Visceral Heterotaxy 8

Mendelian MONDO:0014967 Pathograph 37 Show in embeddings browser Visceral heterotaxy Congenital Disorder

Visceral heterotaxy 8 (HTX8) is an autosomal recessive laterality disorder caused by biallelic loss-of-function variants in PKD1L1, which encodes polycystin-1-like 1, an eleven-pass transmembrane polycystin-1 family protein that partners with the cation channel PKD2 in cilia of the embryonic left-right organizer. PKD1L1 is not needed to build or move the organizer cilia: in mutant mice node and cilia morphology and cilia motility are normal and leftward nodal flow is generated. It is needed to interpret that flow, so that the right-biased expression of the Nodal antagonist CERL2 (DAND5) at the node and the left-sided Nodal, Lefty2 and Pitx2 cascade in the lateral plate mesoderm fail to arise. Affected individuals have situs inversus totalis or situs ambiguus (heterotaxy), usually with complex congenital heart disease such as unbalanced atrioventricular septal defects, double-outlet right ventricle, transposition of the great arteries, pulmonary atresia or stenosis and single-ventricle physiology, together with splenic anomalies (polysplenia or asplenia), right-sided stomach, midline or left-sided liver and intestinal malrotation. Several affected pregnancies have shown nonimmune hydrops, and PKD1L1 variants have also been reported in biliary atresia splenic malformation syndrome. There is no airway or sperm motility disease, because motile cilia are intact. Severity varies within families carrying the same genotype.

Ask OpenScientist

Ask a research question about Visceral Heterotaxy 8. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

🔗

Mappings

MONDO
MONDO:0014967 heterotaxy, visceral, 8, autosomal
skos:exactMatch MONDO
MONDO:0014967 is the primary term for this entry. MONDO defines it as visceral heterotaxy caused by mutation in PKD1L1, carries OMIM:617205 as an xref, and records PKD1L1 as the causal gene, all of which match the curated content of this entry.
👪

Inheritance

1
Autosomal recessive HP:0000007
Affected individuals carry biallelic PKD1L1 variants, homozygous (including in a consanguineous family) or compound heterozygous, and heterozygous parents are unaffected. Situs and cardiac severity can differ between affected relatives with the same genotype.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:27616478 SUPPORT Human clinical
"WES also showed that the variant is present in the heterozygous state in both parents, consistent with autosomal-recessive Mendelian expectations"
Both parents of the first family were heterozygous carriers of the homozygous splice variant found in the affected children.
PMID:31026592 SUPPORT Human clinical
"Individuals affected with this autosomal recessive condition have variable thoracic and abdominal situs."
A further family with compound heterozygous PKD1L1 variants, described as an autosomal recessive condition.
◈

Mechanistic Hypotheses

1
PKD1L1 loss causes biliary atresia through cholangiocyte cilia dysfunction
pkd1l1_biliary_cilia EMERGING
Evidence balance 2 support
Beyond its role at the left-right organizer, PKD1L1 is expressed in bile duct epithelium, and Pkd1l1-deficient mice show reduced cholangiocyte primary cilia, decreased Hedgehog pathway gene expression and fibrotic extrahepatic bile duct remodeling. This would explain why PKD1L1 variants are found in biliary atresia splenic malformation syndrome, which combines laterality defects with biliary atresia.
EMERGING because the mouse ducts remain patent without an added biliary injury, and the human data are rare biallelic and heterozygous variants in a BASM cohort, described there as a candidate gene. None of the heterotaxy families carrying the alleles discussed above was reported with biliary atresia.
Pathograph links
PKD1L1 Loss of Function -> Biliary Epithelial Primary Cilia Deficiency In mice, Pkd1l1 loss also reduces primary cilia on biliary epithelial cells, a candidate route to the biliary atresia reported in some PKD1L1-variant carriers.
Biliary Epithelial Primary Cilia Deficiency -> Biliary atresia Proposed link: cholangiocyte ciliary dysfunction drives fibro-obliterative bile duct disease, phenocopying syndromic biliary atresia in mice.
Show evidence (2 references)
PMID:38460793 SUPPORT Model organism
"Pkd1l1 loss causes both laterality defects and fibro-proliferative EHBD transformation through disrupted ciliary signaling, phenocopying syndromic biliary atresia."
The mouse study on which the hypothesis principally rests.
PMID:30664273 SUPPORT Human clinical
"Five BASM subjects harbored rare and potentially deleterious biallelic variants in polycystic kidney disease 1 like 1 (PKD1L1), a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice, and humans."
Human genetic association of PKD1L1 variants with the BASM presentation.
?

Discussions and Knowledge Gaps

1
Do human PKD1L1 alleles abolish left-sided Nodal (as the mouse rks point mutant does) or make it bilateral (as the mouse null does), and does this explain why some patients have isomerism with heterotaxy and others situs inversus totalis?
HUMAN MODEL MISMATCH OPEN pkd1l1_allele_specific_nodal_outcome
Attached to
pathophysiology#Lateral Plate Mesoderm Nodal Cascade Mispatterning
Two mouse alleles of the same gene give opposite lateral plate Nodal outcomes, right versus left lung isomerism, and different survival. Human patients range from situs inversus totalis without heart disease to lethal heterotaxy, and siblings with the same genotype differ, but no human allele has been tested for which mouse outcome it resembles. Until that is known, the edge from flow-sensing failure to a particular situs outcome is an inference from mouse.
Show evidence (3 references)
PMID:27272319 SUPPORT Model organism
"In conclusion, the Pkd1l1tm1 allele has a strikingly different impact on both survival and L-R patterning compared to the Pkd1l1rks point mutation."
Two Pkd1l1 alleles give distinct laterality outcomes in mice.
PMID:42630107 SUPPORT Human clinical
"We observed that while PKD1L1 mutations are often severe, familial cases like FR-02 and FR-03 show that identical genotypes can result in strikingly different cardiac severities."
In humans, the same PKD1L1 genotype gives different severity within a family.
PMID:31026592 SUPPORT Human clinical
"Features of CHD and other anomalies vary between and within families."
Cardiac and other features vary within PKD1L1 families.
⚙

Pathophysiology

6
PKD1L1 Loss of Function
Biallelic PKD1L1 variants remove or disable the protein. The recurrent intron 42 splice-donor deletion abolishes the canonical donor site, nonsense alleles truncate the protein before the transmembrane and PKD2-binding regions, and the p.Cys1691Ser missense change is predicted to destabilize the GPS motif needed for protein maturation. In cultured cells PKD1L1 is sufficient to support a calcium signaling response to fluid flow, and destabilizing its extracellular PKD domain abolishes that response.
PKD1L1 loss causes biliary atresia through cholangiocyte cilia dysfunction
PKD1L1 hgnc:18053 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PKD1L1 (hgnc:18053). hgnc:18053 is a gene from the HUGO Gene Nomenclature Committee.
calcium channel activity (as a PKD2 channel partner) GO:0005262 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased calcium channel activity (as a PKD2 channel partner), annotated with calcium channel activity (GO:0005262). GO:0005262 is a molecular function from the Gene Ontology.
Downstream
Failure of Nodal Flow Sensing at the Left-Right Organizer Without PKD1L1, the PKD1L1-PKD2 complex in organizer cilia cannot form or signal, so the leftward flow is not converted into a left-sided signal.
Biliary Epithelial Primary Cilia Deficiency In mice, Pkd1l1 loss also reduces primary cilia on biliary epithelial cells, a candidate route to the biliary atresia reported in some PKD1L1-variant carriers. PKD1L1 loss causes biliary atresia through cholangiocyte cilia dysfunction
Show evidence (5 references)
PMID:27616478 SUPPORT Human clinical
"WES identified a homozygous splicing mutation, c.6473+2_6473+3delTG, which disrupts the invariant splice donor site in intron 42, in both affected individuals."
A canonical splice-site deletion predicted to abolish normal PKD1L1 splicing segregates with disease.
PMID:27616478 SUPPORT Computational
"The p.Cys1691Ser substitution affects a highly conserved cysteine residue and is predicted by molecular modeling to disrupt a disulfide bridge essential for the proper folding of the G protein-coupled receptor proteolytic site (GPS) motif."
Structural modeling predicts that the disease missense variant destabilizes the GPS motif.
PMID:35691949 SUPPORT Human clinical
"This homozygous variant caused the domain of PKD1L1 complete absence."
A homozygous nonsense allele removes the downstream PKD1L1 domains.
+ 2 more references
Failure of Nodal Flow Sensing at the Left-Right Organizer
PKD1L1 is expressed in the ventral node and node crown cells (mouse) and in Kupffer's vesicle (medaka) at the time leftward flow breaks symmetry, and it co-localizes and physically interacts with PKD2 in cilia. Flow carries PKD1L1-containing fibrous strands to the left margin of the node, where they associate with Nodal. In Pkd1l1 mutants the cilia beat and flow is generated, but the flow is not sensed, so the organizer never acquires its left-right bias. This places HTX8 among the flow-sensing laterality disorders, distinct from the primary ciliary dyskinesias in which the cilia cannot move.
cellular response to fluid shear stress (nodal flow) GO:0071498 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cellular response to fluid shear stress (nodal flow), annotated with cellular response to fluid shear stress (GO:0071498). GO:0071498 is a biological process from the Gene Ontology. determination of left/right symmetry GO:0007368 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal determination of left/right symmetry (GO:0007368). GO:0007368 is a biological process from the Gene Ontology.
cilium GO:0005929 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves cilium (GO:0005929). GO:0005929 is a cellular component from the Gene Ontology.
embryonic node UBERON:0003062 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in embryonic node, annotated with primitive knot (UBERON:0003062). UBERON:0003062 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Pkd1l1 rks ENU point mutant mouse Mouse recapitulates Laterality fails although the node and its motile cilia are normal, isolating the flow-sensing step.
Downstream
Loss of Right-Biased Cerl2 Expression at the Node Crown Flow sensing through PKD1L1 normally biases Cerl2 (Dand5) expression to the right side of the node; without it Cerl2 stays symmetrical.
Lateral Plate Mesoderm Nodal Cascade Mispatterning Failure to sense flow means the left-sided Nodal cascade in the lateral plate mesoderm is not properly established.
Show evidence (5 references)
PMID:21307093 SUPPORT Model organism
"By contrast, we detected strongly regionalised expression of Pkd1l1, with expression in the node, extending into the node crown cells, and in the midline in late streak embryos"
Localizes Pkd1l1 expression to the mouse left-right organizer.
PMID:21307093 SUPPORT In vitro / ex vivo
"Cell biological analysis reveals that Pkd1l1 and Pkd2 localise to the cilium and biochemical experiments demonstrate that they can physically interact."
Pkd1l1 and Pkd2 form a ciliary complex, the proposed flow sensor.
PMID:21307098 SUPPORT Model organism
"These results suggest that Pkd1l1 and Pkd2 form a complex that functions as the nodal flow sensor in the motile cilia of the medaka KV."
Independent medaka evidence that Pkd1l1-Pkd2 acts as the organizer flow sensor.
+ 2 more references
Loss of Right-Biased Cerl2 Expression at the Node Crown
In normal embryos flow represses the Nodal antagonist Cerl2 (Dand5) on the left side of the node crown, so Nodal activity there becomes left-biased. In Pkd1l1-null embryos Cerl2 expression remains symmetrical. Epistasis places Pkd1l1 as an upstream genetic repressor of Pkd2 in this step.
negative regulation of nodal signaling pathway (Cerl2) GO:1900108 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal negative regulation of nodal signaling pathway (Cerl2), annotated with negative regulation of nodal signaling pathway (GO:1900108). GO:1900108 is a biological process from the Gene Ontology.
embryonic node UBERON:0003062 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in embryonic node, annotated with primitive knot (UBERON:0003062). UBERON:0003062 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Pkd1l1 tm1 targeted null mouse Mouse recapitulates Null embryos lose node-crown Cerl2 asymmetry and activate Nodal bilaterally.
Downstream
Lateral Plate Mesoderm Nodal Cascade Mispatterning Symmetrical node-crown signaling is relayed to the lateral plate, where Nodal is no longer confined to the left side.
Show evidence (2 references)
PMID:27272319 SUPPORT Model organism
"In contrast, Cerl2 asymmetry failed to manifest in Pkd1l1tm1/tm1 mutants, which instead exhibited a symmetrical pattern of Cerl2 expression"
Direct observation that Cerl2 asymmetry is lost in Pkd1l1-null embryos.
PMID:27272319 SUPPORT Model organism
"Epistasis analysis shows that Pkd1l1 acts as an upstream genetic repressor of Pkd2."
Positions Pkd1l1 relative to Pkd2 in the flow-response pathway.
Lateral Plate Mesoderm Nodal Cascade Mispatterning
The left-sided Nodal, Lefty2 and Pitx2 cascade in the lateral plate mesoderm is either not activated (Pkd1l1 rks point mutant) or activated on both sides (Pkd1l1 null), so the left-right identity cue that patterns the heart, lungs, spleen, liver and gut is lost or randomized. In the mouse, absent signaling gave right lung isomerism and bilateral signaling gave mostly left lung isomerism, while residual stochastic bias gives situs solitus, situs inversus or heterotaxy.
nodal signaling pathway GO:0038092 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal nodal signaling pathway (GO:0038092). GO:0038092 is a biological process from the Gene Ontology. left/right pattern formation GO:0060972 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal left/right pattern formation (GO:0060972). GO:0060972 is a biological process from the Gene Ontology.
lateral plate mesoderm UBERON:0003081 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lateral plate mesoderm (UBERON:0003081). UBERON:0003081 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Medaka abecobe (pkd1l1) mutant Medaka recapitulates Asymmetric Nodal-family expression is lost despite normal flow.
Downstream
Cardiac Laterality and Outflow Tract Malformation Loss of the left-right cue leaves heart position, atrial arrangement and the alignment of the ventricles and great arteries unspecified.
Heterotaxy
Situs inversus totalis
Atrial situs ambiguous
Right-sided stomach
Midline liver
Polysplenia
Asplenia
Intestinal malrotation
Abnormal lung lobation
Show evidence (2 references)
PMID:21307093 SUPPORT Model organism
"both mutants fail to activate asymmetric gene expression at the node or in the lateral plate and exhibit right isomerism of the lungs"
The Pkd1l1 rks point mutant fails to activate left-sided lateral plate gene expression.
PMID:27272319 SUPPORT Model organism
"the majority of Pkd1l1tm1/tm1 embryos displayed the complete opposite phenotype of bilaterally mono-lobed lungs, called left lung isomerism"
The Pkd1l1 null allele, with bilateral Nodal, mostly gives left lung isomerism.
Cardiac Laterality and Outflow Tract Malformation
Without a reliable left-right cue the direction of heart looping and the connections of atria, ventricles and great arteries are randomized. In Pkd1l1 mutant mice about three quarters of embryos have outflow tract defects (double-outlet right ventricle or transposition), and in patients this gives the unbalanced atrioventricular septal defects, conotruncal defects and single-ventricle hearts that dominate the clinical course.
heart looping GO:0001947 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal heart looping (GO:0001947). GO:0001947 is a biological process from the Gene Ontology.
heart tube UBERON:0004141 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart tube (UBERON:0004141). UBERON:0004141 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Pkd1l1 rks ENU point mutant mouse Mouse recapitulates Mutant embryos develop double-outlet right ventricle and transposition.
Downstream
Dextrocardia
Unbalanced atrioventricular canal defect
Hypoplastic left ventricle
Double outlet right ventricle
Levotransposition of the great arteries
Pulmonary artery atresia
Pulmonic stenosis
Ventricular septal defect
Single ventricle
Right aortic arch
Systemic venous anomalies
Pulmonary venous anomalies
Nonimmune hydrops fetalis
Show evidence (1 reference)
PMID:21307093 SUPPORT Model organism
"revealing a significant incidence of apparent double outlet right ventricle (DORV) and transposition of the great arteries (TGA)"
Outflow tract malformations in Pkd1l1 rks mutant mouse embryos.
Biliary Epithelial Primary Cilia Deficiency
Constitutive or conditional Pkd1l1 knockout mice have fewer primary cilia on biliary epithelial cells and reduced ciliary Hedgehog signaling gene expression, with hypertrophic, fibrotic extrahepatic bile ducts, delayed biliary drainage and ductular reaction, progressing to obstruction under a biliary injury diet. This is a candidate mechanism for the biliary atresia splenic malformation presentation; human evidence is limited to rare biallelic and heterozygous PKD1L1 variants in BASM cohorts.
PKD1L1 loss causes biliary atresia through cholangiocyte cilia dysfunction
cholangiocyte CL:1000488 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cholangiocyte (CL:1000488). CL:1000488 is a cell type from the Cell Ontology.
cilium assembly GO:0060271 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cilium assembly (GO:0060271). GO:0060271 is a biological process from the Gene Ontology.
extrahepatic bile duct UBERON:0003703 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in extrahepatic bile duct (UBERON:0003703). UBERON:0003703 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Pkd1l1 constitutive and conditional knockout mice (biliary) Mouse recapitulates Reduced cholangiocyte cilia and fibrotic bile duct remodeling.
Downstream
Biliary atresia Proposed link: cholangiocyte ciliary dysfunction drives fibro-obliterative bile duct disease, phenocopying syndromic biliary atresia in mice. PKD1L1 loss causes biliary atresia through cholangiocyte cilia dysfunction
Show evidence (2 references)
PMID:38460793 SUPPORT Model organism
"Primary cilia were reduced on biliary epithelial cells and altered expression of ciliogenesis genes occurred in Pkd1l1-deficient mice."
Direct observation of reduced cholangiocyte cilia in Pkd1l1-deficient mice.
PMID:38460793 SUPPORT Model organism
"Pkd1l1-deficient EHBDs were hypertrophic and fibrotic."
The extrahepatic bile duct pathology that follows Pkd1l1 loss in mice.
⬡

