Renal Tubular Dysgenesis - ACE

Mendelian MONDO:0700337 Pathograph 38 Show in embeddings browser Renal Tubular Dysgenesis of Genetic Origin

Renal tubular dysgenesis - ACE is the autosomal recessive form of renal tubular dysgenesis caused by biallelic loss-of-function variants in ACE, the gene encoding angiotensin I-converting enzyme. Without ACE the fetus cannot convert angiotensin I to angiotensin II, so the renin-angiotensin system cannot sustain fetal blood pressure and renal perfusion. The chronically underperfused fetal kidney fails to differentiate proximal tubules, which is the histological hallmark of the disease. Fetal anuria follows, producing early-onset oligohydramnios or anhydramnios and the Potter sequence with pulmonary hypoplasia, together with skull ossification defects. Most affected fetuses and neonates die from anuria, pulmonary hypoplasia and refractory arterial hypotension, but a growing number of children survive the neonatal period with intensive blood pressure and renal support, and some biallelic ACE genotypes present later as progressive chronic kidney disease with anemia and polyuria. ACE variants are the most frequent cause of renal tubular dysgenesis, found in about two-thirds of families.

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1
Inheritance
11
Pathophys.
3
Histopath.
24
Phenotypes
3
Hypotheses
38
Pathograph
1
Genes
5
Medical Actions
3
Differentials
2
Models
2
References
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected individuals carry homozygous or compound heterozygous loss-of-function ACE variants; heterozygous parents are unaffected and have about half-normal plasma ACE activity.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:16116425 SUPPORT Human Clinical
"found that they had homozygous or compound heterozygous mutations in the genes encoding renin, angiotensinogen, angiotensin converting enzyme or angiotensin II receptor type 1"
The founding molecular study identified biallelic (homozygous or compound heterozygous) RAS gene variants, including ACE, in affected individuals.
PMID:20454656 SUPPORT Human Clinical
"both parents and a brother who are heterozygous carriers of this mutation had exactly half-normal plasma ACE activity compared to healthy individuals"
Unaffected heterozygous relatives with half-normal plasma ACE activity are consistent with recessive inheritance of a loss-of-function allele.
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Mechanistic Hypotheses

3
Fetal renal hypoperfusion arrests proximal tubule differentiation
renal_hypoperfusion CANONICAL
Evidence balance 1 support
Loss of angiotensin II leaves the fetal kidney chronically underperfused, and renal hypoperfusion of any cause prevents proximal tubules from developing and differentiating.
Pathograph links
Loss of Renin-Angiotensin Blood Pressure Support -> Fetal Renal Hypoperfusion DIRECT
Fetal Renal Hypoperfusion -> Proximal Tubule Dysgenesis DIRECT
Show evidence (1 reference)
PMID:22095942 SUPPORT Human Clinical
"Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules."
States the hypoperfusion model across genetic and acquired forms of renal tubular dysgenesis.
Delayed angiogenesis starves developing proximal tubules
delayed_angiogenesis EMERGING
Evidence balance 1 support
Kidney organoid work suggests that proximal tubule dysgenesis is not a cell-autonomous failure of tubular epithelium but a consequence of delayed, VEGF-A-dependent angiogenesis that deprives developing proximal tubules of vascular supply at a critical stage. The engraftment experiments were done in AGTR1-null organoids; ACE-null organoids were shown only to form normal proximal tubules in vitro, so the angiogenesis step is extrapolated to ACE deficiency rather than shown for it.
Pathograph links
Loss of Tissue Angiotensin II Generation -> Delayed Nephrogenic Angiogenesis UNKNOWN Derived from AGTR1-null organoids, in which loss of angiotensin II type 1 receptor signalling left VEGF-A expression insufficient; hypoxia raised VEGF-A and rescued engraftment, so the defect is not attributed to hypoperfusion. Extending it to ACE deficiency is an inference.
Delayed Nephrogenic Angiogenesis -> Proximal Tubule Dysgenesis UNKNOWN
Show evidence (1 reference)
PMID:38071212 SUPPORT In Vitro
"We propose that PT dysgenesis in AR-RTD is primarily a non-autonomous consequence of delayed angiogenesis, starving PT at a critical time in their development."
The authors propose delayed angiogenesis as the proximate cause of proximal tubule dysgenesis.
Lost angiotensin II drive to erythropoiesis explains disproportionate anemia
angiotensin_erythropoiesis EMERGING
Evidence balance 1 support
Proposed explanation for anemia out of proportion to renal failure in biallelic ACE patients. It rests on angiotensinogen- and renin-null mice and a review of angiotensin II actions on erythropoiesis; it has not been tested in ACE-deficient patients, and chronic kidney disease is itself a cause of anemia.
Pathograph links
Loss of Tissue Angiotensin II Generation -> Loss of Angiotensin II-Driven Erythropoiesis UNKNOWN
Loss of Angiotensin II-Driven Erythropoiesis -> Anemia UNKNOWN
Show evidence (1 reference)
PMID:20400218 SUPPORT REVIEW SYNTHESIS Other
"we present evidence that angiotensin II (Ang II) is a physiologically important regulator of erythropoiesis"
Review supporting angiotensin II as a regulator of erythropoiesis.
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Pathophysiology

11
ACE Loss of Function
Biallelic nonsense, frameshift, canonical splice, missense and exon deletion variants leave no functional membrane-bound ACE. Some lethal variants still encode a catalytically active protein (the truncated R762X protein is secreted, and Q1069R retains catalytic properties when it can be rescued to the cell surface), so the loss is of tissue-bound enzyme rather than uniformly of catalytic activity. ACE variants account for about two-thirds of families with renal tubular dysgenesis.
ACE hgnc:2707 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ACE (hgnc:2707). hgnc:2707 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
tissue-bound peptidyl-dipeptidase activity GO:0008241 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased tissue-bound peptidyl-dipeptidase activity, annotated with peptidyl-dipeptidase activity (GO:0008241). GO:0008241 is a molecular function from the Gene Ontology.
Downstream
Loss of Cell-Surface ACE Truncating variants that remove the membrane anchor, and missense variants that misfold, both prevent ACE from reaching the plasma membrane.
Show evidence (3 references)
CGGV:assertion_14a5efd4-d71f-40b1-91ff-90f7f8d63ec7-2024-12-11T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"many nonsense, frameshift, canonical splice, missense, and single and/or multi-exon deletions have been reported in affected individuals"
ClinGen summarizes the range of variant classes reported in affected individuals.
CGGV:assertion_14a5efd4-d71f-40b1-91ff-90f7f8d63ec7-2024-12-11T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"The molecular mechanism of disease is loss-of-function."
ClinGen identifies loss of function as the disease mechanism.
PMID:22095942 SUPPORT Human Clinical
"Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%)."
In a series of 48 families, ACE was the most frequently mutated RAS gene.
Loss of Cell-Surface ACE
Disease-causing ACE variants leave no enzyme at the cell surface. Some missense proteins, such as Q1069R, are retained in the endoplasmic reticulum and degraded by the proteasome; the truncated R762X protein is catalytically active but secreted rather than membrane-anchored. Tissue-bound rather than circulating ACE is what matters: a variant that still reaches the membrane (R1180P) was compatible with survival after transient neonatal renal insufficiency.
Downstream
Loss of Tissue Angiotensin II Generation
Show evidence (4 references)
PMID:24163131 SUPPORT In Vitro
"These results highlight the importance of tissue-bound ACE versus circulating ACE and show that the total absence of cell surface expression of ACE is incompatible with life."
Links absence of cell-surface ACE to lethality and distinguishes it from the presence of circulating enzyme.
PMID:21695262 SUPPORT In Vitro
"ACE Q1069R is found sequestered in the endoplasmic reticulum and is also subject to increased proteasomal degradation, preventing its transport to the cell surface and extracellular fluids."
A patient missense variant causes endoplasmic reticulum retention and degradation rather than loss of catalysis.
PMID:20454656 SUPPORT In Vitro
"CHO cells expressing wild-type (WT) vs. Q1069R-ACE demonstrated the mutant accumulates intracellularly and also that it is significantly degraded by intracellular proteases."
An independent study of the same variant confirms intracellular accumulation and degradation.
+ 1 more reference
Loss of Tissue Angiotensin II Generation
ACE catalyzes the conversion of angiotensin I to angiotensin II. Without membrane-bound ACE, tissue and intrarenal angiotensin II generation fails and the fetal renin-angiotensin system is functionally inactive, even where some circulating enzyme persists.
Delayed angiogenesis starves developing proximal tubules Lost angiotensin II drive to erythropoiesis explains disproportionate anemia
angiotensin maturation GO:0002003 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased angiotensin maturation (GO:0002003). GO:0002003 is a biological process from the Gene Ontology.
Downstream
Loss of Renin-Angiotensin Blood Pressure Support
Reduced Aldosterone Secretion Angiotensin II drives aldosterone secretion from the adrenal zona glomerulosa, so its absence lowers aldosterone.
Compensatory Renin Overexpression Without angiotensin II, feedback inhibition of renin release is lost.
Loss of Angiotensin II-Driven Erythropoiesis Lost angiotensin II drive to erythropoiesis explains disproportionate anemia
Delayed Nephrogenic Angiogenesis Derived from AGTR1-null organoids, in which loss of angiotensin II type 1 receptor signalling left VEGF-A expression insufficient; hypoxia raised VEGF-A and rescued engraftment, so the defect is not attributed to hypoperfusion. Extending it to ACE deficiency is an inference. Delayed angiogenesis starves developing proximal tubules
Microcolon Proposed role of the renin-angiotensin system in intestinal development.
Intestinal perforation Proposed role of the renin-angiotensin system in intestinal development.
Urine Concentrating Defect
Show evidence (3 references)
CGGV:assertion_14a5efd4-d71f-40b1-91ff-90f7f8d63ec7-2024-12-11T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"Angiotensin I-Converting Enzyme (ACE; MIM#106180) catalyzes the conversion of angiotensin I into physiologically active peptide angiotensin II, within the angiotensin-renin system."
States the enzymatic step that is lost.
PMID:20454656 SUPPORT Human Clinical
"was found to have a homozygous substitution of Arg for Glu at position 1069 in the C-terminal domain of ACE (Q1069R) resulting in absence of plasma ACE activity"
A patient with renal tubular dysgenesis had no measurable plasma ACE activity; this is supporting rather than primary, since circulating ACE can persist in lethal cases.
PMID:24163131 SUPPORT In Vitro
"One truncated mutant, R762X, responsible for neonatal death was found to be an enzymatically active, secreted form, not inserted in the plasma membrane."
A lethal variant retained catalytic activity but not membrane insertion, so it is tissue-bound angiotensin II generation that is lost.
Compensatory Renin Overexpression
Renal renin expression is strikingly increased in most autosomal recessive renal tubular dysgenesis kidneys, with renin accumulating in preglomerular arterioles and the glomerular hilum, and plasma renin activity is markedly raised. This is the expected feedback response to absent angiotensin II downstream of renin.
renin-secreting juxtaglomerular granular cell CL:0000648 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves renin-secreting juxtaglomerular granular cell, annotated with kidney granular cell (CL:0000648). CL:0000648 is a cell type from the Cell Ontology.
renin secretion into blood stream GO:0002001 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased renin secretion into blood stream (GO:0002001). GO:0002001 is a biological process from the Gene Ontology.
Downstream
Increased circulating renin concentration
Show evidence (2 references)
PMID:16790508 SUPPORT Human Clinical
"Renal renin expression was strikingly increased in 19 of 24 patients studied, from 13 families, whereas no renal renin was detected in four patients from three families."
Renin is overexpressed in most RTD kidneys; the families without renal renin are consistent with REN or other upstream defects, so the series is not ACE-specific.
PMID:32808512 SUPPORT Human Clinical
"Basal plasma renin activity was markedly elevated and angiotensin-converting enzyme was undetectable."
A neonate with compound heterozygous ACE frameshift variants had markedly elevated plasma renin activity.
Loss of Angiotensin II-Driven Erythropoiesis
Angiotensin II promotes erythropoiesis both as a growth factor for erythroid progenitors and as an erythropoietin secretagogue. Its absence is the proposed reason that anemia in biallelic ACE patients is out of proportion to the degree of renal failure. The supporting data are from angiotensinogen- and renin-null mice and a review, not from ACE-deficient patients.
Lost angiotensin II drive to erythropoiesis explains disproportionate anemia
erythrocyte differentiation GO:0030218 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased erythrocyte differentiation (GO:0030218). GO:0030218 is a biological process from the Gene Ontology.
Downstream
Anemia Lost angiotensin II drive to erythropoiesis explains disproportionate anemia
Show evidence (2 references)
PMID:26107632 SUPPORT INDIRECT Model Organism
"Here we report that knockout mice that lack angiotensin II, including angiotensinogen and renin knockout mice, exhibit anemia. The anemia of angiotensinogen knockout mice was rescued by angiotensin II infusion"
Angiotensin II deficiency causes anemia rescued by angiotensin II in mice; ACE-null mice were not studied, so this is an inference across RAS genes.
PMID:20400218 SUPPORT REVIEW SYNTHESIS Other
"First, Ang II is a growth factor of erythroid progenitors and, in cooperation with erythropoietin, increases red blood cell mass. Second, Ang II acts as an erythropoietin secretagogue to maintain increased erythropoietin levels despite increments in hematocrit."
Review of the two pro-erythropoietic actions of angiotensin II.
Urine Concentrating Defect
Inability to concentrate urine, with papillary hypoplasia in ACE-null mice; in later-presenting patients it appears as polyuria and polydipsia.
renal water absorption GO:0070295 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased renal water absorption (GO:0070295). GO:0070295 is a biological process from the Gene Ontology.
Downstream
Polyuria
Show evidence (2 references)
PMID:8642790 SUPPORT Model Organism
"These animals cannot effectively concentrate urine."
ACE-null mice have a urine concentrating defect.
PMID:18158355 SUPPORT Model Organism
"ACE13/13 mice have a normal renal structure, but they are not able to concentrate urine after dehydration as effectively as wild-type mice."
Even loss of ACE C-domain activity alone impairs urine concentration in mice.
Loss of Renin-Angiotensin Blood Pressure Support
Without angiotensin II the renin-angiotensin system cannot maintain fetal systemic blood pressure and renal blood flow, which are RAS-dependent during human fetal life. Postnatally this appears as refractory arterial hypotension.
Fetal renal hypoperfusion arrests proximal tubule differentiation
regulation of systemic arterial blood pressure by renin-angiotensin GO:0003081 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of systemic arterial blood pressure by renin-angiotensin (GO:0003081). GO:0003081 is a biological process from the Gene Ontology.
Animal models
Ace-null mouse Mouse recapitulates
Downstream
Fetal Renal Hypoperfusion Fetal renal hypoperfusion arrests proximal tubule differentiation
Hypotension
Decreased skull ossification Calvarial underdevelopment has been linked to fetal hypotension or chronic hypoxia. The link is proposed, not demonstrated.
Show evidence (2 references)
PMID:22095942 SUPPORT Human Clinical
"The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during the life of a human fetus."
The same severe course with any RAS gene defect points to RAS-dependent fetal blood pressure and renal blood flow.
PMID:8642790 SUPPORT Model Organism
"Mice homozygous for this mutant allele lack both ACE isozymes and have markedly reduced blood pressures."
ACE-null mice are markedly hypotensive.
Fetal Renal Hypoperfusion
Chronically low perfusion pressure in the fetal kidney, the immediate consequence of renin-angiotensin system inactivity.
Fetal renal hypoperfusion arrests proximal tubule differentiation
Downstream
Proximal Tubule Dysgenesis Fetal renal hypoperfusion arrests proximal tubule differentiation
Anuria
Show evidence (1 reference)
PMID:16116425 SUPPORT Human Clinical
"We propose that renal lesions and early anuria result from chronic low perfusion pressure of the fetal kidney, a consequence of renin-angiotensin system inactivity."
The founding study proposes chronic fetal renal hypoperfusion as the central lesion.
Delayed Nephrogenic Angiogenesis
Insufficient VEGF-A expression, attributed to lost angiotensin II type 1 receptor signalling, delays vascularization of developing nephrons. In AGTR1-null kidney organoids, renal-vesicle-stage grafts failed to engraft for lack of pro-angiogenic VEGF-A, and hypoxia or ectopic VEGF-A rescued engraftment.
Delayed angiogenesis starves developing proximal tubules
kidney vasculature development GO:0061440 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased kidney vasculature development (GO:0061440). GO:0061440 is a biological process from the Gene Ontology.
Downstream
Proximal Tubule Dysgenesis Delayed angiogenesis starves developing proximal tubules
Show evidence (1 reference)
PMID:38071212 SUPPORT INDIRECT In Vitro
"By contrast, d14 AGTR1-/- organoids fail to engraft due to insufficient pro-angiogenic VEGF-A expression. Notably, growth under hypoxic conditions induces VEGF-A expression and rescues engraftment of AGTR1-/- organoids at d14, as does ectopic expression of VEGF-A."
Shows the angiogenesis defect in AGTR1-null organoids; applying it to ACE deficiency is an inference across RAS genes.
Proximal Tubule Dysgenesis
Proximal tubules are absent or poorly differentiated, the histological hallmark of renal tubular dysgenesis. Glomeruli are preserved; distal tubules can appear normal, although in a larger series lesions also involved other tubular segments.
kidney proximal convoluted tubule epithelial cell CL:1000838 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves kidney proximal convoluted tubule epithelial cell (CL:1000838). CL:1000838 is a cell type from the Cell Ontology.
proximal tubule development GO:0072014 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased proximal tubule development (GO:0072014). GO:0072014 is a biological process from the Gene Ontology.
Experimental models
ACE-null iPSC-derived kidney organoids ORGANOID ACE-null organoids formed proximal tubules indistinguishable from controls in vitro.
Downstream
Absent or poorly differentiated proximal tubules
Anuria
Chronic kidney disease Survivors carry the developmental tubular deficit forward as chronic kidney disease.
Show evidence (3 references)
PMID:16116425 SUPPORT Human Clinical
"Absence or paucity of differentiated proximal tubules is the histopathological hallmark of the disease"
Defines the tissue lesion.
PMID:20607303 SUPPORT Human Clinical
"A revision of renal tissue obtained from a sibling that died shortly after birth revealed normal glomeruli and distal tubules but no identifiable proximal tubules."
Renal histology in a sibling of an ACE-mutated child showed selective absence of proximal tubules.
PMID:16790508 SUPPORT Human Clinical
"Severe defects in proximal tubules were observed in all fetuses from 18 gestational weeks onward, and lesions also involved other tubular segments."
Dates the proximal tubule defect to at least 18 weeks of gestation in a 29-case autosomal recessive RTD series of mixed RAS genotypes.
Reduced Aldosterone Secretion
Low angiotensin II leaves aldosterone low, contributing to hyperkalemia and salt wasting; this is the rationale for mineralocorticoid replacement with fludrocortisone in survivors.
aldosterone secretion GO:0035932 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased aldosterone secretion (GO:0035932). GO:0035932 is a biological process from the Gene Ontology.
Animal models
Ace-null mouse Mouse recapitulates
Downstream
Hyperkalemia
Decreased circulating aldosterone concentration
Show evidence (1 reference)
PMID:25899979 SUPPORT Human Clinical
"In light of the molecular diagnosis, identification, and treatment of associated low aldosterone level resulted in further improvement in renal function"
A neonate with compound heterozygous ACE frameshift variants had low aldosterone.
✶

