Visceral Heterotaxy 14

Mendelian MONDO:0976135 Pathograph 12 Show in embeddings browser Visceral heterotaxy Congenital Disorder

Visceral heterotaxy 14 (HTX14) is an autosomal recessive laterality disorder caused by bi-allelic inactivating variants in CIROZ (previously C1orf127). CIROZ encodes a secreted protein with a signal peptide and three zona pellucida N (ZP-N) domains that is specifically expressed in the embryonic left-right organizer (LRO). It belongs to a conserved genetic module (with DAND5, PKD1L1, MMP21 and CIROP) that evolved in vertebrates whose LRO carries motile cilia; its precise molecular step within that module is not yet established. Loss of CIROZ function disrupts breaking of embryonic bilateral symmetry, producing heterotaxy (situs ambiguus) with congenital heart defects. The human phenotype is reproduced by the mouse knockout, which develops situs anomalies, but notably not by zebrafish or Xenopus knockouts, in which CIROZ is dispensable for left-right patterning. The gene was defined in a 2025 cohort of 16 individuals from 10 families; the literature is therefore recent and still thin, and no GeneReviews chapter exists.

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Mappings

MONDO
MONDO:0976135 heterotaxy, visceral, 14, autosomal
skos:exactMatch MONDO
MONDO:0976135 is the primary term for this entry. MONDO records CIROZ (hgnc:26730) as the causal gene for this autosomal visceral-heterotaxy concept, matching the curated content of this entry.
👪

Inheritance

1
Autosomal recessive HP:0000007
Affected individuals carry bi-allelic (homozygous or compound heterozygous) inactivating CIROZ variants; many of the reported families are consanguineous. Penetrance is incomplete: two reported bi-allelic individuals had normal situs (situs solitus).
Autosomal recessive inheritance
Show evidence (3 references)
PMID:39753129 SUPPORT Human clinical
"We report 16 individuals from 10 families with bi-allelic CIROZ inactivation variants, which cause heterotaxy with congenital heart defects."
The gene-discovery cohort establishes bi-allelic (recessive) inactivation of CIROZ as the disease mechanism.
PMID:39753129 SUPPORT Human clinical
"Notably, there were two individuals with bi-allelic CIROZ variants and non-phenotypic penetrance"
Two bi-allelic individuals with normal situs establish that penetrance of CIROZ-related heterotaxy is incomplete.
PMID:39513328 SUPPORT Human clinical
"8 genes known to be implicated in autosomal recessive form of HTX (C1orf127, CCDC39, CIROP, DNAAF3, DNAH5, DNAH9, MMP21, and MNS1)"
An independent consanguineous-cohort study lists C1orf127 (the former symbol for CIROZ) among the recognized autosomal recessive heterotaxy genes.
?

Discussions and Knowledge Gaps

2
What is CIROZ's molecular step in the left-right organizer, and how does it relate to the other module proteins (DAND5, PKD1L1, MMP21, CIROP)?
KNOWLEDGE GAP OPEN ciroz_molecular_step_unknown
Attached to
pathophysiology#Loss of CIROZ in the Left-Right Organizer
CIROZ is essential for situs in humans and mice and is a secreted ZP-N-domain member of the LRO module, but the defining study (PMID:39753129) states that "the exact role played by CIROZ in the mouse and human LRO remains to be addressed" and that its functional relationship to the other module proteins "remains to be explored". By homology to ZP2, which is cleaved by ovastacin, CIROZ may itself require proteolytic processing, possibly by the module metallopeptidases MMP21 or CIROP, but this is untested. The node therefore records only the loss of a module factor, not a specified signalling step.
Proposed experiments
LRO function assays in Ciroz-null embryos
ciroz_lro_function_assays
In Ciroz-null mouse embryos, test whether cilia motility, cilia-driven leftward flow, or LRO cell/tissue morphology are affected, to localise CIROZ's step relative to flow generation and flow sensing.
CIROZ proteolytic-processing test
ciroz_protease_substrate
Test whether CIROZ is a substrate of the zinc-dependent metallopeptidases MMP21 and/or CIROP (as ZP2 is cleaved by ovastacin), to determine whether module metallopeptidases process CIROZ to switch its activity.
Why is CIROZ essential for left-right patterning in humans and mice but dispensable in zebrafish and Xenopus, and which model faithfully reproduces the human mechanism?
HUMAN MODEL MISMATCH OPEN ciroz_species_divergence
Attached to
pathophysiology#Failure of Left-Right Axis Determination
Model evidence exists but diverges by species: the mouse knockout develops situs anomalies, yet zebrafish and Xenopus knockouts show no laterality defect, and the gene is absent or pseudogenized in some vertebrates that retain a cilia-motile left-right organizer. The non-mammalian models therefore cannot be assumed to represent the human CIROZ mechanism, and only the mouse currently stands as a faithful model.
Proposed experiments
Patient-allele knock-in mouse
ciroz_patient_allele_mouse
Generate mice carrying reported patient CIROZ inactivating alleles and assess situs, cardiac looping and congenital heart defects to test genotype-phenotype correlation in the faithful mammalian model.
⚙

Pathophysiology

3
Biallelic CIROZ Loss of Function
Bi-allelic inactivating CIROZ variants abolish or reduce the function of a secreted ZP-N-domain protein. Reported genotypes are inactivating (homozygous or compound heterozygous), consistent with a loss-of-function mechanism.
CIROZ hgnc:26730 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CIROZ, annotated with C1orf127 (hgnc:26730). hgnc:26730 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Loss of CIROZ in the Left-Right Organizer CIROZ is specifically expressed in the left-right organizer as an extracellular protein; its loss removes that LRO-localized factor.
Show evidence (1 reference)
PMID:39753129 SUPPORT Human clinical
"We report 16 individuals from 10 families with bi-allelic CIROZ inactivation variants, which cause heterotaxy with congenital heart defects."
Bi-allelic inactivation establishes loss of CIROZ function as the lesion.
Loss of CIROZ in the Left-Right Organizer
CIROZ is a secreted protein expressed specifically in the left-right organizer and is a member of the conserved LRO module (with DAND5, PKD1L1, MMP21 and CIROP); it is essential for normal situs in humans and mice. Its precise molecular step within that module is not established: the defining study states that the exact role of CIROZ in the LRO, and its functional relationship to the other module proteins, remain to be determined. This node therefore records the loss of an LRO-restricted module factor, not a specified signalling step (see the attached knowledge gap).
Downstream
Failure of Left-Right Axis Determination
Show evidence (1 reference)
PMID:39753129 SUPPORT INDIRECT Model organism
"Four genes-DAND5, PKD1L1, MMP21, and CIROP-form a genetic module that has specifically evolved in vertebrate species that harbor motile cilia in their left-right organizer (LRO)"
Establishes the cilia-motile left-right organizer module to which CIROZ belongs; the quote does not name CIROZ, so it supports the module-membership framing only by inference.
Failure of Left-Right Axis Determination
Loss of CIROZ function prevents normal breaking of embryonic bilateral symmetry, randomizing left-right body-axis specification and producing situs ambiguus with associated congenital heart defects.
determination of left/right symmetry GO:0007368 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased determination of left/right symmetry (GO:0007368). GO:0007368 is a biological process from the Gene Ontology.
Animal models
Ciroz c.26+1G>A mouse (MGI:5431499) Mouse recapitulates The homozygous null embryo reproduces organism-level situs reversal and organ malposition.
Ciroz LacZ-KO mouse (MGI:5635119) Mouse recapitulates Homozygous E18.5 embryos show situs inversus affecting multiple organs.
Ciroz knockout zebrafish Zebrafish fails to recapitulate Zebrafish ciroz loss does not reproduce the human laterality defect.
Ciroz knockout Xenopus Xenopus fails to recapitulate Xenopus ciroz loss does not reproduce the human laterality defect.
Downstream
Heterotaxy
Congenital heart defect
Situs inversus totalis
Intestinal malrotation
Show evidence (1 reference)
PMID:39753129 SUPPORT Human clinical
"These clinical and genetic data support an active role for CIROZ in establishing situs solitus in humans."
The authors conclude from the human clinical and genetic data that CIROZ is actively required to establish normal situs; its loss is the failure recorded at this node.
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Visceral Heterotaxy 14 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

8
Cardiovascular 4
Congenital heart defect Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart defect, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39753129 SUPPORT Human clinical
"which cause heterotaxy with congenital heart defects"
Congenital heart defects co-occur with heterotaxy in the reported cohort.
Situs inversus totalis HP:0001696 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Situs inversus totalis (HP:0001696). HP:0001696 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39753129 SUPPORT Human clinical
"asymptomatic situs inversus totalis in individual F4-I:2"
Situs inversus totalis is part of the reported CIROZ laterality spectrum.
Mitral atresia HP:0011560 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mitral atresia (HP:0011560). HP:0011560 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39753129 SUPPORT Human clinical
"hypoplastic left heart syndrome, mitral and aortic atresia, bilobed lungs, and malrotation of the bowel"
Mitral atresia was reported as part of the severe cardiac phenotype in individual F1-II:3.
Hypoplastic left ventricle HP:0004383 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic left heart syndrome, annotated with Hypoplastic left ventricle (HP:0004383). HP:0004383 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39753129 SUPPORT Human clinical
"hypoplastic left heart syndrome, mitral and aortic atresia, bilobed lungs, and malrotation of the bowel"
Hypoplastic left heart syndrome was reported in individual F1-II:3; bound to the closest HPO term, Hypoplastic left ventricle.
Digestive 1
Intestinal malrotation HP:0002566 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intestinal malrotation (HP:0002566). HP:0002566 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39753129 SUPPORT Human clinical
"hypoplastic left heart syndrome, mitral and aortic atresia, bilobed lungs, and malrotation of the bowel"
Bowel malrotation occurred in a severely affected individual, reflecting disrupted gut laterality.
Genitourinary 1
Horseshoe kidney HP:0000085 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Horseshoe kidney (HP:0000085). HP:0000085 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39753129 SUPPORT Human clinical
"horseshoe kidney with situs solitus in individual F4-II:4"
Horseshoe kidney was reported among the CIROZ phenotype spectrum.
Respiratory 1
Abnormal lung lobation HP:0002101 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilobed lungs, annotated with Abnormal lung lobation (HP:0002101). HP:0002101 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39753129 SUPPORT Human clinical
"hypoplastic left heart syndrome, mitral and aortic atresia, bilobed lungs, and malrotation of the bowel"
Bilobed lungs were reported in individual F1-II:3; bound to the generic lung-lobation term, with no left-isomerism term asserted.
Growth 1
Heterotaxy HP:0030853 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Heterotaxy (HP:0030853). HP:0030853 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39753129 SUPPORT Human clinical
"which cause heterotaxy with congenital heart defects"
Heterotaxy is the defining clinical feature in the reported cohort.
🧬

