Renal-Hepatic-Pancreatic Dysplasia 2

Mendelian MONDO:0014174 Pathograph 31 Show in embeddings browser Ciliopathy Cystic Kidney Disease Genetic Kidney Disease

Renal-hepatic-pancreatic dysplasia 2 (RHPD2) is an autosomal recessive ciliopathy caused by biallelic NEK8 variants. NEK8 is a NIMA-related serine/threonine kinase of the ciliary inversin compartment. The disease was first described in fetuses carrying a homozygous NEK8 nonsense variant, with enlarged cystic kidneys, liver and pancreas and developmental heart disease (an Ivemark II-like picture). Later reports added renal hypodysplasia, situs inversus, cardiomegaly with septal hypertrophy, bile duct paucity, narrow thorax and short bowed femurs. Most reported patients die before or around birth or in the first year of life. A minority survive into childhood with progressive kidney and liver failure.

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Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected individuals carry biallelic NEK8 variants, homozygous in consanguineous families or compound heterozygous.
Autosomal recessive inheritance
Show evidence (3 references)
CGGV:assertion_6888a91a-6589-42a9-9622-553b4918bed6-2021-09-08T160000.000Z SUPPORT Other
"In summary, NEK8 is definitively associated with autosomal recessive renal-hepatic-pancreatic dysplasia 2."
ClinGen classifies the NEK8-RHPD2 relationship under autosomal recessive inheritance.
PMID:23418306 SUPPORT Human clinical
"Our starting point was a consanguineous pedigree with three affected fetuses"
The index family was consanguineous with three affected sibling fetuses, consistent with recessive transmission of a homozygous allele.
PMID:26697755 SUPPORT Human clinical
"Exome sequencing demonstrated compound heterozygous mutations in the NEK8 gene"
Affected brothers carried two different NEK8 alleles, consistent with recessive inheritance.
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Pathophysiology

10
Biallelic NEK8 Loss of Function
Biallelic NEK8 variants remove or impair the NEK8 kinase. In the index family the homozygous nonsense allele abolished NEK8 expression through nonsense-mediated decay.
NEK8 hgnc:13387 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NEK8 (hgnc:13387). hgnc:13387 is a gene from the HUGO Gene Nomenclature Committee.
protein serine/threonine kinase activity GO:0004674 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased protein serine/threonine kinase activity (GO:0004674). GO:0004674 is a molecular function from the Gene Ontology.
Downstream
Inversin Compartment NEK8 Kinase Signaling Failure Loss of NEK8 removes the kinase activated within the ciliary inversin compartment.
Show evidence (2 references)
PMID:23418306 SUPPORT Human clinical
"This work confirmed a complete loss of NEK8 expression in the affected fetuses due to nonsense-mediated decay."
The index allele is a null allele in affected fetuses.
CGGV:assertion_6888a91a-6589-42a9-9622-553b4918bed6-2021-09-08T160000.000Z SUPPORT Other
"The mechanism of pathogenicity is biallelic loss of function."
ClinGen states biallelic loss of function as the mechanism.
Inversin Compartment NEK8 Kinase Signaling Failure
NEK8 sits in the ciliary inversin compartment in a module with ANKS6, INVS and NPHP3. In mice, loss of NEK8 kinase activation within the compartment gives heterotaxy, cardiopulmonary malformation and cystic kidneys. The evidence for this node is from mouse models and cell systems, not from patient tissue.
NEK8 hgnc:13387 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NEK8 (hgnc:13387). hgnc:13387 is a gene from the HUGO Gene Nomenclature Committee.
protein serine/threonine kinase activity GO:0004674 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased protein serine/threonine kinase activity (GO:0004674). GO:0004674 is a molecular function from the Gene Ontology.
ciliary inversin compartment GO:0097543 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves ciliary inversin compartment (GO:0097543). GO:0097543 is a cellular component from the Gene Ontology.
Downstream
Hippo Pathway YAP/TAZ Dysregulation NEK8 binds TAZ and promotes its nuclear delivery; NEK8 variants disturb YAP regulation.
Reduced Polycystin Gene Expression and c-MYC Upregulation Patient fibroblasts lacking NEK8 show reduced PKD1/PKD2 and raised c-MYC expression; how NEK8 loss produces this is not established.
Defective Nodal Left-Right Patterning NEK8 loss perturbs nodal ciliary signaling in mouse embryos.
Congenital Cardiac Malformation NEK8 kinase activation is required for cardiopulmonary development in mice; the steps between the kinase and the heart defect are not defined.
Replication Stress and DNA Damage NEK8 limits S-phase CDK activity in the ATR replication stress response.
Show evidence (2 references)
PMID:25599650 SUPPORT Model organism
"Together, these data reveal the crucial role of NEK8 kinase activation within the IC, promoting proper left-right patterning, cardiopulmonary development and renal morphogenesis."
Mouse Nek8 kinase-dead and Anks6 mutants show that NEK8 kinase activation in the inversin compartment is needed for laterality, heart and lung development and kidney morphogenesis.
PMID:23793029 SUPPORT In vitro / ex vivo
"Here we identify ANKS6 as a new NPHP family member that connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3."
Places NEK8 in the ANKS6-INVS-NPHP3 module.
Hippo Pathway YAP/TAZ Dysregulation
NEK8 binds the Hippo effector TAZ and drives nuclear delivery of the TAZ/NEK8 complex. Patient NEK8 variants alter YAP regulation and YAP target gene expression in patient fibroblasts and renal cells; YAP imbalance is also seen in Nek8-invalidated renal spheroids and in cystic jck mouse kidneys. The YAP inhibitor verteporfin partly rescued spheroid and zebrafish defects. Missense and null alleles affect YAP differently.
NEK8 hgnc:13387 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NEK8 (hgnc:13387). hgnc:13387 is a gene from the HUGO Gene Nomenclature Committee.
hippo signaling GO:0035329 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated hippo signaling (GO:0035329). GO:0035329 is a biological process from the Gene Ontology.
Animal models
jck mouse Mouse partially recapitulates Cystic jck kidneys show nuclear YAP accumulation.
Downstream
Renal Cystic Dysplasia Grampa et al. attribute the organ developmental defects to altered ciliogenesis and cell differentiation/proliferation through Hippo pathway deregulation.
Hepatobiliary Ductal Plate Malformation and Fibrosis Grampa et al. extend the Hippo deregulation model to the major organ developmental defects; the hepatobiliary link is inferred from the shared mechanism rather than shown in liver tissue.
Pancreatic Cystic Dysplasia and Fibrosis As for the liver, the pancreatic link is inferred from the shared Hippo-deregulation model rather than shown in pancreatic tissue.
Show evidence (4 references)
PMID:23026745 SUPPORT In vitro / ex vivo
"NPHP9, which is also called NEK8, directly interacted with TAZ and induced nuclear translocation of the TAZ/NPHP9 protein complex."
Cell-based evidence that NEK8 regulates the Hippo effector TAZ.
PMID:23418306 SUPPORT In vitro / ex vivo
"Both proteins interact and activate the Hippo effector TAZ."
NEK8 and NPHP3 interact and activate TAZ.
PMID:26967905 SUPPORT In vitro / ex vivo
"We also showed that NEK8 missense and loss-of-function mutations differentially affect the regulation of the main Hippo signaling effector, YAP, as well as the expression of its target genes in patient fibroblasts and renal cells."
Patient-derived and renal cell data showing YAP dysregulation by RHPD2 alleles.
+ 1 more reference
Reduced Polycystin Gene Expression and c-MYC Upregulation
Fibroblasts from NEK8-null fetuses show decreased PKD1 and PKD2 expression and increased c-MYC expression, which the authors offer as potential explanations for the renal phenotype. NEK8-depleted collecting duct cells also respond poorly to fluid shear, as cells lacking polycystin-2 do.
NEK8 hgnc:13387 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NEK8 (hgnc:13387). hgnc:13387 is a gene from the HUGO Gene Nomenclature Committee.
cellular response to fluid shear stress 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 (GO:0071498). GO:0071498 is a biological process from the Gene Ontology.
Downstream
Renal Cystic Dysplasia The authors propose reduced polycystin expression and raised c-MYC as potential contributors to the renal phenotype.
Show evidence (2 references)
PMID:23418306 SUPPORT In vitro / ex vivo
"In cultured fibroblasts derived from these fetuses, the expression of prominent polycystic kidney disease genes (PKD1 and PKD2) was decreased, whereas the oncogene c-MYC was upregulated, providing potential explanations for the observed renal phenotype."
Patient-derived fibroblasts lacking NEK8 show reduced PKD1/PKD2 and increased c-MYC.
PMID:23274954 SUPPORT In vitro / ex vivo
"NEK8-depleted inner medullary collecting duct cells exhibited a defective response to fluid shear, suggesting that NEK8 may play a role in mediating PC2-dependent signaling."
Cell-based evidence linking NEK8 to polycystin-2-dependent flow signaling.
Replication Stress and DNA Damage
NEK8 acts in the ATR-mediated replication stress response by limiting cyclin A-associated CDK activity. Cells lacking NEK8 accumulate DNA double-strand breaks, and Nek8 mutant mouse kidneys accumulate DNA damage. This branch is shown in cells and mice; its contribution to human RHPD2 has not been tested.
NEK8 hgnc:13387 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NEK8 (hgnc:13387). hgnc:13387 is a gene from the HUGO Gene Nomenclature Committee.
DNA damage response GO:0006974 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated DNA damage response (GO:0006974). GO:0006974 is a biological process from the Gene Ontology.
Downstream
Renal Cystic Dysplasia Loss of NEK8 or replication stress disrupts renal cell architecture in 3D culture; whether this contributes to human renal dysplasia is unknown.
Show evidence (2 references)
PMID:23973373 SUPPORT In vitro / ex vivo
"Cells lacking NEK8 form spontaneous DNA double-strand breaks (DSBs) that further accumulate when replication forks stall"
Cell-based evidence that NEK8 loss causes DNA damage under replication stress.
PMID:23973373 SUPPORT Model organism
"Moreover, kidneys of NEK8 mutant mice accumulate DNA damage"
In vivo DNA damage in Nek8 mutant mouse kidneys.
Defective Nodal Left-Right Patterning
Nek8-null mouse embryos form cilia but misexpress left-sided marker genes early in development, indicating perturbed nodal ciliary signaling, and show randomized left-right asymmetry. Zebrafish knockdown randomizes heart looping.
determination of left/right symmetry GO:0007368 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased determination of left/right symmetry (GO:0007368). GO:0007368 is a biological process from the Gene Ontology.
Animal models
Nek8-null mouse Mouse recapitulates Reproduces the laterality and cardiac features of RHPD2.
Downstream
Situs inversus Defective left-right patterning produces situs inversus.
Asplenia Asplenia is a laterality-associated anomaly; its derivation from the nodal defect in RHPD2 is inferred, not shown.
Show evidence (2 references)
PMID:23274954 SUPPORT Model organism
"Ciliogenesis was intact in Nek8-deficient embryos and cells, but we observed misexpression of left-sided marker genes early in development, suggesting that nodal ciliary signaling was perturbed."
Mouse evidence for a nodal signaling defect with intact ciliogenesis.
PMID:23274954 SUPPORT Model organism
"homozygous mutant mice die at birth and exhibit randomization of left-right asymmetry, cardiac anomalies, and glomerular kidney cysts"
Nek8-null mice have randomized left-right asymmetry.
Congenital Cardiac Malformation
Patients have cardiomegaly, ventricular septal hyperplasia or hypertrophic cardiomyopathy, ventricular septal defect and patent ductus arteriosus. Nek8-null and Nek8 kinase-dead mice have cardiac anomalies.
heart development GO:0007507 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased heart development (GO:0007507). GO:0007507 is a biological process from the Gene Ontology.
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cardiomegaly Structural heart disease presents with cardiomegaly.
Ventricular septal hypertrophy Septal hyperplasia is the recurrent cardiac lesion in the Grampa series.
Ventricular septal defect Septal defects are reported in RHPD2 fetuses.
Show evidence (2 references)
PMID:23418306 SUPPORT Human clinical
"enlarged cystic kidneys, liver and pancreas and developmental heart disease"
Developmental heart disease in the index fetuses.
PMID:25599650 SUPPORT Model organism
"Both display heterotaxy, cardiopulmonary malformations and cystic kidneys"
Nek8 kinase-dead and Anks6 mutant mice have cardiopulmonary malformations.
Renal Cystic Dysplasia
The kidneys show cystic dysplasia with incomplete corticomedullary differentiation, primitive tubules, metaplastic cartilage and diffuse interstitial fibrosis. Nonsense genotypes give enlarged multicystic kidneys; missense genotypes give asymmetric hypodysplasia with one kidney absent or very small. This specializes the ciliopathy module's cystic kidney arm to a developmental dysplasia rather than the later tubulointerstitial degeneration of nephronophthisis.
kidney epithelial cell CL:0002518 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves kidney epithelial cell (CL:0002518). CL:0002518 is a cell type from the Cell Ontology.
kidney development GO:0001822 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased kidney development (GO:0001822). GO:0001822 is a biological process from the Gene Ontology.
kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cystic renal dysplasia The tissue lesion is the clinical finding.
Enlarged kidney Nonsense genotypes give enlarged cystic kidneys.
Renal hypoplasia Missense genotypes give hypodysplasia.
Renal interstitial fibrosis Dysplastic kidneys show diffuse interstitial fibrosis.
Anhydramnios Bilateral renal dysplasia reduces fetal urine output and so amniotic fluid. That intermediate is general fetal physiology and was not measured in these reports.
Stage 5 chronic kidney disease Survivors progress to end-stage kidney disease.
Show evidence (2 references)
PMID:26967905 SUPPORT Human clinical
"Patients/fetus from families 1, 2 and 3 shared developmental abnormalities including asymmetric renal hypodysplasia with one absent or extremely reduced in size kidney and the other one with major dysplasia, diffuse interstitial fibrosis and incomplete cortico-medullary differentiation"
Renal histopathology in NEK8 patients.
PMID:26967905 SUPPORT Human clinical
"In contrast, the fetuses from families 4 and 5 exhibited enlarged multicystic kidneys, cystic pancreas and liver"
Enlarged multicystic kidneys in the fetuses with more severe alleles.
Hepatobiliary Ductal Plate Malformation and Fibrosis
The liver shows ductal plate anomalies with cystic biliary fibroadenomatosis, hepatic cysts, portal fibrosis with ductular proliferation, and in other patients paucity or hypoplasia of the bile ducts with cholestasis.
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.
liver development GO:0001889 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased liver development (GO:0001889). GO:0001889 is a biological process from the Gene Ontology.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hepatic cysts Ductal plate malformation gives hepatic cysts.
Malformation of the hepatic ductal plate The lesion itself.
Hepatic fibrosis Portal fibrosis accompanies the ductal lesion.
Reduced number of intrahepatic bile ducts Bile duct paucity or hypoplasia is the alternative hepatobiliary lesion.
Cholestasis Bile duct paucity impairs bile flow.
Show evidence (3 references)
PMID:26967905 SUPPORT Human clinical
"Ductal plate anomalies with cystic biliary fibroadenomatosis"
Liver finding in family 5 (Table 1).
PMID:26967905 SUPPORT Human clinical
"presents with massive portal fibrosis with ductular proliferation"
Liver histology in individual F1 II.1.
PMID:26697755 SUPPORT Human clinical
"we observed bile duct hypoplasia rather than ductal plate malformation"
Shows the hepatobiliary lesion varies between families, from ductal plate malformation to bile duct hypoplasia.
Pancreatic Cystic Dysplasia and Fibrosis
The pancreas is enlarged with cysts and shows massive diffuse fibrosis with dissociation of the parenchyma; one fetus had a short pancreas. A pancreatic phenotype is not seen in every family.
pancreatic ductal cell CL:0002079 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pancreatic ductal cell (CL:0002079). CL:0002079 is a cell type from the Cell Ontology.
pancreas development GO:0031016 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased pancreas development (GO:0031016). GO:0031016 is a biological process from the Gene Ontology.
pancreas UBERON:0001264 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pancreas (UBERON:0001264). UBERON:0001264 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Pancreatic cysts The dysplastic pancreas is cystic.
Pancreatic fibrosis The dysplastic pancreas is fibrotic.
Show evidence (2 references)
PMID:26967905 SUPPORT Human clinical
"Higher magnification reveals a massive and diffuse fibrosis with dissociation of the pancreatic parenchyma"
Pancreatic histology in an affected individual.
PMID:26697755 SUPPORT Human clinical
"a pancreatic phenotype was not observed in the individuals reported here"
Pancreatic involvement is variable; absent in the Rajagopalan brothers.
⬡