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 8 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

23
Cardiovascular 16
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 (3 references)
PMID:27616478 SUPPORT Human clinical
"In the second family, a homozygous c.5072G>C (p.Cys1691Ser) missense mutation was detected in an individual with SIT and congenital heart disease."
Situs inversus totalis in a homozygous PKD1L1 missense carrier.
PMID:32111882 SUPPORT Human clinical
"One non-PCD SI case had recessive mutations in PKD1L1, and another in CFAP52 (also known as WDR16)."
Recessive PKD1L1 variants in an adult with situs inversus without primary ciliary dyskinesia.
PMID:27272319 SUPPORT Model organism
"Surviving mutants either exhibited normal (57%) or reversed (43%) situs based on stomach position in neonates"
Pkd1l1-null mice that survive have normal or reversed situs, the mouse counterpart of situs inversus.
Dextrocardia FREQUENT HP:0001651 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dextrocardia (HP:0001651). HP:0001651 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42630107 SUPPORT REVIEW SYNTHESIS Human clinical
"Atrial arrangement abnormalities and dextrocardia were present in 70% (7/10) and 77% (10/13) of cases, respectively."
Dextrocardia in 10 of 13 assessed published PKD1L1 cases.
Atrial situs ambiguous FREQUENT HP:0011539 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial situs ambiguous (HP:0011539). HP:0011539 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27616478 SUPPORT Human clinical
"He had atrial situs ambiguus, unbalanced atrioventricular septal defect with left ventricular hypoplasia, pulmonary atresia, right-sided stomach, left-sided liver, and right-sided spleen"
Atrial situs ambiguus in a homozygous PKD1L1 patient.
PMID:42630107 SUPPORT REVIEW SYNTHESIS Human clinical
"Atrial arrangement abnormalities and dextrocardia were present in 70% (7/10) and 77% (10/13) of cases, respectively."
Atrial arrangement abnormalities in 7 of 10 assessed published PKD1L1 cases.
Unbalanced atrioventricular canal defect HP:0011579 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Unbalanced atrioventricular septal defect, annotated with Unbalanced atrioventricular canal defect (HP:0011579). HP:0011579 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27616478 SUPPORT Human clinical
"The fetus presented with situs ambiguus with atrial situs solitus, unbalanced atrioventricular septal defect with left ventricular hypoplasia, double outlet right ventricle with malposed great arteries, right-sided stomach, left-sided liver, and right-sided spleen"
Unbalanced atrioventricular septal defect in both affected siblings of the first family.
Hypoplastic left ventricle HP:0004383 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic left ventricle (HP:0004383). HP:0004383 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27616478 SUPPORT Human clinical
"He had atrial situs ambiguus, unbalanced atrioventricular septal defect with left ventricular hypoplasia, pulmonary atresia, right-sided stomach, left-sided liver, and right-sided spleen"
Left ventricular hypoplasia accompanying the unbalanced atrioventricular septal defect.
Double outlet right ventricle HP:0001719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Double outlet right ventricle (HP:0001719). HP:0001719 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27616478 SUPPORT Human clinical
"The fetus presented with situs ambiguus with atrial situs solitus, unbalanced atrioventricular septal defect with left ventricular hypoplasia, double outlet right ventricle with malposed great arteries, right-sided stomach, left-sided liver, and right-sided spleen"
Double outlet right ventricle in a homozygous PKD1L1 fetus.
PMID:42630107 SUPPORT Human clinical
"fetopathology revealed a complex presentation of dextrocardia, single ventricle, double-outlet right ventricle (DORV), right aortic arch, and pulmonary stenosis"
Double outlet right ventricle in a compound heterozygous PKD1L1 fetus.
Levotransposition of the great arteries HP:0011540 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenitally corrected transposition of the great arteries, annotated with Levotransposition of the great arteries (HP:0011540). HP:0011540 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27616478 SUPPORT Human clinical
"She was diagnosed in the first weeks of life with SIT and congenital heart disease including congenitally corrected transposition of the great arteries (ventricular inversion) with a small left ventricle, pulmonary atresia, and ventricular septal defect"
Congenitally corrected transposition in the homozygous p.Cys1691Ser patient.
Pulmonary artery atresia HP:0004935 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary atresia, annotated with Pulmonary artery atresia (HP:0004935). HP:0004935 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27616478 SUPPORT Human clinical
"She was diagnosed in the first weeks of life with SIT and congenital heart disease including congenitally corrected transposition of the great arteries (ventricular inversion) with a small left ventricle, pulmonary atresia, and ventricular septal defect"
Pulmonary atresia in the homozygous p.Cys1691Ser patient.
PMID:27616478 SUPPORT Human clinical
"He had atrial situs ambiguus, unbalanced atrioventricular septal defect with left ventricular hypoplasia, pulmonary atresia, right-sided stomach, left-sided liver, and right-sided spleen"
Pulmonary atresia in the affected brother of the first family.
Pulmonic stenosis HP:0001642 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonic stenosis (HP:0001642). HP:0001642 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42630107 SUPPORT Human clinical
"fetopathology revealed a complex presentation of dextrocardia, single ventricle, double-outlet right ventricle (DORV), right aortic arch, and pulmonary stenosis"
Pulmonary stenosis in a compound heterozygous PKD1L1 fetus.
Ventricular septal defect HP:0001629 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular septal defect (HP:0001629). HP:0001629 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27616478 SUPPORT Human clinical
"She was diagnosed in the first weeks of life with SIT and congenital heart disease including congenitally corrected transposition of the great arteries (ventricular inversion) with a small left ventricle, pulmonary atresia, and ventricular septal defect"
Ventricular septal defect in the homozygous p.Cys1691Ser patient.
PMID:42630107 SUPPORT REVIEW SYNTHESIS Human clinical
"Septation defects were reported in all assessed cases (11/11), while outflow tract obstructions and systemic venous anomalies were each observed in 78% (7/9) of documented cases."
Septation defects were present in every assessed published PKD1L1 case.
Single ventricle HP:0001750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Single ventricle (HP:0001750). HP:0001750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42630107 SUPPORT Human clinical
"fetopathology revealed a complex presentation of dextrocardia, single ventricle, double-outlet right ventricle (DORV), right aortic arch, and pulmonary stenosis"
Single ventricle in a compound heterozygous PKD1L1 fetus.
Right aortic arch HP:0012020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Right aortic arch (HP:0012020). HP:0012020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42630107 SUPPORT Human clinical
"fetopathology revealed a complex presentation of dextrocardia, single ventricle, double-outlet right ventricle (DORV), right aortic arch, and pulmonary stenosis"
Right aortic arch in a compound heterozygous PKD1L1 fetus.
Systemic venous anomalies FREQUENT Abnormal vena cava morphology HP:0005345 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Systemic venous anomalies, annotated with Abnormal vena cava morphology (HP:0005345). HP:0005345 is a phenotype from the Human Phenotype Ontology.
Bound to HP:0005345 Abnormal vena cava morphology rather than to HP:0005301 Persistent left superior vena cava, HP:0033379 Bilateral superior vena cava or HP:0011671 Interrupted inferior vena cava with azygous continuation, because the PKD1L1-specific count in the source is for the whole category and no per-case vein type for a PKD1L1 patient is in the cached text.
Show evidence (2 references)
PMID:42630107 SUPPORT REVIEW SYNTHESIS Human clinical
"Septation defects were reported in all assessed cases (11/11), while outflow tract obstructions and systemic venous anomalies were each observed in 78% (7/9) of documented cases."
Systemic venous anomalies in 7 of 9 assessed published PKD1L1 cases.
PMID:42630107 SUPPORT INDIRECT REVIEW SYNTHESIS Human clinical
"Additionally, systemic and pulmonary venous anomalies were recurrent features, characterized by a persistent left superior vena cava, an interrupted inferior vena cava, and anomalous pulmonary venous return."
Names the vena caval anomalies that make up this category across the reviewed heterotaxy genes, including PKD1L1.
Pulmonary venous anomalies FREQUENT Abnormality of the pulmonary veins HP:0011718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary venous anomalies, annotated with Abnormality of the pulmonary veins (HP:0011718). HP:0011718 is a phenotype from the Human Phenotype Ontology.
Bound to HP:0011718 Abnormality of the pulmonary veins, which matches the source's category, rather than to HP:0005160 Total or HP:0010773 Partial anomalous pulmonary venous return, because whether each PKD1L1 case was total or partial is not in the cached text.
Show evidence (1 reference)
PMID:42630107 SUPPORT REVIEW SYNTHESIS Human clinical
"Pulmonary venous anomalies | Yes | 3/3 (25 NR) | No | No | No | 4/6 (15 NR)"
Pooled table row: pulmonary venous anomalies in 4 of 6 assessed PKD1L1 cases (the PKD1L1 column follows the three French PKD1L1 cases).
Polysplenia FREQUENT HP:0001748 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polysplenia (HP:0001748). HP:0001748 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42630107 SUPPORT REVIEW SYNTHESIS Human clinical
"Within this cohort, eight individuals presented with polysplenia, two with asplenia, and 13 with gastrointestinal abnormalities"
Polysplenia is the more common splenic anomaly among published PKD1L1 cases.
PMID:42630107 SUPPORT REVIEW SYNTHESIS Human clinical
"Asplenia/polysplenia | Yes | 3/9 (19 NR) | Yes | Yes | N/A | 10/14 (7 NR)"
Pooled table row: 10 of 14 PKD1L1 cases with splenic data had asplenia or polysplenia (the text gives 8 polysplenia and 2 asplenia).
Asplenia OCCASIONAL HP:0001746 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asplenia (HP:0001746). HP:0001746 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:35691949 SUPPORT Human clinical
"We identified a novel nonsense variant in PKD1L1(c.1387 C > T; p.463Gln*) in a Chinese patient with heterotaxy syndrome and congenital asplenia."
Congenital asplenia in a homozygous PKD1L1 nonsense carrier.
PMID:42630107 SUPPORT REVIEW SYNTHESIS Human clinical
"Within this cohort, eight individuals presented with polysplenia, two with asplenia, and 13 with gastrointestinal abnormalities"
Two asplenia cases among the published PKD1L1 cases.
PMID:42630107 SUPPORT REVIEW SYNTHESIS Human clinical
"Asplenia/polysplenia | Yes | 3/9 (19 NR) | Yes | Yes | N/A | 10/14 (7 NR)"
Pooled table row: 10 of 14 PKD1L1 cases with splenic data had asplenia or polysplenia (the text gives 8 polysplenia and 2 asplenia).
Digestive 4
Right-sided stomach Malposition of the stomach HP:0100802 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Right-sided stomach, annotated with Malposition of the stomach (HP:0100802). HP:0100802 is a phenotype from the Human Phenotype Ontology.
Bound to the broader Malposition of the stomach because HPO has no right-sided stomach term: `runoak -i ols:hp search "right-sided stomach"` and `runoak -i ols:hp search "dextroposition of the stomach"` return nothing, and `runoak -i ols:hp search "stomach"` returns HP:0100802 Malposition of the stomach and HP:0002577 Abnormal stomach morphology as the only position or morphology terms. The side is carried in preferred_term.
Show evidence (2 references)
PMID:27616478 SUPPORT Human clinical
"He had atrial situs ambiguus, unbalanced atrioventricular septal defect with left ventricular hypoplasia, pulmonary atresia, right-sided stomach, left-sided liver, and right-sided spleen"
Right-sided stomach in a homozygous PKD1L1 patient.
PMID:42630107 SUPPORT Human clinical
"Extracardiac abnormalities involved bilobed, hypoplastic lungs, right-sided polysplenia, midline liver, right-sided stomach, and intestinal malrotation."
Right-sided stomach in a compound heterozygous PKD1L1 fetus.
Midline liver HP:0034188 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Midline liver (HP:0034188). HP:0034188 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42630107 SUPPORT Human clinical
"Extracardiac abnormalities involved bilobed, hypoplastic lungs, right-sided polysplenia, midline liver, right-sided stomach, and intestinal malrotation."
Midline liver in a compound heterozygous PKD1L1 fetus.
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:42630107 SUPPORT Human clinical
"Extracardiac abnormalities involved bilobed, hypoplastic lungs, right-sided polysplenia, midline liver, right-sided stomach, and intestinal malrotation."
Intestinal malrotation in a compound heterozygous PKD1L1 fetus.
Biliary atresia HP:0005912 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Biliary atresia (HP:0005912). HP:0005912 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30664273 SUPPORT Human clinical
"Five BASM subjects harbored rare and potentially deleterious biallelic variants in polycystic kidney disease 1 like 1 (PKD1L1), a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice, and humans."
Biallelic PKD1L1 variants in children with biliary atresia and laterality defects.
Metabolism 1
Nonimmune hydrops fetalis HP:0001790 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nonimmune hydrops fetalis (HP:0001790). HP:0001790 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33655537 SUPPORT Human clinical
"We describe the first Indian family with two affected foetuses with PKD1L1-related nonimmune hydrops, congenital heart disease, situs inversus, and heterotaxy, with biallelic variants in the compound heterozygous state."
Nonimmune hydrops in two compound heterozygous PKD1L1 fetuses.
PMID:21307093 SUPPORT Model organism
"Here, we report the identification of a point mutation in the mouse Pkd1l1 locus named rks that results in right pulmonary isomerism, cardiac outflow defects, overt oedema and lethality by 15.5 dpc."
Pkd1l1 mutant mouse embryos also develop overt oedema with their cardiac defects.
Respiratory 1
Abnormal lung lobation HP:0002101 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilobed lungs (bronchopulmonary isomerism), annotated with Abnormal lung lobation (HP:0002101). HP:0002101 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42630107 SUPPORT Human clinical
"Extracardiac abnormalities involved bilobed, hypoplastic lungs, right-sided polysplenia, midline liver, right-sided stomach, and intestinal malrotation."
Bilobed lungs in a compound heterozygous PKD1L1 fetus.
PMID:21307093 SUPPORT Model organism
"both mutants fail to activate asymmetric gene expression at the node or in the lateral plate and exhibit right isomerism of the lungs"
Pkd1l1 mutant mice reproduce pulmonary isomerism.
Growth 1
Heterotaxy FREQUENT 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 (2 references)
PMID:27616478 SUPPORT Human clinical
"Family 1 had one fetus and one deceased child with heterotaxy and complex congenital heart malformations."
Heterotaxy in two siblings homozygous for a PKD1L1 splice variant.
PMID:42630107 SUPPORT REVIEW SYNTHESIS Human clinical
"Among the 21 reported PKD1L1 cases, 3 presented with SI and 16 exhibited a HTX phenotype."
Pooled literature count giving heterotaxy in 16 of 21 PKD1L1 cases.
🧬

Genetic Associations

1
PKD1L1
Gene: PKD1L1 hgnc:18053 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PKD1L1 (hgnc:18053). hgnc:18053 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
PMID:27616478 SUPPORT Human clinical
"Via whole-exome sequencing (WES), we identified homozygous mutations in PKD1L1 from three affected individuals in two unrelated families."
The gene-discovery report establishing biallelic PKD1L1 variants as a cause of human laterality defects.
PMID:35691949 SUPPORT Human clinical
"We identified a novel nonsense variant in PKD1L1(c.1387 C > T; p.463Gln*) in a Chinese patient with heterotaxy syndrome and congenital asplenia."
An independent homozygous truncating PKD1L1 allele in a heterotaxy patient from a cohort of 110 laterality cases.
PMID:42630107 SUPPORT Human clinical
"In both siblings, the molecular analysis identified the recurrent c.6473+2_6473+3del variant in trans with a nonsense variant, c.1279G>T (p.Glu427*)."
Shows the recurrent splice allele in trans with a nonsense allele in a further family.
+ 1 more reference
💊

