindness, clinodactyly, and early pubertal development."
    explanation: Clinodactyly in the fourteenth reported patient.
- category: Ophthalmological
  name: Congenital blindness
  description: Congenital blindness, reported in one patient.
  phenotype_term:
    preferred_term: Congenital blindness
    term:
      id: HP:0007875
      label: Congenital blindness
  evidence:
  - reference: PMID:42641982
    reference_title: "WLS-related Zaki syndrome: New clinical features and evidence for p.(Tyr478Cys) variant as a possible mutational hotspot."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, our patient exhibited distinct clinical characteristics compared to previously reported cases, including hyperphagia, congenital blindness, clinodactyly, and early pubertal development."
    explanation: Congenital blindness in the fourteenth reported patient.
- category: Behavioral
  name: Polyphagia
  description: Hyperphagia, reported in one patient.
  phenotype_term:
    preferred_term: Hyperphagia
    term:
      id: HP:0002591
      label: Polyphagia
  evidence:
  - reference: PMID:42641982
    reference_title: "WLS-related Zaki syndrome: New clinical features and evidence for p.(Tyr478Cys) variant as a possible mutational hotspot."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, our patient exhibited distinct clinical characteristics compared to previously reported cases, including hyperphagia, congenital blindness, clinodactyly, and early pubertal development."
    explanation: Hyperphagia in the fourteenth reported patient.
- category: Ophthalmological
  name: Astigmatism
  description: Astigmatism in the compound heterozygous patient.
  phenotype_term:
    preferred_term: Astigmatism
    term:
      id: HP:0000483
      label: Astigmatism
  evidence:
  - reference: PMID:37005218
    reference_title: "Compound heterozygous variants in WLS gene causes Zaki syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome gene sequencing (WES) identified compound heterozygous variants in the WLS gene (c.1427A > G; p.Tyr476Cys and c.415C > T, p.Arg139Cys; NM_001002292) in a 16-year-old boy presenting with facial dysmorphism, astigmatism, renal agenesis, and cryptorchidism."
    explanation: Astigmatism in the compound heterozygous patient.
- category: Musculoskeletal
  name: Skeletal dysplasia
  description: Skeletal dysplasia with spontaneous fractures in a severe case.
  phenotype_term:
    preferred_term: Skeletal dysplasia
    term:
      id: HP:0002652
      label: Skeletal dysplasia
  evidence:
  - reference: PMID:37106064
    reference_title: "Expanding the phenotypic spectrum and clinical severity associated with WLS gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a detailed clinical assessment, our patient also displayed microphthalmia, dental anomalies, skeletal dysplasia with spontaneous fractures and Dandy-Walker malformation."
    explanation: Skeletal dysplasia with fractures in the p.Gly527Arg patient.
- category: Neurological
  name: Dandy-Walker malformation
  description: Dandy-Walker malformation in a severe case.
  phenotype_term:
    preferred_term: Dandy-Walker malformation
    term:
      id: HP:0001305
      label: Dandy-Walker malformation
  evidence:
  - reference: PMID:37106064
    reference_title: "Expanding the phenotypic spectrum and clinical severity associated with WLS gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a detailed clinical assessment, our patient also displayed microphthalmia, dental anomalies, skeletal dysplasia with spontaneous fractures and Dandy-Walker malformation."
    explanation: Dandy-Walker malformation in the p.Gly527Arg patient.
- category: Craniofacial
  name: Abnormality of the dentition
  description: Dental anomalies, including tooth agenesis or malformation.
  phenotype_term:
    preferred_term: Dental anomalies
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  evidence:
  - reference: PMID:37106064
    reference_title: "Expanding the phenotypic spectrum and clinical severity associated with WLS gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a detailed clinical assessment, our patient also displayed microphthalmia, dental anomalies, skeletal dysplasia with spontaneous fractures and Dandy-Walker malformation."
    explanation: Dental anomalies in the p.Gly527Arg patient.
- category: Genitourinary
  name: Cryptorchidism
  description: Undescended testes in at least one male patient.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:37005218
    reference_title: "Compound heterozygous variants in WLS gene causes Zaki syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome gene sequencing (WES) identified compound heterozygous variants in the WLS gene (c.1427A > G; p.Tyr476Cys and c.415C > T, p.Arg139Cys; NM_001002292) in a 16-year-old boy presenting with facial dysmorphism, astigmatism, renal agenesis, and cryptorchidism."
    explanation: Cryptorchidism in the compound heterozygous patient.
genetic:
- name: WLS
  gene_term:
    preferred_term: WLS
    term:
      id: hgnc:30238
      label: WLS
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    WLS (1p31.3; also called Wntless, EVI or GPR177) encodes the multi-pass
    membrane cargo receptor that escorts palmitoleated Wnt proteins through the
    secretory pathway. Zaki syndrome is the only recessive disease known to be
    caused by WLS variants.
  evidence:
  - reference: PMID:36374649
    reference_title: "Mutations in the WLS are associated with dental anomalies, torus palatinus, and torus mandibularis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Biallelic pathogenic variants in WLS are implicated in autosomal recessive Zaki syndrome (ZKS; MIM 619648), the only genetic condition known to be caused by pathogenic variants in WLS."
    explanation: Background statement tying WLS to Zaki syndrome.
  - reference: PMID:34587386
    reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified homozygous mutations in WLS, which encodes the Wnt ligand secretion mediator (also known as Wntless or WLS) in 10 affected persons from 5 unrelated families."
    explanation: Five unrelated families with biallelic WLS variants.
  variants:
  - name: NM_024911.7:c.1433A>G (p.Tyr478Cys)
    type: MISSENSE
    description: >-
      Recurrent allele, homozygous in five patients across more than one
      ancestry. It is the same residue as p.Tyr476Cys on NM_001002292: both
      RefSeq proteins carry the motif FFTGIY once, with the tyrosine at 476 in
      the 543-residue NM_001002292 product and at 478 in the 541-residue
      NM_024911.7 product, and the cDNA positions differ by the same 6 nt.
    evidence:
    - reference: PMID:42641982
      reference_title: "WLS-related Zaki syndrome: New clinical features and evidence for p.(Tyr478Cys) variant as a possible mutational hotspot."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "She represents the fifth ZKS patient identified with this variant, indicating a possible mutational hotspot."
      explanation: Fifth patient homozygous for p.Tyr478Cys.
  - name: c.1579G>A (p.Gly527Arg)
    type: MISSENSE
    description: Homozygous in a boy with a severe phenotype.
    evidence:
    - reference: PMID:37106064
      reference_title: "Expanding the phenotypic spectrum and clinical severity associated with WLS gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified a likely disease-causing variant in WLS (c.1579G>A, p.Gly527Arg) in a boy presented with a broad range of MCA including microcephaly, facial dysmorphism, alopecia, ophthalmologic anomalies, and complete soft tissue syndactyly."
      explanation: Reports the allele and phenotype.
  - name: c.1427A>G (p.Tyr476Cys) and c.415C>T (p.Arg139Cys)
    type: COMPOUND_HETEROZYGOUS
    description: >-
      Compound heterozygous in a Chinese boy. p.Tyr476Cys on NM_001002292 is
      the recurrent p.Tyr478Cys allele on NM_024911.7 (c.1433A>G), so this
      patient carries the hotspot allele in trans with p.Arg139Cys.
    evidence:
    - reference: PMID:37005218
      reference_title: "Compound heterozygous variants in WLS gene causes Zaki syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Whole-exome gene sequencing (WES) identified compound heterozygous variants in the WLS gene (c.1427A > G; p.Tyr476Cys and c.415C > T, p.Arg139Cys; NM_001002292) in a 16-year-old boy presenting with facial dysmorphism, astigmatism, renal agenesis, and cryptorchidism."
      explanation: Reports the two alleles.
  - name: c.271G>A (p.Val91Met) and c.1279-1G>C
    type: COMPOUND_HETEROZYGOUS
    description: Missense and splice-acceptor alleles in an infant diagnosed early.
    evidence:
    - reference: PMID:40618129
      reference_title: "Early diagnosed Zaki syndrome: identification of two novel WLS variants and a literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A missense variant c.271G > A (p.Val91Met) and a splice site variant c.1279-1G > C in the WLS gene were identified."
      explanation: Reports the two alleles.
differential_diagnoses:
- name: Zaki-Gleeson syndrome
  disease_term:
    preferred_term: microcephaly-cerebellar hypoplasia-cardiac conduction defect syndrome
    term:
      id: MONDO:0013735
      label: microcephaly-cerebellar hypoplasia-cardiac conduction defect syndrome
  distinguishing_features:
  - Caused by DDX59, not WLS
  - Shares the eponym and microcephaly, which invites confusion in database searches
treatments:
- name: Prenatal Wnt agonist (preclinical)
  description: >-
    A small-molecule Wnt agonist given to pregnant knock-in mice partially
    restored embryonic development. It acts downstream of the secretion
    defect. The cited abstract does not name the agent, so no
    therapeutic_agent is bound. It has not been tried in patients.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: prenatal Wnt agonist pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Deficient Developmental Wnt Signaling
    description: Activates Wnt signaling downstream of the secretion defect.
  evidence:
  - reference: PMID:34587386
    reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Administration of a pharmacologic Wnt agonist partially restored embryonic development."
    explanation: Partial prenatal rescue in knock-in mice.
- name: 4-Phenylbutyric acid (preclinical)
  description: >-
    The chemical chaperone 4-phenylbutyric acid restored the reduced levels of
    mutant WLS protein in cells. It acts on the unstable protein itself. It
    has not been tested in animals or patients.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: chemical chaperone pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: 4-phenylbutyric acid
      term:
        id: CHEBI:41500
        label: 4-phenylbutyric acid
  target_mechanisms:
  - target: Biallelic WLS Hypomorphic Variants
    description: Restores the reduced level of mutant WLS protein.
  evidence:
  - reference: PMID:37005218
    reference_title: "Compound heterozygous variants in WLS gene causes Zaki syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We also found that the decreased mutant WLS expression can be rescued by 4-Phenylbutyric acid (4-PBA)."
    explanation: A chemical chaperone restores mutant WLS levels in vitro.
animal_models:
- name: Wls patient-variant knock-in mice
  species: Mouse
  genotype: Wls knock-in of two patient missense alleles (two lines)
  publication: PMID:34587386
  description: Two knock-in lines, each carrying one patient WLS variant.
  modeled_mechanisms:
  - target: Deficient Developmental Wnt Signaling
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Tissue defects follow each tissue's Wnt dependence, and a Wnt agonist
      partially rescues development.
    limitations: >-
      Mouse embryology differs from human, and only the abstract of the source
      is cached, so the specific tissue readouts are not curated.
    evidence:
    - reference: PMID:34587386
      reference_title: "A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis."
      explanation: Mice reproduce the Wnt-dependence pattern.
📚