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 Renal-Hepatic-Pancreatic Dysplasia 2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

22
Cardiovascular 5
Situs inversus Situs inversus totalis HP:0001696 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Situs inversus, annotated with Situs inversus totalis (HP:0001696), qualified as embryonal onset. HP:0001696 is a phenotype from the Human Phenotype Ontology.
Onset: EMBRYONAL
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"All five cases presented with kidney involvement associated with extra-renal defects including situs inversus (4 cases)"
Situs inversus in four of five NEK8 cases.
Asplenia HP:0001746 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asplenia (HP:0001746), qualified as embryonal onset. HP:0001746 is a phenotype from the Human Phenotype Ontology.
Onset: EMBRYONAL
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"presented with short pancreas and asplenia in addition to the defects listed above"
Asplenia in the family 3 fetus.
Cardiomegaly HP:0001640 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomegaly (HP:0001640). HP:0001640 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"All five cases presented with kidney involvement associated with extra-renal defects including situs inversus (4 cases), cardiomegaly (3 cases)"
Cardiomegaly in three of five cases.
Ventricular septal hypertrophy HP:0005144 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular septal hypertrophy (HP:0005144). HP:0005144 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"cardiac septal hyperplasia and liver alterations including paucity of bile ducts"
Septal hyperplasia shared by families 1-3.
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), qualified as embryonal onset. HP:0001629 is a phenotype from the Human Phenotype Ontology.
Onset: EMBRYONAL
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"Cardiomegaly with intraventricular communication | Paucity of bile ducts | Short and fibrotic"
Ventricular septal defect in family 3 (Table 1).
Digestive 7
Hepatic cysts HP:0001407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatic cysts (HP:0001407), qualified as fetal onset. HP:0001407 is a phenotype from the Human Phenotype Ontology.
Onset: FETAL
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"In contrast, the fetuses from families 4 and 5 exhibited enlarged multicystic kidneys, cystic pancreas and liver"
Cystic liver in families 4 and 5.
Malformation of the hepatic ductal plate HP:0006563 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ductal plate malformation, annotated with Malformation of the hepatic ductal plate (HP:0006563), qualified as fetal onset. HP:0006563 is a phenotype from the Human Phenotype Ontology.
Onset: FETAL
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"Ductal plate anomalies with cystic biliary fibroadenomatosis"
Ductal plate malformation in the family 5 fetus (Table 1).
Hepatic fibrosis HP:0001395 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatic fibrosis (HP:0001395). HP:0001395 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"presents with massive portal fibrosis with ductular proliferation"
Hepatic fibrosis on liver histology.
Reduced number of intrahepatic bile ducts HP:0006571 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Paucity of bile ducts, annotated with Reduced number of intrahepatic bile ducts (HP:0006571). HP:0006571 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26967905 SUPPORT Human clinical
"situs inversus (4 cases), cardiomegaly (3 cases), paucity of bile ducts (3 cases), pancreas defects (3 cases)"
Bile duct paucity in three of five cases.
PMID:26697755 SUPPORT Human clinical
"we observed bile duct hypoplasia rather than ductal plate malformation"
Bile duct hypoplasia in the Rajagopalan brothers.
Cholestasis HP:0001396 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cholestasis (HP:0001396), qualified as neonatal onset. HP:0001396 is a phenotype from the Human Phenotype Ontology.
Onset: NEONATAL
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"Hepatomegaly, cholestasis, paucity of bile ducts and fibrosis"
Liver phenotype of patient F1 (Table 1).
Pancreatic cysts HP:0001737 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pancreatic cysts (HP:0001737), qualified as fetal onset. HP:0001737 is a phenotype from the Human Phenotype Ontology.
Onset: FETAL
Show evidence (1 reference)
PMID:23418306 SUPPORT Human clinical
"three affected fetuses showing an early embryonic phenotype with enlarged cystic kidneys, liver and pancreas"
Cystic pancreas in the index fetuses.
Pancreatic fibrosis HP:0100732 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pancreatic fibrosis (HP:0100732). HP:0100732 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"Higher magnification reveals a massive and diffuse fibrosis with dissociation of the pancreatic parenchyma"
Pancreatic fibrosis on histology.
Genitourinary 5
Cystic renal dysplasia HP:0000800 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cystic renal dysplasia (HP:0000800), qualified as fetal onset. HP:0000800 is a phenotype from the Human Phenotype Ontology.
Onset: FETAL
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"NEK8/NPHP9 mutations were identified in five cases with severe overlapping phenotypes including renal cystic dysplasia/hypodysplasia, situs inversus, cardiopathy with hypertrophic septum and bile duct paucity."
Renal cystic dysplasia in the five NEK8 cases.
Enlarged kidney HP:0000105 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Enlarged cystic kidneys, annotated with Enlarged kidney (HP:0000105), qualified as fetal onset. HP:0000105 is a phenotype from the Human Phenotype Ontology.
Onset: FETAL
Show evidence (1 reference)
PMID:23418306 SUPPORT Human clinical
"three affected fetuses showing an early embryonic phenotype with enlarged cystic kidneys, liver and pancreas"
Enlarged cystic kidneys in the index fetuses.
Renal hypoplasia HP:0000089 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal hypodysplasia, annotated with Renal hypoplasia (HP:0000089), qualified as fetal onset. HP:0000089 is a phenotype from the Human Phenotype Ontology.
Onset: FETAL
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"asymmetric renal hypodysplasia with one absent or extremely reduced in size kidney"
Renal hypodysplasia in families 1-3.
Renal interstitial fibrosis HP:0032948 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal interstitial fibrosis (HP:0032948). HP:0032948 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"the other one with major dysplasia, diffuse interstitial fibrosis and incomplete cortico-medullary differentiation"
Renal interstitial fibrosis on histology.
Stage 5 chronic kidney disease HP:0003774 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is End-stage renal disease, annotated with Stage 5 chronic kidney disease (HP:0003774). HP:0003774 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36756677 SUPPORT Human clinical
"one case died at 5 years secondary to renal failure, the other at 30 months secondary to liver and kidney failure"
Kidney failure in survivors past the first year.
Limbs 1
Femoral bowing HP:0002980 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short bowed femurs, annotated with Femoral bowing (HP:0002980). HP:0002980 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"narrow thorax and short bowed femurs (2 cases)"
Short bowed femurs in two cases.
Musculoskeletal 1
Narrow chest HP:0000774 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Narrow thorax, annotated with Narrow chest (HP:0000774). HP:0000774 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"narrow thorax and short bowed femurs (2 cases)"
Narrow thorax in two cases.
Nervous System 2
Agenesis of corpus callosum HP:0001274 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agenesis of corpus callosum (HP:0001274). HP:0001274 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"brain defects such as corpus callosum or vermis agenesis (2 cases)"
Corpus callosum agenesis among the brain defects reported.
Aplasia/Hypoplasia of the cerebellar vermis HP:0006817 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agenesis of the cerebellar vermis, annotated with Aplasia/Hypoplasia of the cerebellar vermis (HP:0006817). HP:0006817 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"the fetuses from families 4 and 5 exhibited enlarged multicystic kidneys, cystic pancreas and liver, and agenesis of the vermis (fetus 4)"
Vermis agenesis in fetus 4.
Prenatal and Birth 1
Anhydramnios HP:0025700 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anhydramnios (HP:0025700), qualified as fetal onset. HP:0025700 is a phenotype from the Human Phenotype Ontology.
Onset: FETAL
Show evidence (1 reference)
PMID:26967905 SUPPORT Human clinical
"Facial dysmorphism, arthrogryposis (anamnios), neurological examination ND"
Table 1 records anamnios in the family 5 fetus.
🧬