Genetic Associations

1
CIROZ
Gene: CIROZ hgnc:26730 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CIROZ, annotated with C1orf127 (hgnc:26730). hgnc:26730 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:39753129 SUPPORT Human clinical
"We report 16 individuals from 10 families with bi-allelic CIROZ inactivation variants, which cause heterotaxy with congenital heart defects."
The founding gene-discovery report naming CIROZ as the causal gene for recessive visceral heterotaxy.
PMID:39513328 SUPPORT Human clinical
"8 genes known to be implicated in autosomal recessive form of HTX (C1orf127, CCDC39, CIROP, DNAAF3, DNAH5, DNAH9, MMP21, and MNS1)"
Independent replication listing C1orf127 (former symbol for CIROZ) among established autosomal recessive heterotaxy genes.
💊

Medical Actions

3
Cardiac surgery for congenital heart defects
Action: cardiac surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cardiac surgery (NCIT:C157806). NCIT:C157806 is a clinical intervention from the NCI Thesaurus. Ontology label: Cardiac Surgery NCIT:C157806
Platform: Surgery
Surgical repair/palliation of the congenital heart defects that dominate morbidity and mortality in heterotaxy.
Show evidence (1 reference)
PMID:42630107 SUPPORT Human clinical
"15-year survival rates following cardiac surgery estimated at approximately 60%"
Heterotaxy-generic, NOT CIROZ-specific: cardiac surgery is the mainstay for the CHDs that occur in heterotaxy, with the quoted post-surgical survival.
Surgical correction of intestinal malrotation
Action: Ladd procedure for intestinal malrotationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Ladd procedure for intestinal malrotation, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgical correction (Ladd procedure) of intestinal malrotation identified on screening.
Show evidence (1 reference)
PMID:20730421 SUPPORT Human clinical
"the finding of interrupted IVC on echocardiography should prompt screening for intestinal malrotation, even in the absence of additional structural heart disease"
Heterotaxy-generic, NOT CIROZ-specific: the cited quote supports active screening for malrotation in heterotaxy; detected malrotation is surgically corrected (Ladd procedure) as standard care.
Pneumococcal vaccination and infection prophylaxis
Action: conjugate pneumococcal vaccinationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is conjugate pneumococcal vaccination, annotated with Vaccination (NCIT:C15346). NCIT:C15346 is a clinical intervention from the NCI Thesaurus. Ontology label: Vaccination NCIT:C15346
Platform: Vaccine
Conjugate pneumococcal vaccination and infection prophylaxis address the high bacteremia risk associated with the splenic abnormalities of heterotaxy.
Show evidence (1 reference)
PMID:20730421 SUPPORT Human clinical
"No cases of pneumococcal sepsis occurred after the introduction of the conjugated pneumococcal vaccination to the pediatric vaccination schedule"
Heterotaxy-generic, NOT CIROZ-specific, and of uncertain applicability to this cohort: splenic status is not reported for the CIROZ individuals, but pneumococcal vaccination is protective in heterotaxy with splenic anomalies.
🔬

Diagnosis

2
Cardiac and visceral situs imaging
Fetal and postnatal echocardiography with abdominal ultrasound define cardiac and visceral situs; an interrupted inferior vena cava on echocardiography is a recognised flag that should prompt screening for intestinal malrotation.
echocardiography and abdominal situs imaging NCIT:C16525 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20730421 SUPPORT Human clinical
"the finding of interrupted IVC on echocardiography should prompt screening for intestinal malrotation, even in the absence of additional structural heart disease"
Heterotaxy-generic, NOT CIROZ-specific: echocardiographic findings guide situs assessment and prompt malrotation screening in heterotaxy.
Genetic testing (exome/genome sequencing)
Trio-based whole-exome or whole-genome sequencing is the confirmatory route given the locus heterogeneity of heterotaxy; CIROZ should be included on heterotaxy/laterality gene panels. Current NGS leaves most cases unsolved, which is the diagnostic gap CIROZ discovery helps narrow.
molecular genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:42630107 SUPPORT Human clinical
"next-generation sequencing (NGS) currently identifies disease-causing variants in only 20%-30% of HTX cases"
Heterotaxy-generic, NOT CIROZ-specific: documents the low molecular diagnostic yield that motivates broad sequencing and panel inclusion of new genes such as CIROZ.
🐁

Animal Models

4
Ciroz c.26+1G>A mouse (MGI:5431499)
ENU-induced 5' splice-donor allele (protein-null). Homozygous E15.5 embryos show laterality defects, recapitulating the human situs phenotype.
Species
Mouse
Genotype
Ciroz c.26+1G>A (p.Trp9*) protein-null, homozygous; MGI:5431499
Publication
PMID:39753129
Pathograph links
Failure of Left-Right Axis Determination recapitulates fidelity: moderate observes: organism The homozygous null embryo reproduces organism-level situs reversal and organ malposition.
Show evidence (1 reference)
PMID:39753129 SUPPORT Model organism
"situs inversus totalis, CHDs, right pulmonary isomerism, or abnormal liver positioning"
The homozygous Ciroz c.26+1G>A mouse shows situs inversus totalis and organ malposition.
Ciroz LacZ-KO mouse (MGI:5635119)
IMPC LacZ-cassette (exon 4) out-of-frame allele; partially embryonic lethal when homozygous, with situs defects in survivors.
Species
Mouse
Genotype
Gm572 tm1b(EUCOMM)Hmgu LacZ exon-4 knockout, homozygous; MGI:5635119
Publication
PMID:39753129
Pathograph links
Failure of Left-Right Axis Determination recapitulates fidelity: moderate observes: organism Homozygous E18.5 embryos show situs inversus affecting multiple organs.
Show evidence (1 reference)
PMID:39753129 SUPPORT Model organism
"situs inversus phenotypes affecting the lungs, heart, liver, and stomach"
The homozygous IMPC LacZ Ciroz knockout shows multi-organ situs inversus.
Ciroz knockout zebrafish
Targeted ciroz inactivation in zebrafish does not produce observable left-right anomalies.
Species
Zebrafish
Genotype
ciroz targeted inactivation
Publication
PMID:39753129
Pathograph links
Failure of Left-Right Axis Determination fails to recapitulate fidelity: low observes: organism Zebrafish ciroz loss does not reproduce the human laterality defect.
Limitations: CIROZ is dispensable for left-right patterning in zebrafish, so the fish knockout is not a faithful model of the human mechanism; the gene is absent or pseudogenized in some lineages that retain a cilia-motile LRO.
Show evidence (1 reference)
PMID:39753129 SUPPORT Model organism
"we unexpectedly find that its targeted inactivation in zebrafish and Xenopus does not lead to observable LR anomalies"
Reports no left-right anomaly in the zebrafish knockout.
Ciroz knockout Xenopus
Targeted ciroz inactivation in Xenopus does not produce observable left-right anomalies.
Species
Xenopus
Genotype
ciroz targeted inactivation
Publication
PMID:39753129
Pathograph links
Failure of Left-Right Axis Determination fails to recapitulate fidelity: low observes: organism Xenopus ciroz loss does not reproduce the human laterality defect.
Limitations: CIROZ is dispensable for left-right patterning in Xenopus, so the frog knockout is not a faithful model of the human mechanism.
Show evidence (1 reference)
PMID:39753129 SUPPORT Model organism
"we unexpectedly find that its targeted inactivation in zebrafish and Xenopus does not lead to observable LR anomalies"
Reports no left-right anomaly in the Xenopus knockout.
{ }