References & Deep Research

Deep Research

1

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

Evaluations and curation notes (2)

Record notes

The entry is anchored on MONDO:0859209 (OMIM 619648) and WLS (hgnc:30238). Zaki-Gleeson syndrome (OMIM 614407, MONDO:0013735, DDX59) shares the eponym and is a different disease; none of its sources is cited here. About fourteen patients have been reported. A 2025 literature review (PMID:40618129) tabulates feature frequencies across 13 of them, but only its abstract is cached, so no frequency band is recorded and each phenotype is supported by the patient reports that describe it. Cupped ears, sparse scalp hair, high-arched palate, short philtrum, wide nose, strabismus and corpus callosum or cerebellar vermis hypoplasia are listed among frequent features in the deep-research report, which takes them from the PMID:40618129 review table. None is named in any cached abstract. The review is open access (PMC12229024), but just fetch-reference PMID:40618129 cached the abstract only and just fetch-reference DOI:10.1186/s13052-025-02067-8 returned no text, so these features are not curated. The review abstract also links transmembrane missense variants to fewer cases of long fingers or toes. That phrase does not say which digits, and HPO has separate terms for long fingers and long toes, so it is not curated as a phenotype. Heterozygous WLS missense variants have been reported in patients with dental anomalies and oral exostoses (PMID:36374649). That is a carrier observation outside this recessive syndrome and is not curated as a phenotype here.

Create: Zaki Syndrome · 2026-10-15T08:21:55Z · View source

New entry for Zaki syndrome (MONDO:0859209, WLS). Source report: research/Zaki_Syndrome-deep-research-perplexity.md, generated with Perplexity sonar-deep-research at reasoning_effort=low, because two runs at the default effort were disconnected at about 300 seconds. Reference validation (added afterwards with just validate-research-reference) resolved 8/8 references. The report has no term-validation section: just validate-research-terms failed three times on a 5-second OLS read timeout for NCIt:C15308, so every CURIE in the entry was looked up independently and passed just validate-terms. preflight-dr returned WARN because the report cites OMIM 614407 only to say Zaki-Gleeson syndrome (DDX59) is a different disease, and because its heuristic lexicon counted CDC as a gene. Primary sources were fetched from a PubMed search: PMID:34587386, 37005218, 37106064, 40618129, 42641982, 36374649. The report's 13-patient frequency table comes from PMID:40618129, which is cached as abstract only, so no frequency bands were curated. Validated with just validate, count-verified-snippets (43/43), validate-terms, check-genereviews (NO_CHAPTER), check-causal-targets and check-snippet-grading.

Perplexity ▸
Zaki syndrome: disease-characteristics research report
sonar-deep-research 55 citations 2026-10-15T07:44:39.937302

Zaki syndrome: disease-characteristics research report

Assessment date: October 15, 2026
Disease: Zaki syndrome
Preferred identifier: MONDO:0859209
Mendelian category: Autosomal-recessive developmental disorder caused by biallelic WLS variants

Executive summary

Zaki syndrome is an ultra-rare, congenital and postnatally evolving multisystem disorder caused by biallelic germline loss-of-function or hypomorphic variants in WLS, the transmembrane cargo receptor required for secretion of Wnt ligands. It is characterized most consistently by developmental delay, progressive postnatal microcephaly, short stature, distinctive facial appearance, sparse hair, ocular anomalies, and variable brain, limb, renal, cardiac, dental, and genital abnormalities. OMIM designates the disorder ZKS, #619648; MedGen is C5562037, and MONDO is MONDO:0859209. It must not be confused with Zaki–Gleeson syndrome, a separate disorder associated with DDX59. [Web:16][Web:22]

The defining 2021 study identified four homozygous missense alleles in 10 people from five families and demonstrated impaired WLS stability, a 60–80% reduction in Wnt secretion, reduced downstream reporter activity, developmental abnormalities in two knock-in mouse lines, and partial prenatal rescue with the GSK3 inhibitor/Wnt-pathway agonist CHIR99021 (PMID: 34587386, published September 30, 2021). [Web:32][Web:91] Reports from 2023 added compound-heterozygous inheritance and a severe phenotype including skeletal dysplasia, fractures, dental anomalies and Dandy–Walker malformation (PMIDs 37005218 and 37106064). [Web:34][Web:109] A literature review through October 2024 found only 13 molecularly confirmed patients and nine pathogenic/likely pathogenic variants, emphasizing that all frequency and prognosis estimates remain provisional. [Web:24]

1. Disease information

1.1 Definition

Zaki syndrome is a WLS-related congenital malformation–neurodevelopmental syndrome resulting from deficient secretion of multiple Wnt ligands during embryogenesis and subsequent tissue growth. Common findings include:

  • developmental delay or intellectual disability;
  • progressive, predominantly postnatal microcephaly;
  • short stature;
  • cupped ears, sparse scalp hair/eyebrows, wide nose and mouth, short philtrum and high-arched palate;
  • eye, brain, skeletal, renal and cardiac malformations.