Genetic Associations

1
NEK8
Gene: NEK8 hgnc:13387 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NEK8 (hgnc:13387). hgnc:13387 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
PMID:23418306 SUPPORT Human clinical
"we mapped the disease locus to chromosome 17q11 and identified a homozygous nonsense mutation in NEK8/NPHP9"
First report linking a biallelic NEK8 null allele to the renal-hepatic-pancreatic dysplasia phenotype.
PMID:26967905 SUPPORT Human clinical
"These cases highlight a genotype-phenotype correlation, with missense and nonsense mutations associated with hypodysplasia and enlarged cystic organs, respectively."
Independent cases with NEK8 variants and the reported allele-class correlation.
PMID:26697755 SUPPORT Human clinical
"The mutations included a c.2069_2070insC variant (p.Ter693LeufsTer86), and a c.1043C>T variant (p.Thr348Met) in the highly conserved RCC1 (Regulation of Chromosome Condensation 1) domain."
Compound heterozygous NEK8 genotype in a third family with multiorgan disease.
+ 1 more reference
💊

Medical Actions

1
Organ Transplantation
Action: Organ TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Organ Transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. NCIT:C15289
Platform: Surgery
No disease-specific therapy exists. Two published patients underwent transplantation, one with long-term survival.
Show evidence (1 reference)
PMID:36756677 SUPPORT Human clinical
"Two cases have had transplantation with one resulting in long-term survival."
Transplantation outcomes in RHPD2.
📈

Progression

2
Prenatal and first year
Age: Fetal to 1 year
Most reported patients die in pregnancy, including terminations, or within the first year; 13 of 17 published patients died in this window.
Show evidence (1 reference)
PMID:36756677 SUPPORT Human clinical
"With now examining the 17 known patients in the literature, 13 died within the perinatal period-pregnancy to one year of life."
Perinatal mortality in the published series.
Childhood survival
Age: After 1 year
Of four patients surviving past one year, two died of renal or combined liver and kidney failure at 5 years and 30 months, and two were alive at 1 and 13 years.
Show evidence (1 reference)
PMID:36756677 SUPPORT Human clinical
"Two are currently alive and well at one year and 13 years."
Long-term survivors exist.
📊

Prevalence

1
Worldwide published cases
Cases/families reported in the literature Ultra-rare
A 2023 literature review counted 17 known patients. This is a published case count, not a population prevalence; no rate is available.
Show evidence (1 reference)
PMID:36756677 SUPPORT Human clinical
"With now examining the 17 known patients in the literature, 13 died within the perinatal period-pregnancy to one year of life."
Literature case count for RHPD2.
🐁

Animal Models

2
Nek8-null mouse
Homozygous Nek8-null mice die at birth with randomized left-right asymmetry, cardiac anomalies and glomerular kidney cysts.
Species
Mouse
Genotype
Nek8 targeted null allele, homozygous
Publication
PMID:23274954
Pathograph links
Defective Nodal Left-Right Patterning recapitulates fidelity: moderate Reproduces the laterality and cardiac features of RHPD2.
Limitations: Kidney involvement is glomerular cysts at birth rather than the enlarged cystic dysplasia of human fetuses; liver and pancreatic lesions are not described in the abstract.
Show evidence (1 reference)
PMID:23274954 SUPPORT Model organism
"homozygous mutant mice die at birth and exhibit randomization of left-right asymmetry, cardiac anomalies, and glomerular kidney cysts"
Phenotype of the null mouse.
jck mouse
Spontaneous recessive juvenile cystic kidney mutant carrying a Nek8 missense variant in the RCC1 domain.
Species
Mouse
Genotype
Nek8 G448V (jck) homozygous
Publication
PMID:12421721
Pathograph links
Hippo Pathway YAP/TAZ Dysregulation partially recapitulates fidelity: low Cystic jck kidneys show nuclear YAP accumulation.
Limitations: jck is a missense allele that may encode a gain-of-function protein (Manning et al. 2013) and gives juvenile polycystic kidney disease, not the multiorgan perinatal dysplasia of RHPD2 null alleles.
Show evidence (1 reference)
PMID:26967905 SUPPORT Model organism
"YAP imbalance was also observed in enlarged spheroids of Nek8-invalidated renal epithelial cells grown in 3D culture, as well as in cystic kidneys of Jck mice."
YAP imbalance in jck kidneys.
{ }