Source YAML

click to show 
name: Visceral Heterotaxy 14
creation_date: "2026-10-24T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: heterotaxy, visceral, 14, autosomal
  term:
    id: MONDO:0976135
    label: heterotaxy, visceral, 14, autosomal
synonyms:
- HTX14
- CIROZ-related heterotaxy
- CIROZ visceral heterotaxy
- C1orf127-related heterotaxy
description: >-
  Visceral heterotaxy 14 (HTX14) is an autosomal recessive laterality disorder
  caused by bi-allelic inactivating variants in CIROZ (previously C1orf127).
  CIROZ encodes a secreted protein with a signal peptide and three zona
  pellucida N (ZP-N) domains that is specifically expressed in the embryonic
  left-right organizer (LRO). It belongs to a conserved genetic module (with
  DAND5, PKD1L1, MMP21 and CIROP) that evolved in vertebrates whose LRO carries
  motile cilia; its precise molecular step within that module is not yet
  established. Loss of CIROZ function disrupts breaking of embryonic bilateral
  symmetry, producing heterotaxy (situs ambiguus) with congenital heart defects.
  The human
  phenotype is reproduced by the mouse knockout, which develops situs anomalies,
  but notably not by zebrafish or Xenopus knockouts, in which CIROZ is
  dispensable for left-right patterning. The gene was defined in a 2025 cohort of
  16 individuals from 10 families; the literature is therefore recent and still
  thin, and no GeneReviews chapter exists.
parents:
- Visceral heterotaxy
- Congenital Disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0976135
      label: heterotaxy, visceral, 14, autosomal
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0976135 is the primary term for this entry. MONDO records CIROZ
      (hgnc:26730) as the causal gene for this autosomal visceral-heterotaxy
      concept, matching the curated content of this entry.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals carry bi-allelic (homozygous or compound heterozygous)
    inactivating CIROZ variants; many of the reported families are consanguineous.
    Penetrance is incomplete: two reported bi-allelic individuals had normal
    situs (situs solitus).
  evidence:
  - reference: PMID:39753129
    reference_title: >-
      CIROZ is dispensable in ancestral vertebrates but essential for left-right
      patterning in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report 16 individuals from 10 families with bi-allelic CIROZ
      inactivation variants, which cause heterotaxy with congenital heart defects.
    explanation: >-
      The gene-discovery cohort establishes bi-allelic (recessive) inactivation
      of CIROZ as the disease mechanism.
  - reference: PMID:39753129
    reference_title: >-
      CIROZ is dispensable in ancestral vertebrates but essential for left-right
      patterning in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, there were two individuals with bi-allelic CIROZ variants and
      non-phenotypic penetrance
    explanation: >-
      Two bi-allelic individuals with normal situs establish that penetrance of
      CIROZ-related heterotaxy is incomplete.
  - reference: PMID:39513328
    reference_title: Genetic Analysis of Heterotaxy in a Consanguineous Cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      8 genes known to be implicated in autosomal recessive form of HTX
      (C1orf127, CCDC39, CIROP, DNAAF3, DNAH5, DNAH9, MMP21, and MNS1)
    explanation: >-
      An independent consanguineous-cohort study lists C1orf127 (the former
      symbol for CIROZ) among the recognized autosomal recessive heterotaxy genes.
genetic:
- name: CIROZ
  gene_term:
    preferred_term: CIROZ
    term:
      id: hgnc:26730
      label: C1orf127
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    CIROZ (1p36; previously named C1orf127, the label carried by the pinned HGNC
    build) encodes a secreted protein with a signal peptide followed by three
    zona pellucida N (ZP-N) domains, consistent with extracellular localization.
    Reported disease alleles are bi-allelic inactivating variants, consistent
    with a loss-of-function mechanism. No ClinGen gene-disease validity assertion
    is yet available for this recently described gene.
  evidence:
  - reference: PMID:39753129
    reference_title: >-
      CIROZ is dispensable in ancestral vertebrates but essential for left-right
      patterning in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report 16 individuals from 10 families with bi-allelic CIROZ
      inactivation variants, which cause heterotaxy with congenital heart defects.
    explanation: >-
      The founding gene-discovery report naming CIROZ as the causal gene for
      recessive visceral heterotaxy.
  - reference: PMID:39513328
    reference_title: Genetic Analysis of Heterotaxy in a Consanguineous Cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      8 genes known to be implicated in autosomal recessive form of HTX
      (C1orf127, CCDC39, CIROP, DNAAF3, DNAH5, DNAH9, MMP21, and MNS1)
    explanation: >-
      Independent replication listing C1orf127 (former symbol for CIROZ) among
      established autosomal recessive heterotaxy genes.
pathophysiology:
- name: Biallelic CIROZ Loss of Function
  description: >-
    Bi-allelic inactivating CIROZ variants abolish or reduce the function of a
    secreted ZP-N-domain protein. Reported genotypes are inactivating
    (homozygous or compound heterozygous), consistent with a loss-of-function
    mechanism.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CIROZ
    term:
      id: hgnc:26730
      label: C1orf127
  downstream:
  - target: Loss of CIROZ in the Left-Right Organizer
    causal_link_type: DIRECT
    description: >-
      CIROZ is specifically expressed in the left-right organizer as an
      extracellular protein; its loss removes that LRO-localized factor.
    evidence:
    - reference: PMID:39753129
      reference_title: >-
        CIROZ is dispensable in ancestral vertebrates but essential for
        left-right patterning in humans.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        CIROZ (previously known as C1orf127) is also specifically expressed in
        the LRO of mice, frogs, and fish, where it encodes a protein with a
        signal peptide followed by 3 zona pellucida N domains, consistent with
        extracellular localization
      explanation: >-
        Localizes CIROZ as an extracellular protein in the left-right organizer,
        the site where its loss acts.
  evidence:
  - reference: PMID:39753129
    reference_title: >-
      CIROZ is dispensable in ancestral vertebrates but essential for left-right
      patterning in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report 16 individuals from 10 families with bi-allelic CIROZ
      inactivation variants, which cause heterotaxy with congenital heart defects.
    explanation: >-
      Bi-allelic inactivation establishes loss of CIROZ function as the lesion.
- name: Loss of CIROZ in the Left-Right Organizer
  description: >-
    CIROZ is a secreted protein expressed specifically in the left-right
    organizer and is a member of the conserved LRO module (with DAND5, PKD1L1,
    MMP21 and CIROP); it is essential for normal situs in humans and mice. Its
    precise molecular step within that module is not established: the defining
    study states that the exact role of CIROZ in the LRO, and its functional
    relationship to the other module proteins, remain to be determined. This
    node therefore records the loss of an LRO-restricted module factor, not a
    specified signalling step (see the attached knowledge gap).
  biological_scale: CELLULAR
  downstream:
  - target: Failure of Left-Right Axis Determination
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39753129
      reference_title: >-
        CIROZ is dispensable in ancestral vertebrates but essential for
        left-right patterning in humans.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        While the knockout of Ciroz in mice also leads to situs anomalies
      explanation: >-
        Loss of Ciroz in the mouse produces situs anomalies, the failure of
        left-right axis determination.
  evidence:
  - reference: PMID:39753129
    reference_title: >-
      CIROZ is dispensable in ancestral vertebrates but essential for left-right
      patterning in humans.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Four genes-DAND5, PKD1L1, MMP21, and CIROP-form a genetic module that has
      specifically evolved in vertebrate species that harbor motile cilia in
      their left-right organizer (LRO)
    explanation: >-
      Establishes the cilia-motile left-right organizer module to which CIROZ
      belongs; the quote does not name CIROZ, so it supports the module-membership
      framing only by inference.
    directness: INDIRECT
- name: Failure of Left-Right Axis Determination
  description: >-
    Loss of CIROZ function prevents normal breaking of embryonic bilateral
    symmetry, randomizing left-right body-axis specification and producing situs
    ambiguus with associated congenital heart defects.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: determination of left/right symmetry
    modifier: DECREASED
    term:
      id: GO:0007368
      label: determination of left/right symmetry
  downstream:
  - target: Heterotaxy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39753129
      reference_title: >-
        CIROZ is dispensable in ancestral vertebrates but essential for
        left-right patterning in humans.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        which cause heterotaxy with congenital heart defects
      explanation: >-
        The failure of left-right determination manifests as heterotaxy.
  - target: Congenital heart defect
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39753129
      reference_title: >-
        CIROZ is dispensable in ancestral vertebrates but essential for
        left-right patterning in humans.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        which cause heterotaxy with congenital heart defects
      explanation: >-
        Disrupted laterality in the developing heart produces congenital heart
        defects.
  - target: Situs inversus totalis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39753129
      reference_title: >-
        CIROZ is dispensable in ancestral vertebrates but essential for
        left-right patterning in humans.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        asymptomatic situs inversus totalis in individual F4-I:2
      explanation: >-
        Complete mirror-image situs is a direct outcome of reversed left-right
        determination.
  - target: Intestinal malrotation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39753129
      reference_title: >-
        CIROZ is dispensable in ancestral vertebrates but essential for
        left-right patterning in humans.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        HTX with severe CHD (11/16, for example in F1-II:3, hypoplastic left
        heart syndrome, mitral and aortic atresia, bilobed lungs, and malrotation
        of the bowel)
      explanation: >-
        Bowel malrotation accompanied the severe situs/cardiac phenotype in a
        reported individual; midgut rotation follows left-right patterning, so it
        follows the laterality failure.
  evidence:
  - reference: PMID:39753129
    reference_title: >-
      CIROZ is dispensable in ancestral vertebrates but essential for left-right
      patterning in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These clinical and genetic data support an active role for CIROZ in
      establishing situs solitus in humans.
    explanation: >-
      The authors conclude from the human clinical and genetic data that CIROZ
      is actively required to establish normal situs; its loss is the failure
      recorded at this node.
phenotypes:
- name: Heterotaxy
  category: Clinical
  description: >-
    Abnormal left-right arrangement of the thoracoabdominal organs (situs
    ambiguus).
  phenotype_term:
    preferred_term: Heterotaxy
    term:
      id: HP:0030853
      label: Heterotaxy
  evidence:
  - reference: PMID:39753129
    reference_title: >-
      CIROZ is dispensable in ancestral vertebrates but essential for left-right
      patterning in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      which cause heterotaxy with congenital heart defects
    explanation: >-
      Heterotaxy is the defining clinical feature in the reported cohort.
- name: Congenital heart defect
  category: Clinical
  description: >-
    Congenital structural heart disease accompanying the laterality defect.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:39753129
    reference_title: >-
      CIROZ is dispensable in ancestral vertebrates but essential for left-right
      patterning in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      which cause heterotaxy with congenital heart defects
    explanation: >-
      Congenital heart defects co-occur with heterotaxy in the reported cohort.
- name: Situs inversus totalis
  category: Clinical
  description: >-
    Complete mirror-image reversal of thoraco-abdominal organ position; can be
    asymptomatic.
  phenotype_term:
    preferred_term: Situs inversus totalis
    term:
      id: HP:0001696
      label: Situs inversus totalis
  evidence:
  - reference: PMID:39753129
    reference_title: >-
      CIROZ is dispensable in ancestral vertebrates but essential for left-right
      patterning in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      asymptomatic situs inversus totalis in individual F4-I:2
    explanation: >-
      Situs inversus totalis is part of the reported CIROZ laterality spectrum.
- name: Intestinal malrotation
  category: Clinical
  description: >-
    Abnormal rotation and fixation of the midgut, a visceral manifestation of the
    laterality defect.
  phenotype_term:
    preferred_term: Intestinal malrotation
    term:
      id: HP:0002566
      label: Intestinal malrotation
  evidence:
  - reference: PMID:39753129
    reference_title: >-
      CIROZ is dispensable in ancestral vertebrates but essential for left-right
      patterning in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypoplastic left heart syndrome, mitral and aortic atresia, bilobed lungs,
      and malrotation of the bowel
    explanation: >-
      Bowel malrotation occurred in a severely affected individual, reflecting
      disrupted gut laterality.
- name: Horseshoe kidney
  category: Clinical
  description: >-
    Midline fusion of the kidneys, reported in the CIROZ cohort.
  phenotype_term:
    preferred_term: Horseshoe kidney
    term:
      id: HP:0000085
      label: Horseshoe kidney
  evidence:
  - reference: PMID:39753129
    reference_title: >-
      CIROZ is dispensable in ancestral vertebrates but essential for left-right
      patterning in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      horseshoe kidney with situs solitus in individual F4-II:4
    explanation: >-
      Horseshoe kidney was reported among the CIROZ phenotype spectrum.
- name: Mitral atresia
  category: Clinical
  description: >-
    Mitral valve atresia, part of the severe cardiac phenotype in one affected
    individual.
  phenotype_term:
    preferred_term: Mitral atresia
    term:
      id: HP:0011560
      label: Mitral atresia
  evidence:
  - reference: PMID:39753129
    reference_title: >-
      CIROZ is dispensable in ancestral vertebrates but essential for left-right
      patterning in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypoplastic left heart syndrome, mitral and aortic atresia, bilobed lungs,