Medical Actions

3
Cardiac surgery
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
Complex congenital heart disease is managed surgically according to the anatomy, for example ventricular septal defect closure with a ventricle to pulmonary artery conduit. There is no PKD1L1-directed therapy, and several reported affected pregnancies were terminated or the infants died of their heart disease in the neonatal period.
Target Phenotypes: Ventricular septal defect HP:0001629 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Ventricular septal defect (HP:0001629). HP:0001629 is a phenotype from the Human Phenotype Ontology. Pulmonary atresia HP:0004935 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Pulmonary atresia, annotated with Pulmonary artery atresia (HP:0004935). HP:0004935 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27616478 SUPPORT Human clinical
"She underwent placement of a left ventricle to pulmonary artery conduit and ventricular septal defect closure."
Surgical repair in the 46-year-old homozygous p.Cys1691Ser patient.
Antibiotic prophylaxis for asplenia
Action: antibiotic prophylaxisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antibiotic prophylaxis (NCIT:C51993). NCIT:C51993 is a clinical intervention from the NCI Thesaurus. Ontology label: Antibiotic Prophylaxis NCIT:C51993
Platform: Small molecule
Children with heterotaxy and asplenia or poor splenic function are at high risk of bacteremia, and long-term antibiotic prophylaxis is used together with immunization. The evidence is from heterotaxy and congenital asplenia cohorts in general, not PKD1L1 patients specifically, and one isomerism cohort found no association between prophylaxis status and bacteremia risk. No cached source for heterotaxy names the antibiotic, so no therapeutic agent is bound.
Target Phenotypes: Asplenia HP:0001746 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Asplenia (HP:0001746). HP:0001746 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:26557043 SUPPORT Human clinical
"In asplenic children, early diagnosis, antibiotic prophylaxis, and immunisation for encapsulated bacteria can decrease the risk of morbidity and mortality."
Case series of asplenic children with congenital heart disease, including heterotaxy, supporting prophylaxis.
PMID:27425254 SUPPORT INDIRECT REVIEW SYNTHESIS Human clinical
"HTX patients are at high risk for bacteremia leading to mortality, regardless of anatomic splenic type."
Establishes the infection risk in heterotaxy that prophylaxis is meant to reduce.
PMID:28741863 SUPPORT Other
"Three metrics passed all analyses, including those for antibiotic prophylaxis in patients with heterotaxy/asplenia"
An expert consensus process adopted antibiotic prophylaxis in heterotaxy with asplenia as a pediatric cardiology quality metric.
+ 1 more reference
Immunization against encapsulated bacteria
Action: vaccination against encapsulated bacteriaNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is vaccination against encapsulated bacteria, annotated with Vaccination (NCIT:C15346). NCIT:C15346 is a clinical intervention from the NCI Thesaurus. Ontology label: Vaccination NCIT:C15346
Platform: Vaccine
Asplenic children are immunized against encapsulated bacteria alongside antibiotic prophylaxis. As for prophylaxis, the evidence comes from congenital asplenia and heterotaxy cohorts, not PKD1L1 patients.
Target Phenotypes: Asplenia HP:0001746 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Asplenia (HP:0001746). HP:0001746 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26557043 SUPPORT Human clinical
"The rest of the four patients were vaccinated for encapsulated bacteria and were taken under antibiotic prophylaxis."
Asplenic children with congenital heart disease were vaccinated against encapsulated bacteria; none then needed admission for infection.
🔬

Diagnosis

3
Prenatal ultrasound
Many reported cases were first detected on fetal ultrasound because of situs anomalies and complex heart disease.
fetal ultrasound imaging NCIT:C222238 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:27616478 SUPPORT Human clinical
"The family was referred for prenatal genetic assessment after an ultrasound examination performed at 21 weeks and 6 days of gestation revealed complex congenital malformations of the fetus."
Fetal ultrasound first detected the malformations in the index fetus.
Exome or genome sequencing for biallelic PKD1L1 variants
The diagnosis is confirmed by finding biallelic PKD1L1 variants. Exome sequencing found the original families; genome sequencing was needed to detect the recurrent intronic splice-site variant in a French series, and trio analysis helps establish that variants are in trans.
whole genome sequencing NCIT:C101294 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:27616478 SUPPORT Human clinical
"Via whole-exome sequencing (WES), we identified homozygous mutations in PKD1L1 from three affected individuals in two unrelated families."
Exome sequencing identified the causal PKD1L1 variants.
PMID:42630107 SUPPORT Human clinical
"Notably, WGS was essential in detecting the splice-site variants identified in the PKD1L1 cases (FR-01, FR-02, and FR-03), underscoring its superiority over WES for detecting non-coding and regulatory variations."
Genome sequencing was needed to detect the recurrent PKD1L1 splice allele.
Exclusion of primary ciliary dyskinesia
Laterality defects without chronic airway disease or infertility point away from the motile ciliopathies. The row is left unbound, as in the HTX7 entry, which records that OLS NCIT searches returned no ciliary function test procedure.
Show evidence (1 reference)
PMID:32111882 SUPPORT Human clinical
"One non-PCD SI case had recessive mutations in PKD1L1, and another in CFAP52 (also known as WDR16)."
PKD1L1 variants are found among situs inversus cases without primary ciliary dyskinesia.
🐁

Animal Models

4
Pkd1l1 rks ENU point mutant mouse
A recessive ENU line with a missense change in a PKD domain of Pkd1l1 shows right pulmonary isomerism, randomized heart and stomach situs, outflow tract defects, oedema and death by 15.5 dpc, with normal node and cilia motility and absent left-sided lateral plate gene expression.
Species
Mouse
Genotype
Pkd1l1 rks (p.Asp411Gly in a PKD domain) homozygous
Publication
PMID:21307093
Pathograph links
Failure of Nodal Flow Sensing at the Left-Right Organizer recapitulates fidelity: high observes: organism Laterality fails although the node and its motile cilia are normal, isolating the flow-sensing step.
Limitations: A single missense allele on one genetic background; it gives almost exclusively right isomerism with absent Nodal, whereas the null allele gives bilateral Nodal, so allele effects differ.
Show evidence (1 reference)
PMID:21307093 SUPPORT Model organism
"Node and cilia morphology were normal in mutants and cilia demonstrated typical motility, consistent with Pkd1l1 and Pkd2 activity downstream of nodal flow."
Shows the model informs the flow-sensing node.
Cardiac Laterality and Outflow Tract Malformation recapitulates fidelity: moderate observes: organism Mutant embryos develop double-outlet right ventricle and transposition.
Limitations: Embryonic lethality by 15.5 dpc prevents study of later cardiac remodeling and survival.
Show evidence (1 reference)
PMID:21307093 SUPPORT Model organism
"revealing a significant incidence of apparent double outlet right ventricle (DORV) and transposition of the great arteries (TGA)"
Outflow tract defects in the model.
Show evidence (1 reference)
PMID:21307093 SUPPORT Model organism
"Here, we report the identification of a point mutation in the mouse Pkd1l1 locus named rks that results in right pulmonary isomerism, cardiac outflow defects, overt oedema and lethality by 15.5 dpc."
Establishes the rks line and its phenotype.
Pkd1l1 tm1 targeted null mouse
A targeted, likely null, Pkd1l1 allele with reduced viability; survivors have normal or reversed situs without respiratory, hydrocephalus or fertility phenotypes, and embryos show bilateral Nodal activity, mostly left lung isomerism and loss of node Cerl2 asymmetry.
Species
Mouse
Genotype
Pkd1l1 tm1Lex homozygous
Publication
PMID:27272319
Pathograph links
Loss of Right-Biased Cerl2 Expression at the Node Crown recapitulates fidelity: high observes: organism Null embryos lose node-crown Cerl2 asymmetry and activate Nodal bilaterally.
Limitations: The human left-right organizer has not been studied directly, so the link from this mouse readout to particular human alleles is inferred.
Show evidence (1 reference)
PMID:27272319 SUPPORT Model organism
"In contrast, Cerl2 asymmetry failed to manifest in Pkd1l1tm1/tm1 mutants, which instead exhibited a symmetrical pattern of Cerl2 expression"
Direct readout of the Cerl2 node in the null model.
Show evidence (1 reference)
PMID:27272319 SUPPORT Model organism
"Surviving mutants either exhibited normal (57%) or reversed (43%) situs based on stomach position in neonates"
Randomized situs in surviving null mice.
Medaka abecobe (pkd1l1) mutant
The medaka laterality mutant abecobe carries a pkd1l1 mutation; its Kupffer's vesicle generates normal flow but asymmetric southpaw, lefty and charon expression fails.
Species
Medaka
Genotype
pkd1l1 abecobe (abc) homozygous
Publication
PMID:21307098
Pathograph links
Lateral Plate Mesoderm Nodal Cascade Mispatterning recapitulates fidelity: moderate observes: organism Asymmetric Nodal-family expression is lost despite normal flow.
Limitations: In medaka the Kupffer's vesicle cilia that carry Pkd1l1 are motile, whereas in mouse the flow-sensing cilia are thought to be the immotile cilia of crown cells, so the cellular site of sensing may differ between species.
Show evidence (1 reference)
PMID:21307098 SUPPORT Model organism
"These results suggest that Pkd1l1 and Pkd2 form a complex that functions as the nodal flow sensor in the motile cilia of the medaka KV."
Supports the model's relevance to organizer flow sensing.
Show evidence (1 reference)
PMID:21307098 SUPPORT Model organism
"we show that the medaka left-right mutant abecobe (abc) is defective for left-right asymmetric expression of southpaw, lefty and charon, but not for nodal flow"
Establishes the medaka pkd1l1 model and its flow-sensing defect.
Pkd1l1 constitutive and conditional knockout mice (biliary)
Knockout mice show malrotation and heterotaxy together with hypertrophic, fibrotic extrahepatic bile ducts, delayed biliary drainage, fewer cholangiocyte primary cilia and, after DDC diet, bile duct obstruction.
Species
Mouse
Genotype
Pkd1l1 constitutive or conditional knockout
Publication
PMID:38460793
Pathograph links
Biliary Epithelial Primary Cilia Deficiency recapitulates fidelity: moderate observes: organism Reduced cholangiocyte cilia and fibrotic bile duct remodeling.
Limitations: Bile ducts stay patent unless an injury diet is added, so the model shows susceptibility rather than spontaneous biliary atresia.
Show evidence (1 reference)
PMID:38460793 SUPPORT Model organism
"Primary cilia were reduced on biliary epithelial cells and altered expression of ciliogenesis genes occurred in Pkd1l1-deficient mice."
Direct readout of the biliary cilia node.
Show evidence (1 reference)
PMID:38460793 SUPPORT Model organism
"Pkd1l1-deficient mice exhibited congenital anomalies including malrotation and heterotaxy."
The knockout reproduces the laterality phenotype.
{ }