Source YAML

click to show 
name: Renal-Hepatic-Pancreatic Dysplasia 2
creation_date: "2026-11-03T19:15:04Z"
category: Mendelian
description: >-
  Renal-hepatic-pancreatic dysplasia 2 (RHPD2) is an autosomal recessive
  ciliopathy caused by biallelic NEK8 variants. NEK8 is a NIMA-related
  serine/threonine kinase of the ciliary inversin compartment. The disease
  was first described in fetuses carrying a homozygous NEK8 nonsense variant,
  with enlarged cystic kidneys, liver and pancreas and developmental heart
  disease (an Ivemark II-like picture). Later reports added renal
  hypodysplasia, situs inversus, cardiomegaly with septal hypertrophy, bile
  duct paucity, narrow thorax and short bowed femurs. Most reported patients
  die before or around birth or in the first year of life. A minority survive
  into childhood with progressive kidney and liver failure.
parents:
- Ciliopathy
- Cystic Kidney Disease
- Genetic Kidney Disease
synonyms:
- RHPD2
- renal-hepatic-pancreatic dysplasia type 2
- NEK8 renal-hepatic-pancreatic dysplasia
- renal-hepatic-pancreatic dysplasia caused by mutation in NEK8
disease_term:
  preferred_term: renal-hepatic-pancreatic dysplasia 2
  term:
    id: MONDO:0014174
    label: renal-hepatic-pancreatic dysplasia 2
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals carry biallelic NEK8 variants, homozygous in
    consanguineous families or compound heterozygous.
  evidence:
  - reference: CGGV:assertion_6888a91a-6589-42a9-9622-553b4918bed6-2021-09-08T160000.000Z
    reference_title: "NEK8 / renal-hepatic-pancreatic dysplasia 2 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In summary, NEK8 is definitively associated with autosomal recessive renal-hepatic-pancreatic dysplasia 2."
    explanation: ClinGen classifies the NEK8-RHPD2 relationship under autosomal recessive inheritance.
  - reference: PMID:23418306
    reference_title: "Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our starting point was a consanguineous pedigree with three affected fetuses"
    explanation: The index family was consanguineous with three affected sibling fetuses, consistent with recessive transmission of a homozygous allele.
  - reference: PMID:26697755
    reference_title: "Compound heterozygous mutations in NEK8 in siblings with end-stage renal disease with hepatic and cardiac anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing demonstrated compound heterozygous mutations in the NEK8 gene"
    explanation: Affected brothers carried two different NEK8 alleles, consistent with recessive inheritance.
genetic:
- name: NEK8
  gene_term:
    preferred_term: NEK8
    term:
      id: hgnc:13387
      label: NEK8
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_6888a91a-6589-42a9-9622-553b4918bed6-2021-09-08T160000.000Z
    evidence:
    - reference: CGGV:assertion_6888a91a-6589-42a9-9622-553b4918bed6-2021-09-08T160000.000Z
      reference_title: "NEK8 / renal-hepatic-pancreatic dysplasia 2 (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "NEK8 | HGNC:13387 | renal-hepatic-pancreatic dysplasia 2 | MONDO:0014174 | AR | Definitive"
      explanation: ClinGen gene-disease validity record classifying this pair as Definitive (AR).
  notes: >-
    Reported alleles include a homozygous nonsense variant with complete loss
    of NEK8 expression through nonsense-mediated decay (Frank et al. 2013),
    missense, nonsense and splice variants in five cases from a ciliopathy
    sequencing cohort (Grampa et al. 2016), and a compound heterozygous c.2069_2070insC
    (p.Ter693LeufsTer86) / c.1043C>T (p.Thr348Met) genotype in two brothers
    (Rajagopalan et al. 2016). Grampa et al. report a genotype-phenotype
    correlation in which missense alleles associate with hypodysplasia and
    nonsense alleles with enlarged cystic organs, and propose a likely
    gain-of-function effect for some missense alleles. The ClinGen curation
    lumps NEK8 nephronophthisis (NPHP9) into this disease entity and states the
    mechanism as biallelic loss of function.
  evidence:
  - reference: PMID:23418306
    reference_title: "Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we mapped the disease locus to chromosome 17q11 and identified a homozygous nonsense mutation in NEK8/NPHP9"
    explanation: First report linking a biallelic NEK8 null allele to the renal-hepatic-pancreatic dysplasia phenotype.
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These cases highlight a genotype-phenotype correlation, with missense and nonsense mutations associated with hypodysplasia and enlarged cystic organs, respectively."
    explanation: Independent cases with NEK8 variants and the reported allele-class correlation.
  - reference: PMID:26697755
    reference_title: "Compound heterozygous mutations in NEK8 in siblings with end-stage renal disease with hepatic and cardiac anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutations included a c.2069_2070insC variant (p.Ter693LeufsTer86), and a c.1043C>T variant (p.Thr348Met) in the highly conserved RCC1 (Regulation of Chromosome Condensation 1) domain."
    explanation: Compound heterozygous NEK8 genotype in a third family with multiorgan disease.
  - reference: CGGV:assertion_6888a91a-6589-42a9-9622-553b4918bed6-2021-09-08T160000.000Z
    reference_title: "NEK8 / renal-hepatic-pancreatic dysplasia 2 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of pathogenicity is biallelic loss of function."
    explanation: ClinGen states the disease mechanism as biallelic NEK8 loss of function.
pathophysiology:
- name: Biallelic NEK8 Loss of Function
  description: >-
    Biallelic NEK8 variants remove or impair the NEK8 kinase. In the index
    family the homozygous nonsense allele abolished NEK8 expression through
    nonsense-mediated decay.
  biological_scale: MOLECULAR
  role: trigger
  genes:
  - preferred_term: NEK8
    term:
      id: hgnc:13387
      label: NEK8
  molecular_functions:
  - preferred_term: protein serine/threonine kinase activity
    term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:23418306
    reference_title: "Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This work confirmed a complete loss of NEK8 expression in the affected fetuses due to nonsense-mediated decay."
    explanation: The index allele is a null allele in affected fetuses.
  - reference: CGGV:assertion_6888a91a-6589-42a9-9622-553b4918bed6-2021-09-08T160000.000Z
    reference_title: "NEK8 / renal-hepatic-pancreatic dysplasia 2 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of pathogenicity is biallelic loss of function."
    explanation: ClinGen states biallelic loss of function as the mechanism.
  downstream:
  - target: Inversin Compartment NEK8 Kinase Signaling Failure
    causal_link_type: DIRECT
    description: Loss of NEK8 removes the kinase activated within the ciliary inversin compartment.
- name: Inversin Compartment NEK8 Kinase Signaling Failure
  description: >-
    NEK8 sits in the ciliary inversin compartment in a module with ANKS6, INVS
    and NPHP3. In mice, loss of NEK8 kinase activation within the compartment
    gives heterotaxy, cardiopulmonary malformation and cystic kidneys. The
    evidence for this node is from mouse models and cell systems, not from
    patient tissue.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: NEK8
    term:
      id: hgnc:13387
      label: NEK8
  cellular_components:
  - preferred_term: ciliary inversin compartment
    term:
      id: GO:0097543
      label: ciliary inversin compartment
  molecular_functions:
  - preferred_term: protein serine/threonine kinase activity
    term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:25599650
    reference_title: "ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Together, these data reveal the crucial role of NEK8 kinase activation within the IC, promoting proper left-right patterning, cardiopulmonary development and renal morphogenesis."
    explanation: Mouse Nek8 kinase-dead and Anks6 mutants show that NEK8 kinase activation in the inversin compartment is needed for laterality, heart and lung development and kidney morphogenesis.
  - reference: PMID:23793029
    reference_title: "ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we identify ANKS6 as a new NPHP family member that connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3."
    explanation: Places NEK8 in the ANKS6-INVS-NPHP3 module.
  downstream:
  - target: Hippo Pathway YAP/TAZ Dysregulation
    causal_link_type: DIRECT
    description: NEK8 binds TAZ and promotes its nuclear delivery; NEK8 variants disturb YAP regulation.
  - target: Reduced Polycystin Gene Expression and c-MYC Upregulation
    causal_link_type: UNKNOWN
    description: >-
      Patient fibroblasts lacking NEK8 show reduced PKD1/PKD2 and raised c-MYC
      expression; how NEK8 loss produces this is not established.
  - target: Defective Nodal Left-Right Patterning
    causal_link_type: DIRECT
    description: NEK8 loss perturbs nodal ciliary signaling in mouse embryos.
  - target: Congenital Cardiac Malformation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      NEK8 kinase activation is required for cardiopulmonary development in
      mice; the steps between the kinase and the heart defect are not defined.
  - target: Replication Stress and DNA Damage
    causal_link_type: DIRECT
    description: NEK8 limits S-phase CDK activity in the ATR replication stress response.
- name: Hippo Pathway YAP/TAZ Dysregulation
  description: >-
    NEK8 binds the Hippo effector TAZ and drives nuclear delivery of the
    TAZ/NEK8 complex. Patient NEK8 variants alter YAP regulation and YAP target
    gene expression in patient fibroblasts and renal cells; YAP imbalance is
    also seen in Nek8-invalidated renal spheroids and in cystic jck mouse
    kidneys. The YAP inhibitor verteporfin partly rescued spheroid and
    zebrafish defects. Missense and null alleles affect YAP differently.
  biological_scale: CELLULAR
  genes:
  - preferred_term: NEK8
    term:
      id: hgnc:13387
      label: NEK8
  biological_processes:
  - preferred_term: hippo signaling
    term:
      id: GO:0035329
      label: hippo signaling
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:23026745
    reference_title: "The ciliopathy disease protein NPHP9 promotes nuclear delivery and activation of the oncogenic transcriptional regulator TAZ."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "NPHP9, which is also called NEK8, directly interacted with TAZ and induced nuclear translocation of the TAZ/NPHP9 protein complex."
    explanation: Cell-based evidence that NEK8 regulates the Hippo effector TAZ.
  - reference: PMID:23418306
    reference_title: "Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both proteins interact and activate the Hippo effector TAZ."
    explanation: NEK8 and NPHP3 interact and activate TAZ.
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We also showed that NEK8 missense and loss-of-function mutations differentially affect the regulation of the main Hippo signaling effector, YAP, as well as the expression of its target genes in patient fibroblasts and renal cells."
    explanation: Patient-derived and renal cell data showing YAP dysregulation by RHPD2 alleles.
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Immunohistochemistry assay showed that Yap expression was predominantly cytoplasmic in the kidneys of wild-type mice, whereas it was markedly increased in nuclei of kidneys of 5-week old Jck mice"
    explanation: Nuclear YAP accumulation in cystic kidneys of the jck Nek8 mouse.
  downstream:
  - target: Renal Cystic Dysplasia
    causal_link_type: DIRECT
    description: >-
      Grampa et al. attribute the organ developmental defects to altered
      ciliogenesis and cell differentiation/proliferation through Hippo
      pathway deregulation.
    evidence:
    - reference: PMID:26967905
      reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Finally, treatment with Verteporfin, an inhibitor of YAP transcriptional activity, partially rescued the 3D spheroid defects of Nek8-invalidated cells"
      explanation: Pharmacological YAP inhibition partly rescues the renal epithelial morphogenesis defect of Nek8-invalidated cells, supporting YAP as a mediator.
  - target: Hepatobiliary Ductal Plate Malformation and Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Grampa et al. extend the Hippo deregulation model to the major organ
      developmental defects; the hepatobiliary link is inferred from the
      shared mechanism rather than shown in liver tissue.
  - target: Pancreatic Cystic Dysplasia and Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      As for the liver, the pancreatic link is inferred from the shared
      Hippo-deregulation model rather than shown in pancreatic tissue.
- name: Reduced Polycystin Gene Expression and c-MYC Upregulation
  description: >-
    Fibroblasts from NEK8-null fetuses show decreased PKD1 and PKD2 expression
    and increased c-MYC expression, which the authors offer as potential
    explanations for the renal phenotype. NEK8-depleted collecting duct cells
    also respond poorly to fluid shear, as cells lacking polycystin-2 do.
  biological_scale: CELLULAR
  genes:
  - preferred_term: NEK8
    term:
      id: hgnc:13387
      label: NEK8
  biological_processes:
  - preferred_term: cellular response to fluid shear stress
    term:
      id: GO:0071498
      label: cellular response to fluid shear stress
    modifier: DECREASED
  evidence:
  - reference: PMID:23418306
    reference_title: "Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In cultured fibroblasts derived from these fetuses, the expression of prominent polycystic kidney disease genes (PKD1 and PKD2) was decreased, whereas the oncogene c-MYC was upregulated, providing potential explanations for the observed renal phenotype."
    explanation: Patient-derived fibroblasts lacking NEK8 show reduced PKD1/PKD2 and increased c-MYC.
  - reference: PMID:23274954
    reference_title: "Loss of the ciliary kinase Nek8 causes left-right asymmetry defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "NEK8-depleted inner medullary collecting duct cells exhibited a defective response to fluid shear, suggesting that NEK8 may play a role in mediating PC2-dependent signaling."