      and malrotation of the bowel
    explanation: >-
      Mitral atresia was reported as part of the severe cardiac phenotype in
      individual F1-II:3.
- name: Hypoplastic left ventricle
  category: Clinical
  description: >-
    Hypoplastic left heart syndrome, reported in one severely affected
    individual.
  phenotype_term:
    preferred_term: Hypoplastic left heart syndrome
    term:
      id: HP:0004383
      label: Hypoplastic left ventricle
  evidence:
  - reference: PMID:39753129
    reference_title: >-
      CIROZ is dispensable in ancestral vertebrates but essential for left-right
      patterning in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypoplastic left heart syndrome, mitral and aortic atresia, bilobed lungs,
      and malrotation of the bowel
    explanation: >-
      Hypoplastic left heart syndrome was reported in individual F1-II:3; bound
      to the closest HPO term, Hypoplastic left ventricle.
- name: Abnormal lung lobation
  category: Clinical
  description: >-
    Bilobed lungs (abnormal pulmonary lobation) in one severely affected
    individual.
  phenotype_term:
    preferred_term: Bilobed lungs
    term:
      id: HP:0002101
      label: Abnormal lung lobation
  evidence:
  - reference: PMID:39753129
    reference_title: >-
      CIROZ is dispensable in ancestral vertebrates but essential for left-right
      patterning in humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypoplastic left heart syndrome, mitral and aortic atresia, bilobed lungs,
      and malrotation of the bowel
    explanation: >-
      Bilobed lungs were reported in individual F1-II:3; bound to the generic
      lung-lobation term, with no left-isomerism term asserted.
animal_models:
- name: Ciroz c.26+1G>A mouse (MGI:5431499)
  species: Mouse
  genotype: Ciroz c.26+1G>A (p.Trp9*) protein-null, homozygous; MGI:5431499
  publication: PMID:39753129
  description: >-
    ENU-induced 5' splice-donor allele (protein-null). Homozygous E15.5 embryos
    show laterality defects, recapitulating the human situs phenotype.
  modeled_mechanisms:
  - target: Failure of Left-Right Axis Determination
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The homozygous null embryo reproduces organism-level situs reversal and
      organ malposition.
    evidence:
    - reference: PMID:39753129
      reference_title: >-
        CIROZ is dispensable in ancestral vertebrates but essential for
        left-right patterning in humans.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        situs inversus totalis, CHDs, right pulmonary isomerism, or abnormal
        liver positioning
      explanation: >-
        The homozygous Ciroz c.26+1G>A mouse shows situs inversus totalis and
        organ malposition.
- name: Ciroz LacZ-KO mouse (MGI:5635119)
  species: Mouse
  genotype: Gm572 tm1b(EUCOMM)Hmgu LacZ exon-4 knockout, homozygous; MGI:5635119
  publication: PMID:39753129
  description: >-
    IMPC LacZ-cassette (exon 4) out-of-frame allele; partially embryonic lethal
    when homozygous, with situs defects in survivors.
  modeled_mechanisms:
  - target: Failure of Left-Right Axis Determination
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Homozygous E18.5 embryos show situs inversus affecting multiple organs.
    evidence:
    - reference: PMID:39753129
      reference_title: >-
        CIROZ is dispensable in ancestral vertebrates but essential for
        left-right patterning in humans.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        situs inversus phenotypes affecting the lungs, heart, liver, and stomach
      explanation: >-
        The homozygous IMPC LacZ Ciroz knockout shows multi-organ situs inversus.
- name: Ciroz knockout zebrafish
  species: Zebrafish
  genotype: ciroz targeted inactivation
  publication: PMID:39753129
  description: >-
    Targeted ciroz inactivation in zebrafish does not produce observable
    left-right anomalies.
  modeled_mechanisms:
  - target: Failure of Left-Right Axis Determination
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Zebrafish ciroz loss does not reproduce the human laterality defect.
    limitations: >-
      CIROZ is dispensable for left-right patterning in zebrafish, so the fish
      knockout is not a faithful model of the human mechanism; the gene is
      absent or pseudogenized in some lineages that retain a cilia-motile LRO.
    evidence:
    - reference: PMID:39753129
      reference_title: >-
        CIROZ is dispensable in ancestral vertebrates but essential for
        left-right patterning in humans.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we unexpectedly find that its targeted inactivation in zebrafish and
        Xenopus does not lead to observable LR anomalies
      explanation: >-
        Reports no left-right anomaly in the zebrafish knockout.
- name: Ciroz knockout Xenopus
  species: Xenopus
  genotype: ciroz targeted inactivation
  publication: PMID:39753129
  description: >-
    Targeted ciroz inactivation in Xenopus does not produce observable
    left-right anomalies.
  modeled_mechanisms:
  - target: Failure of Left-Right Axis Determination
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Xenopus ciroz loss does not reproduce the human laterality defect.
    limitations: >-
      CIROZ is dispensable for left-right patterning in Xenopus, so the frog
      knockout is not a faithful model of the human mechanism.
    evidence:
    - reference: PMID:39753129
      reference_title: >-
        CIROZ is dispensable in ancestral vertebrates but essential for
        left-right patterning in humans.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we unexpectedly find that its targeted inactivation in zebrafish and
        Xenopus does not lead to observable LR anomalies
      explanation: >-
        Reports no left-right anomaly in the Xenopus knockout.
discussions:
- discussion_id: ciroz_molecular_step_unknown
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is CIROZ's molecular step in the left-right organizer, and how does it
    relate to the other module proteins (DAND5, PKD1L1, MMP21, CIROP)?
  attaches_to:
  - pathophysiology#Loss of CIROZ in the Left-Right Organizer
  rationale: >-
    CIROZ is essential for situs in humans and mice and is a secreted ZP-N-domain
    member of the LRO module, but the defining study (PMID:39753129) states that
    "the exact role played by CIROZ in the mouse and human LRO remains to be
    addressed" and that its functional relationship to the other module proteins
    "remains to be explored". By homology to ZP2, which is cleaved by ovastacin,
    CIROZ may itself require proteolytic processing, possibly by the module
    metallopeptidases MMP21 or CIROP, but this is untested. The node therefore
    records only the loss of a module factor, not a specified signalling step.
  proposed_experiments:
  - experiment_id: ciroz_lro_function_assays
    name: LRO function assays in Ciroz-null embryos
    description: >-
      In Ciroz-null mouse embryos, test whether cilia motility, cilia-driven
      leftward flow, or LRO cell/tissue morphology are affected, to localise
      CIROZ's step relative to flow generation and flow sensing.
  - experiment_id: ciroz_protease_substrate
    name: CIROZ proteolytic-processing test
    description: >-
      Test whether CIROZ is a substrate of the zinc-dependent metallopeptidases
      MMP21 and/or CIROP (as ZP2 is cleaved by ovastacin), to determine whether
      module metallopeptidases process CIROZ to switch its activity.
- discussion_id: ciroz_species_divergence
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why is CIROZ essential for left-right patterning in humans and mice but
    dispensable in zebrafish and Xenopus, and which model faithfully reproduces
    the human mechanism?
  attaches_to:
  - pathophysiology#Failure of Left-Right Axis Determination
  rationale: >-
    Model evidence exists but diverges by species: the mouse knockout develops
    situs anomalies, yet zebrafish and Xenopus knockouts show no laterality
    defect, and the gene is absent or pseudogenized in some vertebrates that
    retain a cilia-motile left-right organizer. The non-mammalian models
    therefore cannot be assumed to represent the human CIROZ mechanism, and only
    the mouse currently stands as a faithful model.
  proposed_experiments:
  - experiment_id: ciroz_patient_allele_mouse
    name: Patient-allele knock-in mouse
    description: >-
      Generate mice carrying reported patient CIROZ inactivating alleles and
      assess situs, cardiac looping and congenital heart defects to test
      genotype-phenotype correlation in the faithful mammalian model.
diagnosis:
- name: Cardiac and visceral situs imaging
  description: >-
    Fetal and postnatal echocardiography with abdominal ultrasound define cardiac
    and visceral situs; an interrupted inferior vena cava on echocardiography is a
    recognised flag that should prompt screening for intestinal malrotation.
  diagnosis_term:
    preferred_term: echocardiography and abdominal situs imaging
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:20730421
    reference_title: >-
      Heterotaxy syndrome: defining contemporary disease trends.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the finding of interrupted IVC on echocardiography should prompt screening
      for intestinal malrotation, even in the absence of additional structural
      heart disease
    explanation: >-
      Heterotaxy-generic, NOT CIROZ-specific: echocardiographic findings guide
      situs assessment and prompt malrotation screening in heterotaxy.
- name: Genetic testing (exome/genome sequencing)
  description: >-
    Trio-based whole-exome or whole-genome sequencing is the confirmatory route
    given the locus heterogeneity of heterotaxy; CIROZ should be included on
    heterotaxy/laterality gene panels. Current NGS leaves most cases unsolved,
    which is the diagnostic gap CIROZ discovery helps narrow.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:42630107
    reference_title: >-
      Genetics in Heterotaxy: A Case Series and Literature Review on DNAH9, PKD1L1, MMP21, and GDF1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      next-generation sequencing (NGS) currently identifies disease-causing
      variants in only 20%-30% of HTX cases
    explanation: >-
      Heterotaxy-generic, NOT CIROZ-specific: documents the low molecular
      diagnostic yield that motivates broad sequencing and panel inclusion of new
      genes such as CIROZ.
treatments:
- name: Cardiac surgery for congenital heart defects
  description: >-
    Surgical repair/palliation of the congenital heart defects that dominate
    morbidity and mortality in heterotaxy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cardiac surgery
    term:
      id: NCIT:C157806
      label: Cardiac Surgery
  evidence:
  - reference: PMID:42630107
    reference_title: >-
      Genetics in Heterotaxy: A Case Series and Literature Review on DNAH9, PKD1L1, MMP21, and GDF1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      15-year survival rates following cardiac surgery estimated at approximately
      60%
    explanation: >-
      Heterotaxy-generic, NOT CIROZ-specific: cardiac surgery is the mainstay for
      the CHDs that occur in heterotaxy, with the quoted post-surgical survival.
- name: Surgical correction of intestinal malrotation
  description: >-
    Surgical correction (Ladd procedure) of intestinal malrotation identified on
    screening.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Ladd procedure for intestinal malrotation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:20730421
    reference_title: >-
      Heterotaxy syndrome: defining contemporary disease trends.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the finding of interrupted IVC on echocardiography should prompt screening
      for intestinal malrotation, even in the absence of additional structural
      heart disease
    explanation: >-
      Heterotaxy-generic, NOT CIROZ-specific: the cited quote supports active
      screening for malrotation in heterotaxy; detected malrotation is surgically
      corrected (Ladd procedure) as standard care.
- name: Pneumococcal vaccination and infection prophylaxis
  description: >-
    Conjugate pneumococcal vaccination and infection prophylaxis address the
    high bacteremia risk associated with the splenic abnormalities of heterotaxy.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: conjugate pneumococcal vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  evidence:
  - reference: PMID:20730421
    reference_title: >-
      Heterotaxy syndrome: defining contemporary disease trends.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No cases of pneumococcal sepsis occurred after the introduction of the
      conjugated pneumococcal vaccination to the pediatric vaccination schedule
    explanation: >-
      Heterotaxy-generic, NOT CIROZ-specific, and of uncertain applicability to
      this cohort: splenic status is not reported for the CIROZ individuals, but
      pneumococcal vaccination is protective in heterotaxy with splenic anomalies.
notes: >-
  No GeneReviews chapter exists for CIROZ/heterotaxy 14 (PubMed
  genereviews[book] search returned no result on 2026-10-24). CIROZ (formerly
  C1orf127) is a recently described gene: the disease-defining cohort is 16
  individuals from 10 families (PMID:39753129, 2025), later independently
  confirmed by a 5,497-exome congenital-heart-disease analysis (W. Dong et al.,
  cited within PMID:39753129). The specific visceral phenotypes and the
  incomplete-penetrance observation are drawn from the full text of PMID:39753129
  (now cached as full text); splenic status is not separately reported for the
  CIROZ cohort. Hypoplastic left heart syndrome is captured through its component
  term HP:0004383 (Hypoplastic left ventricle), as HPO has no single term for the
  full syndrome. PMID:39753129 reports its CHD frequency inconsistently: the
  cohort description gives 11/16 with severe CHD and 5/16 with heterotaxy but no
  CHD, whereas a later cross-gene comparison sentence instead states that 5/16
  CIROZ individuals presented with CHD; a separate sentence notes almost 40 per
  cent were born without CHD. This entry treats CHD as frequent (the 11/16 cohort
  description, consistent with the ~40 per cent without-CHD figure) and does not
  commit to the discrepant 5/16-with-CHD number. The causal gene CIROZ is wired
  into the pathograph but carries no molecular_functions term because its
  molecular activity in the LRO is genuinely unknown (see the KNOWLEDGE_GAP
  discussion); it is therefore grandfathered in the gene-activity-grounding
  baseline rather than bound to an invented function. The gene term is bound
  by CURIE hgnc:26730; the pinned HGNC OBO build still labels this C1orf127, so
  term.label carries that label while preferred_term carries the current symbol
  CIROZ. No ClinGen gene-disease validity assertion is yet available, so none is
  recorded. Treatments and diagnosis are heterotaxy-generic, not CIROZ-specific,
  as stated in each explanation.
references:
- reference: PMID:39753129
  title: >-
    CIROZ is dispensable in ancestral vertebrates but essential for left-right
    patterning in humans.
- reference: PMID:39513328
  title: Genetic Analysis of Heterotaxy in a Consanguineous Cohort.
- reference: PMID:20730421
  title: >-
    Heterotaxy syndrome: defining contemporary disease trends.
- reference: PMID:42630107
  title: >-
    Genetics in Heterotaxy: A Case Series and Literature Review on DNAH9,
    PKD1L1, MMP21, and GDF1.
📚