Histopathology

3
Absence or paucity of differentiated proximal tubules
Cortical tubules lack proximal differentiation from at least 18 weeks of gestation; this is the defining lesion.
Show evidence (2 references)
PMID:16116425 SUPPORT Human Clinical
"Absence or paucity of differentiated proximal tubules is the histopathological hallmark of the disease"
Defines the diagnostic histological lesion.
PMID:16790508 SUPPORT Human Clinical
"Severe defects in proximal tubules were observed in all fetuses from 18 gestational weeks onward, and lesions also involved other tubular segments."
Mixed-genotype autosomal recessive RTD series dating the lesion.
Thickening of the renal arterial wall
Thickened renal arterial vasculature from the arcuate to the afferent arteries. Shown in a mixed-genotype autosomal recessive RTD series, not reported separately for ACE cases; ACE-null and secreted-ACE mice show intrarenal vascular hyperplasia and thickening.
Show evidence (2 references)
PMID:16790508 SUPPORT Human Clinical
"They were associated with thickening of the renal arterial vasculature, from the arcuate to the afferent arteries."
Arterial wall thickening accompanies the tubular lesions in human RTD.
PMID:8642790 SUPPORT Model Organism
"the intrarenal arteries exhibit vascular hyperplasia associated with a perivascular inflammatory infiltrate"
ACE-null mice show intrarenal vascular hyperplasia.
Increased renal renin expression
Strikingly increased renin in the juxtaglomerular apparatus and preglomerular arterioles in most autosomal recessive RTD kidneys.
Show evidence (1 reference)
PMID:16790508 SUPPORT Human Clinical
"Renal renin expression was strikingly increased in 19 of 24 patients studied, from 13 families, whereas no renal renin was detected in four patients from three families."
Renin overexpression in most cases of a mixed-genotype series.
⬡

Pathograph

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

24
Blood 1
Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32198635 SUPPORT Human Clinical
"In all cases, patients were affected with anemia whose severity was unexpected regarding the level of renal failure and with important polyuro-polydipsia."
Disproportionate anemia in three unrelated patients with biallelic ACE variants.
Cardiovascular 1
Hypotension VERY_FREQUENT HP:0002615 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Refractory arterial hypotension, annotated with Hypotension (HP:0002615), qualified as neonatal onset. HP:0002615 is a phenotype from the Human Phenotype Ontology.
Onset: NEONATAL
Show evidence (2 references)
PMID:22095942 SUPPORT Human Clinical
"Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension."
Refractory hypotension is a principal cause of death.
PMID:25899979 SUPPORT Human Clinical
"Vasopressin was used to successfully treat refractory hypotension and anuria in the neonate born at 27 weeks of gestation."
A neonate with ACE frameshift variants had refractory hypotension.
Digestive 2
Microcolon HP:0004388 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcolon (HP:0004388). HP:0004388 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30071301 SUPPORT Human Clinical
"We report three patients from two unrelated families with RTD due to pathogenic variants of the angiotensin-converting enzyme (ACE) gene, in whom RTD was associated with microcolon."
Microcolon in three patients with ACE-related RTD.
Intestinal perforation HP:0031368 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intestinal perforation (HP:0031368). HP:0031368 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30071301 SUPPORT Human Clinical
"The severe intestinal developmental abnormality culminating in microcolon and early terminal ileum perforation/necrotizing enterocolitis is a novel finding not previously associated with RTD"
Terminal ileum perforation in patients with ACE-related RTD.
Endocrine 2
Increased circulating renin concentration HP:0000848 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased plasma renin, annotated with Increased circulating renin concentration (HP:0000848). HP:0000848 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32808512 SUPPORT Human Clinical
"Basal plasma renin activity was markedly elevated and angiotensin-converting enzyme was undetectable."
Elevated plasma renin activity in a neonate with ACE variants.
Decreased circulating aldosterone concentration HP:0004319 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low aldosterone, annotated with Decreased circulating aldosterone concentration (HP:0004319). HP:0004319 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25899979 SUPPORT Human Clinical
"identification, and treatment of associated low aldosterone level resulted in further improvement in renal function"
Low aldosterone was found in a neonate with ACE frameshift variants.
Genitourinary 6
Absent or poorly differentiated proximal tubules VERY_FREQUENT Renotubular dysgenesis HP:0008660 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renotubular dysgenesis (HP:0008660). HP:0008660 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16116425 SUPPORT Human Clinical
"Absence or paucity of differentiated proximal tubules is the histopathological hallmark of the disease"
Defines the histological hallmark.
PMID:38091257 SUPPORT Human Clinical
"Additional post-mortem histopathological examination from the renal tissue of the second fetus showed renal tubular hypoplasia."
Post-mortem histology in a fetus with a homozygous ACE nonsense variant.
Anuria VERY_FREQUENT HP:0100519 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anuria (HP:0100519), qualified as fetal onset. HP:0100519 is a phenotype from the Human Phenotype Ontology.
Onset: FETAL
Sequelae: Oligohydramnios Anhydramnios
Show evidence (2 references)
PMID:16116425 SUPPORT Human Clinical
"Autosomal recessive renal tubular dysgenesis is a severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death"
Persistent fetal anuria is a defining feature.
PMID:20607303 SUPPORT Human Clinical
"The infant survived the neonatal period after 2 weeks of anuria subsequently subsiding."
In an ACE-mutated survivor, neonatal anuria resolved after two weeks.
Hyperechogenic kidneys HP:0004719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperechogenic kidneys (HP:0004719). HP:0004719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35848000 SUPPORT Human Clinical
"renal ultrasound showing normal-sized echogenic noncystic kidneys with poor corticomedullary differentiation"
Describes the ultrasound pattern in an infant with biallelic ACE variants.
Reduced renal corticomedullary differentiation HP:0005565 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced renal corticomedullary differentiation (HP:0005565). HP:0005565 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35848000 SUPPORT Human Clinical
"renal ultrasound showing normal-sized echogenic noncystic kidneys with poor corticomedullary differentiation"
Poor corticomedullary differentiation on ultrasound.
Chronic kidney disease HP:0012622 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic kidney disease (HP:0012622). HP:0012622 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20607303 SUPPORT Human Clinical
"A novel mutation in the ACE gene was found in the surviving child, who remains with stage 4 chronic kidney disease and normal neurodevelopment."
A three-year-old ACE-mutated survivor has stage 4 CKD.
PMID:32198635 SUPPORT Human Clinical
"Bi-allelic loss of function mutation of ACE can have atypical and sometimes late presentation with chronic renal failure, anemia (out of proportion with the level of renal failure), and polyuro-polydipsia."
Biallelic ACE variants can present late as chronic renal failure.
Polyuria HP:0000103 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polyuria (HP:0000103). HP:0000103 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32198635 SUPPORT Human Clinical
"In all cases, patients were affected with anemia whose severity was unexpected regarding the level of renal failure and with important polyuro-polydipsia."
Marked polyuria-polydipsia in patients with biallelic ACE variants.
Head and Neck 4
Potter sequence facies Potter facies HP:0002009 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Potter facies (HP:0002009). HP:0002009 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35286024 SUPPORT BACKGROUND Human Clinical
"manifests as fetal anuria leading to oligohydramnios and Potter sequence"
The Potter sequence, of which Potter facies is a component, is part of the presentation.
Decreased skull ossification HP:0004331 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased skull ossification (HP:0004331). HP:0004331 is a phenotype from the Human Phenotype Ontology.
Sequelae: Large fontanelles Wide cranial sutures
Show evidence (2 references)
PMID:22095942 SUPPORT Human Clinical
"leading to oligohydramnios and the Potter sequence, associated with skull ossification defects"
Skull ossification defects are part of the phenotype.
PMID:20607303 SUPPORT Human Clinical
"It is characterized by oligohydramnios, prematurity, hypotension, hypocalvaria, and neonatal renal failure."
Hypocalvaria is listed among the characteristic features.
Large fontanelles HP:0000239 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Large fontanelles (HP:0000239). HP:0000239 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32808512 SUPPORT Human Clinical
"skull X-ray showed large fontanelles and wide sutures suggestive of ossification delay"
Skull radiograph findings in a neonate with compound heterozygous ACE variants.
Wide cranial sutures HP:0010537 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide cranial sutures (HP:0010537). HP:0010537 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32808512 SUPPORT Human Clinical
"skull X-ray showed large fontanelles and wide sutures suggestive of ossification delay"
Skull radiograph findings in a neonate with compound heterozygous ACE variants.
Metabolism 1
Hyperkalemia HP:0002153 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperkalemia (HP:0002153). HP:0002153 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20607303 SUPPORT Human Clinical
"Hypotension and hyperkalemia normalized eventually with administration of fludrocortisone."
An ACE-mutated survivor had hyperkalemia responsive to fludrocortisone.
Musculoskeletal 1
Joint contractures HP:0034392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint contracture (HP:0034392). HP:0034392 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
CGGV:assertion_14a5efd4-d71f-40b1-91ff-90f7f8d63ec7-2024-12-11T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"prenatal phenotypes including oligo- or anhydramnios, contractures, increased renal echogenicity, skull ossification defects, intrauterine fetal demise or stillbirth"
ClinGen lists contractures among scored prenatal phenotypes.
Prenatal and Birth 3
Oligohydramnios VERY_FREQUENT HP:0001562 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oligohydramnios (HP:0001562). HP:0001562 is a phenotype from the Human Phenotype Ontology.
Sequelae: Pulmonary hypoplasia Potter sequence facies Joint contractures
Show evidence (2 references)
PMID:22095942 SUPPORT Human Clinical
"early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence"
Oligohydramnios is a core prenatal feature.
PMID:26069751 SUPPORT BACKGROUND Human Clinical
"The typical revealing symptom is oligohydramnios resulting from reduced fetal urine production."
Oligohydramnios is the usual presenting sign.
Anhydramnios HP:0025700 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anhydramnios (HP:0025700). HP:0025700 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38091257 SUPPORT Human Clinical
"We report two cases of fetuses with anhydramnios and invisible urinary bladder."
Two fetuses with homozygous ACE nonsense variants had anhydramnios.
Premature birth HP:0001622 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Premature birth (HP:0001622). HP:0001622 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20607303 SUPPORT Human Clinical
"It is characterized by oligohydramnios, prematurity, hypotension, hypocalvaria, and neonatal renal failure."
Prematurity is a characteristic feature.
Respiratory 2
Pulmonary hypoplasia FREQUENT HP:0002089 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary hypoplasia (HP:0002089). HP:0002089 is a phenotype from the Human Phenotype Ontology.
Sequelae: Respiratory insufficiency
Show evidence (1 reference)
PMID:22095942 SUPPORT Human Clinical
"Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension."
Pulmonary hypoplasia is a leading cause of early death.
Respiratory insufficiency HP:0002093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory insufficiency (HP:0002093). HP:0002093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40519134 SUPPORT Human Clinical
"Postnatally, the patient had anuric renal failure, medically refractory hypotension, and respiratory failure in the setting of pulmonary hypoplasia."
A neonate with biallelic ACE loss-of-function variants had respiratory failure with pulmonary hypoplasia.
Growth 1
Intrauterine growth retardation HP:0001511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intrauterine growth retardation (HP:0001511). HP:0001511 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40519134 SUPPORT Human Clinical
"a premature female neonate with prenatal oligohydramnios and growth restriction"
Growth restriction in a neonate with biallelic ACE variants.
🧬

Genetic Associations

1
ACE (Causative biallelic loss-of-function variants)
Gene: ACE hgnc:2707 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ACE (hgnc:2707). hgnc:2707 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (4 references)
PMID:16116425 SUPPORT Human Clinical
"found that they had homozygous or compound heterozygous mutations in the genes encoding renin, angiotensinogen, angiotensin converting enzyme or angiotensin II receptor type 1"
First identification of biallelic ACE variants in RTD.
PMID:25899979 SUPPORT Human Clinical
"Truncating alterations in ACE most often result in fetal demise during gestation or in the first days of life and typically as a result of the Potter sequence."
Summarizes the usual outcome of truncating ACE variants.
PMID:24163131 SUPPORT Human Clinical
"In contrast, another mutant, R1180P, was compatible with life after transient neonatal renal insufficiency."
The R1180P carrier survived after transient neonatal renal insufficiency.
+ 1 more reference
🗃️

External Assertions

1
ClinGen ACE-renal tubular dysgenesis assertion
ClinGen gene disease validity CGGV:assertion_14a5efd4-d71f-40b1-91ff-90f7f8d63ec7-2024-12-11T170000.000Z
The ClinGen Prenatal Gene Curation Expert Panel classifies the autosomal recessive ACE-renal tubular dysgenesis relationship (MONDO:0700337) as definitive.
Show evidence (1 reference)
CGGV:assertion_14a5efd4-d71f-40b1-91ff-90f7f8d63ec7-2024-12-11T170000.000Z SUPPORT Other
"ACE | HGNC:2707 | renal tubular dysgenesis - ACE | MONDO:0700337 | AR | Definitive"
The ClinGen structured assertion records a definitive autosomal recessive relationship between ACE and this disease concept.
💊