Source YAML

click to show 
name: Visceral Heterotaxy 8
creation_date: "2026-10-20T23:34:44Z"
category: Mendelian
disease_term:
  preferred_term: heterotaxy, visceral, 8, autosomal
  term:
    id: MONDO:0014967
    label: heterotaxy, visceral, 8, autosomal
synonyms:
- HTX8
- PKD1L1 visceral heterotaxy
- visceral heterotaxy caused by mutation in PKD1L1
- PKD1L1-related heterotaxy
description: >-
  Visceral heterotaxy 8 (HTX8) is an autosomal recessive laterality disorder
  caused by biallelic loss-of-function variants in PKD1L1, which encodes
  polycystin-1-like 1, an eleven-pass transmembrane polycystin-1 family protein
  that partners with the cation channel PKD2 in cilia of the embryonic
  left-right organizer. PKD1L1 is not needed to build or move the organizer
  cilia: in mutant mice node and cilia morphology and cilia motility are normal
  and leftward nodal flow is generated. It is needed to interpret that flow, so
  that the right-biased expression of the Nodal antagonist CERL2 (DAND5) at the
  node and the left-sided Nodal, Lefty2 and Pitx2 cascade in the lateral plate
  mesoderm fail to arise. Affected individuals have situs inversus totalis or
  situs ambiguus (heterotaxy), usually with complex congenital heart disease
  such as unbalanced atrioventricular septal defects, double-outlet right
  ventricle, transposition of the great arteries, pulmonary atresia or stenosis
  and single-ventricle physiology, together with splenic anomalies (polysplenia
  or asplenia), right-sided stomach, midline or left-sided liver and intestinal
  malrotation. Several affected pregnancies have shown nonimmune hydrops, and
  PKD1L1 variants have also been reported in biliary atresia splenic
  malformation syndrome. There is no airway or sperm motility disease, because
  motile cilia are intact. Severity varies within families carrying the same
  genotype.
parents:
- Visceral heterotaxy
- Congenital Disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014967
      label: heterotaxy, visceral, 8, autosomal
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0014967 is the primary term for this entry. MONDO defines it as
      visceral heterotaxy caused by mutation in PKD1L1, carries OMIM:617205 as an
      xref, and records PKD1L1 as the causal gene, all of which match 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 biallelic PKD1L1 variants, homozygous (including
    in a consanguineous family) or compound heterozygous, and heterozygous
    parents are unaffected. Situs and cardiac severity can differ between
    affected relatives with the same genotype.
  evidence:
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES also showed that the variant is present in the heterozygous state in
      both parents, consistent with autosomal-recessive Mendelian expectations
    explanation: >-
      Both parents of the first family were heterozygous carriers of the
      homozygous splice variant found in the affected children.
  - reference: PMID:31026592
    reference_title: >-
      Compound heterozygous Pkd1l1 variants in a family with two fetuses
      affected by heterotaxy and complex Chd.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals affected with this autosomal recessive condition have variable
      thoracic and abdominal situs.
    explanation: >-
      A further family with compound heterozygous PKD1L1 variants, described as
      an autosomal recessive condition.
genetic:
- name: PKD1L1
  gene_term:
    preferred_term: PKD1L1
    term:
      id: hgnc:18053
      label: PKD1L1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    PKD1L1 (7p12.3) encodes a 2,849-residue polycystin-1 family protein with two
    extracellular Ig-like PKD domains, a REJ domain, a GPS autoproteolysis
    motif, eleven transmembrane segments, a PLAT domain and a C-terminal
    coiled-coil that binds PKD2. Reported pathogenic alleles include a recurrent
    canonical splice-donor deletion in intron 42 (c.6473+2_6473+3delTG, found
    homozygous and in trans with other alleles), nonsense variants (for example
    p.Gln463* and p.Glu427*), and a homozygous missense change (p.Cys1691Ser)
    predicted to break a disulfide bond in the GPS motif. The truncating and
    splice alleles and the mouse null phenotype indicate loss of function.
  evidence:
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Via whole-exome sequencing (WES), we identified homozygous mutations in
      PKD1L1 from three affected individuals in two unrelated families.
    explanation: >-
      The gene-discovery report establishing biallelic PKD1L1 variants as a
      cause of human laterality defects.
  - reference: PMID:35691949
    reference_title: >-
      A novel nonsense PKD1L1 variant cause heterotaxy syndrome with congenital
      asplenia in a Han Chinese patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a novel nonsense variant in PKD1L1(c.1387 C > T; p.463Gln*)
      in a Chinese patient with heterotaxy syndrome and congenital asplenia.
    explanation: >-
      An independent homozygous truncating PKD1L1 allele in a heterotaxy
      patient from a cohort of 110 laterality cases.
  - 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: >-
      In both siblings, the molecular analysis identified the recurrent
      c.6473+2_6473+3del variant in trans with a nonsense variant, c.1279G>T
      (p.Glu427*).
    explanation: >-
      Shows the recurrent splice allele in trans with a nonsense allele in a
      further family.
  - reference: ORPHA:157769
    reference_title: Situs ambiguus
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PKD1L1 | polycystin 1 like 1, transient receptor potential channel
      interacting | hgnc:18053 | Disease-causing germline mutation(s) in
    explanation: >-
      Orphanet lists PKD1L1 as a gene with disease-causing germline mutations
      in situs ambiguus.
pathophysiology:
- name: PKD1L1 Loss of Function
  description: >-
    Biallelic PKD1L1 variants remove or disable the protein. The recurrent
    intron 42 splice-donor deletion abolishes the canonical donor site, nonsense
    alleles truncate the protein before the transmembrane and PKD2-binding
    regions, and the p.Cys1691Ser missense change is predicted to destabilize
    the GPS motif needed for protein maturation. In cultured cells PKD1L1 is
    sufficient to support a calcium signaling response to fluid flow, and
    destabilizing its extracellular PKD domain abolishes that response.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: PKD1L1
    term:
      id: hgnc:18053
      label: PKD1L1
  molecular_functions:
  - preferred_term: calcium channel activity (as a PKD2 channel partner)
    modifier: DECREASED
    term:
      id: GO:0005262
      label: calcium channel activity
  evidence:
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES identified a homozygous splicing mutation, c.6473+2_6473+3delTG, which
      disrupts the invariant splice donor site in intron 42, in both affected
      individuals.
    explanation: >-
      A canonical splice-site deletion predicted to abolish normal PKD1L1
      splicing segregates with disease.
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The p.Cys1691Ser substitution affects a highly conserved cysteine residue
      and is predicted by molecular modeling to disrupt a disulfide bridge
      essential for the proper folding of the G protein-coupled receptor
      proteolytic site (GPS) motif.
    explanation: >-
      Structural modeling predicts that the disease missense variant
      destabilizes the GPS motif.
  - reference: PMID:35691949
    reference_title: >-
      A novel nonsense PKD1L1 variant cause heterotaxy syndrome with congenital
      asplenia in a Han Chinese patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This homozygous variant caused the domain of PKD1L1 complete absence.
    explanation: >-
      A homozygous nonsense allele removes the downstream PKD1L1 domains.
  - reference: PMID:27272319
    reference_title: >-
      Genetic Analysis Reveals a Hierarchy of Interactions between
      Polycystin-Encoding Genes and Genes Controlling Cilia Function during
      Left-Right Determination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      using a system in which cultured cells are supplied artificial flow, we
      demonstrate that PKD1L1 is sufficient to mediate a Ca2+ signaling response
      after flow stimulation.
    explanation: >-
      Establishes the flow-induced calcium signaling activity that PKD1L1 loss
      removes.
  - reference: PMID:27272319
    reference_title: >-
      Genetic Analysis Reveals a Hierarchy of Interactions between
      Polycystin-Encoding Genes and Genes Controlling Cilia Function during
      Left-Right Determination.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Finally, we show that an extracellular PKD domain within PKD1L1 is crucial
      for PKD1L1 function; as such, destabilizing the domain causes L-R defects
      in the mouse.
    explanation: >-
      A single destabilizing change in an extracellular domain is enough to
      abolish PKD1L1 function and cause laterality defects.
  downstream:
  - target: Failure of Nodal Flow Sensing at the Left-Right Organizer
    description: >-
      Without PKD1L1, the PKD1L1-PKD2 complex in organizer cilia cannot form or
      signal, so the leftward flow is not converted into a left-sided signal.
    evidence:
    - reference: PMID:21307093
      reference_title: >-
        Pkd1l1 establishes left-right asymmetry and physically interacts with
        Pkd2.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Node and cilia morphology were normal in mutants and cilia demonstrated
        typical motility, consistent with Pkd1l1 and Pkd2 activity downstream of
        nodal flow.
      explanation: >-
        Pkd1l1 mutant mice generate normal motile cilia, placing the defect in
        the response to flow rather than its generation.
  - target: Biliary Epithelial Primary Cilia Deficiency
    hypothesis_groups:
    - pkd1l1_biliary_cilia
    description: >-
      In mice, Pkd1l1 loss also reduces primary cilia on biliary epithelial
      cells, a candidate route to the biliary atresia reported in some
      PKD1L1-variant carriers.
    evidence:
    - reference: PMID:38460793
      reference_title: >-
        Pkd1l1-deficiency drives biliary atresia through ciliary dysfunction in
        biliary epithelial cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Primary cilia were reduced on biliary epithelial cells and altered
        expression of ciliogenesis genes occurred in Pkd1l1-deficient mice.
      explanation: >-
        Links Pkd1l1 deficiency to loss of cholangiocyte primary cilia in mice.
- name: Failure of Nodal Flow Sensing at the Left-Right Organizer
  description: >-
    PKD1L1 is expressed in the ventral node and node crown cells (mouse) and in
    Kupffer's vesicle (medaka) at the time leftward flow breaks symmetry, and it
    co-localizes and physically interacts with PKD2 in cilia. Flow carries
    PKD1L1-containing fibrous strands to the left margin of the node, where they
    associate with Nodal. In Pkd1l1 mutants the cilia beat and flow is
    generated, but the flow is not sensed, so the organizer never acquires its
    left-right bias. This places HTX8 among the flow-sensing laterality
    disorders, distinct from the primary ciliary dyskinesias in which the cilia
    cannot move.
  biological_scale: CELLULAR
  locations:
  - preferred_term: embryonic node
    term:
      id: UBERON:0003062
      label: primitive knot
  cellular_components:
  - preferred_term: cilium
    term:
      id: GO:0005929
      label: cilium
  biological_processes:
  - preferred_term: cellular response to fluid shear stress (nodal flow)
    modifier: DECREASED
    term:
      id: GO:0071498
      label: cellular response to fluid shear stress
  - preferred_term: determination of left/right symmetry
    modifier: ABNORMAL
    term:
      id: GO:0007368
      label: determination of left/right symmetry
  evidence:
  - reference: PMID:21307093
    reference_title: >-
      Pkd1l1 establishes left-right asymmetry and physically interacts with
      Pkd2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      By contrast, we detected strongly regionalised expression of Pkd1l1, with
      expression in the node, extending into the node crown cells, and in the
      midline in late streak embryos
    explanation: >-
      Localizes Pkd1l1 expression to the mouse left-right organizer.
  - reference: PMID:21307093
    reference_title: >-
      Pkd1l1 establishes left-right asymmetry and physically interacts with
      Pkd2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cell biological analysis reveals that Pkd1l1 and Pkd2 localise to the
      cilium and biochemical experiments demonstrate that they can physically
      interact.
    explanation: >-
      Pkd1l1 and Pkd2 form a ciliary complex, the proposed flow sensor.
  - reference: PMID:21307098
    reference_title: >-
      Pkd1l1 complexes with Pkd2 on motile cilia and functions to establish the
      left-right axis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results suggest that Pkd1l1 and Pkd2 form a complex that functions
      as the nodal flow sensor in the motile cilia of the medaka KV.
    explanation: >-
      Independent medaka evidence that Pkd1l1-Pkd2 acts as the organizer flow
      sensor.
  - reference: PMID:37413993
    reference_title: >-
      Nodal flow transfers polycystin to determine mouse left-right asymmetry.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      As PKD1L1 N-term is predominantly associated with Nodal on the left margin
      and that PKD1L1/PKD2 overexpression significantly augments cellular Nodal
      sensitivity, we propose that leftward transfer of polycystin-containing
      fibrous strands determines left-right asymmetry in developing embryos.
    explanation: >-
      Live imaging of tagged PKD1L1 in mouse embryos shows flow-directed
      leftward transfer of PKD1L1 to the left node margin.
  - reference: PMID:20080492
    reference_title: >-
      Situs inversus in Dpcd/Poll-/-, Nme7-/- , and Pkd1l1-/- mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In contrast, the absence of respiratory tract lesions, hydrocephalus, and
      male infertility in Pkd1l1(-/-) mice (for: polycystic kidney disease 1
      like 1) suggested that dysfunction of motile cilia was not involved in the
      development of SI in this line.
    explanation: >-
      Pkd1l1-null mice lack the motile-cilia disease features, separating this
      mechanism from primary ciliary dyskinesia.
  downstream:
  - target: Loss of Right-Biased Cerl2 Expression at the Node Crown
    description: >-
      Flow sensing through PKD1L1 normally biases Cerl2 (Dand5) expression to
      the right side of the node; without it Cerl2 stays symmetrical.
    evidence:
    - reference: PMID:27272319
      reference_title: >-
        Genetic Analysis Reveals a Hierarchy of Interactions between
        Polycystin-Encoding Genes and Genes Controlling Cilia Function during
        Left-Right Determination.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Moreover, Pkd1l1 acts genetically upstream of Pkd2 and downstream of
        flow; this regulates Cerl2 asymmetry in a cilia-dependent fashion.
      explanation: >-
        Places Pkd1l1 between flow and Cerl2 asymmetry in the mouse node.
  - target: Lateral Plate Mesoderm Nodal Cascade Mispatterning
    description: >-
      Failure to sense flow means the left-sided Nodal cascade in the lateral
      plate mesoderm is not properly established.
    evidence:
    - reference: PMID:21307098
      reference_title: >-
        Pkd1l1 complexes with Pkd2 on motile cilia and functions to establish
        the left-right axis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we show that the medaka left-right mutant abecobe (abc) is defective for
        left-right asymmetric expression of southpaw, lefty and charon, but not
        for nodal flow
      explanation: >-
        In pkd1l1 mutant medaka, flow is present but the asymmetric Nodal-family
        expression that should follow it is lost.
- name: Loss of Right-Biased Cerl2 Expression at the Node Crown
  description: >-
    In normal embryos flow represses the Nodal antagonist Cerl2 (Dand5) on the
    left side of the node crown, so Nodal activity there becomes left-biased.
    In Pkd1l1-null embryos Cerl2 expression remains symmetrical. Epistasis
    places Pkd1l1 as an upstream genetic repressor of Pkd2 in this step.
  biological_scale: CELLULAR
  locations:
  - preferred_term: embryonic node
    term:
      id: UBERON:0003062
      label: primitive knot
  biological_processes:
  - preferred_term: negative regulation of nodal signaling pathway (Cerl2)
    modifier: ABNORMAL
    term:
      id: GO:1900108
      label: negative regulation of nodal signaling pathway
  evidence:
  - reference: PMID:27272319
    reference_title: >-
      Genetic Analysis Reveals a Hierarchy of Interactions between
      Polycystin-Encoding Genes and Genes Controlling Cilia Function during
      Left-Right Determination.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In contrast, Cerl2 asymmetry failed to manifest in Pkd1l1tm1/tm1 mutants,
      which instead exhibited a symmetrical pattern of Cerl2 expression
    explanation: >-
      Direct observation that Cerl2 asymmetry is lost in Pkd1l1-null embryos.
  - reference: PMID:27272319
    reference_title: >-
      Genetic Analysis Reveals a Hierarchy of Interactions between
      Polycystin-Encoding Genes and Genes Controlling Cilia Function during
      Left-Right Determination.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Epistasis analysis shows that Pkd1l1 acts as an upstream genetic repressor
      of Pkd2.
    explanation: >-
      Positions Pkd1l1 relative to Pkd2 in the flow-response pathway.
  downstream:
  - target: Lateral Plate Mesoderm Nodal Cascade Mispatterning
    description: >-
      Symmetrical node-crown signaling is relayed to the lateral plate, where
      Nodal is no longer confined to the left side.
    evidence:
    - reference: PMID:27272319
      reference_title: >-
        Genetic Analysis Reveals a Hierarchy of Interactions between
        Polycystin-Encoding Genes and Genes Controlling Cilia Function during
        Left-Right Determination.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we characterize a Pkd1l1 mutant line in which Nodal is activated
        bilaterally, suggesting that PKD1L1 is not required for LPM Nodal
        pathway activation per se, but rather to restrict Nodal to the left side
        downstream of nodal flow.
      explanation: >-
        Loss of Pkd1l1 leads to bilateral lateral plate Nodal activity.
- name: Lateral Plate Mesoderm Nodal Cascade Mispatterning
  description: >-
    The left-sided Nodal, Lefty2 and Pitx2 cascade in the lateral plate
    mesoderm is either not activated (Pkd1l1 rks point mutant) or activated on
    both sides (Pkd1l1 null), so the left-right identity cue that patterns the
    heart, lungs, spleen, liver and gut is lost or randomized. In the mouse,
    absent signaling gave right lung isomerism and bilateral signaling gave
    mostly left lung isomerism, while residual stochastic bias gives situs
    solitus, situs inversus or heterotaxy.
  biological_scale: TISSUE
  locations:
  - preferred_term: lateral plate mesoderm
    term:
      id: UBERON:0003081
      label: lateral plate mesoderm
  biological_processes:
  - preferred_term: nodal signaling pathway
    modifier: ABNORMAL
    term:
      id: GO:0038092
      label: nodal signaling pathway
  - preferred_term: left/right pattern formation
    modifier: ABNORMAL
    term:
      id: GO:0060972
      label: left/right pattern formation
  evidence:
  - reference: PMID:21307093
    reference_title: >-
      Pkd1l1 establishes left-right asymmetry and physically interacts with
      Pkd2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      both mutants fail to activate asymmetric gene expression at the node or in
      the lateral plate and exhibit right isomerism of the lungs
    explanation: >-
      The Pkd1l1 rks point mutant fails to activate left-sided lateral plate
      gene expression.
  - reference: PMID:27272319
    reference_title: >-
      Genetic Analysis Reveals a Hierarchy of Interactions between
      Polycystin-Encoding Genes and Genes Controlling Cilia Function during
      Left-Right Determination.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the majority of Pkd1l1tm1/tm1 embryos displayed the complete opposite
      phenotype of bilaterally mono-lobed lungs, called left lung isomerism
    explanation: >-
      The Pkd1l1 null allele, with bilateral Nodal, mostly gives left lung
      isomerism.
  downstream:
  - target: Cardiac Laterality and Outflow Tract Malformation
    description: >-
      Loss of the left-right cue leaves heart position, atrial arrangement and
      the alignment of the ventricles and great arteries unspecified.
    evidence:
    - reference: PMID:21307093
      reference_title: >-
        Pkd1l1 establishes left-right asymmetry and physically interacts with
        Pkd2.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we report the identification of a point mutation in the mouse
        Pkd1l1 locus named rks that results in right pulmonary isomerism,
        cardiac outflow defects, overt oedema and lethality by 15.5 dpc.
      explanation: >-
        Pkd1l1 mutant mice with failed lateral plate signaling develop cardiac
        outflow defects.
  - target: Heterotaxy
  - target: Situs inversus totalis
  - target: Atrial situs ambiguous
  - target: Right-sided stomach
  - target: Midline liver
  - target: Polysplenia
  - target: Asplenia
  - target: Intestinal malrotation
  - target: Abnormal lung lobation
- name: Cardiac Laterality and Outflow Tract Malformation
  description: >-
    Without a reliable left-right cue the direction of heart looping and the
    connections of atria, ventricles and great arteries are randomized. In
    Pkd1l1 mutant mice about three quarters of embryos have outflow tract
    defects (double-outlet right ventricle or transposition), and in patients
    this gives the unbalanced atrioventricular septal defects, conotruncal
    defects and single-ventricle hearts that dominate the clinical course.
  biological_scale: TISSUE
  locations:
  - preferred_term: heart tube
    term:
      id: UBERON:0004141
      label: heart tube
  biological_processes:
  - preferred_term: heart looping
    modifier: ABNORMAL
    term:
      id: GO:0001947
      label: heart looping
  evidence:
  - reference: PMID:21307093
    reference_title: >-
      Pkd1l1 establishes left-right asymmetry and physically interacts with
      Pkd2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      revealing a significant incidence of apparent double outlet right
      ventricle (DORV) and transposition of the great arteries (TGA)
    explanation: >-
      Outflow tract malformations in Pkd1l1 rks mutant mouse embryos.
  downstream:
  - target: Dextrocardia
  - target: Unbalanced atrioventricular canal defect
  - target: Hypoplastic left ventricle
  - target: Double outlet right ventricle
  - target: Levotransposition of the great arteries
  - target: Pulmonary artery atresia
  - target: Pulmonic stenosis
  - target: Ventricular septal defect
  - target: Single ventricle
  - target: Right aortic arch
  - target: Systemic venous anomalies
  - target: Pulmonary venous anomalies
  - target: Nonimmune hydrops fetalis
- name: Biliary Epithelial Primary Cilia Deficiency
  description: >-
    Constitutive or conditional Pkd1l1 knockout mice have fewer primary cilia on
    biliary epithelial cells and reduced ciliary Hedgehog signaling gene
    expression, with hypertrophic, fibrotic extrahepatic bile ducts, delayed
    biliary drainage and ductular reaction, progressing to obstruction under a
    biliary injury diet. This is a candidate mechanism for the biliary atresia
    splenic malformation presentation; human evidence is limited to rare
    biallelic and heterozygous PKD1L1 variants in BASM cohorts.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cholangiocyte
    term:
      id: CL:1000488
      label: cholangiocyte
  locations:
  - preferred_term: extrahepatic bile duct
    term:
      id: UBERON:0003703
      label: extrahepatic bile duct
  biological_processes:
  - preferred_term: cilium assembly
    modifier: DECREASED
    term:
      id: GO:0060271
      label: cilium assembly
  evidence:
  - reference: PMID:38460793
    reference_title: >-
      Pkd1l1-deficiency drives biliary atresia through ciliary dysfunction in
      biliary epithelial cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Primary cilia were reduced on biliary epithelial cells and altered
      expression of ciliogenesis genes occurred in Pkd1l1-deficient mice.
    explanation: >-
      Direct observation of reduced cholangiocyte cilia in Pkd1l1-deficient
      mice.
  - reference: PMID:38460793
    reference_title: >-
      Pkd1l1-deficiency drives biliary atresia through ciliary dysfunction in
      biliary epithelial cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Pkd1l1-deficient EHBDs were hypertrophic and fibrotic.
    explanation: >-
      The extrahepatic bile duct pathology that follows Pkd1l1 loss in mice.
  downstream:
  - target: Biliary atresia
    hypothesis_groups:
    - pkd1l1_biliary_cilia
    description: >-
      Proposed link: cholangiocyte ciliary dysfunction drives fibro-obliterative
      bile duct disease, phenocopying syndromic biliary atresia in mice.
    evidence:
    - reference: PMID:38460793
      reference_title: >-
        Pkd1l1-deficiency drives biliary atresia through ciliary dysfunction in
        biliary epithelial cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Pkd1l1 loss causes both laterality defects and fibro-proliferative EHBD
        transformation through disrupted ciliary signaling, phenocopying
        syndromic biliary atresia.
      explanation: >-
        The authors attribute the biliary phenotype to disrupted ciliary
        signaling in Pkd1l1-deficient mice.
mechanistic_hypotheses:
- hypothesis_group_id: pkd1l1_biliary_cilia
  hypothesis_label: PKD1L1 loss causes biliary atresia through cholangiocyte cilia dysfunction
  status: EMERGING
  description: >-
    Beyond its role at the left-right organizer, PKD1L1 is expressed in bile
    duct epithelium, and Pkd1l1-deficient mice show reduced cholangiocyte
    primary cilia, decreased Hedgehog pathway gene expression and fibrotic
    extrahepatic bile duct remodeling. This would explain why PKD1L1 variants
    are found in biliary atresia splenic malformation syndrome, which combines
    laterality defects with biliary atresia.
  notes: >-
    EMERGING because the mouse ducts remain patent without an added biliary
    injury, and the human data are rare biallelic and heterozygous variants in
    a BASM cohort, described there as a candidate gene. None of the heterotaxy
    families carrying the alleles discussed above was reported with biliary
    atresia.
  evidence:
  - reference: PMID:38460793
    reference_title: >-
      Pkd1l1-deficiency drives biliary atresia through ciliary dysfunction in
      biliary epithelial cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Pkd1l1 loss causes both laterality defects and fibro-proliferative EHBD
      transformation through disrupted ciliary signaling, phenocopying
      syndromic biliary atresia.
    explanation: >-
      The mouse study on which the hypothesis principally rests.
  - reference: PMID:30664273
    reference_title: >-
      Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in
      Children With Biliary Atresia Splenic Malformation Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five BASM subjects harbored rare and potentially deleterious biallelic
      variants in polycystic kidney disease 1 like 1 (PKD1L1), a gene
      associated with ciliary calcium signaling and embryonic laterality
      determination in fish, mice, and humans.
    explanation: >-
      Human genetic association of PKD1L1 variants with the BASM presentation.
phenotypes:
- name: Heterotaxy
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Situs ambiguus is the most common presentation; in a 2026 review of 21
    published PKD1L1 cases, 16 had heterotaxy and 3 situs inversus.
  phenotype_term:
    preferred_term: Heterotaxy
    term:
      id: HP:0030853
      label: Heterotaxy
  evidence:
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Family 1 had one fetus and one deceased child with heterotaxy and complex
      congenital heart malformations.
    explanation: >-
      Heterotaxy in two siblings homozygous for a PKD1L1 splice variant.
  - 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
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Among the 21 reported PKD1L1 cases, 3 presented with SI and 16 exhibited a
      HTX phenotype.
    explanation: >-
      Pooled literature count giving heterotaxy in 16 of 21 PKD1L1 cases.
- name: Situs inversus totalis
  category: Cardiovascular
  description: >-
    Complete mirror-image situs occurs in a minority of cases, sometimes
    without congenital heart disease.
  phenotype_term:
    preferred_term: Situs inversus totalis
    term:
      id: HP:0001696
      label: Situs inversus totalis
  evidence:
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the second family, a homozygous c.5072G>C (p.Cys1691Ser) missense
      mutation was detected in an individual with SIT and congenital heart
      disease.
    explanation: >-
      Situs inversus totalis in a homozygous PKD1L1 missense carrier.
  - reference: PMID:32111882
    reference_title: The genetics of situs inversus without primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One non-PCD SI case had recessive mutations in PKD1L1, and another in
      CFAP52 (also known as WDR16).
    explanation: >-
      Recessive PKD1L1 variants in an adult with situs inversus without primary
      ciliary dyskinesia.
  - reference: PMID:27272319
    reference_title: >-
      Genetic Analysis Reveals a Hierarchy of Interactions between
      Polycystin-Encoding Genes and Genes Controlling Cilia Function during
      Left-Right Determination.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Surviving mutants either exhibited normal (57%) or reversed (43%) situs
      based on stomach position in neonates
    explanation: >-
      Pkd1l1-null mice that survive have normal or reversed situs, the mouse
      counterpart of situs inversus.
- name: Dextrocardia
  category: Cardiovascular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dextrocardia
    term:
      id: HP:0001651
      label: Dextrocardia
  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
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Atrial arrangement abnormalities and dextrocardia were present in 70%
      (7/10) and 77% (10/13) of cases, respectively.
    explanation: >-
      Dextrocardia in 10 of 13 assessed published PKD1L1 cases.
- name: Atrial situs ambiguous
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Atrial arrangement abnormalities (atrial isomerism or situs ambiguus) were
    recorded in 7 of 10 assessed published PKD1L1 cases; the review does not
    separate right from left isomerism.
  phenotype_term:
    preferred_term: Atrial situs ambiguous
    term:
      id: HP:0011539
      label: Atrial situs ambiguous
  evidence:
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had atrial situs ambiguus, unbalanced atrioventricular septal defect
      with left ventricular hypoplasia, pulmonary atresia, right-sided stomach,
      left-sided liver, and right-sided spleen
    explanation: >-
      Atrial situs ambiguus in a homozygous PKD1L1 patient.
  - 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
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Atrial arrangement abnormalities and dextrocardia were present in 70%
      (7/10) and 77% (10/13) of cases, respectively.
    explanation: >-
      Atrial arrangement abnormalities in 7 of 10 assessed published PKD1L1
      cases.
- name: Unbalanced atrioventricular canal defect
  category: Cardiovascular
  phenotype_term:
    preferred_term: Unbalanced atrioventricular septal defect
    term:
      id: HP:0011579
      label: Unbalanced atrioventricular canal defect
  evidence:
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The fetus presented with situs ambiguus with atrial situs solitus,
      unbalanced atrioventricular septal defect with left ventricular
      hypoplasia, double outlet right ventricle with malposed great arteries,
      right-sided stomach, left-sided liver, and right-sided spleen
    explanation: >-
      Unbalanced atrioventricular septal defect in both affected siblings of
      the first family.
- name: Hypoplastic left ventricle
  category: Cardiovascular
  phenotype_term:
    preferred_term: Hypoplastic left ventricle
    term:
      id: HP:0004383
      label: Hypoplastic left ventricle
  evidence:
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had atrial situs ambiguus, unbalanced atrioventricular septal defect
      with left ventricular hypoplasia, pulmonary atresia, right-sided stomach,
      left-sided liver, and right-sided spleen
    explanation: >-
      Left ventricular hypoplasia accompanying the unbalanced atrioventricular
      septal defect.
- name: Double outlet right ventricle
  category: Cardiovascular
  phenotype_term:
    preferred_term: Double outlet right ventricle
    term:
      id: HP:0001719
      label: Double outlet right ventricle
  evidence:
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The fetus presented with situs ambiguus with atrial situs solitus,
      unbalanced atrioventricular septal defect with left ventricular
      hypoplasia, double outlet right ventricle with malposed great arteries,
      right-sided stomach, left-sided liver, and right-sided spleen
    explanation: >-