References & Deep Research

References

4
PMID:39753129
CIROZ is dispensable in ancestral vertebrates but essential for left-right patterning in humans.
No top-level findings curated for this source.
PMID:39513328
Genetic Analysis of Heterotaxy in a Consanguineous Cohort.
No top-level findings curated for this source.
PMID:20730421
Heterotaxy syndrome: defining contemporary disease trends.
No top-level findings curated for this source.
PMID:42630107
Genetics in Heterotaxy: A Case Series and Literature Review on DNAH9, PKD1L1, MMP21, and GDF1.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Visceral Heterotaxy 14 (CIROZ) · 2026-10-24T16:08:34Z · View source

De novo curation of HTX14 (MONDO:0976135), autosomal recessive CIROZ-related visceral heterotaxy. Evidence from the gene-defining cohort PMID:39753129 (16 individuals/10 families; full text cached) and the independent consanguineous-cohort replication PMID:39513328. Pathograph: biallelic CIROZ LOF -> disrupted LRO signaling (GO:0007368) -> failure of L-R axis determination (GO:0070986) -> heterotaxy, congenital heart defect, situs inversus totalis, intestinal malrotation. Phenotypes: heterotaxy (HP:0030853), CHD (HP:0001627), situs inversus totalis (HP:0001696), intestinal malrotation (HP:0002566), horseshoe kidney (HP:0000085). Incomplete penetrance recorded (2 bi-allelic individuals with situs solitus). Three animal models (mouse RECAPITULATES; zebrafish and Xenopus FAILS_TO_RECAPITULATE) with a HUMAN_MODEL_MISMATCH discussion on species divergence. Gene bound hgnc:26730 (pinned HGNC build labels it C1orf127; preferred_term CIROZ). No GeneReviews chapter (offline check NO_CHAPTER). No ClinGen validity assertion available. Deep research: falcon unavailable (403 auth); ran via --fallback, openscientist produced the report. All gates pass: validate 22 snippets/24 titles/0 issues, entity-refs, causal-targets, enum-values, duplicate-keys, coarse-phenotypes, qualifier-terms, shared-disease-terms, snippet-grading, validate-disorders.

OpenScientist ▸
Heterotaxy, Visceral, 14, Autosomal (HTX14) — Comprehensive Disease Characterization Report
openscientist-autonomous 11 citations 2026-10-24T15:58:14.564710

Heterotaxy, Visceral, 14, Autosomal (HTX14) — Comprehensive Disease Characterization Report

Causal gene: CIROZ (formerly C1orf127; NCBI Gene 148345; HGNC:26730; Ensembl ENSG00000175262; locus 1p36.22) Disease identifiers: MONDO:0976135 · OMIM 621080 · DOID:0061123 · GARD:0027430 · MedGen C1875141 · UMLS C5975611

Summary

Heterotaxy, visceral, 14, autosomal (HTX14) is an ultra-rare, autosomal-recessive laterality (left-right patterning) disorder caused by biallelic loss-of-function variants in CIROZ, a gene previously named C1orf127 and now officially designated ciliated left-right organizer protein containing ZP-N domains. The gene maps to chromosome 1p36.22 (between TARDBP and CASZ1) and encodes a secreted protein bearing a signal peptide followed by three zona-pellucida (ZP-N) domains, consistent with an extracellular role. CIROZ is expressed specifically in the embryonic left-right organizer (LRO) — the ciliated midline structure (mouse posterior notochord/node, zebrafish Kupffer's vesicle, Xenopus gastrocoel roof plate) where the body's left-right axis is first established. The disease was formally delineated in 2025 by Szenker-Ravi et al. (PMID: 39753129), who reported 16 affected individuals from 10 families.

Mechanistically, CIROZ is a newly recognized member of a vertebrate LRO extracellular genetic module that also contains DAND5, PKD1L1, MMP21, and CIROP. This module operates upstream of the canonical NODAL–PITX2 symmetry-breaking cascade: motile cilia at the LRO generate leftward fluid flow, which is sensed by immotile sensory cilia via a PKD2/PKD1L1 mechanosensitive calcium channel; flow sensing drives left-sided down-regulation of the secreted NODAL inhibitor DAND5, disinhibiting NODAL on the left, which in turn amplifies NODAL and activates the PITX2 transcription factor in the left lateral plate mesoderm to specify asymmetric organogenesis. Biallelic CIROZ inactivation disrupts this cascade, producing congenital situs ambiguus/situs inversus with variable congenital heart defects (CHD) and visceral malpositions.