Medical Actions

5
Vasopressin for refractory hypotension
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: vasopressin CHEBI:9937 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses vasopressin (CHEBI:9937). CHEBI:9937 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Peptide
Vasopressin, acting independently of angiotensin II, has reversed refractory neonatal hypotension and anuria in ACE-deficient neonates.
Mechanism Target:
Hypotension
Show evidence (2 references)
PMID:25899979 SUPPORT Human Clinical
"Vasopressin was used to successfully treat refractory hypotension and anuria in the neonate born at 27 weeks of gestation."
Single-case report of vasopressin reversing hypotension and anuria.
PMID:35286024 SUPPORT Human Clinical
"We show that both vasopressin and fludrocortisone in the neonatal period may provide survival advantages, though outcomes may also be dependent on the type of gene variant, as well as other factors."
A sibling report and literature review of survivors.
Fludrocortisone mineralocorticoid replacement
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: fludrocortisone CHEBI:50885 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses fludrocortisone (CHEBI:50885). CHEBI:50885 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Fludrocortisone replaces the aldosterone deficit and has corrected hyperkalemia, hypotension and acid-base balance in survivors.
Mechanism Target:
Reduced Aldosterone Secretion
Hyperkalemia
Show evidence (2 references)
PMID:20607303 SUPPORT Human Clinical
"Hypotension and hyperkalemia normalized eventually with administration of fludrocortisone."
Fludrocortisone corrected hyperkalemia and hypotension in an ACE-mutated survivor.
PMID:40930738 SUPPORT Human Clinical
"who has not required renal replacement therapy to date and in whom fludrocortisone has achieved electrolyte and acid/base balance"
Fludrocortisone maintained electrolyte and acid-base balance in an ACE-RTD toddler.
Peritoneal dialysis
Action: Peritoneal dialysisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Peritoneal dialysis (NCIT:C15297). NCIT:C15297 is a clinical intervention from the NCI Thesaurus. Ontology label: Peritoneal Dialysis NCIT:C15297
Platform: Other
Early peritoneal dialysis supports anuric neonates; urine output can appear later, so the postnatal urine trajectory informs decisions about continuing dialysis.
Mechanism Target:
Anuria
Show evidence (2 references)
PMID:42831903 SUPPORT Human Clinical
"We report a preterm neonate with genetically confirmed RTD-ACE who survived beyond the neonatal period following early initiation of peritoneal dialysis and targeted supportive management."
Early peritoneal dialysis in a surviving RTD-ACE neonate.
PMID:20454656 SUPPORT Human Clinical
"maintained by peritoneal dialysis since birth"
A patient with homozygous ACE Q1069R maintained on peritoneal dialysis.
Respiratory support
Action: Mechanical ventilationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Mechanical ventilation (NCIT:C70909). NCIT:C70909 is a clinical intervention from the NCI Thesaurus. Ontology label: Mechanical Ventilation NCIT:C70909
Ventilatory support for respiratory failure from pulmonary hypoplasia, part of the intensive neonatal care that underlies reported survival.
Mechanism Target:
Respiratory insufficiency
Show evidence (3 references)
PMID:40245857 SUPPORT Human Clinical
"Postnatally, critical management strategies include respiratory support, blood pressure stabilization, and renal support/replacement."
Lists respiratory support among the critical postnatal measures.
PMID:40245857 SUPPORT Human Clinical
"one infant showed improvement with symptomatic therapies including blood pressure elevation, respiratory support, diuretics, and CRRT and was discharged"
One of three ACE-mutated infants survived with this combined support.
PMID:35848000 SUPPORT Human Clinical
"Initial clinical course was complicated by ventilator requirement, bilateral pneumothoraces, and hypotension managed with multiple inotropes."
An infant with biallelic ACE variants required mechanical ventilation.
Genetic counseling and prenatal diagnosis
Action: Genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Molecular diagnosis allows recurrence-risk counseling and early prenatal diagnosis in subsequent pregnancies.
Show evidence (1 reference)
PMID:22095942 SUPPORT Human Clinical
"The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis."
Genetic diagnosis enables counseling and prenatal diagnosis.
🔬

Biochemical Markers

2
Plasma ACE activity (Absent)
Context: Usually undetectable; it can be present when a truncating variant produces a secreted, catalytically active enzyme. Heterozygous parents have about half of normal activity.
Show evidence (2 references)
PMID:20454656 SUPPORT Human Clinical
"was found to have a homozygous substitution of Arg for Glu at position 1069 in the C-terminal domain of ACE (Q1069R) resulting in absence of plasma ACE activity"
No plasma ACE activity in an affected patient.
PMID:32808512 SUPPORT Human Clinical
"Basal plasma renin activity was markedly elevated and angiotensin-converting enzyme was undetectable."
ACE undetectable in a second affected neonate.
Plasma renin activity (Elevated)
Context: Markedly elevated, reflecting loss of angiotensin II feedback.
Show evidence (1 reference)
PMID:32808512 SUPPORT Human Clinical
"Basal plasma renin activity was markedly elevated and angiotensin-converting enzyme was undetectable."
Elevated plasma renin activity in an ACE-deficient neonate.
🔬

Diagnosis

3
Exome sequencing of amniotic fluid after amnioinfusion
In anhydramnios, amnioinfusion allows amniotic fluid sampling and better ultrasound assessment; clinical exome sequencing then identifies biallelic ACE variants.
clinical whole-exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic ACE variants.
Show evidence (1 reference)
PMID:38091257 SUPPORT Human Clinical
"In cases of oligohydramnios/anhydramnios suspicious for urinary tract anomalies, amnioinfusion is a meaningful technique that facilitates sampling of amniotic fluid for genetic diagnosis."
Amnioinfusion enables prenatal genetic sampling.
Renal histology at biopsy or autopsy
Renal histology showing absent or poorly differentiated proximal tubules establishes renal tubular dysgenesis morphologically, and molecular testing identifies the gene.
kidney biopsy NCIT:C51699 NCI Thesaurus (NCIT)
Results: Absence or paucity of differentiated proximal tubules.
Show evidence (1 reference)
PMID:16790508 SUPPORT Human Clinical
"The identification of the disease on the basis of precise histologic analysis and the research of the genetic defect now allow genetic counseling and early prenatal diagnosis."
Histology plus genetic testing is the diagnostic route.
Plasma renin and ACE measurement
Markedly elevated plasma renin activity with undetectable ACE in an anuric, hypotensive neonate points to RTD-ACE ahead of genetic confirmation.
Results: Elevated plasma renin activity; undetectable ACE.
Show evidence (1 reference)
PMID:32808512 SUPPORT Human Clinical
"Basal plasma renin activity was markedly elevated and angiotensin-converting enzyme was undetectable."
The biochemical pattern that prompted ACE testing.
📈

Progression

2
Perinatal lethality
Age: Late gestation to the first days after birth
Most affected pregnancies end in late-gestation stillbirth or death in the first days of life from anuria, pulmonary hypoplasia and refractory hypotension. Recorded here rather than as phenotypes because the HPO death terms (HP:0003826 Stillbirth, HP:0003811 Neonatal death) sit outside the PhenotypeTerm enum's phenotypic-abnormality root.
Show evidence (2 references)
PMID:38091257 SUPPORT Human Clinical
"nearly all affected fetuses die after birth or have a stillbirth in late gestation"
Late-gestation stillbirth or death after birth is the usual outcome.
PMID:22095942 SUPPORT Human Clinical
"Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension."
Names the causes of early death.
Survival beyond the neonatal period
Age: Infancy onward
A minority survive with intensive support; urine output may appear after days to weeks, and survivors usually have chronic kidney disease. A literature review counted 18 earlier cases with better outcomes.
Show evidence (3 references)
PMID:35286024 SUPPORT Human Clinical
"While AR-RTD is most often a lethal disease in the neonatal period, it is not universally so."
Neonatal lethality is most common but not universal.
PMID:40245857 SUPPORT Human Clinical
"During the 27-month follow-up, this patient exhibited normal renal function and ultrasound findings."
One ACE-mutated survivor had normal renal function at 27 months.
PMID:34957720 SUPPORT Human Clinical
"In 4/5 patients we identified a mutation in angiotensin converting enzyme (ACE) gene. Variable presentation was noticed in the patients, starting with peritoneal dialysis and extreme low blood pressure treated with vasopressors and plasma infusions and ending with no symptoms. Currently, the..."
Five neonatal survivors, four with ACE variants, reached 5 to 20 years with variable chronic kidney disease.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Renal Tubular Dysgenesis - ACE:

Fetal ACE inhibitor or angiotensin receptor blocker fetopathy
Overlapping Features Maternal ACE inhibitor or angiotensin II receptor blocker use in the second or third trimester produces an acquired phenocopy with reduced proximal tubules and hypocalvaria. A history of maternal exposure distinguishes it; it is not modeled as an environmental cause here because this entry is the gene-defined form.
Show evidence (2 references)
PMID:34082612 SUPPORT Human Clinical
"AA fetopathy phenotype is similar to renal tubular dysgenesis including reduced proximal convoluted tubules (PCTs)."
Establishes the drug-induced phenocopy.
PMID:9222960 SUPPORT Human Clinical
"The clinical, pathological, and radiological features are similar to the phenotype associated with fetal exposure to angiotensin converting enzyme (ACE) inhibitors"
Familial RTD closely resembles ACE inhibitor fetopathy.
Renal tubular dysgenesis due to REN, AGT or AGTR1 variants
Overlapping Features Biallelic variants in the other renin-angiotensin genes produce the same phenotype with similar severity; only molecular testing separates them. MONDO has no gene-specific term for these forms.
Show evidence (1 reference)
PMID:22095942 SUPPORT Human Clinical
"The severity of the clinical course was similar whatever the mutated gene"
Clinical course does not distinguish the RAS genes.
Renal tubular dysgenesis due to twin-twin transfusion Not Yet Curated MONDO:0019984
Overlapping Features Acquired renal hypoperfusion in the donor twin of twin-twin transfusion syndrome can also produce renal tubular dysgenesis.
🧫

Experimental Models

1
ACE-null iPSC-derived kidney organoids ORGANOID
ACE-/- and AGTR1-/- iPSC lines and patient-derived iPSCs differentiated into kidney organoids, compared with controls under normoxic and hypoxic culture.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:38071212
Pathograph links
Proximal Tubule Dysgenesis fails to recapitulate fidelity: low observes: tissue ACE-null organoids formed proximal tubules indistinguishable from controls in vitro.
Limitations: Organoids have no perfused vasculature, blood pressure or circulating renin-angiotensin system, which is the compartment the canonical hypoperfusion model invokes; normal proximal tubules in vitro argue against a cell-autonomous tubular defect rather than against the disease mechanism.
Divergences from the human mechanism
boundary omission qualifying
Systemic blood pressure, renal perfusion and the circulating renin-angiotensin cascade are absent from the organoid, so it can only test whether ACE loss acts within developing nephron cells.
Show evidence (1 reference)
PMID:38071212 SUPPORT In Vitro
"Comprehensive marker analyses show that both mutant and control organoids generate indistinguishable PT in vitro under normoxic (21% O2) or hypoxic (2% O2) conditions."
ACE-null and control organoids generated indistinguishable proximal tubules.
🐁

Animal Models

1
Ace-null mouse
Mice lacking both ACE isozymes are markedly hypotensive with severe renal disease, including a reduced papilla, intrarenal vascular hyperplasia and a urine concentrating defect, and reduced aldosterone.
Species
Mouse
Genotype
Ace homozygous targeted null (lacking somatic and testis ACE)
Publication
PMID:8642790
Pathograph links
Loss of Renin-Angiotensin Blood Pressure Support recapitulates fidelity: moderate observes: organism
Limitations: Mouse nephrogenesis continues after birth and the renal lesion is papillary and vascular rather than the absent proximal tubules of human fetal disease, so the model reproduces RAS-dependent hypotension better than the tubular lesion.
Show evidence (1 reference)
PMID:8642790 SUPPORT Model Organism
"Mice homozygous for this mutant allele lack both ACE isozymes and have markedly reduced blood pressures."
ACE-null mice are markedly hypotensive.
Reduced Aldosterone Secretion recapitulates fidelity: moderate observes: organism
Show evidence (1 reference)
PMID:8642790 SUPPORT Model Organism
"They also have an abnormally low urinary sodium to potassium ratio despite reduced levels of aldosterone."
ACE-null mice have reduced aldosterone.
{ }