      Double outlet right ventricle in a homozygous PKD1L1 fetus.
  - 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: >-
      fetopathology revealed a complex presentation of dextrocardia, single
      ventricle, double-outlet right ventricle (DORV), right aortic arch, and
      pulmonary stenosis
    explanation: >-
      Double outlet right ventricle in a compound heterozygous PKD1L1 fetus.
- name: Levotransposition of the great arteries
  category: Cardiovascular
  phenotype_term:
    preferred_term: Congenitally corrected transposition of the great arteries
    term:
      id: HP:0011540
      label: Levotransposition of the great arteries
  evidence:
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was diagnosed in the first weeks of life with SIT and congenital heart
      disease including congenitally corrected transposition of the great
      arteries (ventricular inversion) with a small left ventricle, pulmonary
      atresia, and ventricular septal defect
    explanation: >-
      Congenitally corrected transposition in the homozygous p.Cys1691Ser
      patient.
- name: Pulmonary artery atresia
  category: Cardiovascular
  phenotype_term:
    preferred_term: Pulmonary atresia
    term:
      id: HP:0004935
      label: Pulmonary artery atresia
  evidence:
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was diagnosed in the first weeks of life with SIT and congenital heart
      disease including congenitally corrected transposition of the great
      arteries (ventricular inversion) with a small left ventricle, pulmonary
      atresia, and ventricular septal defect
    explanation: >-
      Pulmonary atresia in the homozygous p.Cys1691Ser patient.
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had atrial situs ambiguus, unbalanced atrioventricular septal defect
      with left ventricular hypoplasia, pulmonary atresia, right-sided stomach,
      left-sided liver, and right-sided spleen
    explanation: >-
      Pulmonary atresia in the affected brother of the first family.
- name: Pulmonic stenosis
  category: Cardiovascular
  phenotype_term:
    preferred_term: Pulmonic stenosis
    term:
      id: HP:0001642
      label: Pulmonic stenosis
  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: >-
      fetopathology revealed a complex presentation of dextrocardia, single
      ventricle, double-outlet right ventricle (DORV), right aortic arch, and
      pulmonary stenosis
    explanation: >-
      Pulmonary stenosis in a compound heterozygous PKD1L1 fetus.
- name: Ventricular septal defect
  category: Cardiovascular
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was diagnosed in the first weeks of life with SIT and congenital heart
      disease including congenitally corrected transposition of the great
      arteries (ventricular inversion) with a small left ventricle, pulmonary
      atresia, and ventricular septal defect
    explanation: >-
      Ventricular septal defect in the homozygous p.Cys1691Ser patient.
  - 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
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Septation defects were reported in all assessed cases (11/11), while
      outflow tract obstructions and systemic venous anomalies were each
      observed in 78% (7/9) of documented cases.
    explanation: >-
      Septation defects were present in every assessed published PKD1L1 case.
- name: Single ventricle
  category: Cardiovascular
  phenotype_term:
    preferred_term: Single ventricle
    term:
      id: HP:0001750
      label: Single ventricle
  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: >-
      fetopathology revealed a complex presentation of dextrocardia, single
      ventricle, double-outlet right ventricle (DORV), right aortic arch, and
      pulmonary stenosis
    explanation: >-
      Single ventricle in a compound heterozygous PKD1L1 fetus.
- name: Right aortic arch
  category: Cardiovascular
  phenotype_term:
    preferred_term: Right aortic arch
    term:
      id: HP:0012020
      label: Right aortic arch
  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: >-
      fetopathology revealed a complex presentation of dextrocardia, single
      ventricle, double-outlet right ventricle (DORV), right aortic arch, and
      pulmonary stenosis
    explanation: >-
      Right aortic arch in a compound heterozygous PKD1L1 fetus.
- name: Systemic venous anomalies
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Systemic venous anomalies were recorded in 7 of 9 assessed published PKD1L1
    cases. Across the four heterotaxy genes reviewed they were a persistent left
    superior vena cava or an interrupted inferior vena cava; the cached text
    does not give the type for each PKD1L1 case.
  notes: >-
    Bound to HP:0005345 Abnormal vena cava morphology rather than to
    HP:0005301 Persistent left superior vena cava, HP:0033379 Bilateral
    superior vena cava or HP:0011671 Interrupted inferior vena cava with
    azygous continuation, because the PKD1L1-specific count in the source is
    for the whole category and no per-case vein type for a PKD1L1 patient is in
    the cached text.
  phenotype_term:
    preferred_term: Systemic venous anomalies
    term:
      id: HP:0005345
      label: Abnormal vena cava morphology
  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
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Septation defects were reported in all assessed cases (11/11), while
      outflow tract obstructions and systemic venous anomalies were each
      observed in 78% (7/9) of documented cases.
    explanation: >-
      Systemic venous anomalies in 7 of 9 assessed published PKD1L1 cases.
  - 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
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Additionally, systemic and pulmonary venous anomalies were recurrent
      features, characterized by a persistent left superior vena cava, an
      interrupted inferior vena cava, and anomalous pulmonary venous return.
    explanation: >-
      Names the vena caval anomalies that make up this category across the
      reviewed heterotaxy genes, including PKD1L1.
    directness: INDIRECT
- name: Pulmonary venous anomalies
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Pulmonary venous anomalies were recorded in 4 of 6 assessed published
    PKD1L1 cases. Across the reviewed heterotaxy genes these were anomalous
    pulmonary venous return.
  notes: >-
    Bound to HP:0011718 Abnormality of the pulmonary veins, which matches the
    source's category, rather than to HP:0005160 Total or HP:0010773 Partial
    anomalous pulmonary venous return, because whether each PKD1L1 case was
    total or partial is not in the cached text.
  phenotype_term:
    preferred_term: Pulmonary venous anomalies
    term:
      id: HP:0011718
      label: Abnormality of the pulmonary veins
  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
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Pulmonary venous anomalies | Yes | 3/3 (25 NR) | No | No | No | 4/6 (15 NR)
    explanation: >-
      Pooled table row: pulmonary venous anomalies in 4 of 6 assessed PKD1L1
      cases (the PKD1L1 column follows the three French PKD1L1 cases).
- name: Right-sided stomach
  category: Gastrointestinal
  notes: >-
    Bound to the broader Malposition of the stomach because HPO has no
    right-sided stomach term: `runoak -i ols:hp search "right-sided stomach"`
    and `runoak -i ols:hp search "dextroposition of the stomach"` return
    nothing, and `runoak -i ols:hp search "stomach"` returns HP:0100802
    Malposition of the stomach and HP:0002577 Abnormal stomach morphology as
    the only position or morphology terms. The side is carried in
    preferred_term.
  phenotype_term:
    preferred_term: Right-sided stomach
    term:
      id: HP:0100802
      label: Malposition of the stomach
  evidence:
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had atrial situs ambiguus, unbalanced atrioventricular septal defect
      with left ventricular hypoplasia, pulmonary atresia, right-sided stomach,
      left-sided liver, and right-sided spleen
    explanation: >-
      Right-sided stomach in a homozygous PKD1L1 patient.
  - 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: >-
      Extracardiac abnormalities involved bilobed, hypoplastic lungs,
      right-sided polysplenia, midline liver, right-sided stomach, and
      intestinal malrotation.
    explanation: >-
      Right-sided stomach in a compound heterozygous PKD1L1 fetus.
- name: Midline liver
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Midline liver
    term:
      id: HP:0034188
      label: Midline liver
  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: >-
      Extracardiac abnormalities involved bilobed, hypoplastic lungs,
      right-sided polysplenia, midline liver, right-sided stomach, and
      intestinal malrotation.
    explanation: >-
      Midline liver in a compound heterozygous PKD1L1 fetus.
- name: Polysplenia
  category: Hematologic
  frequency: FREQUENT
  description: >-
    Polysplenia was reported in 8 published PKD1L1 cases and asplenia in 2, out
    of 14 with splenic data; the frequency band is derived from those two
    figures.
  phenotype_term:
    preferred_term: Polysplenia
    term:
      id: HP:0001748
      label: Polysplenia
  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
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Within this cohort, eight individuals presented with polysplenia, two with
      asplenia, and 13 with gastrointestinal abnormalities
    explanation: >-
      Polysplenia is the more common splenic anomaly among published PKD1L1
      cases.
  - 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
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Asplenia/polysplenia | Yes | 3/9 (19 NR) | Yes | Yes | N/A | 10/14 (7 NR)
    explanation: >-
      Pooled table row: 10 of 14 PKD1L1 cases with splenic data had asplenia or
      polysplenia (the text gives 8 polysplenia and 2 asplenia).
- name: Asplenia
  category: Hematologic
  frequency: OCCASIONAL
  description: >-
    Asplenia was reported in 2 of 14 published PKD1L1 cases with splenic data
    (derived from the pooled review), including a homozygous nonsense carrier
    with congenital asplenia.
  phenotype_term:
    preferred_term: Asplenia
    term:
      id: HP:0001746
      label: Asplenia
  evidence:
  - reference: PMID:35691949
    reference_title: >-
      A novel nonsense PKD1L1 variant cause heterotaxy syndrome with congenital
      asplenia in a Han Chinese patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a novel nonsense variant in PKD1L1(c.1387 C > T; p.463Gln*)
      in a Chinese patient with heterotaxy syndrome and congenital asplenia.
    explanation: >-
      Congenital asplenia in a homozygous PKD1L1 nonsense carrier.
  - 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
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Within this cohort, eight individuals presented with polysplenia, two with
      asplenia, and 13 with gastrointestinal abnormalities
    explanation: >-
      Two asplenia cases among the published PKD1L1 cases.
  - 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
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Asplenia/polysplenia | Yes | 3/9 (19 NR) | Yes | Yes | N/A | 10/14 (7 NR)
    explanation: >-
      Pooled table row: 10 of 14 PKD1L1 cases with splenic data had asplenia or
      polysplenia (the text gives 8 polysplenia and 2 asplenia).
- name: Intestinal malrotation
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Intestinal malrotation
    term:
      id: HP:0002566
      label: Intestinal malrotation
  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: >-
      Extracardiac abnormalities involved bilobed, hypoplastic lungs,
      right-sided polysplenia, midline liver, right-sided stomach, and
      intestinal malrotation.
    explanation: >-
      Intestinal malrotation in a compound heterozygous PKD1L1 fetus.
- name: Abnormal lung lobation
  category: Respiratory
  description: >-
    Bronchopulmonary isomerism was recorded in all five published PKD1L1 cases
    where it was assessed, for example bilaterally bilobed lungs.
  phenotype_term:
    preferred_term: Bilobed lungs (bronchopulmonary isomerism)
    term:
      id: HP:0002101
      label: Abnormal lung lobation
  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: >-
      Extracardiac abnormalities involved bilobed, hypoplastic lungs,
      right-sided polysplenia, midline liver, right-sided stomach, and
      intestinal malrotation.
    explanation: >-
      Bilobed lungs in a compound heterozygous PKD1L1 fetus.
  - reference: PMID:21307093
    reference_title: >-
      Pkd1l1 establishes left-right asymmetry and physically interacts with
      Pkd2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      both mutants fail to activate asymmetric gene expression at the node or in
      the lateral plate and exhibit right isomerism of the lungs
    explanation: >-
      Pkd1l1 mutant mice reproduce pulmonary isomerism.
- name: Nonimmune hydrops fetalis
  category: Cardiovascular
  phenotype_term:
    preferred_term: Nonimmune hydrops fetalis
    term:
      id: HP:0001790
      label: Nonimmune hydrops fetalis
  evidence:
  - reference: PMID:33655537
    reference_title: >-
      Hydrops fetalis in PKD1L1-related heterotaxy: Report of two foetuses and
      expanding the phenotypic and molecular spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe the first Indian family with two affected foetuses with
      PKD1L1-related nonimmune hydrops, congenital heart disease, situs
      inversus, and heterotaxy, with biallelic variants in the compound
      heterozygous state.
    explanation: >-
      Nonimmune hydrops in two compound heterozygous PKD1L1 fetuses.
  - reference: PMID:21307093
    reference_title: >-
      Pkd1l1 establishes left-right asymmetry and physically interacts with
      Pkd2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we report the identification of a point mutation in the mouse
      Pkd1l1 locus named rks that results in right pulmonary isomerism, cardiac
      outflow defects, overt oedema and lethality by 15.5 dpc.
    explanation: >-
      Pkd1l1 mutant mouse embryos also develop overt oedema with their cardiac
      defects.
- name: Biliary atresia
  category: Hepatic
  description: >-
    Reported in biliary atresia splenic malformation syndrome patients carrying
    rare biallelic PKD1L1 variants; the association is at the candidate-gene
    level.
  phenotype_term:
    preferred_term: Biliary atresia
    term:
      id: HP:0005912
      label: Biliary atresia
  evidence:
  - reference: PMID:30664273
    reference_title: >-
      Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in
      Children With Biliary Atresia Splenic Malformation Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five BASM subjects harbored rare and potentially deleterious biallelic
      variants in polycystic kidney disease 1 like 1 (PKD1L1), a gene
      associated with ciliary calcium signaling and embryonic laterality
      determination in fish, mice, and humans.
    explanation: >-
      Biallelic PKD1L1 variants in children with biliary atresia and
      laterality defects.
diagnosis:
- name: Prenatal ultrasound
  description: >-
    Many reported cases were first detected on fetal ultrasound because of
    situs anomalies and complex heart disease.
  diagnosis_term:
    preferred_term: fetal ultrasound imaging
    term:
      id: NCIT:C222238
      label: Fetal Ultrasound Imaging
  evidence:
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The family was referred for prenatal genetic assessment after an
      ultrasound examination performed at 21 weeks and 6 days of gestation
      revealed complex congenital malformations of the fetus.
    explanation: >-
      Fetal ultrasound first detected the malformations in the index fetus.
- name: Exome or genome sequencing for biallelic PKD1L1 variants
  description: >-
    The diagnosis is confirmed by finding biallelic PKD1L1 variants. Exome
    sequencing found the original families; genome sequencing was needed to
    detect the recurrent intronic splice-site variant in a French series, and
    trio analysis helps establish that variants are in trans.
  diagnosis_term:
    preferred_term: whole genome sequencing
    term:
      id: NCIT:C101294
      label: Whole Genome Sequencing
  evidence:
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Via whole-exome sequencing (WES), we identified homozygous mutations in
      PKD1L1 from three affected individuals in two unrelated families.
    explanation: >-
      Exome sequencing identified the causal PKD1L1 variants.
  - 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: >-
      Notably, WGS was essential in detecting the splice-site variants
      identified in the PKD1L1 cases (FR-01, FR-02, and FR-03), underscoring its
      superiority over WES for detecting non-coding and regulatory variations.
    explanation: >-
      Genome sequencing was needed to detect the recurrent PKD1L1 splice allele.
- name: Exclusion of primary ciliary dyskinesia
  description: >-
    Laterality defects without chronic airway disease or infertility point away
    from the motile ciliopathies. The row is left unbound, as in the HTX7 entry,
    which records that OLS NCIT searches returned no ciliary function test
    procedure.
  evidence:
  - reference: PMID:32111882
    reference_title: The genetics of situs inversus without primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One non-PCD SI case had recessive mutations in PKD1L1, and another in
      CFAP52 (also known as WDR16).
    explanation: >-
      PKD1L1 variants are found among situs inversus cases without primary
      ciliary dyskinesia.
animal_models:
- name: Pkd1l1 rks ENU point mutant mouse
  species: Mouse
  genotype: Pkd1l1 rks (p.Asp411Gly in a PKD domain) homozygous
  publication: PMID:21307093
  description: >-
    A recessive ENU line with a missense change in a PKD domain of Pkd1l1 shows
    right pulmonary isomerism, randomized heart and stomach situs, outflow
    tract defects, oedema and death by 15.5 dpc, with normal node and cilia
    motility and absent left-sided lateral plate gene expression.
  evidence:
  - reference: PMID:21307093
    reference_title: >-
      Pkd1l1 establishes left-right asymmetry and physically interacts with
      Pkd2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we report the identification of a point mutation in the mouse
      Pkd1l1 locus named rks that results in right pulmonary isomerism, cardiac
      outflow defects, overt oedema and lethality by 15.5 dpc.
    explanation: >-
      Establishes the rks line and its phenotype.
  modeled_mechanisms:
  - target: Failure of Nodal Flow Sensing at the Left-Right Organizer
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      Laterality fails although the node and its motile cilia are normal,
      isolating the flow-sensing step.
    limitations: >-
      A single missense allele on one genetic background; it gives almost
      exclusively right isomerism with absent Nodal, whereas the null allele
      gives bilateral Nodal, so allele effects differ.
    evidence:
    - reference: PMID:21307093
      reference_title: >-
        Pkd1l1 establishes left-right asymmetry and physically interacts with
        Pkd2.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Node and cilia morphology were normal in mutants and cilia demonstrated
        typical motility, consistent with Pkd1l1 and Pkd2 activity downstream of
        nodal flow.
      explanation: >-
        Shows the model informs the flow-sensing node.
  - target: Cardiac Laterality and Outflow Tract Malformation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Mutant embryos develop double-outlet right ventricle and transposition.
    limitations: >-
      Embryonic lethality by 15.5 dpc prevents study of later cardiac
      remodeling and survival.
    evidence:
    - reference: PMID:21307093
      reference_title: >-
        Pkd1l1 establishes left-right asymmetry and physically interacts with
        Pkd2.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        revealing a significant incidence of apparent double outlet right
        ventricle (DORV) and transposition of the great arteries (TGA)
      explanation: >-
        Outflow tract defects in the model.
- name: Pkd1l1 tm1 targeted null mouse
  species: Mouse
  genotype: Pkd1l1 tm1Lex homozygous
  publication: PMID:27272319
  description: >-
    A targeted, likely null, Pkd1l1 allele with reduced viability; survivors
    have normal or reversed situs without respiratory, hydrocephalus or
    fertility phenotypes, and embryos show bilateral Nodal activity, mostly
    left lung isomerism and loss of node Cerl2 asymmetry.
  evidence:
  - reference: PMID:27272319
    reference_title: >-
      Genetic Analysis Reveals a Hierarchy of Interactions between
      Polycystin-Encoding Genes and Genes Controlling Cilia Function during
      Left-Right Determination.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Surviving mutants either exhibited normal (57%) or reversed (43%) situs
      based on stomach position in neonates
    explanation: >-
      Randomized situs in surviving null mice.
  modeled_mechanisms:
  - target: Loss of Right-Biased Cerl2 Expression at the Node Crown
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      Null embryos lose node-crown Cerl2 asymmetry and activate Nodal
      bilaterally.
    limitations: >-
      The human left-right organizer has not been studied directly, so the
      link from this mouse readout to particular human alleles is inferred.
    evidence:
    - reference: PMID:27272319
      reference_title: >-
        Genetic Analysis Reveals a Hierarchy of Interactions between
        Polycystin-Encoding Genes and Genes Controlling Cilia Function during
        Left-Right Determination.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In contrast, Cerl2 asymmetry failed to manifest in Pkd1l1tm1/tm1
        mutants, which instead exhibited a symmetrical pattern of Cerl2
        expression
      explanation: >-
        Direct readout of the Cerl2 node in the null model.
- name: Medaka abecobe (pkd1l1) mutant
  species: Medaka
  genotype: pkd1l1 abecobe (abc) homozygous
  publication: PMID:21307098
  description: >-
    The medaka laterality mutant abecobe carries a pkd1l1 mutation; its
    Kupffer's vesicle generates normal flow but asymmetric southpaw, lefty and
    charon expression fails.
  evidence:
  - reference: PMID:21307098
    reference_title: >-
      Pkd1l1 complexes with Pkd2 on motile cilia and functions to establish the
      left-right axis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we show that the medaka left-right mutant abecobe (abc) is defective for
      left-right asymmetric expression of southpaw, lefty and charon, but not
      for nodal flow
    explanation: >-
      Establishes the medaka pkd1l1 model and its flow-sensing defect.
  modeled_mechanisms:
  - target: Lateral Plate Mesoderm Nodal Cascade Mispatterning
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Asymmetric Nodal-family expression is lost despite normal flow.
    limitations: >-
      In medaka the Kupffer's vesicle cilia that carry Pkd1l1 are motile,
      whereas in mouse the flow-sensing cilia are thought to be the immotile
      cilia of crown cells, so the cellular site of sensing may differ between
      species.
    evidence:
    - reference: PMID:21307098
      reference_title: >-
        Pkd1l1 complexes with Pkd2 on motile cilia and functions to establish
        the left-right axis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These results suggest that Pkd1l1 and Pkd2 form a complex that functions
        as the nodal flow sensor in the motile cilia of the medaka KV.
      explanation: >-
        Supports the model's relevance to organizer flow sensing.
- name: Pkd1l1 constitutive and conditional knockout mice (biliary)
  species: Mouse
  genotype: Pkd1l1 constitutive or conditional knockout
  publication: PMID:38460793
  description: >-
    Knockout mice show malrotation and heterotaxy together with hypertrophic,
    fibrotic extrahepatic bile ducts, delayed biliary drainage, fewer
    cholangiocyte primary cilia and, after DDC diet, bile duct obstruction.
  evidence:
  - reference: PMID:38460793
    reference_title: >-
      Pkd1l1-deficiency drives biliary atresia through ciliary dysfunction in
      biliary epithelial cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Pkd1l1-deficient mice exhibited congenital anomalies including
      malrotation and heterotaxy.
    explanation: >-
      The knockout reproduces the laterality phenotype.
  modeled_mechanisms:
  - target: Biliary Epithelial Primary Cilia Deficiency
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reduced cholangiocyte cilia and fibrotic bile duct remodeling.
    limitations: >-
      Bile ducts stay patent unless an injury diet is added, so the model shows
      susceptibility rather than spontaneous biliary atresia.
    evidence:
    - reference: PMID:38460793
      reference_title: >-
        Pkd1l1-deficiency drives biliary atresia through ciliary dysfunction in
        biliary epithelial cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Primary cilia were reduced on biliary epithelial cells and altered
        expression of ciliogenesis genes occurred in Pkd1l1-deficient mice.
      explanation: >-
        Direct readout of the biliary cilia node.
treatments:
- name: Cardiac surgery
  description: >-
    Complex congenital heart disease is managed surgically according to the
    anatomy, for example ventricular septal defect closure with a ventricle to
    pulmonary artery conduit. There is no PKD1L1-directed therapy, and several
    reported affected pregnancies were terminated or the infants died of their
    heart disease in the neonatal period.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cardiac surgery
    term:
      id: NCIT:C157806
      label: Cardiac Surgery
  target_phenotypes:
  - preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  - preferred_term: Pulmonary atresia
    term:
      id: HP:0004935
      label: Pulmonary artery atresia
  evidence:
  - reference: PMID:27616478
    reference_title: >-
      Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in
      Humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She underwent placement of a left ventricle to pulmonary artery conduit
      and ventricular septal defect closure.
    explanation: >-
      Surgical repair in the 46-year-old homozygous p.Cys1691Ser patient.
- name: Antibiotic prophylaxis for asplenia
  description: >-
    Children with heterotaxy and asplenia or poor splenic function are at high
    risk of bacteremia, and long-term antibiotic prophylaxis is used together
    with immunization. The evidence is from heterotaxy and congenital asplenia
    cohorts in general, not PKD1L1 patients specifically, and one isomerism
    cohort found no association between prophylaxis status and bacteremia
    risk. No cached source for heterotaxy names the antibiotic, so no
    therapeutic agent is bound.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antibiotic prophylaxis
    term:
      id: NCIT:C51993
      label: Antibiotic Prophylaxis
  target_phenotypes:
  - preferred_term: Asplenia
    term:
      id: HP:0001746
      label: Asplenia
  evidence:
  - reference: PMID:26557043
    reference_title: >-
      Asplenia in children with congenital heart disease as a cause of poor
      outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In asplenic children, early diagnosis, antibiotic prophylaxis, and
      immunisation for encapsulated bacteria can decrease the risk of morbidity
      and mortality.
    explanation: >-
      Case series of asplenic children with congenital heart disease, including
      heterotaxy, supporting prophylaxis.
  - reference: PMID:27425254
    reference_title: >-
      Bacteremia in Patients with Heterotaxy: A Review and Implications for
      Management.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: >-
      HTX patients are at high risk for bacteremia leading to mortality,
      regardless of anatomic splenic type.
    explanation: >-
      Establishes the infection risk in heterotaxy that prophylaxis is meant to
      reduce.
  - reference: PMID:28741863
    reference_title: >-
      Development of quality metrics for ambulatory pediatric cardiology:
      Infection prevention.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Three metrics passed all analyses, including those for antibiotic
      prophylaxis in patients with heterotaxy/asplenia
    explanation: >-
      An expert consensus process adopted antibiotic prophylaxis in
      heterotaxy with asplenia as a pediatric cardiology quality metric.
  - reference: PMID:27679871
    reference_title: >-
      Factors influencing bacteraemia in patients with isomerism and CHD: the
      effects of functional splenic status and antibiotic prophylaxis.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Specific factors such as splenic anatomy, atrial appendage isomerism, and
      antibiotic prophylaxis status are not significantly associated with the
      risk of bacteraemia in patients with CHD and isomerism.
    explanation: >-
      In a retrospective isomerism cohort, mostly nosocomial bacteremia was not
      associated with prophylaxis status, so the benefit is not established.
- name: Immunization against encapsulated bacteria
  description: >-
    Asplenic children are immunized against encapsulated bacteria alongside
    antibiotic prophylaxis. As for prophylaxis, the evidence comes from
    congenital asplenia and heterotaxy cohorts, not PKD1L1 patients.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: vaccination against encapsulated bacteria
    term:
      id: NCIT:C15346
      label: Vaccination
  target_phenotypes:
  - preferred_term: Asplenia
    term:
      id: HP:0001746
      label: Asplenia
  evidence:
  - reference: PMID:26557043
    reference_title: >-
      Asplenia in children with congenital heart disease as a cause of poor
      outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The rest of the four patients were vaccinated for encapsulated bacteria
      and were taken under antibiotic prophylaxis.
    explanation: >-
      Asplenic children with congenital heart disease were vaccinated against
      encapsulated bacteria; none then needed admission for infection.
discussions:
- discussion_id: pkd1l1_allele_specific_nodal_outcome
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Lateral Plate Mesoderm Nodal Cascade Mispatterning
  prompt: >-
    Do human PKD1L1 alleles abolish left-sided Nodal (as the mouse rks point
    mutant does) or make it bilateral (as the mouse null does), and does this
    explain why some patients have isomerism with heterotaxy and others situs
    inversus totalis?
  rationale: >-
    Two mouse alleles of the same gene give opposite lateral plate Nodal
    outcomes, right versus left lung isomerism, and different survival. Human
    patients range from situs inversus totalis without heart disease to
    lethal heterotaxy, and siblings with the same genotype differ, but no human
    allele has been tested for which mouse outcome it resembles. Until that is
    known, the edge from flow-sensing failure to a particular situs outcome is
    an inference from mouse.
  status: OPEN
  evidence:
  - reference: PMID:27272319
    reference_title: >-
      Genetic Analysis Reveals a Hierarchy of Interactions between
      Polycystin-Encoding Genes and Genes Controlling Cilia Function during
      Left-Right Determination.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In conclusion, the Pkd1l1tm1 allele has a strikingly different impact on
      both survival and L-R patterning compared to the Pkd1l1rks point mutation.
    explanation: >-
      Two Pkd1l1 alleles give distinct laterality outcomes in mice.
  - 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: >-
      We observed that while PKD1L1 mutations are often severe, familial cases
      like FR-02 and FR-03 show that identical genotypes can result in
      strikingly different cardiac severities.
    explanation: >-
      In humans, the same PKD1L1 genotype gives different severity within a
      family.
  - reference: PMID:31026592
    reference_title: >-
      Compound heterozygous Pkd1l1 variants in a family with two fetuses
      affected by heterotaxy and complex Chd.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Features of CHD and other anomalies vary between and within families.
    explanation: >-
      Cardiac and other features vary within PKD1L1 families.
notes: >-
  Curated as a standalone entry rather than a subtype of Visceral_Heterotaxy,
  following Visceral_Heterotaxy_7 and Visceral_Heterotaxy_9: HTX8 has its own
  MONDO term and OMIM number (617205), a single causal gene, and a distinct
  mechanism (loss of a ciliary flow sensor with intact cilia motility) that the
  genetically heterogeneous umbrella entry does not describe. No module in
  kb/modules fits: ciliopathy_dysfunction covers motile cilia beat failure and
  primary cilium signaling disorders, not organizer flow sensing, so no
  conforms_to is declared. A family with PKD1L1-related situs inversus and
  sideroblastic anemia (PMID:30791085) is not curated as a phenotype, because
  only one family is reported and no quotable abstract text was retrieved on
  the fetch made. Heterozygous PKD1L1 variants of uncertain significance
  reported in laterality and BASM cohorts are not treated as disease-causing.
  Variable expressivity is recorded in the inheritance description and the
  discussion rather than as an inheritance term, because HP:0003828 is outside
  the InheritanceTerm enum.
  No GeneReviews chapter covers PKD1L1-related heterotaxy (check-genereviews
  --online returns NO_CHAPTER).
📚