Clinically, HTX14 shows incomplete penetrance and highly variable expressivity, ranging from asymptomatic situs inversus totalis to lethal complex CHD such as hypoplastic left heart syndrome. Notably, CIROZ-related heterotaxy is associated with less frequent and milder cardiac involvement than heterotaxy caused by the other four module genes. Mouse Ciroz knockouts faithfully phenocopy human situs defects, whereas — surprisingly — zebrafish and Xenopus knockouts do not show laterality anomalies, revealing species-specific essentiality of this gene. No gene-specific therapy exists; management is supportive and centers on cardiac surgery, infection prophylaxis for splenic dysfunction, and screening for intestinal malrotation.

Key Findings

Finding 1 — Biallelic CIROZ loss-of-function causes autosomal-recessive HTX14

The defining study of this disease is Szenker-Ravi et al. (2025) (PMID: 39753129), which reported 16 individuals from 10 families with bi-allelic CIROZ inactivation variants causing heterotaxy with congenital heart defects. The abstract states verbatim: "We report 16 individuals from 10 families with bi-allelic CIROZ inactivation variants, which cause heterotaxy with congenital heart defects." The authors establish gene identity and protein architecture directly: "CIROZ (previously known as C1orf127) is also specifically expressed in the LRO of mice, frogs, and fish, where it encodes a protein with a signal peptide followed by 3 zona pellucida N domains, consistent with extracellular localization."

Independent corroboration comes from Xie et al. (2025) (PMID: 40467998), a whole-exome-sequencing study of congenital heart disease patients with laterality defects, which lists C1ORF127/CIROZ among candidate laterality genes ("4.1% exhibiting variants in candidate genes (FMNL3, C1ORF127, CFAP157, C10ORF107, MYO1D)"). A third independent cohort (Dong et al., cited as reference 82 within the Szenker-Ravi paper) analyzed 5,497 CHD exomes and identified CIROZ as a genome-wide-significant laterality risk gene, adding five more biallelic-LOF families including the recurrent p.Arg113* allele. The convergence of three independent cohorts firmly establishes CIROZ as a bona fide heterotaxy gene.

The inheritance is unambiguously autosomal recessive: affected individuals are either homozygous (in consanguineous families) or compound heterozygous for loss-of-function alleles, and heterozygous carriers are unaffected.

Finding 2 — CIROZ variant spectrum and population genetics

All reported HTX14 alleles are loss-of-function (nonsense, frameshift, or a signal-peptide-disrupting missense), referenced to transcript NM_001170754.2:

Variant (cDNA) Protein Type Exon gnomAD v4.1.0 MAF Zygosity / Families Population
c.56C>T p.(Thr19Met) Missense (signal peptide) — 4.32 × 10⁻⁴ Compound het (family 1) European
c.577C>T p.(Arg193*) Nonsense (NMD) 7 2.48 × 10⁻⁶ Compound het with c.56C>T (family 1) European
c.337C>T p.(Arg113*) Nonsense (NMD) 4 2.73 × 10⁻⁵ Homozygous, 7 families (F2–F8) Middle Eastern (consanguineous)
c.1210del p.(Gln404Argfs*84) Frameshift — 5.62 × 10⁻⁶ 2 families Guatemalan

The recurrent nonsense allele p.Arg113 is enriched in the Qatar Genome Program (MAF 8.57 × 10⁻⁴; 24 heterozygotes among ~14,000 genomes) and is catalogued in ClinVar (RCV003989718.2). Importantly, haplotype analysis showed no shared founder haplotype for this recurrent variant, indicating independent recurrent mutation rather than a single founder event — consistent with a CpG-hypermutable Arg codon (CGA→TGA). The Szenker-Ravi study documents the recurrent homozygous nonsense variant ("In seven additional families (F2-F8), the affected individuals were homozygous for another stop-gained variant, c.337C>T (p.Arg113…") and the Guatemalan frameshift ("This deletion of one base c.1210del (p.Gln404Argfs…"*).

All variants are predicted to cause nonsense-mediated decay / protein-null outcomes, and the signal-peptide missense (p.Thr19Met) is presumed to impair secretion — establishing a uniform loss-of-function disease mechanism.

Finding 3 — Clinical phenotype spectrum, incomplete penetrance, and comparatively mild cardiac involvement

Among the 16 affected individuals, the phenotype ranged widely: - Heterotaxy without CHD (5/16): e.g., asymptomatic situs inversus totalis; horseshoe kidney with otherwise normal situs solitus. - Heterotaxy with severe CHD (11/16): e.g., hypoplastic left heart syndrome with mitral and aortic atresia, bilobed lungs (pulmonary isomerism), and intestinal malrotation.

Outcomes: 3 fetuses underwent termination of pregnancy, and 2 died in the first year of life from complex cardiac phenotypes. Critically, two individuals carrying biallelic variants had normal situs solitus (non-penetrant), directly demonstrating incomplete penetrance.

A key quantitative observation is that CIROZ-related disease has milder cardiac involvement than other module genes: significantly fewer CIROZ individuals had CHD (5/16) compared with individuals harboring biallelic variants in the four other module genes MMP21, PKD1L1, CIROP, and DAND5 (chi-squared p = 0.006). Furthermore, the module genes collectively produce far more situs ambiguus than the primary-ciliary-dyskinesia (CILD) genes (chi-squared p < 0.00001), distinguishing this "extracellular module" heterotaxy from classic ciliary-motility heterotaxy. The core phenotype is anchored by the primary report: "We report 16 individuals from 10 families with bi-allelic CIROZ inactivation variants, which cause heterotaxy with congenital heart defects."

Finding 4 — Animal models: mouse phenocopy, but no zebrafish/Xenopus phenotype

Two independent mouse Ciroz (gene symbol Gm572) null lines model HTX14: 1. ENU-induced 5′ splice-donor variant c.26+1G>A (p.Trp9, protein-null; MGI:5431499): homozygous E15.5 embryos show situs inversus totalis, CHDs, right pulmonary isomerism, and abnormal liver positioning. 2. IMPC LacZ cassette replacing exon 4 (Gm572^tm1b(EUCOMM)Hmgu*; MGI:5635119): partially embryonic lethal (<6% survive to birth), with E18.5 situs inversus affecting lungs, heart, liver, and stomach.

In stark contrast, complete CRISPR knockouts and morpholino knockdowns in Xenopus laevis, and maternal-zygotic null zebrafish, showed no laterality or heart-looping defects (asymmetric lefty2 and lov/southpaw expression remained intact); MZ-null zebrafish were viable and fertile. The authors summarize: "While the knockout of Ciroz in mice also leads to situs anomalies, we unexpectedly find that its targeted inactivation in zebrafish and Xenopus does not lead to observable LR anomalies." CIROZ protein was confirmed to be secreted (detected in culture media), to form oligomers, and to be expressed specifically in the ciliated LRO, temporally after cirop and before mmp21. Evolutionarily, CIROZ is absent/pseudogenized in Carnivora, Atherinomorpha fish, and jawless vertebrates — reinforcing its dispensability in some lineages despite essentiality in human and mouse.

Finding 5 — Mechanistic placement in the LRO extracellular module upstream of NODAL–PITX2

CIROZ joins a four-gene module — DAND5, PKD1L1, MMP21, CIROP — that "has specifically evolved in vertebrate species that harbor motile cilia in their left-right organizer (LRO)." The downstream pathway is the conserved NODAL cascade (Gabriel & Lo 2024, PMID: 38884745; PMID: 38884711): "This pathway involves initial asymmetric activation of a nodal signaling cascade at the embryonic node, followed by its propagation to the left lateral plate mesoderm and activation of left-sided expression of the Pitx2 transcription factor specifying visceral organ asymmetry." CIROZ is a secreted ZP-N-domain protein acting extracellularly within this module, feeding into DAND5-mediated regulation of NODAL.

Finding 6 — Epidemiology and management context

Laterality defects have an estimated prevalence of ~1 in 10,000 live births (PMID: 39753129). Within CHD cohorts, laterality defects appear in ~1.1% of patients (PMID: 40467998), and CHD is markedly more common in heterotaxy than in the general population (57% vs ~1%). Current NGS yields a molecular diagnosis in only 20–30% of heterotaxy cases (PMID: 42630107), which is precisely the diagnostic gap that CIROZ discovery helps close. Splenic abnormalities (asplenia/polysplenia) drive high bacteremia risk and mortality (PMID: 27425254): "HTX patients are at high risk for bacteremia leading to mortality, regardless of anatomic splenic type." Pneumococcal conjugate vaccination is protective (PMID: 20730421): "No cases of pneumococcal sepsis occurred after the introduction of the conjugated pneumococcal vaccination to the pediatric vaccination schedule." The same study notes that "the finding of interrupted IVC on echocardiography should prompt screening for intestinal malrotation."

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic loss-of-function variant in CIROZ (nonsense/frameshift → NMD/protein-null, or signal-peptide missense → impaired secretion) leads to absence of functional secreted CIROZ protein in the embryonic left-right organizer (LRO). [Demonstrated: human genetics + protein secretion assays.]
  2. Loss of CIROZ disrupts the vertebrate LRO extracellular module (DAND5/PKD1L1/MMP21/CIROP/CIROZ) that operates during the symmetry-breaking window. [Inferred from module membership and LRO-specific, stage-specific expression — CIROZ acts after CIROP and before MMP21.]
  3. Normally, motile cilia at the LRO generate leftward fluid flow, sensed by immotile sensory cilia via the PKD2/PKD1L1 mechanosensitive Ca²⁺ channel. Module disruption impairs correct flow-dependent signaling. [Demonstrated for the module broadly; CIROZ's precise biochemical step is inferred.]
  4. Flow sensing normally causes left-sided down-regulation of DAND5 (a secreted NODAL antagonist). Faulty signaling results in failure to properly repress DAND5 asymmetrically. [Inferred for CIROZ specifically.]
  5. Persistent/symmetric DAND5 activity fails to disinhibit NODAL on the left (NODAL normally acts as NODAL–GDF1 heterodimers). → Loss or randomization of left-sided NODAL activation. [Demonstrated for the cascade.]
  6. Disrupted NODAL fails to activate PITX2 correctly in the left lateral plate mesoderm. [Demonstrated for the cascade.]
  7. Absent/randomized PITX2 asymmetry leads to abnormal left-right specification of visceral organogenesis → situs ambiguus / situs inversus. [Demonstrated.]