The authoritative MedGen definition emphasizes “developmental delay, progressive microcephaly, and short stature,” together with sparse scalp hair, cupped ears, a wide nose/mouth, short philtrum and high-arched palate. [Web:16]

1.2 Identifiers and nomenclature

Resource Identifier/name Status and notes
MONDO MONDO:0859209 Preferred cross-resource disease identifier
OMIM #619648 — Zaki syndrome; ZKS Phenotype entry [Web:16]
MedGen C5562037, UID 1794247 Disease or syndrome [Web:16]
OMIM gene WLS, *611514 Causal gene
HGNC HGNC:30238 — WLS Approved human gene symbol [Web:76][Web:129]
NCBI Gene 79971 — WLS Human gene
Ensembl ENSG00000116729 Human WLS gene [Web:81]
UniProtKB Q5T9L3 Human WLS protein [Web:76]
Cytogenetic location 1p31.3 WLS locus [Web:129]
MedGen synonym “Microcephaly, progressive, with developmental delay, cupped ears, and dysmorphic features” Descriptive alternative name [Web:19]
Orphanet No dedicated Zaki-syndrome ORPHAcode located Do not use ORPHA:329332; that code denotes DDX59-related Zaki–Gleeson syndrome
ICD-10 No specific code Usually coded under congenital malformation, microcephaly, developmental disorder or genetic-syndrome categories according to manifestations
ICD-11 No verified disease-specific code located A general “other specified congenital malformation syndromes” category may be appropriate locally
MeSH No dedicated Zaki syndrome heading located Literature is indexed using broader terms such as Congenital Abnormalities, Microcephaly, Wnt Signaling Pathway and Intellectual Disability
SNOMED CT No specific verified Zaki-syndrome concept found 764732004 refers to Zaki–Gleeson syndrome, not WLS-related Zaki syndrome

Important naming distinction

Zaki syndrome is not Zaki–Gleeson syndrome. Zaki–Gleeson syndrome is microcephaly–cerebellar hypoplasia–cardiac conduction defect syndrome, OMIM 614407/MONDO:0013735/ORPHA:329332, caused by DDX59. [Web:22]

1.3 Source granularity

The evidence base combines:

  • individual-level human cases: pedigree, clinical, imaging and sequencing data;
  • aggregated disease-level resources: OMIM, MedGen, MONDO and ClinVar;
  • aggregated literature review: 13 patients through October 2024;
  • experimental evidence: patient fibroblasts, HEK293T cells, patient-derived iPSCs/embryoid bodies and knock-in mice.

No EHR-derived population cohort, claims-based cohort or national disease registry was identified.

2. Etiology

2.1 Primary causal factor

The established cause is biallelic pathogenic or likely pathogenic germline variation in WLS. WLS binds palmitoleated Wnt proteins in the endoplasmic reticulum and carries them through the Golgi/secretory pathway to the plasma membrane. Reduced WLS abundance or function therefore decreases secretion of several Wnt ligands rather than disrupting only one ligand. [Web:88][Web:91]

The landmark paper’s key abstract statement was:

“We identified homozygous mutations in WLS, which encodes the Wnt ligand secretion mediator … in 10 affected persons from 5 unrelated families.”
— Chai et al., New England Journal of Medicine, September 30, 2021; PMID: 34587386. [Web:32]

2.2 Risk factors

Risk-factor class Evidence
Two pathogenic WLS alleles Necessary molecular risk factor in confirmed cases
Parental carrier status Two heterozygous parents have a 25% recurrence probability in each pregnancy
Consanguinity Increased the probability of homozygous rare alleles in several original families; it is not biologically necessary because compound-heterozygous cases occur
Family history An affected sibling or known carrier parents substantially raises prior probability
Population ancestry Cases have occurred in Emirati, Egyptian, Native American, Indian, Chinese and other backgrounds; no ancestry-specific susceptibility is established
Sex Both sexes can be affected; no sex-linked mechanism
Parental age No established effect
Environmental exposure No toxin, drug, infection, diet or lifestyle exposure has been shown to cause the syndrome

The original discovery cohort was enriched for consanguinity, and families 1 and 2 had first-cousin parents. However, a 2023 Chinese case carried compound-heterozygous variants, demonstrating that homozygosity and consanguinity are not required. [Web:34]

2.3 Protective factors

No validated human genetic or environmental protective factor is known.

Residual WLS function may act as a severity modifier, because all reported disease alleles appear compatible with survival and many are hypomorphic missense substitutions rather than complete null alleles. Apparent milder findings in the small number of compound-heterozygous patients are hypothesis-generating, not an established protective genotype.

Prenatal CHIR99021 partially rescued mutant mice, but this is experimental model-organism evidence, not an established human protective exposure or preventive treatment. [Web:91]

2.4 Gene–environment interaction

No human gene–environment interaction has been demonstrated. The variable expressivity among people carrying the same p.Tyr392Cys allele could reflect modifiers, stochastic developmental effects, epigenetic state or environmental context, but these remain inferred. The 2025 review specifically cautioned that phenotype differences may reflect other genes, polymorphisms, epigenetic influences or external factors. [Web:24]

3. Phenotypes

3.1 Aggregate phenotype frequencies

The most systematic summary is the literature review of 13 patients available through October 2024. Denominators differ because reporting was incomplete. [Web:24]