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 (1)

Create: Visceral_Heterotaxy_8 (HTX8, PKD1L1) · 2026-10-21T00:18:11Z · View source

New entry for heterotaxy, visceral, 8, autosomal (MONDO:0014967), curated as a standalone Disease entry following Visceral_Heterotaxy_7 and Visceral_Heterotaxy_9; stub stubs/Heterotaxy_Visceral_8_Autosomal.yaml deleted. One OpenScientist deep-research report was generated (research/Visceral_Heterotaxy_8-deep-research-openscientist.md); its reference validation resolved 17/17 identifiers, with 3 quotes flagged as not found because the report elided text with ellipses (the closest source text matched), and its term validation flagged mislabelled CURIEs (for example HP:0004935 used for visceral heterotaxy; it is Pulmonary artery atresia), none of which were copied. just preflight-dr returned PASS (PKD1L1 mentioned 60 times, OMIM 617205 matches). Report content was used as leads only; every claim was re-sourced from cached PubMed records, chiefly PMID:27616478 (gene discovery), PMID:21307093, PMID:21307098, PMID:27272319, PMID:37413993 and PMID:20080492 (mouse and medaka mechanism), PMID:42630107 (2026 case series and literature review), PMID:35691949, PMID:33655537, PMID:31026592, PMID:32111882, PMID:30664273 and PMID:38460793 (biliary branch, recorded as an EMERGING hypothesis). PMID:30791085 (sideroblastic anemia) cached without abstract text and is not cited. Validation: just validate, validate-terms and count-verified-snippets (79/79) passed; check-genereviews --online returned NO_CHAPTER.