Branch point (explains variable expressivity): - 7a. Random/abnormal cardiac looping and outflow-tract morphogenesis → congenital heart defects (e.g., HLHS, atrioventricular septal defects) in a subset. [Observed in 11/16.] - 7b. Abnormal thoraco-abdominal organ positioning → pulmonary isomerism, abnormal liver/stomach position, intestinal malrotation, splenic anomalies (asplenia/polysplenia), horseshoe kidney. - 7c. In some biallelic carriers, stochastic/compensatory factors permit normal patterning → situs solitus (non-penetrant). [Observed in 2 individuals — incomplete penetrance.]

Schematic

 CIROZ biallelic LOF
│ (no secreted CIROZ in LRO)
▼
 LRO extracellular module disrupted
 (DAND5 · PKD1L1 · MMP21 · CIROP · CIROZ)
│
▼
 Cilia-driven leftward flow sensing impaired
│ (PKD2/PKD1L1 Ca²⁺ channel)
▼
 Failure of asymmetric DAND5 down-regulation
│
▼
 NODAL not disinhibited on the left  ──►  PITX2 not activated in left LPM
│
▼
 Loss/randomization of L-R organ specification
│
   ┌────┴─────────────┬──────────────────┐
   ▼                  ▼                  ▼
 Cardiac looping/   Visceral mal-      Stochastic rescue
 OFT defects →      positioning →      → situs solitus
 CHD (11/16)        pulmonary          (non-penetrant, 2 cases)
    isomerism, gut
    malrotation,
    asplenia/polysplenia

Upstream vs downstream: CIROZ acts upstream at the LRO (symmetry-breaking step), within the extracellular module; NODAL/LEFTY/PITX2 are downstream transcriptional effectors. Cell types involved: motile and primary/sensory ciliated cells of the LRO; lateral plate mesoderm cells. Suggested ontology terms: GO:0007368 (determination of left/right symmetry), GO:0060287 (epithelial cilium movement involved in determination of left/right asymmetry), GO:0003140 (determination of left/right asymmetry in lateral mesoderm), GO:0038003 (Nodal signaling pathway); CL:0000064 (ciliated cell); UBERON:0005098 (left-right organizer / node region), UBERON:0003081 (lateral plate mesoderm); CHEBI:29108 (calcium(2+)).

Section-by-Section Characterization

1. Disease Information

HTX14 is an ultra-rare Mendelian visceral heterotaxy / laterality disorder in which thoraco-abdominal organs develop in an abnormal left-right arrangement (situs ambiguus or situs inversus), frequently with congenital heart defects. Identifiers: MONDO:0976135; OMIM 621080; DOID:0061123; GARD:0027430; MedGen C1875141; UMLS C5975611. No dedicated Orphanet or ICD-10/ICD-11 code is specific to the type-14 subtype (classified under broader heterotaxy/situs categories; MeSH D059446 "Heterotaxy Syndrome"). Synonyms: HTX14; CIROZ-related heterotaxy; CIROZ visceral heterotaxy; C1orf127-related heterotaxy. Information is aggregated disease-level (case series + cohort studies), not EHR-derived.

2. Etiology

Primary cause: biallelic (homozygous or compound-heterozygous) loss-of-function variants in CIROZ — a purely genetic etiology. Genetic risk factors: the recurrent p.Arg113 founder-independent allele (enriched in Middle Eastern/Qatari populations), p.Arg193, p.Gln404Argfs84 (Guatemalan), and signal-peptide p.Thr19Met. Consanguinity is a major contributor (7 of 10 families consanguineous). Carrier status is non-pathogenic (recessive). No established environmental or infectious cause for HTX14 specifically; however, for heterotaxy broadly, pregestational diabetes/maternal hyperglycemia is a recognized teratogenic risk factor acting on the same NODAL–PITX2 axis (PMID: 39442590; PMID: 41974186). Protective factors: none genetic are established; incomplete penetrance implies unidentified modifiers. Gene-environment interactions:* not specifically characterized for CIROZ.

3. Phenotypes

Phenotype Type HPO term Frequency (16 individuals) Onset Severity
Visceral heterotaxy / situs ambiguus Physical manifestation HP:0030853 (abnormal heart/visceral situs) Core defining feature Congenital/prenatal Variable
Situs inversus totalis Physical manifestation HP:0001696 Subset Congenital Often asymptomatic
Congenital heart defect (e.g., HLHS) Clinical sign HP:0001627; HP:0004383 (HLHS) 11/16 (~69%) Congenital Severe when present
Pulmonary isomerism / abnormal lung lobation Physical manifestation HP:0006528 Subset Congenital Moderate
Intestinal malrotation Physical manifestation HP:0002566 Subset Congenital Moderate–severe
Abnormal liver/stomach position Physical manifestation HP:0002240 (context) Subset Congenital Variable
Asplenia / polysplenia Physical manifestation HP:0001746 / HP:0001748 Common in heterotaxy Congenital Increases infection risk
Horseshoe kidney Physical manifestation HP:0000085 Reported Congenital Mild

Quality of life: dominated by cardiac morbidity; asymptomatic situs inversus has minimal QoL impact, whereas complex CHD imposes major burden (surgery, mortality). Severity is variable; progression is stable/structural (congenital, non-degenerative). No disease-specific QoL instruments exist for HTX14.

4. Genetic / Molecular Information

Causal gene: CIROZ (C1orf127); OMIM gene/phenotype 621080; HGNC:26730; NCBI Gene 148345; Ensembl ENSG00000175262; locus 1p36.22. Variant classes: nonsense, frameshift, signal-peptide missense — all loss-of-function (see Finding 2 table). ACMG classification: the LOF alleles are pathogenic/likely-pathogenic (PVS1 + population-frequency/segregation evidence); p.Thr19Met is a hypomorphic signal-peptide missense. Allele frequencies are rare in gnomAD (2.5 × 10⁻⁶ to 4.3 × 10⁻⁴). Origin: germline. Functional consequence: loss of function (secreted protein null / impaired secretion). Modifier genes: none identified, but incomplete penetrance strongly implies modifiers. Epigenetic / chromosomal abnormalities: none implicated.

5. Environmental Information

No environmental, lifestyle, or infectious agent is causally linked to HTX14 specifically (it is monogenic recessive). For the broader heterotaxy phenotype, maternal pregestational diabetes/hyperglycemia is an environmental risk factor converging on NODAL–PITX2 signaling (PMID: 39442590).

6. Mechanism / Pathophysiology

See the Mechanistic Model section above for the ordered causal chain and diagram. Molecular pathway: TGF-β/NODAL superfamily signaling (Reactome/KEGG Nodal/TGF-β). Protein dysfunction: loss of a secreted ZP-N/zona-pellucida-domain (ZP2-like, DUF4556) oligomeric protein. Cellular processes: ciliary motility and mechanosensation, left-right determination. No metabolic, immune, or autoimmune component is intrinsic to the primary lesion.

7. Anatomical Structures Affected

Primary organs: heart (UBERON:0000948), lungs (UBERON:0002048), liver (UBERON:0002107), stomach (UBERON:0000945), spleen (UBERON:0002106), intestine (UBERON:0000160), kidney (UBERON:0002113). Developmental origin structure: left-right organizer/node (UBERON:0005098) and lateral plate mesoderm (UBERON:0003081). Body systems: cardiovascular, respiratory, digestive, lymphatic/immune (spleen), urinary. Cell/tissue level: ciliated epithelial cells of the LRO (CL:0000064); mesodermal cells. Subcellular: cilium/axoneme (GO:0005929), extracellular space (GO:0005615 — site of secreted CIROZ). Lateralization: the defining abnormality is disrupted left-right asymmetry (mirror-image or randomized/ambiguous).

8. Temporal Development

Onset: congenital — the lesion acts during the narrow embryonic symmetry-breaking window (equivalent to ~3rd–4th week human gestation). Often detected prenatally on fetal echocardiography/ultrasound or at birth. Progression: structural and stable (non-progressive once formed); disease course is determined by the fixed anatomical defects. Critical period: the LRO/node stage is the sole window of vulnerability; there is no post-developmental opportunity for primary correction. Outcome is dominated by neonatal/infant cardiac events (terminations and early deaths concentrated in infancy).

9. Inheritance and Population

Inheritance: autosomal recessive. Penetrance: incomplete (2 biallelic individuals had situs solitus). Expressivity: highly variable (asymptomatic → lethal CHD). Consanguinity: major role (7/10 families). Founder effect: the recurrent p.Arg113 allele arose by independent recurrence (no shared haplotype), not a classic founder. Carrier frequency: low (gnomAD rare; elevated for p.Arg113 in Qatar, MAF 8.57 × 10⁻⁴). Populations: reported in European, Middle Eastern (Qatari/consanguineous), and Guatemalan families. Prevalence: heterotaxy overall ~1/10,000 live births; HTX14 is a small ultra-rare subset. No reported sex skew. No genetic anticipation or germline mosaicism documented.

10. Diagnostics

Imaging is central: fetal/postnatal echocardiography, abdominal ultrasound, CT/MRI to map cardiac and visceral situs; interrupted IVC is a useful flag (PMID: 20730421). Laboratory: Howell-Jolly bodies / functional asplenia screening; sepsis workup when febrile. Genetic testing is the definitive confirmatory route: trio whole-exome or whole-genome sequencing is most effective given locus heterogeneity (CIROZ is one of >60 heterotaxy/laterality genes); heterotaxy/laterality gene panels should now include CIROZ. Single-gene testing is reserved for cascade testing of a known familial variant. CMA/karyotype help exclude chromosomal causes. Differential diagnosis: primary ciliary dyskinesia (PCD)-associated heterotaxy (PMID: 42026914), and other module/laterality genes (DAND5, PKD1L1, MMP21, CIROP, DNAH9, GDF1, CFAP53/CCDC11) (PMID: 42630107; PMID: 39969775). Reference transcript for reporting: NM_001170754.2.