Source YAML

click to show 
name: Renal Tubular Dysgenesis - ACE
creation_date: "2026-10-09T13:24:52Z"
category: Mendelian
description: >-
  Renal tubular dysgenesis - ACE is the autosomal recessive form of renal
  tubular dysgenesis caused by biallelic loss-of-function variants in ACE, the
  gene encoding angiotensin I-converting enzyme. Without ACE the fetus cannot
  convert angiotensin I to angiotensin II, so the renin-angiotensin system
  cannot sustain fetal blood pressure and renal perfusion. The chronically
  underperfused fetal kidney fails to differentiate proximal tubules, which is
  the histological hallmark of the disease. Fetal anuria follows, producing
  early-onset oligohydramnios or anhydramnios and the Potter sequence with
  pulmonary hypoplasia, together with skull ossification defects. Most affected
  fetuses and neonates die from anuria, pulmonary hypoplasia and refractory
  arterial hypotension, but a growing number of children survive the neonatal
  period with intensive blood pressure and renal support, and some biallelic
  ACE genotypes present later as progressive chronic kidney disease with
  anemia and polyuria. ACE variants are the most frequent cause of renal
  tubular dysgenesis, found in about two-thirds of families.
synonyms:
- ACE related renal tubular dysgenesis
- ACE-related autosomal recessive renal tubular dysgenesis
- RTD-ACE
disease_term:
  preferred_term: renal tubular dysgenesis - ACE
  term:
    id: MONDO:0700337
    label: renal tubular dysgenesis - ACE
parents:
- Renal Tubular Dysgenesis of Genetic Origin
external_assertions:
- name: ClinGen ACE-renal tubular dysgenesis assertion
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: "CGGV:assertion_14a5efd4-d71f-40b1-91ff-90f7f8d63ec7-2024-12-11T170000.000Z"
  description: >-
    The ClinGen Prenatal Gene Curation Expert Panel classifies the autosomal
    recessive ACE-renal tubular dysgenesis relationship (MONDO:0700337) as
    definitive.
  evidence:
  - reference: "CGGV:assertion_14a5efd4-d71f-40b1-91ff-90f7f8d63ec7-2024-12-11T170000.000Z"
    reference_title: ACE / renal tubular dysgenesis - ACE (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ACE | HGNC:2707 | renal tubular dysgenesis - ACE | MONDO:0700337 | AR |
      Definitive
    explanation: >-
      The ClinGen structured assertion records a definitive autosomal recessive
      relationship between ACE and this disease concept.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Affected individuals carry homozygous or compound heterozygous
    loss-of-function ACE variants; heterozygous parents are unaffected and have
    about half-normal plasma ACE activity.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:16116425
    reference_title: >-
      Mutations in genes in the renin-angiotensin system are associated with
      autosomal recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      found that they had homozygous or compound heterozygous mutations in the
      genes encoding renin, angiotensinogen, angiotensin converting enzyme or
      angiotensin II receptor type 1
    explanation: >-
      The founding molecular study identified biallelic (homozygous or
      compound heterozygous) RAS gene variants, including ACE, in affected
      individuals.
  - reference: PMID:20454656
    reference_title: >-
      Angiotensin I-converting enzyme Gln1069Arg mutation impairs trafficking
      to the cell surface resulting in selective denaturation of the C-domain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      both parents and a brother who are heterozygous carriers of this mutation
      had exactly half-normal plasma ACE activity compared to healthy
      individuals
    explanation: >-
      Unaffected heterozygous relatives with half-normal plasma ACE activity
      are consistent with recessive inheritance of a loss-of-function allele.
mechanistic_hypotheses:
- hypothesis_group_id: renal_hypoperfusion
  hypothesis_label: Fetal renal hypoperfusion arrests proximal tubule differentiation
  status: CANONICAL
  description: >-
    Loss of angiotensin II leaves the fetal kidney chronically underperfused,
    and renal hypoperfusion of any cause prevents proximal tubules from
    developing and differentiating.
  evidence:
  - reference: PMID:22095942
    reference_title: >-
      Spectrum of mutations in the renin-angiotensin system genes in autosomal
      recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renal hypoperfusion, whether genetic or secondary to a variety of
      diseases, precludes the normal development/ differentiation of proximal
      tubules.
    explanation: >-
      States the hypoperfusion model across genetic and acquired forms of
      renal tubular dysgenesis.
- hypothesis_group_id: delayed_angiogenesis
  hypothesis_label: Delayed angiogenesis starves developing proximal tubules
  status: EMERGING
  description: >-
    Kidney organoid work suggests that proximal tubule dysgenesis is not a
    cell-autonomous failure of tubular epithelium but a consequence of delayed,
    VEGF-A-dependent angiogenesis that deprives developing proximal tubules of
    vascular supply at a critical stage. The engraftment experiments were done
    in AGTR1-null organoids; ACE-null organoids were shown only to form normal
    proximal tubules in vitro, so the angiogenesis step is extrapolated to ACE
    deficiency rather than shown for it.
  evidence:
  - reference: PMID:38071212
    reference_title: >-
      RAAS-deficient organoids indicate delayed angiogenesis as a possible
      cause for autosomal recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We propose that PT dysgenesis in AR-RTD is primarily a non-autonomous
      consequence of delayed angiogenesis, starving PT at a critical time in
      their development.
    explanation: >-
      The authors propose delayed angiogenesis as the proximate cause of
      proximal tubule dysgenesis.
- hypothesis_group_id: angiotensin_erythropoiesis
  hypothesis_label: Lost angiotensin II drive to erythropoiesis explains disproportionate anemia
  status: EMERGING
  description: >-
    Proposed explanation for anemia out of proportion to renal failure in
    biallelic ACE patients. It rests on angiotensinogen- and renin-null mice
    and a review of angiotensin II actions on erythropoiesis; it has not been
    tested in ACE-deficient patients, and chronic kidney disease is itself a
    cause of anemia.
  evidence:
  - reference: PMID:20400218
    reference_title: >-
      The role of the renin-angiotensin system in the regulation of
      erythropoiesis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      we present evidence that angiotensin II (Ang II) is a physiologically
      important regulator of erythropoiesis
    explanation: Review supporting angiotensin II as a regulator of erythropoiesis.
pathophysiology:
- name: ACE Loss of Function
  description: >-
    Biallelic nonsense, frameshift, canonical splice, missense and exon
    deletion variants leave no functional membrane-bound ACE. Some lethal
    variants still encode a catalytically active protein (the truncated R762X
    protein is secreted, and Q1069R retains catalytic properties when it can be
    rescued to the cell surface), so the loss is of tissue-bound enzyme rather
    than uniformly of catalytic activity. ACE variants account for about
    two-thirds of families with renal tubular dysgenesis.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ACE
    term:
      id: hgnc:2707
      label: ACE
  molecular_functions:
  - preferred_term: tissue-bound peptidyl-dipeptidase activity
    term:
      id: GO:0008241
      label: peptidyl-dipeptidase activity
    modifier: DECREASED
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: "CGGV:assertion_14a5efd4-d71f-40b1-91ff-90f7f8d63ec7-2024-12-11T170000.000Z"
    reference_title: ACE / renal tubular dysgenesis - ACE (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      many nonsense, frameshift, canonical splice, missense, and single and/or
      multi-exon deletions have been reported in affected individuals
    explanation: >-
      ClinGen summarizes the range of variant classes reported in affected
      individuals.
  - reference: "CGGV:assertion_14a5efd4-d71f-40b1-91ff-90f7f8d63ec7-2024-12-11T170000.000Z"
    reference_title: ACE / renal tubular dysgenesis - ACE (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The molecular mechanism of disease is loss-of-function.
    explanation: >-
      ClinGen identifies loss of function as the disease mechanism.
  - reference: PMID:22095942
    reference_title: >-
      Spectrum of mutations in the renin-angiotensin system genes in autosomal
      recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most of them are novel and ACE mutations are the most frequent, observed
      in two-thirds of families (64.6%).
    explanation: >-
      In a series of 48 families, ACE was the most frequently mutated RAS gene.
  downstream:
  - target: Loss of Cell-Surface ACE
    causal_link_type: DIRECT
    description: >-
      Truncating variants that remove the membrane anchor, and missense
      variants that misfold, both prevent ACE from reaching the plasma
      membrane.
    evidence:
    - reference: PMID:24163131
      reference_title: >-
        Absence of cell surface expression of human ACE leads to perinatal
        death.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        two missense mutants (W594R and R828H) and two truncated mutants
        (Q1136X and G1145AX) were also studied. These mutants were neither
        inserted in the plasma membrane nor secreted.
      explanation: >-
        Expression of patient missense and truncating ACE variants showed loss
        of membrane insertion.
- name: Loss of Cell-Surface ACE
  description: >-
    Disease-causing ACE variants leave no enzyme at the cell surface. Some
    missense proteins, such as Q1069R, are retained in the endoplasmic
    reticulum and degraded by the proteasome; the truncated R762X protein is
    catalytically active but secreted rather than membrane-anchored. Tissue-bound
    rather than circulating ACE is what matters: a variant that still reaches
    the membrane (R1180P) was compatible with survival after transient neonatal
    renal insufficiency.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:24163131
    reference_title: >-
      Absence of cell surface expression of human ACE leads to perinatal death.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results highlight the importance of tissue-bound ACE versus
      circulating ACE and show that the total absence of cell surface
      expression of ACE is incompatible with life.
    explanation: >-
      Links absence of cell-surface ACE to lethality and distinguishes it from
      the presence of circulating enzyme.
  - reference: PMID:21695262
    reference_title: Impaired proteostasis contributes to renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ACE Q1069R is found sequestered in the endoplasmic reticulum and is also
      subject to increased proteasomal degradation, preventing its transport to
      the cell surface and extracellular fluids.
    explanation: >-
      A patient missense variant causes endoplasmic reticulum retention and
      degradation rather than loss of catalysis.
  - reference: PMID:20454656
    reference_title: >-
      Angiotensin I-converting enzyme Gln1069Arg mutation impairs trafficking
      to the cell surface resulting in selective denaturation of the C-domain.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CHO cells expressing wild-type (WT) vs. Q1069R-ACE demonstrated the
      mutant accumulates intracellularly and also that it is significantly
      degraded by intracellular proteases.
    explanation: >-
      An independent study of the same variant confirms intracellular
      accumulation and degradation.
  - reference: PMID:9153279
    reference_title: >-
      The critical role of tissue angiotensin-converting enzyme as revealed by
      gene targeting in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice that express only this modified ACE have significant plasma ACE
      activity but no tissue-bound enzyme. These animals have low blood
      pressure, renal vascular thickening, and a urine concentrating defect.
    explanation: >-
      Mice with only secreted ACE reproduce hypotension and renal disease,
      showing that tissue-bound ACE is required.
  downstream:
  - target: Loss of Tissue Angiotensin II Generation
    causal_link_type: DIRECT
- name: Loss of Tissue Angiotensin II Generation
  description: >-
    ACE catalyzes the conversion of angiotensin I to angiotensin II. Without
    membrane-bound ACE, tissue and intrarenal angiotensin II generation fails
    and the fetal renin-angiotensin system is functionally inactive, even
    where some circulating enzyme persists.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: angiotensin maturation
    term:
      id: GO:0002003
      label: angiotensin maturation
    modifier: DECREASED
  evidence:
  - reference: "CGGV:assertion_14a5efd4-d71f-40b1-91ff-90f7f8d63ec7-2024-12-11T170000.000Z"
    reference_title: ACE / renal tubular dysgenesis - ACE (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Angiotensin I-Converting Enzyme (ACE; MIM#106180) catalyzes the
      conversion of angiotensin I into physiologically active peptide
      angiotensin II, within the angiotensin-renin system.
    explanation: >-
      States the enzymatic step that is lost.
  - reference: PMID:20454656
    reference_title: >-
      Angiotensin I-converting enzyme Gln1069Arg mutation impairs trafficking
      to the cell surface resulting in selective denaturation of the C-domain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      was found to have a homozygous substitution of Arg for Glu at position
      1069 in the C-terminal domain of ACE (Q1069R) resulting in absence of
      plasma ACE activity
    explanation: >-
      A patient with renal tubular dysgenesis had no measurable plasma ACE
      activity; this is supporting rather than primary, since circulating ACE
      can persist in lethal cases.
  - reference: PMID:24163131
    reference_title: >-
      Absence of cell surface expression of human ACE leads to perinatal death.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      One truncated mutant, R762X, responsible for neonatal death was found to
      be an enzymatically active, secreted form, not inserted in the plasma
      membrane.
    explanation: >-
      A lethal variant retained catalytic activity but not membrane insertion,
      so it is tissue-bound angiotensin II generation that is lost.
  downstream:
  - target: Loss of Renin-Angiotensin Blood Pressure Support
    causal_link_type: DIRECT
  - target: Reduced Aldosterone Secretion
    causal_link_type: DIRECT
    description: >-
      Angiotensin II drives aldosterone secretion from the adrenal zona
      glomerulosa, so its absence lowers aldosterone.
    evidence:
    - reference: PMID:8642790
      reference_title: >-
        Mice lacking angiotensin-converting enzyme have low blood pressure,
        renal pathology, and reduced male fertility.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        They also have an abnormally low urinary sodium to potassium ratio
        despite reduced levels of aldosterone.
      explanation: >-
        ACE-deficient mice have reduced aldosterone; the mouse result supports
        the edge by analogy.
  - target: Compensatory Renin Overexpression
    causal_link_type: DIRECT
    description: >-
      Without angiotensin II, feedback inhibition of renin release is lost.
  - target: Loss of Angiotensin II-Driven Erythropoiesis
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - angiotensin_erythropoiesis
    evidence:
    - reference: PMID:26107632
      reference_title: >-
        Erythropoiesis and Blood Pressure Are Regulated via AT1 Receptor by
        Distinctive Pathways.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Here we report that knockout mice that lack angiotensin II, including
        angiotensinogen and renin knockout mice, exhibit anemia.
      explanation: >-
        Angiotensin II deficiency causes anemia in angiotensinogen- and
        renin-null mice; ACE-null mice were not studied.
  - target: Delayed Nephrogenic Angiogenesis
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - delayed_angiogenesis
    description: >-
      Derived from AGTR1-null organoids, in which loss of angiotensin II type 1
      receptor signalling left VEGF-A expression insufficient; hypoxia raised
      VEGF-A and rescued engraftment, so the defect is not attributed to
      hypoperfusion. Extending it to ACE deficiency is an inference.
  - target: Microcolon
    causal_link_type: UNKNOWN
    description: Proposed role of the renin-angiotensin system in intestinal development.
    evidence:
    - reference: PMID:30071301
      reference_title: >-
        Renal tubular dysgenesis and microcolon, a novel association. Report of
        three cases.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The severe intestinal developmental abnormality culminating in microcolon
        and early terminal ileum perforation/necrotizing enterocolitis is a novel
        finding not previously associated with RTD, which points to a role of the
        renin-angiotensin system in gut development.
      explanation: >-
        The authors infer a renin-angiotensin role in gut development from three
        ACE-related cases; the mechanism is not shown.
  - target: Intestinal perforation
    causal_link_type: UNKNOWN
    description: Proposed role of the renin-angiotensin system in intestinal development.
    evidence:
    - reference: PMID:30071301
      reference_title: >-
        Renal tubular dysgenesis and microcolon, a novel association. Report of
        three cases.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The severe intestinal developmental abnormality culminating in microcolon
        and early terminal ileum perforation/necrotizing enterocolitis is a novel
        finding not previously associated with RTD, which points to a role of the
        renin-angiotensin system in gut development.
      explanation: >-
        The authors infer a renin-angiotensin role in gut development from three
        ACE-related cases; the mechanism is not shown.
  - target: Urine Concentrating Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:8642790
      reference_title: >-
        Mice lacking angiotensin-converting enzyme have low blood pressure,
        renal pathology, and reduced male fertility.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        The renal papilla is markedly reduced, and the intrarenal arteries
        exhibit vascular hyperplasia associated with a perivascular
        inflammatory infiltrate. These animals cannot effectively concentrate
        urine.
      explanation: >-
        In ACE-null mice, loss of angiotensin II generation is accompanied by
        papillary hypoplasia and a concentrating defect.
- name: Compensatory Renin Overexpression
  description: >-
    Renal renin expression is strikingly increased in most autosomal recessive
    renal tubular dysgenesis kidneys, with renin accumulating in preglomerular
    arterioles and the glomerular hilum, and plasma renin activity is markedly
    raised. This is the expected feedback response to absent angiotensin II
    downstream of renin.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: renin-secreting juxtaglomerular granular cell
    term:
      id: CL:0000648
      label: kidney granular cell
  biological_processes:
  - preferred_term: renin secretion into blood stream
    term:
      id: GO:0002001
      label: renin secretion into blood stream
    modifier: INCREASED
  evidence:
  - reference: PMID:16790508
    reference_title: >-
      Renal tubular dysgenesis, a not uncommon autosomal recessive disorder
      leading to oligohydramnios: Role of the Renin-Angiotensin system.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renal renin expression was strikingly increased in 19 of 24 patients
      studied, from 13 families, whereas no renal renin was detected in four
      patients from three families.
    explanation: >-
      Renin is overexpressed in most RTD kidneys; the families without renal
      renin are consistent with REN or other upstream defects, so the series
      is not ACE-specific.
  - reference: PMID:32808512
    reference_title: >-
      A Premature Baby with Severe Oligohydramnios and Hypotension: a Case
      Report of Renal Tubular Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Basal plasma renin activity was markedly elevated and