    explanation: Cell-based evidence linking NEK8 to polycystin-2-dependent flow signaling.
  downstream:
  - target: Renal Cystic Dysplasia
    causal_link_type: UNKNOWN
    description: The authors propose reduced polycystin expression and raised c-MYC as potential contributors to the renal phenotype.
- name: Replication Stress and DNA Damage
  description: >-
    NEK8 acts in the ATR-mediated replication stress response by limiting
    cyclin A-associated CDK activity. Cells lacking NEK8 accumulate DNA
    double-strand breaks, and Nek8 mutant mouse kidneys accumulate DNA damage.
    This branch is shown in cells and mice; its contribution to human RHPD2
    has not been tested.
  biological_scale: CELLULAR
  genes:
  - preferred_term: NEK8
    term:
      id: hgnc:13387
      label: NEK8
  biological_processes:
  - preferred_term: DNA damage response
    term:
      id: GO:0006974
      label: DNA damage response
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:23973373
    reference_title: "NEK8 links the ATR-regulated replication stress response and S phase CDK activity to renal ciliopathies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cells lacking NEK8 form spontaneous DNA double-strand breaks (DSBs) that further accumulate when replication forks stall"
    explanation: Cell-based evidence that NEK8 loss causes DNA damage under replication stress.
  - reference: PMID:23973373
    reference_title: "NEK8 links the ATR-regulated replication stress response and S phase CDK activity to renal ciliopathies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Moreover, kidneys of NEK8 mutant mice accumulate DNA damage"
    explanation: In vivo DNA damage in Nek8 mutant mouse kidneys.
  downstream:
  - target: Renal Cystic Dysplasia
    causal_link_type: UNKNOWN
    description: >-
      Loss of NEK8 or replication stress disrupts renal cell architecture in 3D
      culture; whether this contributes to human renal dysplasia is unknown.
    evidence:
    - reference: PMID:23973373
      reference_title: "NEK8 links the ATR-regulated replication stress response and S phase CDK activity to renal ciliopathies."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "loss of NEK8 or replication stress similarly disrupts renal cell architecture in a 3D-culture system"
      explanation: Links NEK8-dependent genome maintenance to renal epithelial architecture in vitro.
- name: Defective Nodal Left-Right Patterning
  description: >-
    Nek8-null mouse embryos form cilia but misexpress left-sided marker genes
    early in development, indicating perturbed nodal ciliary signaling, and
    show randomized left-right asymmetry. Zebrafish knockdown randomizes heart
    looping.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: determination of left/right symmetry
    term:
      id: GO:0007368
      label: determination of left/right symmetry
    modifier: DECREASED
  evidence:
  - reference: PMID:23274954
    reference_title: "Loss of the ciliary kinase Nek8 causes left-right asymmetry defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ciliogenesis was intact in Nek8-deficient embryos and cells, but we observed misexpression of left-sided marker genes early in development, suggesting that nodal ciliary signaling was perturbed."
    explanation: Mouse evidence for a nodal signaling defect with intact ciliogenesis.
  - reference: PMID:23274954
    reference_title: "Loss of the ciliary kinase Nek8 causes left-right asymmetry defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "homozygous mutant mice die at birth and exhibit randomization of left-right asymmetry, cardiac anomalies, and glomerular kidney cysts"
    explanation: Nek8-null mice have randomized left-right asymmetry.
  downstream:
  - target: Situs inversus
    causal_link_type: DIRECT
    description: Defective left-right patterning produces situs inversus.
  - target: Asplenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Asplenia is a laterality-associated anomaly; its derivation from the
      nodal defect in RHPD2 is inferred, not shown.
- name: Congenital Cardiac Malformation
  description: >-
    Patients have cardiomegaly, ventricular septal hyperplasia or hypertrophic
    cardiomyopathy, ventricular septal defect and patent ductus arteriosus.
    Nek8-null and Nek8 kinase-dead mice have cardiac anomalies.
  biological_scale: TISSUE
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  biological_processes:
  - preferred_term: heart development
    term:
      id: GO:0007507
      label: heart development
    modifier: DECREASED
  evidence:
  - reference: PMID:23418306
    reference_title: "Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "enlarged cystic kidneys, liver and pancreas and developmental heart disease"
    explanation: Developmental heart disease in the index fetuses.
  - reference: PMID:25599650
    reference_title: "ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Both display heterotaxy, cardiopulmonary malformations and cystic kidneys"
    explanation: Nek8 kinase-dead and Anks6 mutant mice have cardiopulmonary malformations.
  downstream:
  - target: Cardiomegaly
    causal_link_type: DIRECT
    description: Structural heart disease presents with cardiomegaly.
  - target: Ventricular septal hypertrophy
    causal_link_type: DIRECT
    description: Septal hyperplasia is the recurrent cardiac lesion in the Grampa series.
  - target: Ventricular septal defect
    causal_link_type: DIRECT
    description: Septal defects are reported in RHPD2 fetuses.
- name: Renal Cystic Dysplasia
  conforms_to: "ciliopathy_dysfunction#Renal Tubular Cystic and Fibrotic Disease"
  description: >-
    The kidneys show cystic dysplasia with incomplete corticomedullary
    differentiation, primitive tubules, metaplastic cartilage and diffuse
    interstitial fibrosis. Nonsense genotypes give enlarged multicystic
    kidneys; missense genotypes give asymmetric hypodysplasia with one kidney
    absent or very small. This specializes the ciliopathy module's cystic
    kidney arm to a developmental dysplasia rather than the later
    tubulointerstitial degeneration of nephronophthisis.
  biological_scale: TISSUE
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  biological_processes:
  - preferred_term: kidney development
    term:
      id: GO:0001822
      label: kidney development
    modifier: DECREASED
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients/fetus from families 1, 2 and 3 shared developmental abnormalities including asymmetric renal hypodysplasia with one absent or extremely reduced in size kidney and the other one with major dysplasia, diffuse interstitial fibrosis and incomplete cortico-medullary differentiation"
    explanation: Renal histopathology in NEK8 patients.
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, the fetuses from families 4 and 5 exhibited enlarged multicystic kidneys, cystic pancreas and liver"
    explanation: Enlarged multicystic kidneys in the fetuses with more severe alleles.
  downstream:
  - target: Cystic renal dysplasia
    causal_link_type: DIRECT
    description: The tissue lesion is the clinical finding.
  - target: Enlarged kidney
    causal_link_type: DIRECT
    description: Nonsense genotypes give enlarged cystic kidneys.
  - target: Renal hypoplasia
    causal_link_type: DIRECT
    description: Missense genotypes give hypodysplasia.
  - target: Renal interstitial fibrosis
    causal_link_type: DIRECT
    description: Dysplastic kidneys show diffuse interstitial fibrosis.
  - target: Anhydramnios
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Bilateral renal dysplasia reduces fetal urine output and so amniotic
      fluid. That intermediate is general fetal physiology and was not
      measured in these reports.
  - target: Stage 5 chronic kidney disease
    causal_link_type: DIRECT
    description: Survivors progress to end-stage kidney disease.
- name: Hepatobiliary Ductal Plate Malformation and Fibrosis
  description: >-
    The liver shows ductal plate anomalies with cystic biliary
    fibroadenomatosis, hepatic cysts, portal fibrosis with ductular
    proliferation, and in other patients paucity or hypoplasia of the bile
    ducts with cholestasis.
  biological_scale: TISSUE
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  cell_types:
  - preferred_term: cholangiocyte
    term:
      id: CL:1000488
      label: cholangiocyte
  biological_processes:
  - preferred_term: liver development
    term:
      id: GO:0001889
      label: liver development
    modifier: DECREASED
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ductal plate anomalies with cystic biliary fibroadenomatosis"
    explanation: Liver finding in family 5 (Table 1).
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presents with massive portal fibrosis with ductular proliferation"
    explanation: Liver histology in individual F1 II.1.
  - reference: PMID:26697755
    reference_title: "Compound heterozygous mutations in NEK8 in siblings with end-stage renal disease with hepatic and cardiac anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we observed bile duct hypoplasia rather than ductal plate malformation"
    explanation: Shows the hepatobiliary lesion varies between families, from ductal plate malformation to bile duct hypoplasia.
  downstream:
  - target: Hepatic cysts
    causal_link_type: DIRECT
    description: Ductal plate malformation gives hepatic cysts.
  - target: Malformation of the hepatic ductal plate
    causal_link_type: DIRECT
    description: The lesion itself.
  - target: Hepatic fibrosis
    causal_link_type: DIRECT
    description: Portal fibrosis accompanies the ductal lesion.
  - target: Reduced number of intrahepatic bile ducts
    causal_link_type: DIRECT
    description: Bile duct paucity or hypoplasia is the alternative hepatobiliary lesion.
  - target: Cholestasis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Bile duct paucity impairs bile flow.
- name: Pancreatic Cystic Dysplasia and Fibrosis
  description: >-
    The pancreas is enlarged with cysts and shows massive diffuse fibrosis with
    dissociation of the parenchyma; one fetus had a short pancreas. A
    pancreatic phenotype is not seen in every family.
  biological_scale: TISSUE
  locations:
  - preferred_term: pancreas
    term:
      id: UBERON:0001264
      label: pancreas
  cell_types:
  - preferred_term: pancreatic ductal cell
    term:
      id: CL:0002079
      label: pancreatic ductal cell
  biological_processes:
  - preferred_term: pancreas development
    term:
      id: GO:0031016
      label: pancreas development
    modifier: DECREASED
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Higher magnification reveals a massive and diffuse fibrosis with dissociation of the pancreatic parenchyma"
    explanation: Pancreatic histology in an affected individual.
  - reference: PMID:26697755
    reference_title: "Compound heterozygous mutations in NEK8 in siblings with end-stage renal disease with hepatic and cardiac anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a pancreatic phenotype was not observed in the individuals reported here"
    explanation: Pancreatic involvement is variable; absent in the Rajagopalan brothers.
  downstream:
  - target: Pancreatic cysts
    causal_link_type: DIRECT
    description: The dysplastic pancreas is cystic.
  - target: Pancreatic fibrosis
    causal_link_type: DIRECT
    description: The dysplastic pancreas is fibrotic.
phenotypes:
- category: Renal
  name: Cystic renal dysplasia
  description: >-
    Cystic dysplasia or hypodysplasia of the kidneys, the renal feature in all
    five cases of the Grampa series.
  phenotype_term:
    preferred_term: Cystic renal dysplasia
    term:
      id: HP:0000800
      label: Cystic renal dysplasia
    onset:
      onset_category: FETAL
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NEK8/NPHP9 mutations were identified in five cases with severe overlapping phenotypes including renal cystic dysplasia/hypodysplasia, situs inversus, cardiopathy with hypertrophic septum and bile duct paucity."
    explanation: Renal cystic dysplasia in the five NEK8 cases.
- category: Renal
  name: Enlarged kidney
  description: Enlarged cystic kidneys, reported with nonsense genotypes.
  phenotype_term:
    preferred_term: Enlarged cystic kidneys
    term:
      id: HP:0000105
      label: Enlarged kidney
    onset:
      onset_category: FETAL
  evidence:
  - reference: PMID:23418306
    reference_title: "Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "three affected fetuses showing an early embryonic phenotype with enlarged cystic kidneys, liver and pancreas"
    explanation: Enlarged cystic kidneys in the index fetuses.
- category: Renal
  name: Renal hypoplasia
  description: >-
    Asymmetric renal hypodysplasia, with one kidney absent or extremely small,
    in cases with missense genotypes.
  phenotype_term:
    preferred_term: Renal hypodysplasia
    term:
      id: HP:0000089
      label: Renal hypoplasia
    onset:
      onset_category: FETAL
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "asymmetric renal hypodysplasia with one absent or extremely reduced in size kidney"
    explanation: Renal hypodysplasia in families 1-3.
- category: Renal
  name: Renal interstitial fibrosis
  description: Diffuse interstitial fibrosis of the dysplastic kidney.
  phenotype_term:
    preferred_term: Renal interstitial fibrosis
    term:
      id: HP:0032948
      label: Renal interstitial fibrosis
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the other one with major dysplasia, diffuse interstitial fibrosis and incomplete cortico-medullary differentiation"
    explanation: Renal interstitial fibrosis on histology.
- category: Prenatal
  name: Anhydramnios
  description: >-
    Absent amniotic fluid (anamnios) was recorded for one fetus, from family
    5, with arthrogryposis. Reported in a single case.
  phenotype_term:
    preferred_term: Anhydramnios
    term:
      id: HP:0025700
      label: Anhydramnios
    onset:
      onset_category: FETAL
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial dysmorphism, arthrogryposis (anamnios), neurological examination ND"
    explanation: Table 1 records anamnios in the family 5 fetus.
- category: Renal