OpenScientist ▸
Visceral Heterotaxy 8 (HTX8) — Comprehensive Disease Characteristics Report
openscientist-autonomous 2026-10-20T23:47:57.179013

Visceral Heterotaxy 8 (HTX8) — Comprehensive Disease Characteristics Report

Disease: Visceral Heterotaxy 8 (HTX8) · MONDO: MONDO:0014967 · Gene: PKD1L1 · Category: Mendelian (autosomal recessive) Report date: 2026-10-20 · Evidence base: human clinical case reports, model-organism genetics, in-vitro/biochemical, and computational/database sources.

Summary answer. Visceral Heterotaxy 8 (HTX8; OMIM #617205) is a rare autosomal-recessive laterality (left–right patterning) disorder caused by biallelic loss-of-function or damaging variants in PKD1L1 (polycystin-1-like 1, chr 7p12.3). PKD1L1 partners with PKD2 (polycystin-2/TRPP2) on motile cilia of the embryonic node/Kupffer's vesicle to sense leftward "nodal flow"; its loss disrupts the earliest left-biased Ca²⁺/Nodal signal, randomizing or bilateralizing organ situs and producing a spectrum from situs inversus totalis to situs ambiguus (heterotaxy) with frequent complex congenital heart disease and splenic anomalies (including asplenia). There is no gene-specific therapy; management is anatomy-driven (cardiac surgery, infection prophylaxis for asplenia), and prognosis is governed mainly by the severity of congenital heart disease.

1. Disease Information

Overview. HTX8 is a Mendelian subtype of visceral heterotaxy — a congenital disorder of left–right (L-R) body-axis determination in which thoracic and abdominal organs are abnormally arranged across the midline. Clinically it ranges from situs inversus totalis (SIT) (complete mirror-image reversal) to situs ambiguus / heterotaxy (discordant, randomized organ positioning), typically with congenital heart disease (CHD). "Disruption of the establishment of left-right (L-R) asymmetry leads to situs anomalies ranging from situs inversus totalis (SIT) to situs ambiguus (heterotaxy)" (PMID 27616478).

Key identifiers. - MONDO: MONDO:0014967 (Visceral heterotaxy 8) - OMIM: #617205 (phenotype, HTX8, autosomal recessive); gene PKD1L1 *609721 - Gene/HGNC: PKD1L1, HGNC:18053; Ensembl ENSG00000158683; NCBI Gene 168507; UniProt Q8TDX9 - Orphanet: broad entry ORPHA:450 (Heterotaxia); no PKD1L1-specific ORPHA code - MeSH: D059446 (Heterotaxy Syndrome) - ICD-10: Q89.3 (Situs inversus); ICD-11: LB01.1 (Situs ambiguous / heterotaxy) - HPO anchor: HP:0004935 (Visceral heterotaxy)

Synonyms / alternative names. Heterotaxy, visceral, 8, autosomal recessive; HTX8; PKD1L1-related heterotaxy/laterality defect; situs ambiguus/situs inversus due to PKD1L1.

Information source type. Derived from aggregated disease-level resources (OMIM, Orphanet, ClinVar, UniProt, gnomAD) combined with individual patient case reports (small families); not from large EHR cohorts.

2. Etiology

Primary cause — genetic. Biallelic (homozygous or compound-heterozygous) pathogenic variants in PKD1L1. Whole-exome sequencing "identified homozygous mutations in PKD1L1 from three affected individuals in two unrelated families" (PMID 27616478). This is a monogenic, recessive developmental disorder; it is not infectious and has no established acquired cause.

Genetic risk factors. - Causal variants: loss-of-function (splice, nonsense) and damaging missense alleles in PKD1L1 (see §4). - Consanguinity is a key risk context — reported probands are homozygous, consistent with autosomal-recessive inheritance and increased in consanguineous or founder settings. - Carrier status: heterozygotes are unaffected (gene is not haploinsufficient; gnomAD pLI≈0).

Environmental risk factors. None established specifically for HTX8. For heterotaxy broadly, maternal pregestational diabetes mellitus is associated with laterality/abdominal-situs phenotypes (PMID 41974186) and is a recognized teratogenic risk factor for L-R defects; this is a disease-level association, not demonstrated for PKD1L1 cases.

Protective factors. None identified (genetic or environmental). A single wild-type PKD1L1 allele is "protective" in the Mendelian sense (carriers are healthy).

Gene–environment interactions. Not specifically characterized for PKD1L1. Laterality determination is a threshold/stochastic developmental process; modifier/background effects are plausible (variable expressivity between SIT and heterotaxy even within families) but unproven.

3. Phenotypes

All manifestations are congenital (prenatal/neonatal onset), structural/physical, lifelong, and non-progressive as malformations (clinical course is driven by complications). Frequencies below are qualitative given the very small reported cohort.

Phenotype Type HPO term Notes / frequency
Visceral heterotaxy / situs ambiguus Physical malformation HP:0004935 Core feature
Situs inversus totalis Physical malformation HP:0001696 Reported (p.Cys1691Ser family)
Complex congenital heart disease Clinical sign/structural HP:0001627 (Abnormal heart morphology) Very frequent; often lethal
Dextrocardia / abnormal cardiac position Physical HP:0001651 Common in situs defects
Atrioventricular septal defect, DORV, TAPVC, transposition Structural HP:0006695 / HP:0011565 etc. Seen across heterotaxy spectrum
Asplenia Physical/laboratory HP:0001746 Reported (p.Gln463*); confers infection risk
Polysplenia / abnormal spleen Physical HP:0001748 / HP:0025059 Part of spectrum
Intestinal malrotation Physical HP:0002566 Common heterotaxy complication
Abnormal inferior vena cava / vascular laterality Structural HP:0005301 Interrupted IVC in left isomerism

Onset: neonatal/congenital (often detected prenatally). Severity: variable — from isolated SIT (potentially mild) to lethal complex CHD. Progression: stable malformation; secondary deterioration from cardiac failure, arrhythmia, or infection. Quality of life: dominated by cardiac disease burden (surgeries, heart failure, arrhythmia) and, in asplenia, lifelong infection vigilance; no disease-specific QoL instruments exist — generic pediatric CHD tools (PedsQL, PROMIS) apply.

4. Genetic / Molecular Information

Causal gene. PKD1L1 (polycystin-1-like 1), HGNC:18053, Ensembl ENSG00000158683, gene OMIM *609721, GRCh38 chr7:47,740,202–47,948,466 (7p12.3), canonical transcript ENST00000289672; protein UniProt Q8TDX9, 2849 aa.

Protein architecture (UniProt Q8TDX9). 11-transmembrane polycystin-1-family receptor with a large extracellular N-terminus (res. 1–1748): two PKD domains (508–590; 592–673), a large REJ (receptor-for-egg-jelly) domain (674–1571), a GAIN-B domain (1587–1735) containing the GPS autoproteolysis motif (1691–1735), and a cytoplasmic PLAT/LH2 domain (1796–1913); ~20 N-glycosylation sites and disulfide bonding.

Reported pathogenic variants (germline). | Variant (cDNA) | Protein | Class | Consequence | Phenotype | PMID | |---|---|---|---|---|---| | c.6473+2_6473+3delTG | splice-donor, intron 42 | Splice-site, LoF | Loss of function | Heterotaxy + complex CHD | 27616478 | | c.5072G>C | p.Cys1691Ser | Missense (GPS motif) | Disrupts GPS disulfide, folding/autoproteolysis | SIT + CHD | 27616478 | | c.1387C>T | p.Gln463* | Nonsense, LoF | Truncation (loss of REJ/TM/channel region) | Heterotaxy + congenital asplenia | 35691949 |

"the p.Cys1691Ser substitution affects a highly conserved cysteine residue and is predicted by molecular modeling to disrupt a disulfide bridge essential for the proper folding of the … (GPS) motif" (PMID 27616478).

Variant classification & frequency. ClinVar lists ~1,417 PKD1L1 variants, the large majority variants of uncertain significance (VUS) (~1,157 VUS vs ~170 pathogenic / ~72 likely pathogenic), reflecting limited functional/segregation data. Pathogenic HTX8 alleles are individually rare/absent in population databases (gnomAD). Origin: germline. Functional consequence: loss of function (recessive); no gain-of-function or dominant-negative mechanism established.

Population constraint (gnomAD). pLI ≈ 0, oe_lof = 0.73 (90% CI 0.66–0.81), missense oe = 0.95, mis_z = 1.35. The gene is not haploinsufficient, consistent with asymptomatic heterozygous carriers and recessive disease.

Modifier genes. None proven. Variable expressivity (SIT vs heterotaxy) suggests modifiers/stochastic effects. In mouse genetics, Pkd1l1 acts as an upstream repressor of Pkd2 (PMID 27272319), so dosage of polycystin-pathway genes is biologically relevant.

Epigenetics / chromosomal abnormalities. No HTX8-specific epigenetic signature reported. HTX8 is caused by point/small variants, not large chromosomal rearrangements; however, CNVs in body-patterning pathways (NODAL/BMP/WNT, e.g., NIPBL, TBX6, FGF12, RBFOX1) contribute to the broader heterotaxy population (PMID 27637763).

5. Environmental Information

  • Environmental factors / toxins / infectious agents: none causal for HTX8 (purely genetic).
  • Lifestyle factors: not applicable to disease causation.
  • Disease-level association: maternal pregestational diabetes correlates with laterality-spectrum phenotypes (PMID 41974186) — relevant to heterotaxy broadly, not to monogenic PKD1L1 cases.
  • Infectious agents: not causal, but secondary infection risk is central in patients with asplenia (see §11/§13).

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. Biallelic PKD1L1 loss-of-function/damaging variant → results in absent or misfolded PKD1L1 protein (truncation; GPS-motif disulfide disruption for p.Cys1691Ser). [demonstrated: human genetics + molecular modeling]
  2. Loss of functional PKD1L1 → prevents assembly of the PKD1L1–PKD2 (polycystin-1-like-1 / polycystin-2) receptor–channel complex on cilia of the embryonic node / Kupffer's vesicle. [demonstrated: co-localization + physical interaction, mouse & medaka]
  3. Motile node cilia still generate normal leftward "nodal flow" (cilia motility is intact) → but the flow cannot be interpreted without the PKD1L1–PKD2 sensor. [demonstrated: normal flow/cilia in mutants]
  4. Flow normally transfers PKD1L1-containing fibrous strands leftward, facilitating a left-dominant intracellular Ca²⁺ elevation at the left node margin (FGFR/Shh-dependent) → in mutants this earliest left-biased signal fails. [demonstrated in mouse; Tanaka 2023]
  5. Failed/symmetric Ca²⁺ signaling → loss of left-restricted repression such that the Nodal–Lefty–Pitx2 cascade is not confined to the left (becomes absent, bilateral, or randomized) in the lateral plate mesoderm. [demonstrated: PKD1L1 restricts Nodal to the left; Pkd1l1 mutant activates Nodal bilaterally]
  6. Loss of asymmetric Pitx2 patterning → randomized/discordant morphogenesis and looping of heart, gut, spleen, lungs and great vessels. [inferred from conserved L-R pathway]
  7. Abnormal situs → situs inversus totalis OR situs ambiguus/heterotaxy with complex CHD, splenic anomalies, intestinal malrotation, vascular laterality defects → clinical disease. [demonstrated: human phenotypes]

Branch point at step 5: depending on whether Nodal is lost, bilateral, or randomized, the organism develops SIT (coordinated reversal), left isomerism (polysplenia), or right isomerism (asplenia) — explaining the phenotypic spectrum, including the asplenia case (PMID 35691949).

Supporting detail by category. - Molecular pathways: Nodal/TGF-β signaling (Nodal–Lefty2–Pitx2), upstream FGFR and Sonic hedgehog (Shh) signaling, calcium signaling. Reactome "Nodal signaling"; KEGG TGF-β pathway. - Protein dysfunction: loss of function via truncation or GPS-domain misfolding; PKD1L1 normally undergoes GPS autoproteolysis and forms a Ca²⁺-permeable channel complex with PKD2/TRPP2. "PKD1L1 is sufficient to mediate a Ca2+ signaling response after flow stimulation … an extracellular PKD domain within PKD1L1 is crucial for PKD1L1 function" (PMID 27272319). - Cellular processes: ciliary mechanosensation/chemosensation and ciliary Ca²⁺ signaling; embryonic L-R symmetry breaking. - Biochemical abnormality: defective ciliary cation (Ca²⁺) channel/receptor complex. - Immune involvement: not primary; functional/anatomic asplenia causes secondary immunodeficiency to encapsulated bacteria. - Metabolic/epigenetic changes: none characteristic.

GO term suggestions: GO:0007368 (determination of left/right symmetry); GO:0003351 (epithelial cilium movement involved in determination of L/R asymmetry); GO:0060287 (epithelial cilium / "nodal cilium"); GO:0060170 (ciliary membrane); GO:0005929 (cilium); GO:0072372 (primary cilium assembly); GO:0005262 (calcium channel activity); GO:0019228/GO:0070588 (Ca²⁺ ion transmembrane transport). Cell Ontology (CL): node/pit cells & crown cells of the embryonic organizer → CL:0000222 (mesodermal cell), ciliated embryonic node cells; CL:0000057 (fibroblast, LPM context). CHEBI: CHEBI:29108 (calcium(2+)).

7. Anatomical Structures Affected

Organ level (primary): heart and great vessels (cardiovascular), spleen (asplenia/polysplenia), stomach/intestine (malrotation), liver (midline/abnormal lobation), lungs (isomerism), inferior vena cava/systemic veins. Body systems: cardiovascular (primary), digestive, respiratory, lymphatic/immune (spleen), hepatobiliary. Secondary involvement: immune deficiency from asplenia; biliary atresia in some left-isomerism heterotaxy; pulmonary consequences of CHD.

Developmental origin (where the defect acts): the embryonic node / Kupffer's vesicle (midline left–right organizer) and lateral plate mesoderm — UBERON:0005725 (ciliated embryonic node) / UBERON:0004341 (node), UBERON:0003081 (lateral plate mesoderm). Resulting organ UBERON terms: UBERON:0000948 (heart), UBERON:0002106 (spleen), UBERON:0000160 (intestine), UBERON:0002048 (lung), UBERON:0001072 (inferior vena cava).

Tissue/cell level: ciliated epithelial cells of the node/KV; lateral-plate mesoderm; cardiac progenitor mesoderm. Subcellular (GO Cellular Component): primary/motile cilium (GO:0005929), ciliary membrane (GO:0060170), plasma membrane.

Localization & lateralization: defect is of body-axis laterality itself — manifestations are intrinsically bilateral/asymmetric/randomized (loss of normal left-right asymmetry; isomerism = loss of sidedness). HPO HP:0001631 etc. for specific cardiac lesions.