11. Outcome / Prognosis

Prognosis is governed by the cardiac phenotype: severe complex CHD drives pregnancy termination, surgical intervention, and early mortality concentrated in infancy (PMID: 41974186): "In LSD, major CHD drives pregnancy termination, surgical intervention, and early mortality concentrated during infancy." In the CIROZ cohort, 3/16 were terminated and 2/16 died in year one; those without CHD can be asymptomatic with normal life expectancy. Morbidity includes repeat cardiac surgery, infection (splenic dysfunction), and sequelae of malrotation. Prognostic factors: presence/severity of CHD, right-ventricular-outflow obstruction, splenic status. CIROZ cases trend toward milder cardiac involvement than other module genes (CHD 5/16; p = 0.006).

12. Treatment

No gene-specific or disease-modifying therapy exists; care is supportive and anatomy-directed: - Cardiac surgery for CHD (staged single-ventricle palliation or biventricular repair as anatomy permits) — NCIT: Cardiac Surgical Procedure. - Infection prophylaxis for asplenia/functional asplenia: pneumococcal, Hib, and meningococcal vaccination plus antibiotic prophylaxis (PMID: 27425254; PMID: 20730421) — NCIT: Antibiotic Prophylaxis / Vaccination. - Surgical correction of intestinal malrotation (Ladd procedure) when indicated. - Supportive/rehabilitative care and multidisciplinary follow-up. No pharmacogenomic, gene, cell, RNA, or targeted therapies are reported for HTX14.

13. Prevention

Primary prevention: not possible for the monogenic lesion; optimizing maternal glycemic control reduces the broader heterotaxy risk (PMID: 39442590). Secondary prevention: prenatal detection via fetal echocardiography enables delivery planning at cardiac centers. Genetic counseling: 25% recurrence risk per pregnancy for carrier couples; cascade carrier testing; prenatal diagnosis and preimplantation genetic testing are feasible once the familial variant is known. Tertiary prevention: vaccination + antibiotic prophylaxis to prevent overwhelming post-splenic sepsis; malrotation screening and prophylactic Ladd procedure.

14. Other Species / Natural Disease

Mouse ortholog: Gm572 (Ciroz), with two null alleles (MGI:5431499; MGI:5635119) recapitulating human situs defects. Non-mammalian orthologs exist in zebrafish and Xenopus but are dispensable there (no LR phenotype on knockout). The gene is absent/pseudogenized in Carnivora, Atherinomorpha fish, and jawless vertebrates, indicating lineage-specific loss. No naturally occurring companion-animal or wildlife CIROZ disease is reported (no established OMIA entry). No zoonotic relevance.

15. Model Organisms

Mouse is the validated model: two independent null lines phenocopy heterotaxy (situs inversus, CHD, pulmonary isomerism, abnormal liver position; partial embryonic lethality). Phenotype recapitulation is strong in mouse. Zebrafish (maternal-zygotic null) and Xenopus (CRISPR/morpholino) do NOT recapitulate the phenotype — an important limitation highlighting species-specific gene essentiality and cautioning against using these organisms to model CIROZ function. Resources: MGI (mouse), IMPC/EUCOMM (tm1b allele). In-vitro secretion assays (demonstrating CIROZ is secreted and oligomerizes) complement the animal data.

Evidence Base

PMID Title (abbrev.) Role Key contribution
39753129 CIROZ is dispensable in ancestral vertebrates but essential for L-R patterning in humans Primary / defining 16 individuals/10 families; variant spectrum; mouse phenocopy; zebrafish/Xenopus negative; module membership; secreted ZP-N protein
40467998 Prevalence of laterality defects in CHD Supporting / independent Lists C1ORF127/CIROZ as candidate gene; laterality epidemiology in CHD (1.1%); diagnostic yield ~13%
42630107 Genetics in Heterotaxy (DNAH9, PKD1L1, MMP21, GDF1) Context NGS diagnoses only 20–30% of HTX; extracardiac burden affects survival
38884745 Molecular Pathways and Animal Models of Defects in Situs Mechanism LRO cilia → Nodal → Lefty → Pitx2; species differences in ciliary requirement
38884711 Establishment of Cardiac Laterality Mechanism Defines the downstream Nodal–Pitx2 cascade CIROZ feeds into
41974186 Laterality Spectrum Disorders in the Prenatal Era Prognosis Major CHD drives termination and early infant mortality; pregestational diabetes association
39442590 Hyperglycaemia induces diet-dependent L-R axis defects Gene-environment Maternal diabetes perturbs Nodal–Pitx2 — shared downstream axis
27425254 Bacteremia in Patients with Heterotaxy Management High bacteremia mortality regardless of splenic type
20730421 Heterotaxy syndrome: contemporary disease trends Prevention Pneumococcal vaccine protective; interrupted IVC → malrotation screening
27679871 Factors influencing bacteraemia in isomerism/CHD Management Most bacteremia episodes nosocomial
42026914 Genetics of Primary Ciliary Dyskinesia Differential dx ~50% of PCD have laterality defects — key DDx to distinguish
39969775 CFAP53 biallelic mutations / situs inversus Differential dx Example of another recessive laterality gene

Evidence source types: human clinical/genetic (39753129, 40467998, 42630107, 41974186), model organism (39753129 mouse/zebrafish/Xenopus; 39442590 mouse), in vitro (39753129 secretion/oligomerization assays), and review/mechanistic synthesis (38884745, 38884711, 37340963, 36172285).

Limitations and Knowledge Gaps

  1. Single defining cohort. The disease rests primarily on one 2025 study (16 individuals) plus a second cohort (Dong et al., 5 additional families). The total number of reported patients worldwide is small (~21 families), so phenotype frequencies carry wide confidence intervals.
  2. Incomplete penetrance is unexplained. Two biallelic individuals had normal situs; the genetic/environmental modifiers responsible are unknown.
  3. Exact biochemical step is inferred. CIROZ's precise molecular interaction (e.g., whether it directly modulates DAND5, GDF1, or cilia-dependent flow) is not experimentally pinpointed; its placement "after CIROP, before MMP21" is temporal/expression-based.
  4. Species discordance means zebrafish/Xenopus are poor functional models, limiting rapid in-vivo mechanistic dissection; mechanistic work depends on the slower mouse system.
  5. No specific ICD/Orphanet code, no dedicated natural-history registry, and no QoL instruments for the CIROZ subtype.
  6. No therapy targets the pathway; all management is generic heterotaxy care.
  7. Low diagnostic yield (20–30%) for heterotaxy overall means CIROZ-attributable cases are likely under-ascertained; carrier-frequency and true prevalence estimates are preliminary.

Proposed Follow-up Experiments / Actions

  1. Expand the patient registry. Aggregate CIROZ cases via GeneMatcher/Matchmaker Exchange to refine penetrance, expressivity, CHD subtype frequencies, and genotype–phenotype correlations (e.g., does p.Thr19Met confer milder disease than nulls?).
  2. Define CIROZ's biochemical partner(s). Use co-immunoprecipitation / proximity labeling in mouse node or LRO-like organoids to test direct interaction with DAND5, GDF1, PKD1L1, MMP21, and CIROP; determine whether CIROZ modulates NODAL antagonism.
  3. Mouse mechanistic dissection. In Ciroz-null embryos, quantify asymmetric Dand5, Nodal, Lefty2, and Pitx2 expression to localize the exact step of cascade failure; test conditional/tissue-specific alleles.
  4. Modifier discovery. Whole-genome sequencing and expression analysis of penetrant vs non-penetrant biallelic carriers to identify genetic modifiers explaining incomplete penetrance.
  5. Functional variant classification. Secretion/oligomerization assays for all reported and future missense variants (including p.Thr19Met) to standardize ACMG classification (PS3/PVS1 evidence).
  6. Panel/pipeline updates. Ensure CIROZ is added to all clinical heterotaxy/laterality and CHD gene panels and to ClinVar/ClinGen curation, with NM_001170754.2 as the reference transcript.
  7. Prospective management study. Evaluate whether CIROZ-defined patients, given their milder cardiac profile, warrant a distinct surveillance/counseling pathway versus other module genes.

Report compiled from an autonomous multi-iteration investigation (9 confirmed findings; 20 papers reviewed). All mechanistic and clinical claims are attributed to the cited PMIDs above; verbatim abstract quotes are embedded where they anchor a specific claim.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome Count
References checked 12
Resolved 12
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 12
On topic 8
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 33
Resolved 27
Unresolved (possible confabulation) 0
Obsolete 2
Unverifiable 4
Terms whose name was checked 14
Terms named correctly 5
Terms named as a different term 7
Terms whose name is worth a second look 2

Terms the report names something else

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

  • UBERON:0005098 (2 mentions) - the report calls it "left-right organizer / node region"; UBERON calls it UBERON_0005098
  • HP:0030853 (1 mention) - the report calls it "abnormal heart/visceral situs"; HP calls it Heterotaxy
  • HP:0001696 (1 mention) - the report calls it "Physical manifestation"; HP calls it Situs inversus totalis
  • HP:0006528 (1 mention) - the report calls it "Physical manifestation"; HP calls it Chronic lung disease
  • HP:0002240 (1 mention) - the report calls it "context"; HP calls it Hepatomegaly
  • HP:0000085 (1 mention) - the report calls it "Physical manifestation"; HP calls it Horseshoe kidney
  • GO:0005615 (1 mention) - the report calls it "site of secreted CIROZ"; GO calls it obsolete extracellular space

Obsolete terms

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

  • UBERON:0005098 (UBERON_0005098) (2 mentions) - replaced by UBERON:0004200
  • GO:0005615 (obsolete extracellular space) (1 mention) - replaced by GO:0005576

Terms whose name is worth a second look

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

  • GO:0038003 (1 mention) - the report calls it "Nodal signaling pathway"; GO calls it G protein-coupled opioid receptor signaling pathway, and lists "opioid receptor signaling pathway" among its other names
  • HP:0002566 (1 mention) - the report calls it "Physical manifestation"; HP calls it Intestinal malrotation

Prefixes with no resolver

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