      angiotensin-converting enzyme was undetectable.
    explanation: >-
      A neonate with compound heterozygous ACE frameshift variants had
      markedly elevated plasma renin activity.
  downstream:
  - target: Increased circulating renin concentration
    causal_link_type: DIRECT
- name: Loss of Angiotensin II-Driven Erythropoiesis
  description: >-
    Angiotensin II promotes erythropoiesis both as a growth factor for
    erythroid progenitors and as an erythropoietin secretagogue. Its absence
    is the proposed reason that anemia in biallelic ACE patients is out of
    proportion to the degree of renal failure. The supporting data are from
    angiotensinogen- and renin-null mice and a review, not from ACE-deficient
    patients.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: erythrocyte differentiation
    term:
      id: GO:0030218
      label: erythrocyte differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:26107632
    reference_title: >-
      Erythropoiesis and Blood Pressure Are Regulated via AT1 Receptor by
      Distinctive Pathways.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      Here we report that knockout mice that lack angiotensin II, including
      angiotensinogen and renin knockout mice, exhibit anemia. The anemia of
      angiotensinogen knockout mice was rescued by angiotensin II infusion
    explanation: >-
      Angiotensin II deficiency causes anemia rescued by angiotensin II in
      mice; ACE-null mice were not studied, so this is an inference across
      RAS genes.
  - reference: PMID:20400218
    reference_title: >-
      The role of the renin-angiotensin system in the regulation of
      erythropoiesis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      First, Ang II is a growth factor of erythroid progenitors and, in
      cooperation with erythropoietin, increases red blood cell mass. Second,
      Ang II acts as an erythropoietin secretagogue to maintain increased
      erythropoietin levels despite increments in hematocrit.
    explanation: >-
      Review of the two pro-erythropoietic actions of angiotensin II.
  downstream:
  - target: Anemia
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - angiotensin_erythropoiesis
- name: Urine Concentrating Defect
  description: >-
    Inability to concentrate urine, with papillary hypoplasia in ACE-null mice;
    in later-presenting patients it appears as polyuria and polydipsia.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: renal water absorption
    term:
      id: GO:0070295
      label: renal water absorption
    modifier: DECREASED
  evidence:
  - reference: PMID:8642790
    reference_title: >-
      Mice lacking angiotensin-converting enzyme have low blood pressure,
      renal pathology, and reduced male fertility.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: These animals cannot effectively concentrate urine.
    explanation: ACE-null mice have a urine concentrating defect.
  - reference: PMID:18158355
    reference_title: >-
      Angiotensin-converting enzyme C-terminal catalytic domain is the main
      site of angiotensin I cleavage in vivo.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      ACE13/13 mice have a normal renal structure, but they are not able to
      concentrate urine after dehydration as effectively as wild-type mice.
    explanation: >-
      Even loss of ACE C-domain activity alone impairs urine concentration
      in mice.
  downstream:
  - target: Polyuria
    causal_link_type: DIRECT
- name: Loss of Renin-Angiotensin Blood Pressure Support
  description: >-
    Without angiotensin II the renin-angiotensin system cannot maintain fetal
    systemic blood pressure and renal blood flow, which are RAS-dependent
    during human fetal life. Postnatally this appears as refractory arterial
    hypotension.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: regulation of systemic arterial blood pressure by renin-angiotensin
    term:
      id: GO:0003081
      label: regulation of systemic arterial blood pressure by renin-angiotensin
    modifier: DECREASED
  evidence:
  - reference: PMID:22095942
    reference_title: >-
      Spectrum of mutations in the renin-angiotensin system genes in autosomal
      recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The severity of the clinical course was similar whatever the mutated
      gene, which underlines the importance of a functional RAS in the
      maintenance of blood pressure and renal blood flow during the life of a
      human fetus.
    explanation: >-
      The same severe course with any RAS gene defect points to RAS-dependent
      fetal blood pressure and renal blood flow.
  - reference: PMID:8642790
    reference_title: >-
      Mice lacking angiotensin-converting enzyme have low blood pressure,
      renal pathology, and reduced male fertility.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice homozygous for this mutant allele lack both ACE isozymes and have
      markedly reduced blood pressures.
    explanation: >-
      ACE-null mice are markedly hypotensive.
  downstream:
  - target: Fetal Renal Hypoperfusion
    causal_link_type: DIRECT
    hypothesis_groups:
    - renal_hypoperfusion
    evidence:
    - reference: PMID:16116425
      reference_title: >-
        Mutations in genes in the renin-angiotensin system are associated with
        autosomal recessive renal tubular dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We propose that renal lesions and early anuria result from chronic low
        perfusion pressure of the fetal kidney, a consequence of
        renin-angiotensin system inactivity.
      explanation: >-
        Links RAS inactivity to low fetal renal perfusion pressure.
  - target: Hypotension
    causal_link_type: DIRECT
  - target: Decreased skull ossification
    causal_link_type: UNKNOWN
    description: >-
      Calvarial underdevelopment has been linked to fetal hypotension or
      chronic hypoxia. The link is proposed, not demonstrated.
    evidence:
    - reference: PMID:1771591
      reference_title: >-
        ACE inhibitor fetopathy and hypocalvaria: the kidney-skull connection.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        possible links between calvarial development and fetal hypotension
        and/or chronic hypoxia are explored
      explanation: >-
        Proposes, from ACE inhibitor fetopathy and other hypocalvaria cases,
        that fetal hypotension underlies the skull defect; this is an
        acquired phenocopy and the link is speculative.
- name: Fetal Renal Hypoperfusion
  description: >-
    Chronically low perfusion pressure in the fetal kidney, the immediate
    consequence of renin-angiotensin system inactivity.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:16116425
    reference_title: >-
      Mutations in genes in the renin-angiotensin system are associated with
      autosomal recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We propose that renal lesions and early anuria result from chronic low
      perfusion pressure of the fetal kidney, a consequence of
      renin-angiotensin system inactivity.
    explanation: >-
      The founding study proposes chronic fetal renal hypoperfusion as the
      central lesion.
  downstream:
  - target: Proximal Tubule Dysgenesis
    causal_link_type: DIRECT
    hypothesis_groups:
    - renal_hypoperfusion
    evidence:
    - reference: PMID:22095942
      reference_title: >-
        Spectrum of mutations in the renin-angiotensin system genes in
        autosomal recessive renal tubular dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Renal hypoperfusion, whether genetic or secondary to a variety of
        diseases, precludes the normal development/ differentiation of
        proximal tubules.
      explanation: >-
        States the causal step from hypoperfusion to failed proximal tubule
        differentiation.
  - target: Anuria
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16116425
      reference_title: >-
        Mutations in genes in the renin-angiotensin system are associated with
        autosomal recessive renal tubular dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We propose that renal lesions and early anuria result from chronic low
        perfusion pressure of the fetal kidney
      explanation: >-
        Attributes early anuria to low fetal renal perfusion pressure.
- name: Delayed Nephrogenic Angiogenesis
  description: >-
    Insufficient VEGF-A expression, attributed to lost angiotensin II type 1
    receptor signalling, delays vascularization of developing nephrons. In AGTR1-null kidney organoids, renal-vesicle-stage grafts
    failed to engraft for lack of pro-angiogenic VEGF-A, and hypoxia or
    ectopic VEGF-A rescued engraftment.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: kidney vasculature development
    term:
      id: GO:0061440
      label: kidney vasculature development
    modifier: DECREASED
  evidence:
  - reference: PMID:38071212
    reference_title: >-
      RAAS-deficient organoids indicate delayed angiogenesis as a possible
      cause for autosomal recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      By contrast, d14 AGTR1-/- organoids fail to engraft due to insufficient
      pro-angiogenic VEGF-A expression. Notably, growth under hypoxic
      conditions induces VEGF-A expression and rescues engraftment of
      AGTR1-/- organoids at d14, as does ectopic expression of VEGF-A.
    explanation: >-
      Shows the angiogenesis defect in AGTR1-null organoids; applying it to
      ACE deficiency is an inference across RAS genes.
  downstream:
  - target: Proximal Tubule Dysgenesis
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - delayed_angiogenesis
    evidence:
    - reference: PMID:38071212
      reference_title: >-
        RAAS-deficient organoids indicate delayed angiogenesis as a possible
        cause for autosomal recessive renal tubular dysgenesis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We propose that PT dysgenesis in AR-RTD is primarily a non-autonomous
        consequence of delayed angiogenesis, starving PT at a critical time in
        their development.
      explanation: >-
        The authors' proposed causal step from delayed angiogenesis to
        proximal tubule dysgenesis.
- name: Proximal Tubule Dysgenesis
  description: >-
    Proximal tubules are absent or poorly differentiated, the histological
    hallmark of renal tubular dysgenesis. Glomeruli are preserved; distal
    tubules can appear normal, although in a larger series lesions also
    involved other tubular segments.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: kidney proximal convoluted tubule epithelial cell
    term:
      id: CL:1000838
      label: kidney proximal convoluted tubule epithelial cell
  biological_processes:
  - preferred_term: proximal tubule development
    term:
      id: GO:0072014
      label: proximal tubule development
    modifier: DECREASED
  evidence:
  - reference: PMID:16116425
    reference_title: >-
      Mutations in genes in the renin-angiotensin system are associated with
      autosomal recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Absence or paucity of differentiated proximal tubules is the
      histopathological hallmark of the disease
    explanation: >-
      Defines the tissue lesion.
  - reference: PMID:20607303
    reference_title: Inherited renal tubular dysgenesis may not be universally fatal.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A revision of renal tissue obtained from a sibling that died shortly
      after birth revealed normal glomeruli and distal tubules but no
      identifiable proximal tubules.
    explanation: >-
      Renal histology in a sibling of an ACE-mutated child showed selective
      absence of proximal tubules.
  - reference: PMID:16790508
    reference_title: >-
      Renal tubular dysgenesis, a not uncommon autosomal recessive disorder
      leading to oligohydramnios: Role of the Renin-Angiotensin system.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe defects in proximal tubules were observed in all fetuses from 18
      gestational weeks onward, and lesions also involved other tubular
      segments.
    explanation: >-
      Dates the proximal tubule defect to at least 18 weeks of gestation in a
      29-case autosomal recessive RTD series of mixed RAS genotypes.
  downstream:
  - target: Absent or poorly differentiated proximal tubules
    causal_link_type: DIRECT
  - target: Anuria
    causal_link_type: DIRECT
  - target: Chronic kidney disease
    causal_link_type: DIRECT
    description: Survivors carry the developmental tubular deficit forward as chronic kidney disease.
    evidence:
    - reference: PMID:20607303
      reference_title: Inherited renal tubular dysgenesis may not be universally fatal.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        A novel mutation in the ACE gene was found in the surviving child, who
        remains with stage 4 chronic kidney disease and normal neurodevelopment.
      explanation: >-
        A survivor whose sibling's kidney lacked proximal tubules has stage 4
        CKD; the link from the tubular lesion to CKD is inferred.
- name: Reduced Aldosterone Secretion
  description: >-
    Low angiotensin II leaves aldosterone low, contributing to hyperkalemia and
    salt wasting; this is the rationale for mineralocorticoid replacement with
    fludrocortisone in survivors.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: aldosterone secretion
    term:
      id: GO:0035932
      label: aldosterone secretion
    modifier: DECREASED
  evidence:
  - reference: PMID:25899979
    reference_title: >-
      Resolution of refractory hypotension and anuria in a premature newborn
      with loss-of-function of ACE.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In light of the molecular diagnosis, identification, and treatment of
      associated low aldosterone level resulted in further improvement in renal
      function
    explanation: >-
      A neonate with compound heterozygous ACE frameshift variants had low
      aldosterone.
  downstream:
  - target: Hyperkalemia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20607303
      reference_title: Inherited renal tubular dysgenesis may not be universally fatal.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Hypotension and hyperkalemia normalized eventually with administration of
        fludrocortisone.
      explanation: >-
        Correction by mineralocorticoid replacement implicates the aldosterone
        deficit in the hyperkalemia.
  - target: Decreased circulating aldosterone concentration
    causal_link_type: DIRECT
phenotypes:
- name: Absent or poorly differentiated proximal tubules
  category: Renal
  frequency: VERY_FREQUENT
  description: >-
    Absence or paucity of differentiated proximal tubules on renal histology,
    the diagnostic hallmark.
  phenotype_term:
    preferred_term: Renotubular dysgenesis
    term:
      id: HP:0008660
      label: Renotubular dysgenesis
  evidence:
  - reference: PMID:16116425
    reference_title: >-
      Mutations in genes in the renin-angiotensin system are associated with
      autosomal recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Absence or paucity of differentiated proximal tubules is the
      histopathological hallmark of the disease
    explanation: Defines the histological hallmark.
  - reference: PMID:38091257
    reference_title: >-
      Prenatal diagnosis of autosomal recessive renal tubular dysgenesis caused
      by variants in the ACE gene: Two fetuses with anhydramnios.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional post-mortem histopathological examination from the renal
      tissue of the second fetus showed renal tubular hypoplasia.
    explanation: >-
      Post-mortem histology in a fetus with a homozygous ACE nonsense variant.
- name: Anuria
  category: Renal
  frequency: VERY_FREQUENT
  description: >-
    Persistent fetal anuria and anuric renal failure after birth. In some
    survivors urine output appears after days to weeks.
  phenotype_term:
    preferred_term: Anuria
    term:
      id: HP:0100519
      label: Anuria
    onset:
      onset_category: FETAL
  evidence:
  - reference: PMID:16116425
    reference_title: >-
      Mutations in genes in the renin-angiotensin system are associated with
      autosomal recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal recessive renal tubular dysgenesis is a severe disorder of
      renal tubular development characterized by persistent fetal anuria and
      perinatal death
    explanation: Persistent fetal anuria is a defining feature.
  - reference: PMID:20607303
    reference_title: Inherited renal tubular dysgenesis may not be universally fatal.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The infant survived the neonatal period after 2 weeks of anuria
      subsequently subsiding.
    explanation: >-
      In an ACE-mutated survivor, neonatal anuria resolved after two weeks.
  sequelae:
  - target: Oligohydramnios
    description: Fetal urine is the main source of amniotic fluid after mid-gestation.
    evidence:
    - reference: PMID:22095942
      reference_title: >-
        Spectrum of mutations in the renin-angiotensin system genes in
        autosomal recessive renal tubular dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        early onset and persistent fetal anuria leading to oligohydramnios and
        the Potter sequence
      explanation: Fetal anuria leads to oligohydramnios.
  - target: Anhydramnios
    description: Complete fetal anuria produces anhydramnios, the severe end of the same sequence.
- name: Oligohydramnios
  category: Prenatal
  frequency: VERY_FREQUENT
  description: >-
    Early-onset oligohydramnios, typically the presenting sign on prenatal
    ultrasound.
  phenotype_term:
    preferred_term: Oligohydramnios
    term:
      id: HP:0001562
      label: Oligohydramnios
  evidence:
  - reference: PMID:22095942
    reference_title: >-
      Spectrum of mutations in the renin-angiotensin system genes in autosomal
      recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      early onset and persistent fetal anuria leading to oligohydramnios and
      the Potter sequence
    explanation: Oligohydramnios is a core prenatal feature.
  - reference: PMID:26069751
    reference_title: Survival over 2 years of autosomal-recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      The typical revealing symptom is oligohydramnios resulting from reduced
      fetal urine production.
    explanation: >-
      Oligohydramnios is the usual presenting sign.
  sequelae:
  - target: Pulmonary hypoplasia
    evidence:
    - reference: PMID:16116425
      reference_title: >-
        Mutations in genes in the renin-angiotensin system are associated with
        autosomal recessive renal tubular dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        probably due to pulmonary hypoplasia from early-onset oligohydramnios
        (Potter phenotype)
      explanation: Pulmonary hypoplasia follows early-onset oligohydramnios.
  - target: Potter sequence facies
    evidence:
    - reference: PMID:22095942
      reference_title: >-
        Spectrum of mutations in the renin-angiotensin system genes in
        autosomal recessive renal tubular dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        early onset and persistent fetal anuria leading to oligohydramnios and
        the Potter sequence
      explanation: Oligohydramnios produces the Potter sequence.
  - target: Joint contractures
- name: Anhydramnios
  category: Prenatal
  description: Complete absence of amniotic fluid on prenatal ultrasound.
  phenotype_term:
    preferred_term: Anhydramnios
    term:
      id: HP:0025700
      label: Anhydramnios
  evidence:
  - reference: PMID:38091257
    reference_title: >-
      Prenatal diagnosis of autosomal recessive renal tubular dysgenesis caused
      by variants in the ACE gene: Two fetuses with anhydramnios.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report two cases of fetuses with anhydramnios and invisible urinary
      bladder.
    explanation: Two fetuses with homozygous ACE nonsense variants had anhydramnios.
- name: Potter sequence facies
  category: Craniofacial
  description: >-
    Facial and positional features of the Potter (oligohydramnios) sequence.
  phenotype_term:
    preferred_term: Potter facies
    term:
      id: HP:0002009
      label: Potter facies
  evidence:
  - reference: PMID:35286024
    reference_title: >-
      Expanding the clinical spectrum of autosomal-recessive renal tubular
      dysgenesis: Two siblings with neonatal survival and review of the
      literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      manifests as fetal anuria leading to oligohydramnios and Potter sequence
    explanation: >-
      The Potter sequence, of which Potter facies is a component, is part of
      the presentation.
- name: Pulmonary hypoplasia
  category: Respiratory
  frequency: FREQUENT
  description: >-
    Pulmonary hypoplasia from early oligohydramnios, a main cause of neonatal
    death.
  phenotype_term:
    preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  evidence:
  - reference: PMID:22095942
    reference_title: >-
      Spectrum of mutations in the renin-angiotensin system genes in autosomal
      recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early death occurs in most cases from anuria, pulmonary hypoplasia, and
      refractory arterial hypotension.
    explanation: Pulmonary hypoplasia is a leading cause of early death.
  sequelae:
  - target: Respiratory insufficiency
- name: Respiratory insufficiency
  category: Respiratory
  description: Neonatal respiratory distress or failure requiring ventilatory support.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:40519134
    reference_title: Diagnostic Challenges of Inherited Renal Tubular Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Postnatally, the patient had anuric renal failure, medically refractory
      hypotension, and respiratory failure in the setting of pulmonary
      hypoplasia.
    explanation: >-
      A neonate with biallelic ACE loss-of-function variants had respiratory
      failure with pulmonary hypoplasia.
- name: Joint contractures
  category: Musculoskeletal
  description: Positional limb contractures from fetal compression.
  phenotype_term:
    preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: "CGGV:assertion_14a5efd4-d71f-40b1-91ff-90f7f8d63ec7-2024-12-11T170000.000Z"
    reference_title: ACE / renal tubular dysgenesis - ACE (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      prenatal phenotypes including oligo- or anhydramnios, contractures,
      increased renal echogenicity, skull ossification defects, intrauterine
      fetal demise or stillbirth
    explanation: ClinGen lists contractures among scored prenatal phenotypes.
- name: Hypotension
  category: Cardiovascular
  frequency: VERY_FREQUENT
  description: >-
    Severe neonatal arterial hypotension refractory to volume and inotropes;
    vasopressin has been effective in several survivors.
  phenotype_term:
    preferred_term: Refractory arterial hypotension
    term:
      id: HP:0002615
      label: Hypotension
    onset:
      onset_category: NEONATAL
  evidence:
  - reference: PMID:22095942
    reference_title: >-
      Spectrum of mutations in the renin-angiotensin system genes in autosomal
      recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early death occurs in most cases from anuria, pulmonary hypoplasia, and
      refractory arterial hypotension.
    explanation: Refractory hypotension is a principal cause of death.
  - reference: PMID:25899979
    reference_title: >-
      Resolution of refractory hypotension and anuria in a premature newborn
      with loss-of-function of ACE.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vasopressin was used to successfully treat refractory hypotension and
      anuria in the neonate born at 27 weeks of gestation.
    explanation: A neonate with ACE frameshift variants had refractory hypotension.
- name: Decreased skull ossification
  category: Skeletal
  description: >-
    Skull ossification defects (hypocalvaria) with wide sutures and large
    fontanelles.
  phenotype_term:
    preferred_term: Decreased skull ossification
    term:
      id: HP:0004331
      label: Decreased skull ossification
  evidence:
  - reference: PMID:22095942
    reference_title: >-
      Spectrum of mutations in the renin-angiotensin system genes in autosomal
      recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      leading to oligohydramnios and the Potter sequence, associated with skull
      ossification defects
    explanation: Skull ossification defects are part of the phenotype.
  - reference: PMID:20607303
    reference_title: Inherited renal tubular dysgenesis may not be universally fatal.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is characterized by oligohydramnios, prematurity, hypotension,
      hypocalvaria, and neonatal renal failure.
    explanation: Hypocalvaria is listed among the characteristic features.
  sequelae:
  - target: Large fontanelles
    evidence:
    - reference: PMID:32808512
      reference_title: >-
        A Premature Baby with Severe Oligohydramnios and Hypotension: a Case
        Report of Renal Tubular Dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        skull X-ray showed large fontanelles and wide sutures suggestive of
        ossification delay
      explanation: The radiologists read large fontanelles as a sign of delayed ossification.
  - target: Wide cranial sutures
    evidence:
    - reference: PMID:32808512
      reference_title: >-
        A Premature Baby with Severe Oligohydramnios and Hypotension: a Case
        Report of Renal Tubular Dysgenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        skull X-ray showed large fontanelles and wide sutures suggestive of
        ossification delay
      explanation: The radiologists read wide sutures as a sign of delayed ossification.
- name: Large fontanelles
  category: Skeletal
  phenotype_term:
    preferred_term: Large fontanelles
    term:
      id: HP:0000239
      label: Large fontanelles
  evidence:
  - reference: PMID:32808512
    reference_title: >-
      A Premature Baby with Severe Oligohydramnios and Hypotension: a Case
      Report of Renal Tubular Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      skull X-ray showed large fontanelles and wide sutures suggestive of
      ossification delay
    explanation: Skull radiograph findings in a neonate with compound heterozygous ACE variants.
- name: Wide cranial sutures
  category: Skeletal
  phenotype_term:
    preferred_term: Wide cranial sutures
    term:
      id: HP:0010537
      label: Wide cranial sutures
  evidence:
  - reference: PMID:32808512
    reference_title: >-
      A Premature Baby with Severe Oligohydramnios and Hypotension: a Case
      Report of Renal Tubular Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      skull X-ray showed large fontanelles and wide sutures suggestive of
      ossification delay
    explanation: Skull radiograph findings in a neonate with compound heterozygous ACE variants.
- name: Increased circulating renin concentration
  category: Endocrine
  description: Markedly elevated plasma renin activity with undetectable ACE.
  phenotype_term:
    preferred_term: Increased plasma renin
    term:
      id: HP:0000848
      label: Increased circulating renin concentration
  evidence:
  - reference: PMID:32808512
    reference_title: >-
      A Premature Baby with Severe Oligohydramnios and Hypotension: a Case
      Report of Renal Tubular Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Basal plasma renin activity was markedly elevated and
      angiotensin-converting enzyme was undetectable.
    explanation: Elevated plasma renin activity in a neonate with ACE variants.
- name: Hyperechogenic kidneys
  category: Renal
  description: >-
    Normal-sized, echogenic, non-cystic kidneys with poor corticomedullary
    differentiation on ultrasound.
  phenotype_term:
    preferred_term: Hyperechogenic kidneys
    term:
      id: HP:0004719
      label: Hyperechogenic kidneys
  evidence:
  - reference: PMID:35848000
    reference_title: Late Preterm Infant With Postnatal Diagnosis of Renal Tubular Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      renal ultrasound showing normal-sized echogenic noncystic kidneys with
      poor corticomedullary differentiation
    explanation: Describes the ultrasound pattern in an infant with biallelic ACE variants.
- name: Reduced renal corticomedullary differentiation
  category: Renal
  phenotype_term:
    preferred_term: Reduced renal corticomedullary differentiation
    term:
      id: HP:0005565
      label: Reduced renal corticomedullary differentiation
  evidence:
  - reference: PMID:35848000
    reference_title: Late Preterm Infant With Postnatal Diagnosis of Renal Tubular Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      renal ultrasound showing normal-sized echogenic noncystic kidneys with
      poor corticomedullary differentiation
    explanation: Poor corticomedullary differentiation on ultrasound.
- name: Premature birth
  category: Prenatal
  phenotype_term:
    preferred_term: Premature birth
    term:
      id: HP:0001622
      label: Premature birth
  evidence:
  - reference: PMID:20607303
    reference_title: Inherited renal tubular dysgenesis may not be universally fatal.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is characterized by oligohydramnios, prematurity, hypotension,
      hypocalvaria, and neonatal renal failure.
    explanation: Prematurity is a characteristic feature.
- name: Intrauterine growth retardation
  category: Prenatal
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:40519134
    reference_title: Diagnostic Challenges of Inherited Renal Tubular Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a premature female neonate with prenatal oligohydramnios and growth
      restriction
    explanation: Growth restriction in a neonate with biallelic ACE variants.
- name: Hyperkalemia
  category: Metabolic
  description: Hyperkalemia in survivors, corrected by fludrocortisone.
  phenotype_term:
    preferred_term: Hyperkalemia
    term:
      id: HP:0002153
      label: Hyperkalemia
  evidence:
  - reference: PMID:20607303
    reference_title: Inherited renal tubular dysgenesis may not be universally fatal.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypotension and hyperkalemia normalized eventually with administration of
      fludrocortisone.
    explanation: An ACE-mutated survivor had hyperkalemia responsive to fludrocortisone.
- name: Decreased circulating aldosterone concentration
  category: Endocrine
  phenotype_term:
    preferred_term: Low aldosterone
    term:
      id: HP:0004319
      label: Decreased circulating aldosterone concentration
  evidence:
  - reference: PMID:25899979
    reference_title: >-
      Resolution of refractory hypotension and anuria in a premature newborn
      with loss-of-function of ACE.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identification, and treatment of associated low aldosterone level
      resulted in further improvement in renal function
    explanation: Low aldosterone was found in a neonate with ACE frameshift variants.
- name: Chronic kidney disease
  category: Renal
  description: >-
    Survivors usually have chronic kidney disease of variable severity, and
    some biallelic ACE genotypes present first as progressive chronic renal
    failure in childhood or later.
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: PMID:20607303
    reference_title: Inherited renal tubular dysgenesis may not be universally fatal.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A novel mutation in the ACE gene was found in the surviving child, who
      remains with stage 4 chronic kidney disease and normal neurodevelopment.
    explanation: A three-year-old ACE-mutated survivor has stage 4 CKD.
  - reference: PMID:32198635
    reference_title: >-
      Bi-allelic mutations in renin-angiotensin system genes, associated with
      renal tubular dysgenesis, can also present as a progressive chronic
      kidney disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bi-allelic loss of function mutation of ACE can have atypical and
      sometimes late presentation with chronic renal failure, anemia (out of
      proportion with the level of renal failure), and polyuro-polydipsia.
    explanation: Biallelic ACE variants can present late as chronic renal failure.
- name: Anemia
  category: Hematologic
  description: Anemia out of proportion to the degree of renal failure.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:32198635
    reference_title: >-
      Bi-allelic mutations in renin-angiotensin system genes, associated with
      renal tubular dysgenesis, can also present as a progressive chronic
      kidney disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all cases, patients were affected with anemia whose severity was
      unexpected regarding the level of renal failure and with important
      polyuro-polydipsia.
    explanation: Disproportionate anemia in three unrelated patients with biallelic ACE variants.
- name: Polyuria
  category: Renal
  description: >-
    Polyuria and polydipsia in later-presenting patients, consistent with a
    urine concentrating defect.
  phenotype_term:
    preferred_term: Polyuria
    term:
      id: HP:0000103
      label: Polyuria
  evidence:
  - reference: PMID:32198635
    reference_title: >-
      Bi-allelic mutations in renin-angiotensin system genes, associated with
      renal tubular dysgenesis, can also present as a progressive chronic
      kidney disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all cases, patients were affected with anemia whose severity was
      unexpected regarding the level of renal failure and with important
      polyuro-polydipsia.
    explanation: Marked polyuria-polydipsia in patients with biallelic ACE variants.
- name: Microcolon
  category: Gastrointestinal
  description: Microcolon reported in three patients from two families with ACE variants.
  phenotype_term:
    preferred_term: Microcolon
    term:
      id: HP:0004388
      label: Microcolon
  evidence:
  - reference: PMID:30071301
    reference_title: >-
      Renal tubular dysgenesis and microcolon, a novel association. Report of
      three cases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report three patients from two unrelated families with RTD due to
      pathogenic variants of the angiotensin-converting enzyme (ACE) gene, in
      whom RTD was associated with microcolon.
    explanation: Microcolon in three patients with ACE-related RTD.
- name: Intestinal perforation
  category: Gastrointestinal
  description: Early terminal ileum perforation or necrotizing enterocolitis.
  phenotype_term:
    preferred_term: Intestinal perforation
    term:
      id: HP:0031368
      label: Intestinal perforation
  evidence:
  - reference: PMID:30071301
    reference_title: >-
      Renal tubular dysgenesis and microcolon, a novel association. Report of
      three cases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The severe intestinal developmental abnormality culminating in microcolon
      and early terminal ileum perforation/necrotizing enterocolitis is a novel
      finding not previously associated with RTD
    explanation: Terminal ileum perforation in patients with ACE-related RTD.
progression:
- phase: Perinatal lethality
  age_range: Late gestation to the first days after birth
  notes: >-
    Most affected pregnancies end in late-gestation stillbirth or death in the
    first days of life from anuria, pulmonary hypoplasia and refractory
    hypotension. Recorded here rather than as phenotypes because the HPO death
    terms (HP:0003826 Stillbirth, HP:0003811 Neonatal death) sit outside the
    PhenotypeTerm enum's phenotypic-abnormality root.
  evidence:
  - reference: PMID:38091257
    reference_title: >-
      Prenatal diagnosis of autosomal recessive renal tubular dysgenesis caused
      by variants in the ACE gene: Two fetuses with anhydramnios.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      nearly all affected fetuses die after birth or have a stillbirth in late
      gestation
    explanation: Late-gestation stillbirth or death after birth is the usual outcome.
  - reference: PMID:22095942
    reference_title: >-
      Spectrum of mutations in the renin-angiotensin system genes in autosomal
      recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early death occurs in most cases from anuria, pulmonary hypoplasia, and
      refractory arterial hypotension.
    explanation: Names the causes of early death.
- phase: Survival beyond the neonatal period
  age_range: Infancy onward
  notes: >-
    A minority survive with intensive support; urine output may appear after
    days to weeks, and survivors usually have chronic kidney disease. A
    literature review counted 18 earlier cases with better outcomes.
  evidence:
  - reference: PMID:35286024
    reference_title: >-
      Expanding the clinical spectrum of autosomal-recessive renal tubular
      dysgenesis: Two siblings with neonatal survival and review of the
      literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While AR-RTD is most often a lethal disease in the neonatal period, it is
      not universally so.
    explanation: Neonatal lethality is most common but not universal.
  - reference: PMID:40245857
    reference_title: >-
      Diagnosis and Treatment of Inherited Renal Tubular Dysgenesis Caused by
      ACE Gene Mutation: A Single-Center Experience.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During the 27-month follow-up, this patient exhibited normal renal
      function and ultrasound findings.
    explanation: One ACE-mutated survivor had normal renal function at 27 months.
  - reference: PMID:34957720
    reference_title: >-
      [RENAL TUBULAR DYSGENESIS SECONDARY TO MUTATIONS IN GENES ENCODING THE
      RENIN-ANGIOTENSIN SYSTEM].
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 4/5 patients we identified a mutation in angiotensin converting enzyme
      (ACE) gene. Variable presentation was noticed in the patients, starting
      with peritoneal dialysis and extreme low blood pressure treated with
      vasopressors and plasma infusions and ending with no symptoms. Currently,
      the patients are 5-20 years old with variable stages of chronic kidney
      disease.
    explanation: >-
      Five neonatal survivors, four with ACE variants, reached 5 to 20 years
      with variable chronic kidney disease.
biochemical:
- name: Plasma ACE activity
  presence: Absent
  context: >-
    Usually undetectable; it can be present when a truncating variant produces
    a secreted, catalytically active enzyme. Heterozygous parents have about
    half of normal activity.
  evidence:
  - reference: PMID:20454656
    reference_title: >-
      Angiotensin I-converting enzyme Gln1069Arg mutation impairs trafficking
      to the cell surface resulting in selective denaturation of the C-domain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      was found to have a homozygous substitution of Arg for Glu at position
      1069 in the C-terminal domain of ACE (Q1069R) resulting in absence of
      plasma ACE activity
    explanation: No plasma ACE activity in an affected patient.
  - reference: PMID:32808512
    reference_title: >-
      A Premature Baby with Severe Oligohydramnios and Hypotension: a Case
      Report of Renal Tubular Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Basal plasma renin activity was markedly elevated and
      angiotensin-converting enzyme was undetectable.
    explanation: ACE undetectable in a second affected neonate.
- name: Plasma renin activity
  presence: Elevated
  context: Markedly elevated, reflecting loss of angiotensin II feedback.
  evidence:
  - reference: PMID:32808512
    reference_title: >-
      A Premature Baby with Severe Oligohydramnios and Hypotension: a Case
      Report of Renal Tubular Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Basal plasma renin activity was markedly elevated and
      angiotensin-converting enzyme was undetectable.
    explanation: Elevated plasma renin activity in an ACE-deficient neonate.
histopathology:
- name: Absence or paucity of differentiated proximal tubules
  diagnostic: true
  description: >-
    Cortical tubules lack proximal differentiation from at least 18 weeks of
    gestation; this is the defining lesion.
  evidence:
  - reference: PMID:16116425
    reference_title: >-
      Mutations in genes in the renin-angiotensin system are associated with
      autosomal recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Absence or paucity of differentiated proximal tubules is the
      histopathological hallmark of the disease
    explanation: Defines the diagnostic histological lesion.
  - reference: PMID:16790508
    reference_title: >-
      Renal tubular dysgenesis, a not uncommon autosomal recessive disorder
      leading to oligohydramnios: Role of the Renin-Angiotensin system.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe defects in proximal tubules were observed in all fetuses from 18