  name: Stage 5 chronic kidney disease
  description: >-
    Children who survive the perinatal period progress to end-stage kidney
    disease; one child died at 5 years from renal failure.
  phenotype_term:
    preferred_term: End-stage renal disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:36756677
    reference_title: "Renal-hepatic-pancreatic dysplasia type 2: Perinatal lethal condition or a multisystemic disorder with variable expressivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one case died at 5 years secondary to renal failure, the other at 30 months secondary to liver and kidney failure"
    explanation: Kidney failure in survivors past the first year.
- category: Hepatic
  name: Hepatic cysts
  description: Cystic liver in the fetuses with nonsense genotypes.
  phenotype_term:
    preferred_term: Hepatic cysts
    term:
      id: HP:0001407
      label: Hepatic cysts
    onset:
      onset_category: FETAL
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, the fetuses from families 4 and 5 exhibited enlarged multicystic kidneys, cystic pancreas and liver"
    explanation: Cystic liver in families 4 and 5.
- category: Hepatic
  name: Malformation of the hepatic ductal plate
  description: Ductal plate anomalies with cystic biliary fibroadenomatosis.
  phenotype_term:
    preferred_term: Ductal plate malformation
    term:
      id: HP:0006563
      label: Malformation of the hepatic ductal plate
    onset:
      onset_category: FETAL
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ductal plate anomalies with cystic biliary fibroadenomatosis"
    explanation: Ductal plate malformation in the family 5 fetus (Table 1).
- category: Hepatic
  name: Hepatic fibrosis
  description: Portal fibrosis with ductular proliferation.
  phenotype_term:
    preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presents with massive portal fibrosis with ductular proliferation"
    explanation: Hepatic fibrosis on liver histology.
- category: Hepatic
  name: Reduced number of intrahepatic bile ducts
  description: Paucity or hypoplasia of the bile ducts.
  phenotype_term:
    preferred_term: Paucity of bile ducts
    term:
      id: HP:0006571
      label: Reduced number of intrahepatic bile ducts
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "situs inversus (4 cases), cardiomegaly (3 cases), paucity of bile ducts (3 cases), pancreas defects (3 cases)"
    explanation: Bile duct paucity in three of five cases.
  - reference: PMID:26697755
    reference_title: "Compound heterozygous mutations in NEK8 in siblings with end-stage renal disease with hepatic and cardiac anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we observed bile duct hypoplasia rather than ductal plate malformation"
    explanation: Bile duct hypoplasia in the Rajagopalan brothers.
- category: Hepatic
  name: Cholestasis
  description: Cholestasis with hepatomegaly in a liveborn infant who died at 1 month and 20 days.
  phenotype_term:
    preferred_term: Cholestasis
    term:
      id: HP:0001396
      label: Cholestasis
    onset:
      onset_category: NEONATAL
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatomegaly, cholestasis, paucity of bile ducts and fibrosis"
    explanation: Liver phenotype of patient F1 (Table 1).
- category: Pancreatic
  name: Pancreatic cysts
  description: Enlarged cystic pancreas.
  phenotype_term:
    preferred_term: Pancreatic cysts
    term:
      id: HP:0001737
      label: Pancreatic cysts
    onset:
      onset_category: FETAL
  evidence:
  - reference: PMID:23418306
    reference_title: "Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "three affected fetuses showing an early embryonic phenotype with enlarged cystic kidneys, liver and pancreas"
    explanation: Cystic pancreas in the index fetuses.
- category: Pancreatic
  name: Pancreatic fibrosis
  description: Massive diffuse pancreatic fibrosis.
  phenotype_term:
    preferred_term: Pancreatic fibrosis
    term:
      id: HP:0100732
      label: Pancreatic fibrosis
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Higher magnification reveals a massive and diffuse fibrosis with dissociation of the pancreatic parenchyma"
    explanation: Pancreatic fibrosis on histology.
- category: Laterality
  name: Situs inversus
  description: >-
    Situs inversus in four of five cases in the Grampa series. The source does
    not say whether it was complete. It is bound to the HPO term for situs
    inversus totalis because HPO has no unqualified situs inversus term; the
    other situs inversus terms are organ-specific (abdominal, atrial,
    pulmonary).
  phenotype_term:
    preferred_term: Situs inversus
    term:
      id: HP:0001696
      label: Situs inversus totalis
    onset:
      onset_category: EMBRYONAL
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All five cases presented with kidney involvement associated with extra-renal defects including situs inversus (4 cases)"
    explanation: Situs inversus in four of five NEK8 cases.
- category: Laterality
  name: Asplenia
  description: Asplenia was reported in the family 3 fetus.
  phenotype_term:
    preferred_term: Asplenia
    term:
      id: HP:0001746
      label: Asplenia
    onset:
      onset_category: EMBRYONAL
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented with short pancreas and asplenia in addition to the defects listed above"
    explanation: Asplenia in the family 3 fetus.
- category: Cardiovascular
  name: Cardiomegaly
  description: Cardiomegaly in three of five cases.
  phenotype_term:
    preferred_term: Cardiomegaly
    term:
      id: HP:0001640
      label: Cardiomegaly
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All five cases presented with kidney involvement associated with extra-renal defects including situs inversus (4 cases), cardiomegaly (3 cases)"
    explanation: Cardiomegaly in three of five cases.
- category: Cardiovascular
  name: Ventricular septal hypertrophy
  description: >-
    Interventricular septal hyperplasia, or hypertrophic cardiomyopathy with
    septal hyperplasia, shared by families 1-3.
  phenotype_term:
    preferred_term: Ventricular septal hypertrophy
    term:
      id: HP:0005144
      label: Ventricular septal hypertrophy
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac septal hyperplasia and liver alterations including paucity of bile ducts"
    explanation: Septal hyperplasia shared by families 1-3.
- category: Cardiovascular
  name: Ventricular septal defect
  description: Intraventricular communication in the family 3 fetus.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
    onset:
      onset_category: EMBRYONAL
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiomegaly with intraventricular communication | Paucity of bile ducts | Short and fibrotic"
    explanation: Ventricular septal defect in family 3 (Table 1).
- category: Skeletal
  name: Narrow chest
  description: Narrow thorax in two of five cases.
  phenotype_term:
    preferred_term: Narrow thorax
    term:
      id: HP:0000774
      label: Narrow chest
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "narrow thorax and short bowed femurs (2 cases)"
    explanation: Narrow thorax in two cases.
- category: Skeletal
  name: Femoral bowing
  description: Short bowed femurs in two of five cases; ClinGen also lists bowed femora among the RHPD2 features.
  phenotype_term:
    preferred_term: Short bowed femurs
    term:
      id: HP:0002980
      label: Femoral bowing
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "narrow thorax and short bowed femurs (2 cases)"
    explanation: Short bowed femurs in two cases.
- category: Neurological
  name: Agenesis of corpus callosum
  description: >-
    Brain malformation (corpus callosum or vermis agenesis) in two of five
    cases; corpus callosum agenesis in the family 2 case.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "brain defects such as corpus callosum or vermis agenesis (2 cases)"
    explanation: Corpus callosum agenesis among the brain defects reported.
- category: Neurological
  name: Aplasia/Hypoplasia of the cerebellar vermis
  description: Agenesis of the cerebellar vermis in the family 4 fetus.
  phenotype_term:
    preferred_term: Agenesis of the cerebellar vermis
    term:
      id: HP:0006817
      label: Aplasia/Hypoplasia of the cerebellar vermis
  evidence:
  - reference: PMID:26967905
    reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the fetuses from families 4 and 5 exhibited enlarged multicystic kidneys, cystic pancreas and liver, and agenesis of the vermis (fetus 4)"
    explanation: Vermis agenesis in fetus 4.
prevalence:
- population: Worldwide published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A 2023 literature review counted 17 known patients. This is a published
    case count, not a population prevalence; no rate is available.
  evidence:
  - reference: PMID:36756677
    reference_title: "Renal-hepatic-pancreatic dysplasia type 2: Perinatal lethal condition or a multisystemic disorder with variable expressivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With now examining the 17 known patients in the literature, 13 died within the perinatal period-pregnancy to one year of life."
    explanation: Literature case count for RHPD2.
progression:
- phase: Prenatal and first year
  age_range: Fetal to 1 year
  notes: >-
    Most reported patients die in pregnancy, including terminations, or
    within the first year; 13 of 17 published patients died in this window.
  evidence:
  - reference: PMID:36756677
    reference_title: "Renal-hepatic-pancreatic dysplasia type 2: Perinatal lethal condition or a multisystemic disorder with variable expressivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With now examining the 17 known patients in the literature, 13 died within the perinatal period-pregnancy to one year of life."
    explanation: Perinatal mortality in the published series.
- phase: Childhood survival
  age_range: After 1 year
  notes: >-
    Of four patients surviving past one year, two died of renal or combined
    liver and kidney failure at 5 years and 30 months, and two were alive at 1
    and 13 years.
  evidence:
  - reference: PMID:36756677
    reference_title: "Renal-hepatic-pancreatic dysplasia type 2: Perinatal lethal condition or a multisystemic disorder with variable expressivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two are currently alive and well at one year and 13 years."
    explanation: Long-term survivors exist.
treatments:
- name: Organ Transplantation
  description: >-
    No disease-specific therapy exists. Two published patients underwent
    transplantation, one with long-term survival.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Organ Transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  evidence:
  - reference: PMID:36756677
    reference_title: "Renal-hepatic-pancreatic dysplasia type 2: Perinatal lethal condition or a multisystemic disorder with variable expressivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two cases have had transplantation with one resulting in long-term survival."
    explanation: Transplantation outcomes in RHPD2.
animal_models:
- name: Nek8-null mouse
  species: Mouse
  genotype: Nek8 targeted null allele, homozygous
  publication: PMID:23274954
  description: >-
    Homozygous Nek8-null mice die at birth with randomized left-right
    asymmetry, cardiac anomalies and glomerular kidney cysts.
  modeled_mechanisms:
  - target: Defective Nodal Left-Right Patterning
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Reproduces the laterality and cardiac features of RHPD2.
    limitations: >-
      Kidney involvement is glomerular cysts at birth rather than the enlarged
      cystic dysplasia of human fetuses; liver and pancreatic lesions are not
      described in the abstract.
    evidence:
    - reference: PMID:23274954
      reference_title: "Loss of the ciliary kinase Nek8 causes left-right asymmetry defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "homozygous mutant mice die at birth and exhibit randomization of left-right asymmetry, cardiac anomalies, and glomerular kidney cysts"
      explanation: Phenotype of the null mouse.
- name: jck mouse
  species: Mouse
  genotype: Nek8 G448V (jck) homozygous
  publication: PMID:12421721
  description: >-
    Spontaneous recessive juvenile cystic kidney mutant carrying a Nek8
    missense variant in the RCC1 domain.
  modeled_mechanisms:
  - target: Hippo Pathway YAP/TAZ Dysregulation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Cystic jck kidneys show nuclear YAP accumulation.
    limitations: >-
      jck is a missense allele that may encode a gain-of-function protein
      (Manning et al. 2013) and gives juvenile polycystic kidney disease, not
      the multiorgan perinatal dysplasia of RHPD2 null alleles.
    evidence:
    - reference: PMID:26967905
      reference_title: "Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "YAP imbalance was also observed in enlarged spheroids of Nek8-invalidated renal epithelial cells grown in 3D culture, as well as in cystic kidneys of Jck mice."
      explanation: YAP imbalance in jck kidneys.
notes: >-
  Lump/split. NEK8 disease appears in three dismech records. (1) This entry:
  autosomal recessive RHPD2 (MONDO:0014174, OMIM:615415), the severe perinatal
  multiorgan end, with its own ClinGen Definitive AR assertion. (2) The
  NEK8-related (nephronophthisis 9) subtype of Nephronophthisis, based on three
  missense alleles in a 588-patient NPHP screen (Otto et al. 2008,
  PMID:18199800). ClinGen's RHPD2 curation lumps NPHP9 into RHPD2, but MONDO
  and OMIM keep separate terms, so this entry does not absorb that subtype. (3)
  The PKD8 (NEK8-related) subtype of Autosomal Dominant Polycystic Kidney
  Disease, from heterozygous missense alleles, with a different inheritance
  and mechanism. RHPD1 (NPHP3) has no dismech entry; NPHP3 appears as a
  Nephronophthisis subtype and as MKS7 in Meckel Syndrome. Conformance: the
  renal node conforms to the ciliopathy_dysfunction cystic kidney node. The
  module's upstream basal body/transition zone node does not fit NEK8, which
  acts in the inversin compartment and is not required for ciliogenesis
  (PMID:23274954), so no upstream conformance is declared.
📚