Phenotype Type Frequency Usual onset/course Suggested HPO term
Distinctive facial features Physical sign 12/12, 100% Congenital/pediatric; persistent HP:0001999, Abnormal facial shape
Cupped outer ears Physical sign 11/12, 91.7% Congenital; stable HP:0000378, Cupped ear
Sparse scalp hair Physical sign 10/11, 90.9% Early childhood; persistent HP:0002209, Sparse scalp hair
Postnatal microcephaly Growth/neurologic sign 10/11, 90.9% Usually emerges after normal birth size; progressive HP:0000252, Microcephaly; HP:0005484, Postnatal microcephaly
Neurodevelopmental disorder Functional phenotype 12/13, 92.3% Infancy/childhood; chronic HP:0012759
Skeletal anomalies Physical sign 10/12, 83.3% Mostly congenital; fractures may be later HP:0000924
Eye anomalies Physical/functional sign 9/11, 81.8% Congenital or early infancy HP:0000478
Delayed global milestones Developmental sign 10/13, 76.9% Infancy/childhood; persistent HP:0001263
Gross-motor delay Developmental sign 10/13, 76.9% Infancy/childhood HP:0002194
Intellectual disability Behavioral/cognitive 9/12, 75.0% Recognized in childhood; variable severity HP:0001249
High-arched palate Physical sign 9/12, 75.0% Congenital; stable HP:0000218
Short philtrum Physical sign 9/12, 75.0% Congenital; stable HP:0000322
Wide/broad nose Physical sign 9/12, 75.0% Congenital; stable HP:0000445, Wide nose
Structural brain anomaly Imaging finding 6/8, 75.0% Congenital; generally non-remitting HP:0012443
Short stature Growth sign 8/12, 66.7% Usually postnatal; may progress HP:0004322
Wide mouth Physical sign 8/12, 66.7% Congenital; stable HP:0000154
Strabismus Ophthalmic sign 6/11, 54.5% Infancy/childhood; potentially treatable HP:0000486
Syndactyly Limb malformation 6/12, 50.0% Congenital; stable without surgery HP:0001159
High forehead Physical sign 6/12, 50.0% Congenital/pediatric HP:0000348
Micrognathia Physical sign 6/12, 50.0% Congenital HP:0000347
Corpus-callosum hypoplasia MRI finding 4/8, 50.0% Congenital HP:0002079
Cerebellar-vermis hypoplasia MRI finding 4/8, 50.0% Congenital HP:0001320
Abnormal neurologic signs Clinical sign 5/11, 45.5% Childhood; variable HP:0012638
Long fingers/toes Skeletal sign 5/12, 41.7% Congenital HP:0100807; HP:0010511
Sparse lateral eyebrows Physical sign 5/12, 41.7% Congenital/pediatric HP:0005338
Median pseudocleft lip Craniofacial sign 5/12, 41.7% Congenital HP:0011340, Abnormal upper-lip morphology
Enlarged fourth ventricle MRI finding 3/8, 37.5% Congenital HP:0002198
Broad distal finger phalanges Skeletal sign 4/12, 33.3% Congenital HP:0009882
Anteverted nares Physical sign 4/12, 33.3% Congenital HP:0000463
Hypotonia Neurologic sign 3/11, 27.2% in table Infancy; variable HP:0001252
Iris coloboma Eye malformation 3/11, 27.3% Congenital; permanent visual risk HP:0000612
Renal defects Organ malformation 3/12, 25.0% Congenital HP:0000077
Patent foramen ovale Cardiac finding 3/13, 23.1% Congenital; may close spontaneously HP:0001655
Microcornea Eye malformation 2/11, 18.2% Congenital HP:0000482
Nystagmus Ophthalmic sign 2/11, 18.2% Infancy/childhood HP:0000639
Optic-disc coloboma Eye malformation 2/11, 18.2% Congenital; permanent HP:0000588
Renal agenesis Organ malformation 2/12, 16.7% Congenital; permanent HP:0000104
Scoliosis Skeletal sign 2/12, 16.7% Childhood; potentially progressive HP:0002650

Additional reported findings

  • Complete soft-tissue syndactyly, ectrodactyly/polysyndactyly and reduced digits.
  • Microphthalmia: HP:0000568.
  • Dandy–Walker malformation: HP:0001305.
  • Skeletal dysplasia and spontaneous fractures: HP:0002652 and HP:0002757.
  • Dental anomalies, including tooth agenesis/malformation.
  • Cryptorchidism: HP:0000028.
  • Congenital diaphragmatic hernia: HP:0000776.
  • Hydronephrosis: HP:0000126.
  • Alopecia: HP:0001596.
  • Seizure in at least one patient: HP:0001250.
  • Spastic or unsteady gait and impaired standing/walking.
  • Congenital umbilical polyp in the 2025 early-diagnosed infant, an association requiring replication. [Web:24][Web:109]

3.2 Severity and quality-of-life impact

Severity is highly variable. Major impacts include:

  • Development and education: delayed language, motor and social milestones; intellectual disability may require lifelong educational and caregiver support.
  • Mobility: syndactyly, ectrodactyly, skeletal dysplasia, scoliosis, fractures, hypotonia or spasticity can impair standing, walking and self-care.
  • Vision: coloboma, microphthalmia, strabismus, nystagmus and optic-disc defects may cause substantial visual disability.
  • Growth and nutrition: progressive microcephaly and short stature require longitudinal surveillance; feeding effects have not been systematically measured.
  • Renal health: unilateral renal agenesis may be asymptomatic initially but reduces renal reserve.
  • Psychosocial health: no syndrome-specific EQ-5D, SF-36, PROMIS or caregiver-burden study has been published.

In the 2025 infant, Gesell developmental quotient was 57.1, mild hypotonia appeared by three months, and head circumference declined from the 25th–50th percentile at birth to approximately −3 SD by eight months, illustrating the postnatal evolution. [Web:24]

4. Genetic and molecular information

4.1 Causal gene

Attribute Value
Gene WLS
Full name Wnt ligand secretion mediator
Aliases Wntless, EVI, GPR177
HGNC HGNC:30238
NCBI Gene 79971
Ensembl ENSG00000116729
OMIM *611514
UniProt Q5T9L3
Location 1p31.3
Product Multi-pass transmembrane Wnt cargo receptor
Disease mechanism Recessive hypomorphic/loss-of-function impairment of Wnt secretion

4.2 Reported disease-associated variants

Transcript numbering differs between reports; therefore HGVS should be normalized against the laboratory’s selected MANE/reference transcript before clinical reporting.

Variant as reported Type/domain Zygosity/report Interpretation/evidence
c.271G>A, p.Val91Met Missense, extracellular loop Compound heterozygous Likely pathogenic; functional reduction of WNT3A and β-catenin; reported population frequency 0.0001087 [Web:24]
c.415C>T, p.Arg139Cys Missense, extracellular loop Compound heterozygous, 2023 Chinese patient Disease-associated; reduced WLS/WNT3A secretion in vitro [Web:28]
c.1175A>G, p.Tyr392Cys Missense, sixth transmembrane domain Homozygous in five Emirati siblings ClinVar pathogenic; absent from gnomAD in the original report; reduced protein and Wnt secretion [Web:46]
c.1427A>G, p.Tyr476Cys Missense; transcript-dependent numbering Compound heterozygous Chinese patient Reported disease-associated; paired with p.Arg139Cys [Web:34]
c.1433A>G, p.Tyr478Cys Missense, eighth transmembrane domain Homozygous in Egyptian and Native American families ClinVar pathogenic; severe cellular and mouse functional evidence [Web:50]
c.1579G>A, p.Gly527Arg Missense near C-terminal ER-targeting region Homozygous Likely disease-causing; severe multisystem phenotype, PMID 37106064 [Web:109]
p.Ile531Thr Missense near ER-targeting motif Homozygous Disease-associated in original cohort
c.1606C>T, p.Arg536Cys Missense in ER-targeting motif Homozygous ClinVar/OMIM pathogenic; WNT3A/WNT5A secretion reduced approximately 60% [Web:33]
c.1279-1G>C Canonical splice-acceptor variant Compound heterozygous Pathogenic by PVS1+PM2+PP3+PP4; predicted splice disruption, but direct RNA assay was not reported [Web:24]

All are germline variants. No somatic origin, repeat expansion or mitochondrial mechanism has been implicated.