8. Temporal Development

  • Onset: congenital; organ situs is specified in early embryogenesis (gastrulation/node stage, ~weeks 3–4 in humans). Frequently diagnosed prenatally by ultrasound/fetal echocardiography (heterotaxy has among the highest prenatal detection rates, ~91% in one series, PMID 42324491).
  • Onset pattern: structural malformation present at birth (not acute/subacute).
  • Progression: the malformation is stable; clinical course is non-progressive as a lesion but complicated by heart failure, arrhythmia (complete heart block), pulmonary venous obstruction, and infection.
  • Critical period: the node/LPM signaling window in early embryogenesis is the only period during which L-R situs can be set — there is no postnatal window to correct the primary patterning defect, only to palliate its consequences.
  • Duration: lifelong (chronic).

9. Inheritance and Population

  • Inheritance: autosomal recessive (biallelic PKD1L1). Heterozygous carriers unaffected.
  • Penetrance/expressivity: biallelic genotypes appear highly penetrant for a laterality phenotype, but expressivity is variable (SIT vs heterotaxy; differing CHD severity, including within the same family).
  • Consanguinity: relevant — reported probands are homozygous; recessive disease risk rises with consanguinity/founder effects.
  • Carrier frequency / founder effects: not precisely established; individual pathogenic alleles are rare; a Chinese nonsense allele (p.Gln463*) was the first reported in that population (PMID 35691949).
  • Anticipation / mitochondrial / germline mosaicism: not applicable / not reported.

Epidemiology. - HTX8 specifically: ultra-rare; only a handful of families reported worldwide — population prevalence unknown. - Heterotaxy / atrial isomerism (parent category): prevalence ~1 in 10,000–20,000 live births, accounting for up to ~4% of all cardiac malformations (PMID 34491249); heterotaxy represents a minority of laterality disorders (e.g., 249 HS among 566 fetal laterality cases over 721,562 deliveries, PMID 42110452). - Sex ratio / geography: no established PKD1L1-specific skew; general heterotaxy shows modest male predominance in some registries. Reported PKD1L1 cases span diverse ancestries (consistent with private recessive alleles).

10. Diagnostics

Imaging (anatomic diagnosis, primary). - Fetal ultrasound + fetal echocardiography — mainstay prenatal detection (very high detection for heterotaxy, PMID 42324491). - Postnatal echocardiography, cardiac CT/MRI/angiography for segmental cardiac/vascular anatomy; abdominal ultrasound/CT for spleen, liver, gut malrotation; upper GI series for malrotation. Laboratory / functional. - Peripheral blood smear for Howell-Jolly bodies → screen for functional asplenia; pitted-RBC counts / spleen scintigraphy to assess splenic function. - ECG/Holter for complete heart block and arrhythmia.

Genetic testing (definitive molecular diagnosis). - Approach: because heterotaxy is highly heterogeneous ("pathogenic genetic lesions are found in less than 20% of HS patients," PMID 35691949), broad testing is preferred: multigene heterotaxy/CHD panels (including PKD1L1, ZIC3, NODAL, CFC1, ACVR2B, LEFTY2, GDF1, MMP21, CCDC11/CFAP53, DNAH5…), whole-exome (WES) or whole-genome sequencing (WGS). WES identified the original PKD1L1 families (PMID 27616478). - Single-gene testing of PKD1L1 is appropriate when a consistent phenotype or family variant is known; confirm biallelic status and parental phase (segregation). - Chromosomal microarray (CMA)/karyotype to exclude CNVs/aneuploidy contributing to heterotaxy (PMID 27637763). - Interpretation caveat: high VUS burden in PKD1L1 — classification benefits from recessive segregation, consanguinity, GPS/LoF functional rationale, and ACMG/AMP criteria.

Clinical criteria / differential diagnosis. No disease-specific criteria; diagnosis = demonstrated situs anomaly + biallelic PKD1L1 variants. Differential: other genetic heterotaxy (X-linked ZIC3 = HTX1; NODAL, CFC1, ACVR2B, GDF1, MMP21, etc.), primary ciliary dyskinesia (PCD) with laterality defects (distinguished by chronic sinopulmonary disease, abnormal ciliary motility/ultrastructure, nasal nitric oxide — features absent in PKD1L1, whose cilia are motile), and syndromic/CNV causes.

Screening. No newborn screening for HTX8; cascade carrier testing of relatives and prenatal/preimplantation genetic testing are options once the familial variants are known.

11. Outcome / Prognosis

  • Prognosis is driven by the cardiac phenotype. In a heterotaxy+CHD cohort (n=197), 5- and 10-year survival ≈71% and ≈68%; left atrial isomerism had better survival than right atrial isomerism; complete heart block (CHB) and ventricular dysfunction predicted fetal demise, and pulmonary venous obstruction + CHB predicted postnatal mortality (PMID 42185088). "CHB and pulmonary venous obstruction remain significant predictors of postnatal mortality…" (PMID 42185088).
  • Infection/asplenia mortality: asplenia confers high risk of overwhelming bacteremia — in a systematic review, "There were 42 documented cases of bacteremia in 32 patients. Approximately, 79% of these had absence of a spleen" (PMID 27425254), mean age ~17 months, with high mortality.
  • Perinatal outcomes (laterality spectrum): major CHD drives termination, surgery and early mortality; live birth ~80%, with infant mortality concentrated in infancy (PMID 41974186).
  • Morbidity: multiple cardiac surgeries, arrhythmia/pacemaker dependence, heart failure, GI morbidity (malrotation/volvulus), feeding/growth problems; lifelong infection risk with asplenia.
  • Prognostic factors: type/severity of CHD, atrial isomerism subtype (RAI worse), CHB, pulmonary venous obstruction, splenic status. No molecular prognostic biomarker specific to PKD1L1.

12. Treatment

No disease-specific or gene-directed therapy exists. Management is symptomatic, anatomy-driven, and multidisciplinary (NCIT terms suggested). - Cardiac surgical/interventional: staged palliation (single-ventricle pathway: Norwood/Glenn/Fontan) or biventricular repair depending on anatomy; repair of AVSD, TAPVC, DORV; pacemaker for complete heart block (NCIT: C157809 Cardiac Surgery; C50106 Pacemaker; C98298 Fontan Procedure). - Gastrointestinal: Ladd procedure for intestinal malrotation/volvulus (NCIT: C157751 surgical procedure). - Asplenia management (critical): vaccination against encapsulated organisms — pneumococcal (PCV + PPSV23), Haemophilus influenzae type b, meningococcal (ACWY + B) — plus antibiotic prophylaxis (e.g., penicillin/amoxicillin) and immediate empiric antibiotics for febrile illness (NCIT: C15346 Vaccination; C154547 Antibiotic Therapy; C15431 Prophylaxis). Patient education and medical-alert measures improve adherence (PMID 32759171; PMID 31937251). - Supportive: heart-failure pharmacotherapy (diuretics e.g. furosemide, afterload reduction, beta-blockade), nutritional support/gastrostomy, arrhythmia management (PMID 41049903 case series). - Advanced/experimental therapeutics: none — no gene therapy, RNA therapy, cell therapy, or targeted/immunotherapy for PKD1L1-heterotaxy (the primary defect is prenatal/developmental and not correctable postnatally). No pharmacogenomic considerations specific to the gene. - Pharmacogenomics / personalized medicine: genotype confirms diagnosis and informs recurrence risk/reproductive counseling rather than drug selection.

13. Prevention

  • Primary prevention: not possible for the genetic lesion. Preconception/prenatal genetic counseling for recessive 25% recurrence risk; carrier screening of partners in known families; PGT/prenatal diagnosis where familial variants are defined. Optimizing maternal glycemic control addresses a disease-level (not PKD1L1-specific) laterality risk factor (PMID 41974186).
  • Secondary prevention: prenatal detection (fetal echo/ultrasound) enabling planned delivery at a cardiac center and early intervention (PMID 42324491); early postnatal spleen-function assessment (Howell-Jolly bodies).
  • Tertiary prevention (prevent complications): the cornerstone — asplenia vaccination + antibiotic prophylaxis to prevent overwhelming post-splenectomy/asplenia sepsis (PMID 27425254; PMID 31937251; PMID 32759171); arrhythmia surveillance/pacing; surgical correction of malrotation before volvulus; endocarditis prophylaxis per cardiac guidelines.
  • Genetic counseling: autosomal-recessive counseling; cascade testing; reproductive options.

14. Other Species / Natural Disease

  • Conservation: PKD1L1's L-R role is highly conserved across vertebrates. Orthologs: mouse Pkd1l1 (NCBI Gene 207225; MGI), medaka pkd1l1 (ZFIN/medaka; the classic L-R mutant abecobe/abc), zebrafish pkd1l1 (ZFIN). Taxa: Mus musculus (NCBI:txid10090), Oryzias latipes (medaka, NCBI:txid8090), Danio rerio (NCBI:txid7955).
  • Natural animal disease / veterinary: no well-characterized naturally occurring PKD1L1 heterotaxy disease in companion animals is documented in OMIA for this gene; situs/laterality anomalies occur sporadically across species but are not established as a PKD1L1 natural disease.
  • Comparative biology: mouse and fish models reproduce the human mechanism (node/KV flow-sensing), making them the key translational systems (see §15). Evolutionary note: the two-cilia/polycystin flow-sensing paradigm is conserved from fish to mammals.
  • Zoonotic potential: not applicable (non-infectious developmental disorder).

15. Model Organisms

Mouse (Mus musculus) — primary mammalian model. - Types: Pkd1l1 knockout (e.g., gene-trap/null line, Vogel 2010, PMID 20080492) and ENU/point mutants (e.g., rks); knock-in reporter KikGR-PKD1L1 for live protein imaging (Tanaka 2023, PMID 37413993). - Phenotype recapitulation (strong): situs inversus/laterality defects; "both mutants fail to activate asymmetric gene expression at the node or in the lateral plate and exhibit right isomerism of the lungs" (PMID 21307093). Node morphology and cilia motility normal → defect is in flow interpretation, matching human mechanism. - Key insight: "the absence of respiratory tract lesions, hydrocephalus, and male infertility in Pkd1l1(-/-) mice … suggested that dysfunction of motile cilia was not involved" (PMID 20080492) — distinguishes HTX8 from PCD. - Limitation: high perinatal lethality of nulls; models the developmental patterning defect but not the postnatal human CHD surgical course.

Medaka (Oryzias latipes). The L-R mutant abecobe (abc) = pkd1l1: "abecobe (abc) is defective for left-right asymmetric expression of southpaw, lefty and charon, but not for nodal flow" (PMID 21307098); PKD1L1 required in Kupffer's vesicle and colocalizes/interacts with Pkd2 on motile KV cilia.

Zebrafish (Danio rerio). pkd1l1 expressed in KV; morpholino/mutant studies implicate polycystin signaling in L-R patterning (Kupffer's vesicle = node equivalent).

In-vitro / cellular. Cultured cells supplied artificial flow show PKD1L1 is "sufficient to mediate a Ca2+ signaling response after flow stimulation" (PMID 27272319); heterologous PKD1L1–PKD2 complexes used for biochemistry/channel studies.

Applications: dissecting node/KV flow sensing, polycystin complex assembly, Nodal cascade restriction, Ca²⁺ signaling, and variant functional testing. Resources: MGI, IMPC, ZFIN, Alliance of Genome Resources.

Supported vs. Refuted Hypotheses

Supported. 1. HTX8 is autosomal-recessive, caused by biallelic PKD1L1 LoF/damaging variants (PMID 27616478, 35691949). 2. PKD1L1–PKD2 ciliary complex is the nodal-flow sensor restricting Nodal to the left (PMID 21307093, 21307098, 27272319, 37413993). 3. The pathology is a flow-interpretation (sensory) defect, not a ciliary-motility defect → mechanistically distinct from PCD (PMID 20080492). 4. Prognosis is governed by CHD severity and asplenia-related infection risk (PMID 42185088, 27425254).

Refuted / not supported. - PKD1L1 is not a dominant/haploinsufficient disease gene (gnomAD pLI≈0; carriers healthy). - HTX8 is not driven by motile-cilia dysfunction (no PCD airway/hydrocephalus phenotype in nulls). - No evidence for gain-of-function, somatic, infectious, or acquired/environmental primary causation.

Limitations and Future Directions

  • Very small human evidence base (few families); PKD1L1-specific prevalence, penetrance, sex ratio, and natural history are not quantified — most clinical figures derive from the broader heterotaxy category.
  • High VUS burden limits molecular diagnosis; functional assays (flow-induced Ca²⁺, GPS autoproteolysis, PKD1L1–PKD2 trafficking) are needed to reclassify variants.
  • No structural model of the human PKD1L1–PKD2 complex at the variant level; cryo-EM would clarify GPS/PKD-domain variant effects.
  • No targeted therapy; research should define modifier genes, improve prenatal risk stratification, and standardize asplenia prophylaxis in this population.

Key references (PMIDs)

27616478 (Vetrini 2016, human biallelic PKD1L1); 35691949 (Gu 2022, nonsense + asplenia); 21307093 (Field 2011, mouse); 21307098 (Kamura 2011, medaka); 27272319 (Grimes 2016, epistasis/Ca²⁺); 37413993 (Tanaka 2023, flow transfers polycystin); 20080492 (Vogel 2010, Pkd1l1−/− mouse); 24756726 (TRPP/polycystin review); 42185088 (heterotaxy+CHD outcomes); 27425254 (bacteremia in heterotaxy); 34491249 (isomerism epidemiology); 42324491 (prenatal detection); 41974186 (laterality spectrum outcomes/PDM); 27637763 (heterotaxy CNVs); 38884744 (human genetics of situs); 32759171 / 31937251 (asplenia prophylaxis).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 17
Resolved 17
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 10
Quoted claims found in source 7
Quoted claims not found in source 3
References weighed for topical relevance 17
On topic 10
Off topic 0

Quotes not found in the cited source

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

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

  • PMID:27616478: "the p.Cys1691Ser substitution affects a highly conserved cysteine residue and is predicted by molecular modeling to disrupt a disulfide bridge essential for the proper folding of the … (GPS) motif"
  • closest text in source: "The p.Cys1691Ser substitution affects a highly conserved cysteine residue and is predicted by molecular modeling to disrupt a disulfide bridge essential for the proper folding of the G protein-coupled receptor proteolytic site (GPS) motif"
  • PMID:27272319: "PKD1L1 is sufficient to mediate a Ca2+ signaling response after flow stimulation … an extracellular PKD domain within PKD1L1 is crucial for PKD1L1 function"
  • closest text in source: "Finally, we show that an extracellular PKD domain within PKD1L1 is crucial for PKD1L1 function; as such, destabilizing the domain causes L-R defects in the mouse"
  • PMID:20080492 (abstract only): "the absence of respiratory tract lesions, hydrocephalus, and male infertility in Pkd1l1(-/-) mice … suggested that dysfunction of motile cilia was not involved"
  • closest text in source: "In contrast, the absence of respiratory tract lesions, hydrocephalus, and male infertility in Pkd1l1(-/-) mice (for: polycystic kidney disease 1 like 1) suggested that dysfunction of motile cilia was not involved in the development of SI in this line"

Term Validation

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

Outcome Count
Terms checked 35
Resolved 32
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 2
Terms whose name was checked 26
Terms named correctly 12
Terms named as a different term 10
Terms whose name is worth a second look 4

Terms the report names something else

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

  • HP:0004935 (2 mentions) - the report calls it "Visceral heterotaxy", "Physical malformation"; HP calls it Pulmonary artery atresia
  • HP:0001696 (1 mention) - the report calls it "Physical malformation"; HP calls it Situs inversus totalis
  • HP:0001651 (1 mention) - the report calls it "Physical"; HP calls it Dextrocardia
  • HP:0001746 (1 mention) - the report calls it "Physical/laboratory"; HP calls it Asplenia
  • HP:0002566 (1 mention) - the report calls it "Physical"; HP calls it Intestinal malrotation
  • HP:0005301 (1 mention) - the report calls it "Structural"; HP calls it Persistent left superior vena cava
  • GO:0060287 (1 mention) - the report calls it "epithelial cilium / "nodal cilium"; GO calls it epithelial cilium movement involved in determination of left/right asymmetry
  • GO:0072372 (1 mention) - the report calls it "primary cilium assembly"; GO calls it GO_0072372
  • UBERON:0005725 (1 mention) - the report calls it "ciliated embryonic node"; UBERON calls it olfactory system
  • UBERON:0004341 (1 mention) - the report calls it "node"; UBERON calls it primitive streak

Obsolete terms

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

  • GO:0072372 (GO_0072372) (1 mention) - replaced by GO:0005929

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:

  • MONDO:0014967 (2 mentions) - the report calls it "Visceral heterotaxy 8"; MONDO calls it heterotaxy, visceral, 8, autosomal, and lists "PKD1L1 visceral heterotaxy" among its other names
  • GO:0003351 (1 mention) - the report calls it "epithelial cilium movement involved in determination of L/R asymmetry"; GO calls it epithelial cilium movement involved in extracellular fluid movement
  • GO:0070588 (1 mention) - the report calls it "Ca²⁺ ion transmembrane transport"; GO calls it calcium ion transmembrane transport
  • CL:0000057 (1 mention) - the report calls it "fibroblast, LPM context"; CL calls it fibroblast

Terms named inconsistently

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

  • HP:0004935 - called "Visceral heterotaxy", "Physical malformation"

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: ORPHA.