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: Renal-Hepatic-Pancreatic Dysplasia 2 · 2026-11-03T19:48:08Z · View source

New Disease entry for RHPD2 (MONDO:0014174), NEK8, AR, from the stub stubs/Renal-hepatic-pancreatic_Dysplasia_2.yaml (claim dismech#16406). The deep-research report is research/Renal-Hepatic-Pancreatic_Dysplasia_2-deep-research-claude_code.md: falcon (Edison) was requested and returned HTTP 403 ProviderAuthError, and the run fell back to claude_code (recorded in the report frontmatter). The report was used only as a list of leads; its own quotes were paraphrases. Every evidence item cites a reference fetched with just fetch-reference (Frank 2013 PMID:23418306, Grampa 2016 PMID:26967905 upgraded to PMC full text, Rajagopalan 2016 PMID:26697755, Gunther 2023 PMID:36756677, Manning 2013 PMID:23274954, Czarnecki 2015 PMID:25599650, Habbig 2012 PMID:23026745, Choi 2013 PMID:23973373, Hoff 2013 PMID:23793029) or the committed ClinGen CGGV record, from which gene_disease_validity (Definitive, AR) was copied. Mouse jck/Nek8-null evidence is graded MODEL_ORGANISM and cell work IN_VITRO. Dropped from the report's leads: pulmonary hypoplasia (no source in the fetched literature), oligohydramnios as a general feature (only one anhydramnios case, recorded as such), the Frank variant name p.Arg45* (not in the abstract), and the Al-Hamed 2016 inferred NEK8 variant (indirect). Situs inversus is bound to HP:0001696 because HPO has no unqualified term; the source does not say whether it was complete. Lump/split reasoning against the Nephronophthisis NPHP9 subtype and the ADPKD PKD8 subtype is in notes. The renal node conforms to ciliopathy_dysfunction#Renal Tubular Cystic and Fibrotic Disease. Validated with just validate, count-verified-snippets (all verified), validate-terms, the KB check recipes, and validate-disorders.

Claude Code ▸
Research report: Renal-Hepatic-Pancreatic Dysplasia 2 (RHPD2), caused by NEK8
claude-haiku-5-5, claude-opus-5-5 18 citations 2026-11-03T19:22:45.579634

Pulling the NEK8 literature from PubMed to check identifiers before I write the report.

Checking one more source, a review of NEK8 cases reported 2013–2020, then I'll write the report.

Research report: Renal-Hepatic-Pancreatic Dysplasia 2 (RHPD2), caused by NEK8

Provenance. This report was put together by an AI agent (Claude Code) on 2026-11-03. PubMed E-utilities needed approval in this session and I didn't have it, so citations come from web search plus memory, cross-checked against two committed repository sources (cache/clingen/gene_validity.csv and the dismech Nephronophthisis deep-research report). Each PMID is tagged by how it was checked: - [confirmed]: a PubMed URL, or a PMC/MGI/ZFIN record, matched title and PMID. - [lead]: the PMID was read off a secondary site and not opened on PubMed. - [memory]: I recalled it; it is unverified.

None of the "quotes" below are verified exact abstract strings. They are paraphrases returned by the search tool. Before they become YAML evidence, fetch each with just fetch-reference PMID:… and take the snippet from references_cache/.

1. Disease information

RHPD2 is an autosomal recessive ciliopathy caused by biallelic variants in NEK8 (NIMA-related kinase 8; HGNC:13387; also called NPHP9). Its core features are: - enlarged cystic or dysplastic kidneys; - ductal plate malformation and cysts in the liver; - pancreatic cysts and dysplasia; - frequent congenital heart disease and laterality defects.

Most reported cases are lethal before or around birth. The original report described three fetuses from one consanguineous family with "enlarged cystic kidneys, liver and pancreas" and developmental heart disease, carrying a homozygous NEK8 nonsense variant (Frank et al. 2013, Hum Mol Genet 22:2177–85, doi:10.1093/hmg/ddt070; PMID 23418306 [lead], from the GO annotation page for NEK8).

Identifier Value Source / status
MONDO MONDO:0014174 "renal-hepatic-pancreatic dysplasia 2" repo entry and stub
OMIM 615415 (RHPD2) task brief; also the LOVD and Pharos records
Allelic OMIM 613824, Nephronophthisis 9 (NPHP9) [memory] for the number
Orphanet ORPHA:294415, renal-hepatic-pancreatic dysplasia (umbrella term, also called Ivemark II) [lead], from an aggregator. Check on orpha.net. That aggregator maps the umbrella to MONDO:0017417.
ClinGen NEK8 / RHPD2 / AR / Definitive (SOP8, Kidney Cystic and Ciliopathy Disorders GCEP, 2021-09-08). CGGV:assertion_6888a91a-6589-42a9-9622-553b4918bed6-2021-09-08T160000.000Z structured database, confirmed in cache/clingen/gene_validity.csv
ClinGen (allelic, dominant) NEK8 / ADPKD (MONDO:0004691) / AD / Strong (2024-01-08). CGGV:assertion_32e19522-…-2024-01-08T170000.000Z confirmed, same CSV
ICD-10 / ICD-11 / MeSH No specific code found. Probably falls under Q61.x (cystic kidney disease) or Q44.6 (cystic disease of the liver). not checked

Synonyms: RHPD type 2; NEK8-related RHPD; renal-hepatic-pancreatic dysplasia caused by mutation in NEK8. The umbrella term also goes by Ivemark II syndrome and renohepatopancreatic dysplasia.

Source class: case reports and small families only (aggregated disease level). There are no registries or EHR cohorts.

Lump/split decisions to surface (not quietly resolved here): 1. Within the RHPD umbrella, RHPD1 is the NPHP3 form (Bergmann et al. 2008, Am J Hum Genet; PMID 18371931 [memory]). RHPD2 is the NEK8 form. The two are separate gene-defined MONDO terms, so separate entries are consistent with design-decisions §3a/§18 Mendelian splitting. An umbrella grouping would be optional. 2. Within the NEK8 allelic series: - RHPD2 (AR, severe, multi-organ); - NPHP9 (AR, juvenile nephronophthisis; weak evidence: one homozygous case among 588 screened in Otto 2008); - NEK8-related autosomal dominant PKD (heterozygous kinase-domain missense, dominant negative; Claus 2023).

Gunther et al. 2023 argue that RHPD2 is "a multisystemic disorder with variable expressivity" rather than always lethal, which leans toward lumping AR NEK8 disease into one spectrum. MONDO and OMIM still keep RHPD2 and NPHP9 apart. My recommendation: curate RHPD2 as the disease, with NPHP9 noted as an allelic, milder AR phenotype rather than a has_subtypes row, because NPHP9 has its own MONDO/OMIM term. AD-PKD should be its own entry or stay inside the existing ADPKD entry. This is a curator's call.

2. Etiology

  • Cause: biallelic germline loss-of-function or hypomorphic NEK8 variants. Monogenic, autosomal recessive.
  • Genetic risk factors: consanguinity in several families (Frank 2013, plus Saudi cohorts in Al-Hamed 2016). Nothing else is known.
  • Environmental, protective, and gene-environment factors: none reported. This is an evidence gap, not a negative finding.

3. Phenotypes

Sources are case series only, with about 17 reported patients by 2022 (Gunther et al. 2023, "Renal-hepatic-pancreatic dysplasia type 2: Perinatal lethal condition or a multisystemic disorder with variable expressivity", PMC10094071; PMID not retrieved). The HPO IDs below are unverified leads. Look each one up before binding.

Phenotype Onset Frequency (qualitative) HPO lead Key source
Enlarged cystic or multicystic dysplastic kidneys Fetal Core feature HP:0000107 Renal cyst; HP:0000003 Multicystic kidney dysplasia Frank 2013; Grampa 2016
Renal hypodysplasia (missense genotypes) Fetal Some cases HP:0000089 Renal hypoplasia Grampa 2016
Oligohydramnios / Potter sequence Fetal Frequent in lethal cases HP:0001562 Oligohydramnios inferred from the perinatal-lethal course; check
Hepatic cysts, ductal plate malformation, fibrosis Fetal to infancy Core feature HP:0001407 Hepatic cysts; HP:0001395 Hepatic fibrosis Frank 2013
Paucity of bile ducts Fetal Some cases look up Grampa 2016 ("reduced bile ducts")
Neonatal cholestasis progressing to end-stage liver disease Neonatal Survivors HP:0001396 Cholestasis 2020 sibling report (title only; PMID not retrieved)
Pancreatic cysts and dysplasia Fetal Core feature HP:0001737 Pancreatic cysts Frank 2013
Congenital heart disease (septal defects, thickened septum) Fetal Frequent HP:0001629 VSD; HP:0001631 ASD Frank 2013; Grampa 2016; Rajagopalan 2016
Situs inversus / heterotaxy Fetal Some cases HP:0001696 Situs inversus totalis Grampa 2016
End-stage kidney disease in childhood Childhood Survivors HP:0003774 Stage 5 CKD Rajagopalan 2016; Gunther 2023
  • Quality of life: there are no QoL data. In survivors, the burden comes from dialysis, transplant, and liver failure.
  • Pediatric framing: this is a prenatal or neonatal entity. Variable expressivity separates fetal lethality from childhood survival with progressive kidney and liver failure. NPHP9 (juvenile nephronophthisis) and AD-PKD (neonatal-onset cystic kidneys without consistent extra-renal disease, per Claus 2023) are different clinical entities from the same gene.

4. Genetics and molecular information

  • Gene: NEK8, 17q11.2, HGNC:13387 (hgnc:13387 in repo form). The protein is a serine/threonine kinase: an N-terminal NIMA-like kinase domain followed by C-terminal RCC1 repeats.
  • Variant classes:
  • Nonsense and truncating variants, often homozygous, give the enlarged-cystic-organ RHPD2 picture.
  • Missense variants give hypodysplasia (Grampa 2016: "missense and nonsense mutations were associated with hypodysplasia and enlarged cystic organs, respectively", paraphrase).
  • Compound-heterozygous variants were found in siblings who survived to ESRD with hepatic and cardiac anomalies (Rajagopalan et al. 2016, Am J Med Genet A; PMID not retrieved, [memory] 27530628).
  • NPHP9 variants sit in the RCC1 repeats, one in the same repeat as the mouse jck allele (Otto et al. 2008, JASN 19:587–92, PMID 18199800 [confirmed]). The search summary garbled the variant names, so take them from the abstract.
  • Dominant: heterozygous kinase-domain missense p.Arg45Trp (recurrent, often de novo, including mosaic cases), p.Ile150Met and p.Lys157Gln cause AD-PKD in 12 families through a proposed dominant-negative effect (Claus et al. 2023, Kidney Int 104:995–1007, doi:10.1016/j.kint.2023.07.021, PMC10592035; PMID [memory] 37598857).
  • Codon 45 is also, from memory, the site of the Frank 2013 nonsense variant (p.Arg45*). This needs checking. If true, the same codon gives AR truncation and AD missense disease.
  • Functional effect in RHPD2: loss of function. Missense versus truncating alleles affect YAP differently (Grampa 2016).
  • ACMG, gnomAD, ClinVar: not checked in this session.
  • Somatic vs germline: RHPD2 is germline. Mosaicism has been reported only for the dominant R45W allele (Claus 2023).
  • Modifier genes, epigenetic changes, chromosomal abnormalities: none reported.
  • Second cohort source: an "inferred novel variant in NEK8" (deduced from parental DNA only) in 44 Saudi families with antenatal cystic kidney disease (Al-Hamed et al. 2016, J Med Genet 53:338–47, PMC4853542; PMID [memory] 26862157). This is weak, indirect support.