4.3 Variant effects

  • Transmembrane p.Tyr392Cys and p.Tyr478Cys reduced ectopically expressed WLS protein by roughly 50%.
  • Patient p.Tyr478Cys fibroblasts had >90% lower WLS protein than control fibroblasts.
  • Mutant cells secreted 60–80% less WNT3A/WNT5A despite similar intracellular ligand abundance.
  • TOPFlash Wnt reporter output fell 50–60%.
  • Mouse embryonic fibroblasts from both knock-in lines had approximately 40% lower WLS protein. [Web:91]

The demonstrated mechanism is therefore predominantly partial loss of function/hypomorphism, not gain of function or dominant negative action.

4.4 Population frequency and penetrance

Most reported alleles are absent or extremely rare in reference databases; p.Val91Met was reported at 0.0001087. Because the condition is recessive, heterozygous carrier alleles can occur in unaffected people.

Penetrance appears high for individuals with two strongly deleterious alleles, but exact penetrance cannot be estimated from 13–14 reported patients. Expression is clearly variable.

4.5 Modifiers, epigenetics and chromosomal abnormalities

  • No validated modifier gene is known.
  • No syndrome-specific methylation signature or histone/chromatin abnormality has been reported.
  • No recurrent deletion, duplication, inversion, translocation or aneuploidy defines the disease.
  • Copy-number or regulatory variants affecting both WLS alleles remain theoretically possible but are not established causes.
  • No founder allele has been formally demonstrated, although p.Tyr392Cys recurred within one consanguineous Emirati pedigree and p.Tyr478Cys occurred in more than one ancestry.

5. Environmental information

Factor Current evidence
Toxins/pollution/radiation No causal association
Maternal medication No established association
Smoking, alcohol, diet or exercise No established disease-specific effect
Occupational exposure No established effect
Infectious agent None; this is not congenital Zika syndrome
Transmission Genetic, not contagious
Gene–environment interaction Unproven
Lifestyle modification of risk Not applicable to disease occurrence once the biallelic genotype is present

Environmental factors may influence general pregnancy or developmental outcomes, but none has been shown specifically to produce or prevent WLS-related Zaki syndrome.

6. Mechanism and pathophysiology

6.1 Ordered causal chain

  1. Biallelic hypomorphic or loss-of-function WLS variants lead to reduced WLS abundance, impaired trafficking, or defective cargo-receptor activity.
  2. Defective WLS leads to reduced ER-to-Golgi-to-plasma-membrane transport and secretion of palmitoleated Wnt ligands.
  3. Reduced extracellular Wnt availability leads to deficient canonical β-catenin and noncanonical Wnt signaling in Wnt-producing and neighboring cells.
  4. Reduced developmental Wnt signaling leads to tissue-specific vulnerability according to each tissue’s Wnt dosage requirements and developmental timing.
  5. In neural progenitors, deficient signaling leads to abnormal cell-cycle progression, with intermediate progenitors stalling in S and G2/M phases, resulting in reduced neurogenesis.
  6. Reduced neurogenesis and abnormal cortical organization lead to small brain size, progressive microcephaly, developmental delay and intellectual disability.
  7. Inferred branch—deficient craniofacial, ocular and ectodermal Wnt signaling leads to facial dysmorphism, coloboma/microphthalmia, sparse hair and dental anomalies.
  8. Deficient limb-bud and somite/tail-bud signaling leads to syndactyly, ectrodactyly, digit-number abnormalities, vertebral/tail defects and skeletal dysplasia.
  9. Deficient metanephric/renal-medullary Wnt signaling leads to renal agenesis, hydronephrosis or other renal malformations.
  10. Deficient cardiac developmental signaling is inferred to lead to patent foramen ovale, patent ductus arteriosus and other congenital heart defects.
  11. Experimental GSK3 inhibition by CHIR99021 leads to β-catenin stabilization downstream of WLS and results in partial rescue of embryoid-body and mouse developmental phenotypes.

6.2 Molecular pathway detail

Wnt proteins are lipid-modified by PORCN in the ER. WLS binds the modified ligands, escorts them through the Golgi and secretory vesicles, and releases them at the plasma membrane. WLS is subsequently recycled through endosomes and the retromer system. It occupies the ER, Golgi, vesicular/endosomal and plasma-membrane compartments. [Web:85][Web:88]

Relevant ontology suggestions:

Biological component/process Suggested ontology term
Wnt signaling GO:0016055
Canonical Wnt signaling GO:0060070
Protein secretion GO:0009306
Intracellular protein transport GO:0006886
Vesicle-mediated transport GO:0016192
Neurogenesis GO:0022008
Cell cycle GO:0007049
Regulation of cell proliferation GO:0042127
Embryonic morphogenesis GO:0048598
Endoplasmic reticulum GO:0005783
Golgi apparatus GO:0005794
Endosome GO:0005768
Plasma membrane GO:0005886

6.3 Cellular and tissue processes

Nervous system

Single-nucleus RNA sequencing of embryonic mutant mouse brain demonstrated markedly reduced neurogenesis and abnormal cell-cycle progression in intermediate neural progenitors. Mutant brains showed reduced size, fewer cortical neurons, defective cortical lamination, ectopias, disrupted pial basement membrane and a severely defective hippocampal dentate gyrus. [Web:91]

Suggested cell terms:

  • neural progenitor cell — CL:0011020;
  • neuron — CL:0000540;
  • cerebral-cortex neuron — use the appropriate subtype-specific CL term where known;
  • fibroblast — CL:0000057;
  • induced pluripotent stem cell — CL:0002248.

Renal, limb and ectodermal development

Mouse findings and known ligand biology suggest:

  • WNT7B-related signaling contributes to renal-medullary morphogenesis;
  • WNT3A/WNT5A signaling contributes to somite, caudal-axis and limb morphogenesis;
  • WNT10B-related biology is relevant to split-foot/digit development;
  • epithelial Wls deletion in mice impairs hair growth.

These mappings are mechanistically plausible but do not establish that any one ligand alone causes each human phenotype.

6.4 Metabolic, immune and tissue-damage findings

  • No primary metabolic-enzyme deficiency has been identified.
  • No reproducible serum, urine, metabolomic, lipidomic or proteomic signature is available.
  • Extensive biochemical testing in the first family was normal.
  • No primary autoimmunity, immunodeficiency or chronic inflammatory mechanism is established.
  • Tissue abnormalities primarily reflect altered developmental specification, proliferation and morphogenesis rather than ischemia, fibrosis or necrosis.
  • No disease-specific epigenomic or spatial-transcriptomic dataset has been published.