      gestational weeks onward, and lesions also involved other tubular
      segments.
    explanation: Mixed-genotype autosomal recessive RTD series dating the lesion.
- name: Thickening of the renal arterial wall
  description: >-
    Thickened renal arterial vasculature from the arcuate to the afferent
    arteries. Shown in a mixed-genotype autosomal recessive RTD series, not
    reported separately for ACE cases; ACE-null and secreted-ACE mice show
    intrarenal vascular hyperplasia and thickening.
  evidence:
  - reference: PMID:16790508
    reference_title: >-
      Renal tubular dysgenesis, a not uncommon autosomal recessive disorder
      leading to oligohydramnios: Role of the Renin-Angiotensin system.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They were associated with thickening of the renal arterial vasculature,
      from the arcuate to the afferent arteries.
    explanation: Arterial wall thickening accompanies the tubular lesions in human RTD.
  - reference: PMID:8642790
    reference_title: >-
      Mice lacking angiotensin-converting enzyme have low blood pressure,
      renal pathology, and reduced male fertility.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the intrarenal arteries exhibit vascular hyperplasia associated with a
      perivascular inflammatory infiltrate
    explanation: ACE-null mice show intrarenal vascular hyperplasia.
- name: Increased renal renin expression
  description: >-
    Strikingly increased renin in the juxtaglomerular apparatus and
    preglomerular arterioles in most autosomal recessive RTD kidneys.
  evidence:
  - reference: PMID:16790508
    reference_title: >-
      Renal tubular dysgenesis, a not uncommon autosomal recessive disorder
      leading to oligohydramnios: Role of the Renin-Angiotensin system.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renal renin expression was strikingly increased in 19 of 24 patients
      studied, from 13 families, whereas no renal renin was detected in four
      patients from three families.
    explanation: Renin overexpression in most cases of a mixed-genotype series.
genetic:
- name: ACE
  gene_term:
    preferred_term: ACE
    term:
      id: hgnc:2707
      label: ACE
  association: Causative biallelic loss-of-function variants
  relationship_type: CAUSATIVE
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_14a5efd4-d71f-40b1-91ff-90f7f8d63ec7-2024-12-11T170000.000Z
    evidence:
    - reference: CGGV:assertion_14a5efd4-d71f-40b1-91ff-90f7f8d63ec7-2024-12-11T170000.000Z
      reference_title: ACE / renal tubular dysgenesis - ACE (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        ACE | HGNC:2707 | renal tubular dysgenesis - ACE | MONDO:0700337 | AR |
        Definitive
      explanation: ClinGen definitive classification for this gene-disease pair.
  features: >-
    Homozygous or compound heterozygous nonsense, frameshift, splice, missense
    and exon deletion variants. Truncating variants typically cause fetal or
    early neonatal death; a variant that preserves cell-surface ACE (R1180P)
    was compatible with survival. The common intron 16 Alu insertion/deletion
    polymorphism is a separate susceptibility locus and not part of this
    disease.
  evidence:
  - reference: PMID:16116425
    reference_title: >-
      Mutations in genes in the renin-angiotensin system are associated with
      autosomal recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      found that they had homozygous or compound heterozygous mutations in the
      genes encoding renin, angiotensinogen, angiotensin converting enzyme or
      angiotensin II receptor type 1
    explanation: First identification of biallelic ACE variants in RTD.
  - reference: PMID:25899979
    reference_title: >-
      Resolution of refractory hypotension and anuria in a premature newborn
      with loss-of-function of ACE.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Truncating alterations in ACE most often result in fetal demise during
      gestation or in the first days of life and typically as a result of the
      Potter sequence.
    explanation: Summarizes the usual outcome of truncating ACE variants.
  - reference: PMID:24163131
    reference_title: >-
      Absence of cell surface expression of human ACE leads to perinatal death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, another mutant, R1180P, was compatible with life after
      transient neonatal renal insufficiency.
    explanation: The R1180P carrier survived after transient neonatal renal insufficiency.
  - reference: PMID:24163131
    reference_title: >-
      Absence of cell surface expression of human ACE leads to perinatal death.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: This mutant was located at the plasma membrane and rapidly secreted.
    explanation: In expression studies the survival-compatible R1180P protein reached the plasma membrane.
treatments:
- name: Vasopressin for refractory hypotension
  description: >-
    Vasopressin, acting independently of angiotensin II, has reversed
    refractory neonatal hypotension and anuria in ACE-deficient neonates.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: vasopressin
      term:
        id: CHEBI:9937
        label: vasopressin
  target_mechanisms:
  - target: Hypotension
  evidence:
  - reference: PMID:25899979
    reference_title: >-
      Resolution of refractory hypotension and anuria in a premature newborn
      with loss-of-function of ACE.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vasopressin was used to successfully treat refractory hypotension and
      anuria in the neonate born at 27 weeks of gestation.
    explanation: Single-case report of vasopressin reversing hypotension and anuria.
  - reference: PMID:35286024
    reference_title: >-
      Expanding the clinical spectrum of autosomal-recessive renal tubular
      dysgenesis: Two siblings with neonatal survival and review of the
      literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show that both vasopressin and fludrocortisone in the neonatal period
      may provide survival advantages, though outcomes may also be dependent on
      the type of gene variant, as well as other factors.
    explanation: A sibling report and literature review of survivors.
- name: Fludrocortisone mineralocorticoid replacement
  description: >-
    Fludrocortisone replaces the aldosterone deficit and has corrected
    hyperkalemia, hypotension and acid-base balance in survivors.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fludrocortisone
      term:
        id: CHEBI:50885
        label: fludrocortisone
  target_mechanisms:
  - target: Reduced Aldosterone Secretion
  - target: Hyperkalemia
  evidence:
  - reference: PMID:20607303
    reference_title: Inherited renal tubular dysgenesis may not be universally fatal.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypotension and hyperkalemia normalized eventually with administration of
      fludrocortisone.
    explanation: Fludrocortisone corrected hyperkalemia and hypotension in an ACE-mutated survivor.
  - reference: PMID:40930738
    reference_title: >-
      Renal tubular dysgenesis due to variants in the gene encoding ACE in a
      child surviving the neonatal period.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      who has not required renal replacement therapy to date and in whom
      fludrocortisone has achieved electrolyte and acid/base balance
    explanation: Fludrocortisone maintained electrolyte and acid-base balance in an ACE-RTD toddler.
- name: Peritoneal dialysis
  description: >-
    Early peritoneal dialysis supports anuric neonates; urine output can
    appear later, so the postnatal urine trajectory informs decisions about
    continuing dialysis.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Peritoneal dialysis
    term:
      id: NCIT:C15297
      label: Peritoneal Dialysis
  target_mechanisms:
  - target: Anuria
  evidence:
  - reference: PMID:42831903
    reference_title: >-
      ACE-related renal tubular dysgenesis (RTD-ACE) in a neonate surviving
      beyond the early neonatal period.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a preterm neonate with genetically confirmed RTD-ACE who
      survived beyond the neonatal period following early initiation of
      peritoneal dialysis and targeted supportive management.
    explanation: Early peritoneal dialysis in a surviving RTD-ACE neonate.
  - reference: PMID:20454656
    reference_title: >-
      Angiotensin I-converting enzyme Gln1069Arg mutation impairs trafficking
      to the cell surface resulting in selective denaturation of the C-domain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: maintained by peritoneal dialysis since birth
    explanation: A patient with homozygous ACE Q1069R maintained on peritoneal dialysis.
- name: Respiratory support
  description: >-
    Ventilatory support for respiratory failure from pulmonary hypoplasia, part
    of the intensive neonatal care that underlies reported survival.
  treatment_term:
    preferred_term: Mechanical ventilation
    term:
      id: NCIT:C70909
      label: Mechanical Ventilation
  target_mechanisms:
  - target: Respiratory insufficiency
  evidence:
  - reference: PMID:40245857
    reference_title: >-
      Diagnosis and Treatment of Inherited Renal Tubular Dysgenesis Caused by
      ACE Gene Mutation: A Single-Center Experience.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Postnatally, critical management strategies include respiratory support,
      blood pressure stabilization, and renal support/replacement.
    explanation: Lists respiratory support among the critical postnatal measures.
  - reference: PMID:40245857
    reference_title: >-
      Diagnosis and Treatment of Inherited Renal Tubular Dysgenesis Caused by
      ACE Gene Mutation: A Single-Center Experience.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      one infant showed improvement with symptomatic therapies including blood
      pressure elevation, respiratory support, diuretics, and CRRT and was
      discharged
    explanation: One of three ACE-mutated infants survived with this combined support.
  - reference: PMID:35848000
    reference_title: Late Preterm Infant With Postnatal Diagnosis of Renal Tubular Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Initial clinical course was complicated by ventilator requirement,
      bilateral pneumothoraces, and hypotension managed with multiple inotropes.
    explanation: An infant with biallelic ACE variants required mechanical ventilation.
- name: Genetic counseling and prenatal diagnosis
  description: >-
    Molecular diagnosis allows recurrence-risk counseling and early prenatal
    diagnosis in subsequent pregnancies.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:22095942
    reference_title: >-
      Spectrum of mutations in the renin-angiotensin system genes in autosomal
      recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identification of the disease on the basis of precise clinical and
      histological analyses and the characterization of the genetic defects
      allow genetic counseling and early prenatal diagnosis.
    explanation: Genetic diagnosis enables counseling and prenatal diagnosis.
diagnosis:
- name: Exome sequencing of amniotic fluid after amnioinfusion
  description: >-
    In anhydramnios, amnioinfusion allows amniotic fluid sampling and better
    ultrasound assessment; clinical exome sequencing then identifies biallelic
    ACE variants.
  diagnosis_term:
    preferred_term: clinical whole-exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  results: Biallelic pathogenic ACE variants.
  evidence:
  - reference: PMID:38091257
    reference_title: >-
      Prenatal diagnosis of autosomal recessive renal tubular dysgenesis caused
      by variants in the ACE gene: Two fetuses with anhydramnios.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In cases of oligohydramnios/anhydramnios suspicious for urinary tract
      anomalies, amnioinfusion is a meaningful technique that facilitates
      sampling of amniotic fluid for genetic diagnosis.
    explanation: Amnioinfusion enables prenatal genetic sampling.
- name: Renal histology at biopsy or autopsy
  description: >-
    Renal histology showing absent or poorly differentiated proximal tubules
    establishes renal tubular dysgenesis morphologically, and molecular testing
    identifies the gene.
  diagnosis_term:
    preferred_term: kidney biopsy
    term:
      id: NCIT:C51699
      label: Kidney Biopsy
  results: Absence or paucity of differentiated proximal tubules.
  evidence:
  - reference: PMID:16790508
    reference_title: >-
      Renal tubular dysgenesis, a not uncommon autosomal recessive disorder
      leading to oligohydramnios: Role of the Renin-Angiotensin system.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identification of the disease on the basis of precise histologic
      analysis and the research of the genetic defect now allow genetic
      counseling and early prenatal diagnosis.
    explanation: Histology plus genetic testing is the diagnostic route.
- name: Plasma renin and ACE measurement
  description: >-
    Markedly elevated plasma renin activity with undetectable ACE in an anuric,
    hypotensive neonate points to RTD-ACE ahead of genetic confirmation.
  results: Elevated plasma renin activity; undetectable ACE.
  evidence:
  - reference: PMID:32808512
    reference_title: >-
      A Premature Baby with Severe Oligohydramnios and Hypotension: a Case
      Report of Renal Tubular Dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Basal plasma renin activity was markedly elevated and
      angiotensin-converting enzyme was undetectable.
    explanation: The biochemical pattern that prompted ACE testing.
experimental_models:
- name: ACE-null iPSC-derived kidney organoids
  experimental_model_type: ORGANOID
  description: >-
    ACE-/- and AGTR1-/- iPSC lines and patient-derived iPSCs differentiated
    into kidney organoids, compared with controls under normoxic and hypoxic
    culture.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:38071212
  modeled_mechanisms:
  - target: Proximal Tubule Dysgenesis
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      ACE-null organoids formed proximal tubules indistinguishable from
      controls in vitro.
    limitations: >-
      Organoids have no perfused vasculature, blood pressure or circulating
      renin-angiotensin system, which is the compartment the canonical
      hypoperfusion model invokes; normal proximal tubules in vitro argue
      against a cell-autonomous tubular defect rather than against the
      disease mechanism.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        Systemic blood pressure, renal perfusion and the circulating
        renin-angiotensin cascade are absent from the organoid, so it can only
        test whether ACE loss acts within developing nephron cells.
    evidence:
    - reference: PMID:38071212
      reference_title: >-
        RAAS-deficient organoids indicate delayed angiogenesis as a possible
        cause for autosomal recessive renal tubular dysgenesis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Comprehensive marker analyses show that both mutant and control
        organoids generate indistinguishable PT in vitro under normoxic (21%
        O2) or hypoxic (2% O2) conditions.
      explanation: >-
        ACE-null and control organoids generated indistinguishable proximal
        tubules.
animal_models:
- name: Ace-null mouse
  species: Mouse
  genotype: Ace homozygous targeted null (lacking somatic and testis ACE)
  publication: PMID:8642790
  description: >-
    Mice lacking both ACE isozymes are markedly hypotensive with severe renal
    disease, including a reduced papilla, intrarenal vascular hyperplasia and a
    urine concentrating defect, and reduced aldosterone.
  modeled_mechanisms:
  - target: Loss of Renin-Angiotensin Blood Pressure Support
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    limitations: >-
      Mouse nephrogenesis continues after birth and the renal lesion is
      papillary and vascular rather than the absent proximal tubules of human
      fetal disease, so the model reproduces RAS-dependent hypotension better
      than the tubular lesion.
    evidence:
    - reference: PMID:8642790
      reference_title: >-
        Mice lacking angiotensin-converting enzyme have low blood pressure,
        renal pathology, and reduced male fertility.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mice homozygous for this mutant allele lack both ACE isozymes and have
        markedly reduced blood pressures.
      explanation: ACE-null mice are markedly hypotensive.
  - target: Reduced Aldosterone Secretion
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    evidence:
    - reference: PMID:8642790
      reference_title: >-
        Mice lacking angiotensin-converting enzyme have low blood pressure,
        renal pathology, and reduced male fertility.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        They also have an abnormally low urinary sodium to potassium ratio
        despite reduced levels of aldosterone.
      explanation: ACE-null mice have reduced aldosterone.
differential_diagnoses:
- name: Fetal ACE inhibitor or angiotensin receptor blocker fetopathy
  description: >-
    Maternal ACE inhibitor or angiotensin II receptor blocker use in the second
    or third trimester produces an acquired phenocopy with reduced proximal
    tubules and hypocalvaria. A history of maternal exposure distinguishes it;
    it is not modeled as an environmental cause here because this entry is the
    gene-defined form.
  evidence:
  - reference: PMID:34082612
    reference_title: >-
      Quantifying Proximal Collecting Tubule Deficiency in Angiotensin-Converting
      Enzyme Inhibitor and Angiotensin II Receptor Blocker Fetopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AA fetopathy phenotype is similar to renal tubular dysgenesis including
      reduced proximal convoluted tubules (PCTs).
    explanation: Establishes the drug-induced phenocopy.
  - reference: PMID:9222960
    reference_title: >-
      Congenital renal tubular dysplasia and skull ossification defects similar
      to teratogenic effects of angiotensin converting enzyme (ACE) inhibitors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical, pathological, and radiological features are similar to the
      phenotype associated with fetal exposure to angiotensin converting enzyme
      (ACE) inhibitors
    explanation: Familial RTD closely resembles ACE inhibitor fetopathy.
- name: Renal tubular dysgenesis due to REN, AGT or AGTR1 variants
  description: >-
    Biallelic variants in the other renin-angiotensin genes produce the same
    phenotype with similar severity; only molecular testing separates them.
    MONDO has no gene-specific term for these forms.
  evidence:
  - reference: PMID:22095942
    reference_title: >-
      Spectrum of mutations in the renin-angiotensin system genes in autosomal
      recessive renal tubular dysgenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The severity of the clinical course was similar whatever the mutated
      gene
    explanation: Clinical course does not distinguish the RAS genes.
- name: Renal tubular dysgenesis due to twin-twin transfusion
  description: >-
    Acquired renal hypoperfusion in the donor twin of twin-twin transfusion
    syndrome can also produce renal tubular dysgenesis.
  disease_term:
    preferred_term: renal tubular dysgenesis due to twin-twin transfusion
    term:
      id: MONDO:0019984
      label: renal tubular dysgenesis due to twin-twin transfusion
notes: >-
  No GeneReviews chapter covers renal tubular dysgenesis
  (`just check-genereviews --online` returned NO_CHAPTER, and a PubMed search
  for "tubular dysgenesis[TI] AND genereviews[book]" returned no records), so
  the phenotype baseline is the Gribouval 2005 and 2012 series and the ClinGen
  curation. Only the ACE form has a gene-specific MONDO term; the REN, AGT and
  AGTR1 forms sit under MONDO:0009970 renal tubular dysgenesis of genetic
  origin, so this entry is gene-specific and a grouping across the four genes
  is left for when those forms are curated. Single case reports of esophageal
  atresia with biallelic ACE variants are not included as phenotypes.
references:
- reference: PMID:16116425
  title: >-
    Mutations in genes in the renin-angiotensin system are associated with
    autosomal recessive renal tubular dysgenesis.
- reference: PMID:22095942
  title: >-
    Spectrum of mutations in the renin-angiotensin system genes in autosomal
    recessive renal tubular dysgenesis.
datasets: []
📚