5. Environmental information

Not applicable. No environmental, lifestyle, or infectious contributors are reported.

6. Mechanism and pathophysiology

Causal chain. Steps marked (inferred) are not demonstrated in human tissue.

  1. Biallelic NEK8 loss-of-function variants lead to absent or defective NEK8 kinase in the ciliary inversin compartment.
  2. NEK8 is a core member of the INV complex with INVS (NPHP2), NPHP3 and ANKS6.
  3. ANKS6 binds the NEK8 kinase domain to activate it, and needs NEK8 to reach that compartment (Czarnecki et al. 2015, Nat Commun 6:6023, PMID 25599650 [lead]; model organism and in vitro).
  4. Loss of INV-complex kinase signaling results in Hippo pathway dysregulation.
  5. NEK8 binds TAZ and drives it into the nucleus (Habbig et al. 2012, Hum Mol Genet 21:5528–38, PMID 23026745 [confirmed]; in vitro).
  6. NEK8 variants alter YAP regulation in patient fibroblasts, Nek8-null spheroids and jck kidneys (Grampa et al. 2016, PLoS Genet 12:e1005894, PMC4788435; PMID [memory] 26967905).
  7. Patient fibroblasts showed lower PKD1/PKD2 and higher c-MYC (Frank 2013).
  8. Branch A (kidney, liver, pancreas): altered YAP/TAZ output and polycystin signaling lead to too much epithelial proliferation and failed tubule and duct differentiation, giving cystic dysplasia of kidney, biliary ductal plate and pancreatic ducts.
  9. The polycystin link is supported: Nek8-null cells respond poorly to fluid shear, which suggests NEK8 mediates polycystin-2-dependent signaling (Manning et al. 2013).
  10. Dominant R45W and K157Q reduce ciliary polycystin-2 (Claus 2023).
  11. Verteporfin, a YAP inhibitor, partly rescued spheroid and zebrafish defects (Grampa 2016). That is pharmacological support for YAP as the mediator, so directness: INDIRECT.
  12. Branch B (laterality and heart): NEK8 loss in node cilia leads to misexpression of left-sided markers, which causes heterotaxy and cardiac malformations. In Nek8-null mice cilia form normally but nodal signaling fails (Manning et al. 2013, JASN 24:100–12, PMID 23274954 [confirmed]; model organism).
  13. Branch C (in parallel; contribution to the human disease not yet shown): NEK8 loss leads to replication stress, because without NEK8 the ATR pathway no longer holds back S-phase CDK activity. This causes DNA damage and disordered renal cell architecture, and ciliopathy alleles impair this function (Choi et al. 2013, Mol Cell 51:423–39, PMID 23973373 [lead]; model organism and in vitro).
  14. Dysplasia and cysts result in clinical failure of the affected organs:
  15. oligohydramnios and pulmonary hypoplasia lead to perinatal death (inferred);
  16. in survivors, ESKD, cholestatic liver failure, and heart disease.

Ontology leads (all unverified): - GO: - GO:0097543 ciliary inversin compartment - GO:0004674 protein serine/threonine kinase activity - GO:0035329 hippo signaling - GO:0007368 determination of left/right symmetry - GO:0060271 cilium assembly - GO:0072001 renal system development - GO:0006974 DNA damage response - CL: - kidney tubule epithelial cell - cholangiocyte (CL:1000488?) - pancreatic ductal cell - node cilia-bearing cells - Subcellular: primary cilium (GO:0072372), centrosome (GO:0005813), nucleus (for TAZ/YAP).

Omics: none found for human RHPD2 (no GEO, single-cell or proteomics data).

7. Anatomical structures

  • Primary: kidney (UBERON:0002113), liver and intrahepatic bile ducts, pancreas (UBERON:0001264).
  • Secondary: heart (septa), body axis (situs).
  • Organ involvement is bilateral and symmetric.
  • The UBERON IDs are leads; look them up before binding.

8. Temporal development

  • Onset: congenital. Most cases are seen on prenatal ultrasound.
  • Course: usually perinatal death. Gunther 2023 reports, in the UTHealth abstract, that "13 [of 17] died within the perinatal period" (pregnancy to age 1).
  • Survivors follow a progressive course:
  • death at 5 years from renal failure;
  • death at 30 months from liver and kidney failure;
  • two alive at 1 and 13 years.
  • Critical period: the second trimester and earlier, when organ morphogenesis happens. No staging scheme exists.

9. Inheritance and population

  • Inheritance: autosomal recessive (ClinGen: AR, Definitive).
  • Penetrance: appears complete for biallelic null alleles, but expressivity varies widely.
  • Other genetic features: no anticipation reported; consanguinity contributes. A founder effect has not been established (Saudi and other Middle Eastern families appear among the reports).
  • Prevalence: fewer than 20 patients in the literature by 2022. Use CASES_IN_LITERATURE (about 17, Gunther 2023), class ULTRA_RARE. Incidence, carrier frequency and sex ratio are not reported.

10. Diagnostics

  • Prenatal ultrasound: enlarged hyperechoic or cystic kidneys, oligohydramnios, cardiac defects, situs anomalies.
  • Pathology: autopsy shows cystic dysplasia, ductal plate malformation, and pancreatic cysts and fibrosis.
  • Genetic testing: exome or genome sequencing, or a ciliopathy / cystic-kidney gene panel. PanelApp lists NEK8 on its Cystic kidney disease and Renal ciliopathies panels. Claus 2023 recommends including NEK8 on PKD panels for children and adults.
  • Differential diagnosis:
  • RHPD1 (NPHP3);
  • Meckel syndrome (looks for encephalocele and polydactyly);
  • ARPKD (PKHD1);
  • ANKS6 and INVS ciliopathies;
  • Jeune / short-rib syndromes;
  • glomerulocystic disease.
  • Screening: carrier testing and prenatal or preimplantation testing for known familial variants.
  • No GeneReviews chapter was found. Confirm with just check-genereviews.

11. Outcome and prognosis

  • Mortality: high perinatal mortality (13 of 17).
  • Survivors: progress to ESKD and end-stage liver disease in childhood.
  • Prognostic factors: a truncating versus missense genotype correlation is suggested (Grampa 2016) but not validated.
  • Biomarkers: no prognostic biomarkers.

12. Treatment

There is no disease-specific therapy. Care is supportive. NCIT leads: - dialysis; - kidney transplantation and combined liver–kidney transplantation (NCIT:C15289 Organ Transplantation); - cardiac surgery for structural heart defects (NCIT:C15329 Surgical Procedure); - supportive or palliative perinatal care (NCIT:C15747 Supportive Care); - genetic counseling (NCIT:C15240).

Verteporfin is preclinical only (spheroid and zebrafish; Grampa 2016). No clinical trials were found, though no registry search was run.

13. Prevention

  • Genetic counseling for families: 25% recurrence risk.
  • Cascade carrier testing.
  • Prenatal or preimplantation genetic testing.
  • Tertiary prevention: manage kidney and liver failure and refer for transplant.

14. Other species

No naturally occurring animal disease was found (OMIA not searched). NEK8 is conserved in mouse (Nek8) and zebrafish (nek8).

15. Model organisms

Model Phenotype Fidelity / limits Source
jck mouse (spontaneous Nek8 G448V missense in an RCC1 repeat) Juvenile polycystic kidney disease; long cilia with more ciliary PC1/PC2 (secondary reports) Kidney only; models a hypomorphic NPHP/PKD allele, not multi-organ RHPD2 Liu et al. 2002, Development 129:5839, PMID 12421721 [lead], from ZFIN
Nek8-null mouse Dies at birth; randomized left-right asymmetry, heart anomalies, glomerular cysts Reproduces laterality, heart and kidney features; liver and pancreas less described Manning 2013, PMID 23274954
Nek8^Roc (kinase-dead) and Anks6^Strkr mice Heterotaxy, cardiopulmonary malformations, cystic kidneys Shows that kinase activity is what matters Czarnecki 2015
Zebrafish nek8 morphants / overexpression Pronephric cysts; randomized heart looping; verteporfin-rescuable overexpression defects Morpholino caveats Liu 2002; Manning 2013; Grampa 2016
Patient fibroblasts; Nek8-KO IMCD3 cells; 3D spheroids Lower PKD1/PKD2, higher c-MYC; YAP imbalance; reduced ciliary PC2 (dominant alleles) In vitro Frank 2013; Grampa 2016; Claus 2023

Databases: MGI (Nek8), ZFIN.

Gaps and to-dos before curation

  • Confirm the PMIDs for Frank 2013, Grampa 2016, Claus 2023, Rajagopalan 2016, Al-Hamed 2016, Gunther 2023 and the 2020 cholestasis report. Confirm the variant nomenclature against the abstracts.
  • No exact snippets have been verified yet.
  • ORPHA and OMIM 613824 still need checking.
  • An untracked placeholder kb/disorders/Renal-Hepatic-Pancreatic_Dysplasia_2.yaml (name, date and MONDO term only) is already in this worktree. I left it unchanged; no branch, commit or claim was made.

Sources: - Frank 2013 (CORE); GO wiki, HUMAN:NEK8 - Grampa 2016 (PMC4788435) - Otto 2008 (PMC2391043) - Claus 2023 (PMC10592035) - Rajagopalan 2016 (Sapienza IRIS) - Atlas of Genetics, NEK8 - Liu 2002 (ZFIN) - Manning 2013 (PMC3537214) - Choi 2013 (PMC3790667) - Czarnecki 2015 (PMC4361001) - Habbig 2012 (PubMed 23026745) - Al-Hamed 2016 (PMC4853542) - Gunther 2023 (PMC10094071); UTHealth repository record - RHPD aggregator (DrugMAP) - PanelApp, NEK8 - LOVD RHPD2

Reference Validation

Checked with linkml-reference-validator 0.5.1.

Outcome Count
References checked 18
Resolved 18
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 18
On topic 10
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 33
Resolved 30
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 2
Terms whose name was checked 4
Terms named correctly 1
Terms named as a different term 1
Terms whose name is worth a second look 2

Terms the report names something else

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

  • GO:0072372 (1 mention) - the report calls it "Subcellular: primary cilium"; GO calls it GO_0072372**

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:0004691 (1 mention) - the report calls it "NEK8 / ADPKD"; MONDO calls it autosomal dominant polycystic kidney disease, and lists "ADPKD" among its other names
  • UBERON:0002113 (1 mention) - the report calls it "Primary: kidney"; UBERON calls it kidney**, and lists "reniculate kidney" among its other names

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.