6.5 Molecular profiling and advanced technologies

Technology Findings
Patient fibroblast proteomics/Western blot >90% lower WLS in p.Tyr478Cys patient cells
Wnt secretion assays 60–80% lower secreted WNT3A/WNT5A
TOPFlash reporter 50–60% lower Wnt-responsive luciferase
Patient iPSC embryoid bodies Approximately 50% smaller; size restored by CHIR99021
Mouse single-nucleus RNA-seq Reduced neurogenesis; intermediate progenitor cell-cycle arrest
Spatial transcriptomics No disease-specific report
Human single-cell profiling No report
CRISPR screen No syndrome-specific screen identified
Metabolomics/lipidomics No report
Multi-omics integration No report

7. Anatomical structures affected

Level Structure/system Role Suggested ontology
Organ Brain Primary; microcephaly, callosal/vermis defects, Dandy–Walker spectrum UBERON:0000955
Organ Eye Primary; coloboma, microphthalmia, microcornea, strabismus UBERON:0000970
Organ Kidney Primary congenital malformation; agenesis/hydronephrosis UBERON:0002113
Organ Heart Variable congenital defects UBERON:0000948
Organ/tissue Skin and hair follicle Sparse hair/alopecia UBERON:0002097; UBERON:0002073
Organ/tissue Skeleton and limb Syndactyly, ectrodactyly, fractures, scoliosis UBERON:0002101
Tissue Cerebral cortex Reduced neuron number, lamination defects in mice UBERON:0000956
Tissue Cerebellar vermis Hypoplasia UBERON:0004728
Tissue Corpus callosum Hypoplasia UBERON:0002336
Tissue Hippocampal dentate gyrus Severe reduction in mouse model UBERON:0001885
Tissue Renal medulla/metanephros Developmental vulnerability in mice UBERON:0000362
Craniofacial Palate, jaw, nose, ears, lips Dysmorphic features Site-specific UBERON/FMA terms
Oral Teeth, palate, jaw Dental anomalies and high-arched palate UBERON:0001091
Genitourinary Testis Cryptorchidism in one reported patient UBERON:0000473

Most findings are bilateral or midline. Eye coloboma, renal agenesis and limb anomalies can be unilateral or asymmetric; no consistent lateralization is established.

At subcellular level, WLS dysfunction involves the ER, Golgi, endosomes, secretory vesicles and plasma membrane.

8. Temporal development

8.1 Onset

The pathogenic process begins prenatally during embryogenesis. Structural malformations are congenital, but growth and neurodevelopmental features may emerge after birth.

Notably, the reviewed patients were generally reported to have term birth with normal birth weight, length and head circumference. Microcephaly and short stature often became evident during infancy or by two years. [Web:24]

8.2 Course

Phase Typical manifestations
Prenatal Mild short femur or reduced fetal biometry may occur; renal, cardiac, eye or limb anomalies may be detectable
Neonatal Congenital dysmorphism, syndactyly, eye/renal/cardiac malformations; head size may still be normal
Infancy Emerging microcephaly, growth faltering, hypotonia, impaired visual response and developmental delay
Childhood Persistent/progressive microcephaly and short stature; intellectual, speech and motor disability become clearer
Later childhood/adolescence Mobility limitations, scoliosis, fracture risk or renal monitoring needs may become more apparent
Adult course Essentially unknown because published cohorts are very small and predominantly pediatric

The disorder is chronic and lifelong. It is not known to have relapsing–remitting episodes or spontaneous remission. Structural abnormalities generally do not regress, although patent foramen ovale, strabismus or surgically correctable skeletal defects may improve with standard care.

The principal inferred critical period is early embryogenesis, when Wnt signaling specifies organs and body pattern. Whether a later postnatal therapeutic window exists is unknown.

9. Inheritance and population

9.1 Epidemiology

No population prevalence or incidence estimate is available. The disorder is appropriately described as ultra-rare.

  • 10 affected people from five families were reported in 2021.
  • Additional 2023 cases raised the molecularly documented total.
  • The literature review through October 2024 analyzed 13 patients with nine pathogenic/likely pathogenic variants. [Web:24]
  • No national registry, newborn-screening estimate or population carrier-frequency study exists.

A prevalence “per 100,000” cannot be calculated reliably from published case counts.

9.2 Mendelian inheritance

Feature Current conclusion
Mode Autosomal recessive
Affected genotype Homozygous or compound heterozygous pathogenic WLS variants
Recurrence risk 25% affected, 50% carrier and 25% unaffected/noncarrier per pregnancy when both parents are carriers
Penetrance Probably high for qualifying biallelic genotypes, but unquantified
Expressivity Variable
Anticipation Not expected; no repeat expansion
Germline mosaicism Not reported, but low residual recurrence risk is theoretically possible after an apparently de novo variant
Consanguinity Present in several original pedigrees but not required
Founder effect Not established
Carrier phenotype Heterozygous relatives in recessive families were clinically unaffected
Carrier frequency Unknown

A 2023 study found extremely rare heterozygous WLS missense variants among patients with isolated dental anomalies, but this does not yet establish a consistent dominant WLS disorder or imply that all Zaki-syndrome carriers have dental disease. PMID: 36374649, published May 31, 2023. [Web:107][Web:108]

9.3 Demographics

No reliable male:female ratio is available. The condition has been reported across geographically and ancestrally diverse populations, arguing against restriction to one population. Ascertainment through consanguineous cohorts likely biases the currently observed distribution.

10. Diagnostics

10.1 Diagnostic principle

There are no consensus clinical criteria. Diagnosis requires:

  1. compatible developmental/malformation phenotype;
  2. identification of two pathogenic or likely pathogenic WLS variants in trans;
  3. segregation analysis where possible;
  4. functional RNA/protein assays when variant interpretation remains uncertain.

10.2 Recommended clinical evaluation

Domain Evaluation
Growth Serial height, weight and occipitofrontal circumference plotted longitudinally
Development Standardized cognitive, motor, language and adaptive assessment
Neurology Neurologic examination; EEG only if seizures or concerning spells
Brain MRI to assess corpus callosum, cerebellar vermis, fourth ventricle and Dandy–Walker spectrum
Ophthalmology Dilated examination, optic-disc/iris evaluation, refraction, ocular alignment and visual-function testing
Renal Renal/bladder ultrasound; blood pressure, serum creatinine/eGFR and urinalysis
Cardiac Echocardiogram and ECG at diagnosis
Skeletal Examination for syndactyly, ectrodactyly, scoliosis and limb-length abnormalities; radiographs as indicated
Bone health Calcium, phosphate, alkaline phosphatase, vitamin D and DXA/radiographs if fractures or skeletal dysplasia
Dental Early dental/orthodontic examination and panoramic imaging when age appropriate
Genital Examination for cryptorchidism or other congenital anomalies
Hearing Baseline audiology, although hearing loss is not a core established feature
Laboratory chemistry No diagnostic biochemical assay; testing is directed by manifestations

Biopsy is not routinely diagnostic. There is no validated circulating biomarker.

10.3 Genetic-testing strategy

  • Trio WES or WGS: preferred when multiple congenital anomalies, microcephaly and developmental delay are unexplained. Both homozygous and compound-heterozygous WLS variants can be detected.
  • Multigene panels: WLS should be included on developmental-disorder, microcephaly, eye-coloboma, fetal-anomaly, CAKUT, congenital-heart and Mendelian-disease panels. PanelApp lists WLS as a biallelic gene across several relevant panels. [Web:125]
  • Single-gene sequencing: appropriate when the phenotype and family segregation strongly indicate Zaki syndrome; deletion/duplication analysis should be added if only one allele is found.
  • CMA: useful for the general work-up of multiple congenital anomalies but does not reliably detect most reported WLS single-nucleotide variants.
  • Karyotype/FISH: not first-line unless a cytogenetic abnormality is suspected.
  • RNA sequencing: useful for suspected splice variants such as c.1279-1G>C, although this particular variant currently lacks direct patient-RNA confirmation.
  • mtDNA and repeat-expansion testing: not specifically indicated.
  • Prenatal testing: targeted familial-variant testing by CVS or amniocentesis; fetal exome/genome sequencing may be considered for multiple anomalies.
  • Preimplantation genetic testing: technically feasible for known familial variants.

The early-diagnosis report recommends targeted skeletal panels for isolated short femur/skeletal findings and WES/WGS when additional structural anomalies are present. [Web:121]

10.4 Differential diagnosis

Differential Distinguishing considerations
DDX59-related Zaki–Gleeson syndrome Severe microcephaly, cerebellar hypoplasia and cardiac conduction block; different gene and identifiers
Focal dermal hypoplasia/PORCN-related disorder X-linked dominant, characteristic dermal hypoplasia and limb defects; mechanistically related Wnt-secretion defect
Robinow syndrome/WNT5A-pathway disorders Mesomelia, genital and vertebral abnormalities; distinct gene/pathway phenotype
WNT10A/WNT10B disorders Ectodermal/dental and limb phenotypes, usually without the full WLS multisystem pattern
Primary autosomal-recessive microcephaly Microcephaly dominates, usually without characteristic eye/renal/limb constellation
Dandy–Walker spectrum disorders Cerebellar malformation may dominate; WLS testing indicated when accompanied by sparse hair, syndactyly and progressive microcephaly
Chromatinopathies Developmental delay and dysmorphism, but molecular testing distinguishes them
Microcephalic osteodysplastic primordial dwarfism Severe prenatal/postnatal growth restriction and skeletal phenotype
Congenital infection, including Zika Exposure/infection evidence; destructive rather than inherited WLS mechanism
Phenylketonuria/metabolic microcephaly Biochemical abnormalities and newborn-screening findings

10.5 Screening

There is no population or newborn screen. Appropriate screening consists of:

  • cascade testing of at-risk relatives;
  • carrier testing for reproductive partners in known families;
  • prenatal or preimplantation testing after familial variants are established.

11. Outcome and prognosis

11.1 Survival

No five-year, ten-year, mortality-rate or life-expectancy data exist. Perinatal lethality occurred in homozygous knock-in mice, but should not be directly extrapolated to humans. Published human patients have survived into childhood and at least adolescence; a compound-heterozygous Chinese patient was reported at age 16. [Web:34]

There is currently no evidence that all affected people have markedly shortened life expectancy, but severe renal, cardiac, neurologic or skeletal complications could affect prognosis.

11.2 Morbidity

Expected long-term morbidity includes:

  • intellectual, speech and motor disability;
  • impaired vision;
  • growth restriction and microcephaly;
  • gait and mobility limitations;
  • fracture or scoliosis complications in severe skeletal disease;
  • reduced renal reserve after unilateral agenesis;
  • need for congenital-heart surveillance;
  • dental and orthodontic burden.

No formal ICF, EQ-5D, SF-36, PROMIS or disease-specific quality-of-life data exist.

11.3 Prognostic factors

Possible but unvalidated factors include:

  • degree of residual WLS protein and Wnt secretion;
  • variant location/domain;
  • homozygous versus compound-heterozygous state;
  • extent of brain, kidney, heart and eye malformations;
  • early developmental trajectory.

Preliminary domain correlations suggested more wide mouth and fewer long digits with transmembrane variants, and more broad distal phalanges with variants near the ER-targeting motif. These analyses involved very small cell counts and multiple comparisons and must not be considered clinically predictive. [Web:24]

No validated prognostic biomarker or severity score exists.

12. Treatment

12.1 Current standard of care

There is no approved disease-modifying therapy. Management is individualized, multidisciplinary and phenotype-directed.

Intervention Indication Suggested NCIt concept
Physical therapy Hypotonia, delayed gross motor development, gait impairment Physical Therapy, NCIt:C15308
Occupational therapy Fine-motor and self-care limitations Occupational Therapy
Speech/language therapy Speech and language delay; augmentative communication if needed Speech Therapy, NCIt:C15313
Developmental/educational intervention Global delay and intellectual disability Early Intervention
Ophthalmologic correction Refraction, amblyopia, strabismus and visual rehabilitation Ophthalmologic Procedure
Strabismus surgery Selected significant ocular misalignment Strabismus Surgery
Orthopedic/hand-foot surgery Function-limiting syndactyly or severe limb deformity Orthopedic Surgery
Scoliosis management Observation, bracing or surgery according to standard criteria Spinal Orthosis; Spinal Fusion
Fracture/bone-health management Fractures or low bone density Fracture Management
Cryptorchidism surgery Undescended testis Orchiopexy
Cardiology care Hemodynamically important congenital defect Cardiac Procedure
Renal surveillance Agenesis, hydronephrosis or reduced function Renal Function Assessment
Dental/orthodontic care Tooth anomalies and malocclusion Dental Procedure; Orthodontic Treatment
Seizure medication Only when epilepsy is documented Anticonvulsant Therapy
Genetic counseling Recurrence risk and reproductive options Genetic Counseling, NCIt:C15238

No disease-specific pharmacogenomic recommendations exist.

12.2 Experimental Wnt-pathway therapy

CHIR99021 is a small-molecule GSK3 inhibitor that stabilizes β-catenin and enhances canonical Wnt transcription. In patient-derived embryoid bodies, it restored reduced body size. In pregnant knock-in mice, twice-daily intraperitoneal administration beginning at embryonic day 4.5 produced:

  • near-complete tail rescue in p.Tyr478Cys mice and partial rescue in p.Tyr392Cys mice;
  • reduction of hydronephrosis from 75.0% to 22.7%;
  • 16.4% greater dorsoventral brain width;
  • 14.3% greater cortical thickness;
  • 25.4% more CUX1-positive neurons;
  • 16.0% more CTIP2-positive neurons;
  • 150.3% more dentate-gyrus cells. [Web:91]

The paper concluded:

“Administration of a pharmacologic Wnt agonist partially restored embryonic development.”
— Chai et al., 2021; PMID 34587386. [Web:32]

This is preclinical evidence only. Systemic prenatal activation of Wnt signaling could disrupt embryogenesis or promote tumorigenic processes, so CHIR99021 should not be used clinically outside appropriately reviewed research. The authors expressly stated that maternal and fetal safety requires careful study. [Web:91]

12.3 Advanced therapeutics and trials

Modality Status
Gene replacement No clinical program identified
CRISPR/gene editing No clinical program identified
Antisense/siRNA/mRNA No clinical program identified
Cell therapy No indication or trial
Immunotherapy Not mechanistically indicated
Approved targeted drug None
Registered Zaki-syndrome interventional trial None identified
Human CHIR99021 trial None identified for this disease
NIH research R01HD119284 studies Wntless mechanisms; it lists no clinical study [Web:93]

13. Prevention

13.1 Primary prevention

Because the disease is genetic, smoking cessation, diet, exercise, vaccination and environmental remediation do not specifically prevent it.

For known carrier couples, primary reproductive options include:

  • preconception genetic counseling;
  • partner testing;
  • IVF with preimplantation genetic testing for monogenic disease;
  • use of donor gametes;
  • prenatal diagnosis by CVS or amniocentesis.

13.2 Secondary prevention/early detection

  • Cascade carrier testing in relatives.
  • Early WES/WGS in infants with progressive microcephaly plus eye, hair, limb, renal or cardiac abnormalities.
  • Prenatal ultrasound surveillance for growth, limb, renal, cardiac and CNS anomalies in at-risk pregnancies.
  • Early ophthalmology, neurodevelopmental, renal and cardiac evaluation after diagnosis.

There is no general-population carrier or newborn-screening program.

13.3 Tertiary prevention

Tertiary measures include:

  • amblyopia prevention and visual rehabilitation;
  • early developmental therapies;
  • renal-protective monitoring and avoidance of unnecessary nephrotoxins in patients with solitary kidney;
  • treatment of scoliosis and bone fragility;
  • timely orchiopexy;
  • management of congenital heart disease;
  • fall and fracture prevention;
  • educational, mobility and communication supports.

No vaccine, antimicrobial prophylaxis or public-health sanitation measure is relevant to disease prevention.

14. Other species and natural disease

Topic Evidence
Naturally occurring veterinary Zaki syndrome No confirmed naturally occurring WLS-associated homologous syndrome identified
Companion-animal breed predisposition None established
Zoonotic potential None
Cross-species transmission Not applicable
Evolutionary conservation WLS/Wntless function is strongly conserved across metazoans
Mouse Mus musculus, NCBI Taxon 10090; Wls knock-in and conditional models
Fruit fly Drosophila melanogaster, Taxon 7227; wls/evi/sprinter controls Wingless secretion and retromer-dependent recycling
Human Homo sapiens, Taxon 9606

Wntless biology was initially delineated in invertebrate and cellular systems. Drosophila studies show that Wls is a multi-pass transmembrane protein required for Wingless secretion and recycled from endosome to Golgi by the retromer. [Web:86]

There is no infectious transmission, zoonosis or veterinary public-health relevance.

15. Model organisms and experimental models

Model Type Key findings Strengths Limitations
Wls p.Tyr392Cys knock-in mouse Mammalian, precise genetic model Approximately 40% lower WLS in fibroblasts; neural-tube, tail, vertebral, digit, kidney and brain defects; perinatal lethality Human-allele-specific; permits prenatal treatment studies More severe/lethal than reported human course
Wls p.Tyr478Cys knock-in mouse Mammalian, precise genetic model Global Wnt-reporter reduction; hydronephrosis, reduced digits, microbrain, cortical and hippocampal abnormalities Strong phenotype recapitulation; single-nucleus profiling Species and dosage differences
TCF/Lef:H2B-GFP reporter cross Mouse pathway reporter Reduced Wnt activity in face, heart, spine, tail bud, metanephros and neural tissues Anatomical mapping of pathway deficit Reporter reflects selected canonical Wnt outputs
Patient fibroblasts Human primary cells >90% lower WLS in p.Tyr478Cys cells; impaired Wnt secretion Direct patient evidence Limited developmental context
WLS-null HEK293T complementation Human in-vitro functional assay Mutant WLS caused 60–80% lower WNT3A/WNT5A secretion and 50–60% lower TOPFlash output Quantitative variant-function testing Artificial overexpression/cell-line context
Patient-derived iPSCs Human cellular model Mutant iPSCs viable Genetically patient-specific Do not independently reproduce organogenesis
Patient-derived embryoid bodies Human 3-D in-vitro model Approximately 50% smaller; size restored with CHIR99021 Models early pregastrulation-like development and drug response Not an intact embryo or organ
Mouse single-nucleus RNA-seq Advanced molecular model Reduced neurogenesis and S/G2-M stalling in intermediate progenitors Cell-type-resolved mechanism Embryonic mouse brain only
Conditional epidermal Wls knockout Mammalian induced genetic model Hair-growth defect Supports ectodermal mechanism Not a full Zaki-syndrome model
Drosophila wls/evi models Invertebrate genetic model Defective Wingless secretion and retromer recycling Highly tractable and evolutionarily conserved Limited correspondence to human organs

The mouse models reproduce nervous-system, kidney and limb abnormalities especially well. They also demonstrate that different tissues have different Wnt-dose thresholds. Their perinatal lethality and severe caudal defects indicate that they may model the severe end of the human allelic spectrum rather than the average reported patient. [Web:91]

Evidence appraisal and research gaps

Strong evidence

  • Biallelic WLS variants cause Zaki syndrome.
  • WLS variants reduce WLS protein stability/function and Wnt secretion.
  • The condition is autosomal recessive and multisystem.
  • Knock-in mice reproduce major developmental abnormalities.
  • CHIR99021 can partially rescue cellular and prenatal mouse phenotypes.

Moderate evidence

  • Progressive postnatal microcephaly, distinctive facial features, neurodevelopmental impairment, sparse hair, eye and skeletal anomalies are core phenotypes.
  • Renal and cardiac defects are recurrent but incompletely penetrant.
  • Compound-heterozygous alleles can cause disease.

Preliminary or uncertain

  • Variant-domain/genotype–phenotype correlations.
  • A systematically milder compound-heterozygous course.
  • Umbilical polyps as part of the phenotype.
  • Dominant dental effects in heterozygous carriers.
  • Human efficacy or safety of prenatal Wnt agonism.
  • Adult natural history, survival, fertility and life expectancy.

Highest-priority research needs

  1. International registry and longitudinal natural-history cohort.
  2. Standardized developmental, ophthalmic, renal, skeletal and quality-of-life outcomes.
  3. Systematic reanalysis of WLS variants using a single reference transcript.
  4. RNA studies for splice variants and assays for all newly reported alleles.
  5. Human neural, renal and ocular organoid models.
  6. Maternal–fetal toxicology and dose-window studies of pathway modulation.
  7. Investigation of safer tissue-selective or temporally restricted Wnt rescue.
  8. Adult follow-up, reproductive outcomes and penetrance studies in carrier families.

Key literature

Publication Date Evidence type Key contribution
Chai et al. A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion. N Engl J Med. 2021;385:1292–1301. PMID 34587386. DOI: 10.1056/NEJMoa2033911. PubMed URL September 30, 2021 Human clinical, in vitro, iPSC and mouse Disease discovery; 10 patients/5 families; mechanism and prenatal mouse rescue [Web:32]
Yu et al. Compound heterozygous variants in WLS gene causes Zaki syndrome. Clin Genet. 2023;104:226–229. PMID 37005218. DOI: 10.1111/cge.14334. PubMed URL August 2023; online April 2, 2023 Human case and in vitro First reported Chinese case and compound-heterozygous alleles [Web:34]
Expanding the phenotypic spectrum and clinical severity associated with WLS gene. J Hum Genet. 2023;68:607–613. PMID 37106064. DOI: 10.1038/s10038-023-01152-2. PubMed URL September 2023; online April 28, 2023 Human case p.Gly527Arg; Dandy–Walker malformation, microphthalmia, dental anomalies, fractures [Web:109]
Kantaputra et al. Mutations in the WLS are associated with dental anomalies, torus palatinus, and torus mandibularis. Eur J Orthod. 2023;45:317–323. PMID 36374649. DOI: 10.1093/ejo/cjac068. Article URL May 31, 2023 Human case series Possible heterozygous WLS contribution to dental phenotypes [Web:107]
Early diagnosed Zaki syndrome: identification of two novel WLS variants and a literature review. Italian Journal of Pediatrics. Full-text URL July 5, 2025 Human infant, functional assay and review through October 2024 p.Val91Met and c.1279-1G>C; 13-patient aggregate frequency analysis [Web:24]

Overall conclusion: Zaki syndrome is a newly delineated, ultra-rare, autosomal-recessive Wnt-secretion disorder with strong human genetic and functional evidence implicating WLS loss of function. Present care is supportive and surveillance-based. Prenatal Wnt-pathway rescue is biologically compelling but remains confined to cellular and mouse models and is not ready for clinical use.

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