References & Deep Research

References

2
PMID:16116425
Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis.
No top-level findings curated for this source.
PMID:22095942
Spectrum of mutations in the renin-angiotensin system genes in autosomal recessive renal tubular dysgenesis.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Renal_Tubular_Dysgenesis_-_ACE · 2026-10-09T13:57:36Z · View source

New gene-specific entry for MONDO:0700337, curated under claim issue #13685. The stub was decided as a Disease: MONDO has a gene-specific term only for the ACE form, and the REN, AGT and AGTR1 forms have no terms of their own, so a four-gene grouping is deferred until those forms are curated. Deep research: one OpenScientist report (research/Renal_Tubular_Dysgenesis_-_ACE-deep-research-openscientist.md). `just preflight-dr` passed (ACE mentioned 61 times). The report's validation listed PMID:32808512 and PMID:18406804 as unresolved; the run log shows both lookups failed with HTTP 429. Both were re-fetched with `just fetch-reference` and resolve to on-topic papers (an ACE-RTD case report and a review of ACE-null mice). PMID:32808512 is cited; 18406804 is not, because PMID:8642790 is the primary mouse report. The report's CL:1000697 for juxtaglomerular cells is a kidney interstitial macrophage term and was not used; CL:0000648 kidney granular cell was bound instead. Report citations not used: 9860997 and 11096065 (AGTR1 and AGT mice), 33768328 and 38649831 (AGTR1 patients), 24061643 and 21359618 (ureteric bud branching, not shown in ACE-RTD). Further sources were found by PubMed search and fetched: Gribouval 2005 and 2012 series, ACE trafficking studies (24163131, 21695262, 20454656), the kidney organoid study (38071212), ACE-null and secreted-ACE mice (8642790, 9153279), survivor reports, the ClinGen Definitive assertion, and ACE inhibitor fetopathy papers for the differential. Pathograph: ACE loss of function, loss of cell-surface ACE, absent angiotensin II, loss of RAS blood pressure support, fetal renal hypoperfusion, proximal tubule dysgenesis, anuria, then oligohydramnios and the Potter sequence. Side branches cover aldosterone, renin overexpression, erythropoiesis (mouse data only) and urine concentration (mouse data only). The organoid delayed-angiogenesis model is an EMERGING hypothesis group, and the organoid itself is recorded as FAILS_TO_RECAPITULATE the tubule lesion in vitro. Stillbirth and neonatal death are under progression because their HPO terms are outside the PhenotypeTerm enum. Maternal ACE inhibitor exposure is a differential diagnosis, not an environmental cause. A pre-PR review by a separate agent led to these changes. The root node no longer claims lost catalytic activity: PMID:24163131 and PMID:21695262 show lethal variants that keep catalysis but lose membrane-bound ACE, so the angiotensin II node now reads as loss of tissue angiotensin II generation. The delayed-angiogenesis edge now comes from that node rather than from hypoperfusion, because hypoxia rescued VEGF-A in the organoid study. The erythropoiesis branch is now an EMERGING hypothesis group. Histopathology, renal histology and plasma renin/ACE diagnosis entries were added, the fludrocortisone evidence now quotes the reported result, and a mixed-source PMID:24163131 item was split by evidence_source. Dropping the root node's GO:0008241 binding left ACE landing on a node with no molecular function, which the PR's CI gate `check_gene_activity_grounding.py` rejects. The binding is restored with preferred term "tissue-bound peptidyl-dipeptidase activity"; the node description already states that the loss is of membrane-bound enzyme. At the PR reviewer's suggestion, the plasma ACE biomarker context now says "usually undetectable", because a secreted truncated enzyme can persist. No GeneReviews chapter exists (`just check-genereviews --online`: NO_CHAPTER). Validation: `just validate` and `just validate-disorders` passed, snippets verified offline (115/115 after the review round), entity refs and causal targets clean, and every reference_title checked against the cache frontmatter. Stub deleted.

OpenScientist ▸
Renal Tubular Dysgenesis, ACE Type (RTD-ACE) — Comprehensive Disease Report
openscientist-autonomous 24 citations 2026-10-09T13:40:15.663298

Renal Tubular Dysgenesis, ACE Type (RTD-ACE) — Comprehensive Disease Report

Disease: Renal Tubular Dysgenesis, ACE type (RTD-ACE) MONDO ID: MONDO:0700337 · OMIM: 267430 (Renal Tubular Dysgenesis) · Orphanet: ORPHA:97369 · Category: Mendelian (autosomal recessive) Causal gene: ACE (angiotensin I–converting enzyme; HGNC:2707; gene OMIM 106180; chromosome 17q23.3)

Summary

Renal Tubular Dysgenesis of the ACE type (RTD-ACE) is a rare, autosomal recessive developmental disorder of the kidney caused by biallelic loss-of-function (LoF) variants in ACE, the gene encoding angiotensin I–converting enzyme. It is one subtype within a broader genetic RTD spectrum produced by inactivating mutations in any of the four core renin–angiotensin system (RAS) genes — AGT (angiotensinogen), REN (renin), ACE, and AGTR1 (angiotensin II receptor type 1). The defining lesion is fetal angiotensin II deficiency: without functional ACE, angiotensin I cannot be converted to the active octapeptide angiotensin II, the fetal RAS is inactive, renal perfusion pressure collapses, proximal tubules fail to differentiate, and the fetus becomes anuric. The clinical hallmark is a combination of persistent fetal anuria → oligohydramnios/anhydramnios → Potter sequence with pulmonary hypoplasia, together with refractory neonatal hypotension and defective skull ossification (large fontanelles, wide sutures). Perinatal mortality is very high.

Across genetically solved RTD families, ACE is the single most common cause, accounting for roughly two-thirds (≈65%) of families (Gribouval et al. 2012, PMID: 22095942). Critically, disease severity is similar regardless of which RAS gene is mutated, which points strongly to a single unifying mechanism — loss of fetal angiotensin II signaling — rather than any ACE-specific effect. This human genetic convergence is mirrored in mouse genetics: knockouts of Ace, Agt, and the combined Agtr1a/Agtr1b receptors all produce a nearly identical renal phenotype of vascular thickening, medullary atrophy/tubular lesions, hypotension, and perinatal lethality.

Although RTD-ACE was historically considered uniformly lethal, the clinical spectrum is expanding. With aggressive neonatal blood-pressure support, mechanical ventilation, and early dialysis, survivors are now reported living from years into adulthood with variable chronic kidney disease (CKD). A distinct atypical presentation of biallelic ACE LoF is also recognized: progressive childhood CKD with polyuria–polydipsia and anemia that is disproportionate to the degree of renal failure. This disproportionate anemia is mechanistically explained by the loss of angiotensin II's direct pro-erythropoietic action (both as an erythropoietin secretagogue and as a direct AT1-mediated growth factor for erythroid progenitors) — the same angiotensin II deficiency that drives the renal phenotype.

Key Findings

Finding 1 — RTD-ACE is caused by biallelic loss-of-function variants in ACE, within a RAS-gene RTD spectrum

RTD is genetically heterogeneous but mechanistically unified. The landmark study by Gribouval et al. 2005 (PMID: 16116425) identified homozygous or compound heterozygous mutations in the genes encoding renin, angiotensinogen, angiotensin-converting enzyme, or angiotensin II receptor type 1 in 11 individuals from 9 families with autosomal recessive RTD, establishing that ACE is one of four RAS genes whose biallelic inactivation causes the disease. The authors wrote that affected individuals "had homozygous or compound heterozygous mutations in the genes encoding renin, angiotensinogen, angiotensin converting enzyme or angiotensin II receptor type 1."

Multiple subsequent ACE-specific case reports and series confirmed biallelic LoF ACE variants — spanning missense, frameshift, nonsense, and splice-site classes — as the most common genetic cause of RTD. For example, novel compound heterozygous ACE variants were reported in a family with recurrent anhydramnios (PMID: 32329243), a homozygous novel 3′ splice-site variant (NM_000789.3:c.2642-1G>A) was found in a fetus with RTD (PMID: 30058238), and ACE variants were associated with RTD plus a novel microcolon association (PMID: 30071301). The progressive-CKD review by Fila et al. 2020 (PMID: 32198635) states plainly: "Bi-allelic loss of function variations in genes encoding proteins of the renin-angiotensin system (AGT, ACE, REN, AGTR1) are associated with autosomal recessive renal tubular dysgenesis."

Variant / molecular detail: - Gene: ACE (HGNC:2707), 17q23.3; reference transcript NM_000789.3. - Variant types observed: missense (e.g., p.Ser346Trp, p.Asn489Asp), frameshift (p.S486Ffs29), nonsense, and canonical splice-site (c.2642-1G>A). - Functional consequence: loss of function — loss of ACE catalytic activity → no angiotensin II generation. In vitro/in silico analyses show such variants disrupt ACE protein structure (PMID: 32329243). - Classification:* reported variants are generally pathogenic/likely pathogenic under ACMG/AMP criteria given the LoF mechanism, recessive segregation, and absence/rarity in population databases.

Finding 2 — Mechanism: fetal RAS inactivity causes low renal perfusion, proximal-tubule maldevelopment, anuria, and Potter sequence

The histopathology of RTD directly demonstrates the developmental lesion. Lacoste et al. 2006 (PMID: 16790508) found that "Severe defects in proximal tubules were observed in all fetuses from 18 gestational weeks onward," establishing the timing of the proximal-tubule differentiation failure. The same study documented a strikingly increased renal renin signal — "Renal renin expression was strikingly increased in 19 of 24 patients studied" — reflecting compensatory upregulation of renin in the face of absent downstream angiotensin II signaling (a feedback hallmark of RAS failure). Thickened renal arterial vasculature (from arcuate to afferent arteries) is also characteristic, and ACE/angiotensinogen protein is absent or reduced in the proximal tubule.

Gribouval et al. 2005 (PMID: 16116425) articulated the core causal chain: "renal lesions and early anuria result from chronic low perfusion pressure of the fetal kidney, a consequence of renin-angiotensin system inactivity." An earlier immunohistochemical study (PMID: 7994002) had already noted large accumulations of renin in preglomerular arterioles and glomerular structures, consistent with faulty feedback and reduced glomerular perfusion.

Clinically, this produces a stereotyped cascade: persistent fetal anuria → oligohydramnios/anhydramnios → pulmonary hypoplasia and limb/facial deformation (Potter sequence); refractory neonatal hypotension unresponsive to vasopressors; and defective skull ossification with large fontanelles and wide cranial sutures (reported consistently across cases, e.g., PMID: 32808512, PMID: 38649831).

Finding 3 — High perinatal mortality but an expanding survivor spectrum, including progressive CKD

Classically, RTD causes near-universal perinatal death from the combination of pulmonary hypoplasia and anuric renal failure — in the Lacoste series all 29 cases resulted in perinatal death. However, the modern clinical picture is shifting. Schreiber et al. 2021 (PMID: 34957720) reported a cohort of survivors in whom "the patients are 5-20 years old with variable stages of chronic kidney disease," with 4 of 5 carrying ACE mutations. Numerous recent single-case reports describe neonates surviving the neonatal period with early peritoneal dialysis and intensive supportive management (PMID: 42831903, PMID: 40930738, PMID: 40709124, PMID: 35848000).

Biallelic ACE LoF can also present atypically as progressive childhood CKD rather than lethal neonatal disease. Fila et al. 2020 (PMID: 32198635) reported that "Bi-allelic loss of function mutation of ACE can have atypical and sometimes late presentation with chronic renal failure, anemia (out of proportion with the level of renal failure), and polyuro-polydipsia," broadening the recognized phenotypic range and emphasizing disproportionate anemia and a urinary concentrating defect as key atypical features. Survival with managed tubular and glomerular dysfunction has even been documented to adulthood in a related AGTR1-LoF patient (28 years old, GFR ~30 mL/min; PMID: 33768328).

Finding 4 — Mouse RAS-gene knockouts recapitulate the RTD renal vascular/tubular pathology and hypotension

The mouse genetics provide convergent, cross-species confirmation of the mechanism. Ace-null mice "have low systolic blood pressures and defects in renal development and function" (PMID: 18406804). Combined AT1 receptor knockouts (Agtr1a−/−Agtr1b−/−) show vascular thickening within the kidney and atrophy of the inner renal medulla, a phenotype described as "virtually identical to that seen in angiotensinogen-deficient (Agt-/-) and angiotensin-converting enzyme-deficient (Ace -/-) mice that are unable to synthesize angiotensin II" (PMID: 9860997). Agt−/− mice die shortly after birth from renal dysfunction with severe renal vascular and tubular lesions (PMID: 11096065). Finally, mice with a catalytically inactivated ACE C-domain cannot concentrate urine effectively after dehydration — "they are not able to concentrate urine after dehydration as effectively as wild-type mice" (PMID: 18158355) — modeling the tubular concentrating defect seen in human RTD survivors.

Finding 5 — ACE is the predominant molecular cause (~65% of families), with gene-independent disease severity

The definitive genotype–phenotype survey, Gribouval et al. 2012 (PMID: 22095942), reviewed 54 distinct RAS-gene mutations across 48 unrelated families with autosomal recessive RTD. ACE mutations were the most frequent, found in two-thirds of families (64.6%), and — crucially — "The severity of the clinical course was similar whatever the mutated gene." This gene-independence is the strongest human-genetic argument that a single downstream endpoint (angiotensin II deficiency / renal hypoperfusion) drives the disease. The same review generalizes the mechanism to acquired forms: "Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules." Developmental studies (Yosypiv, PMID: 24061643; PMID: 21359618) add that loss of angiotensin II impairs ureteric-bud branching morphogenesis, causing medullary/papillary hypoplasia and the urinary concentrating defect.

Finding 6 — Disproportionate anemia in ACE-RTD survivors reflects loss of angiotensin II–driven erythropoiesis

The anemia-out-of-proportion feature of ACE-LoF survivors (PMID: 32198635) has a clear mechanistic basis. Angiotensin II is a physiological regulator of erythropoiesis, acting as both an erythropoietin secretagogue and a direct AT1-mediated growth factor for erythroid progenitors — Vlahakos et al. 2010 (PMID: 20400218) state that "angiotensin II (Ang II) is a physiologically important regulator of erythropoiesis." Genetic proof comes from Kato/Fukamizu 2015 (PMID: 26107632): "knockout mice that lack angiotensin II, including angiotensinogen and renin knockout mice, exhibit anemia. The anemia of angiotensinogen knockout mice was rescued by angiotensin II infusion" — and the rescue was re-blocked by an AT1 antagonist, while AT1a/AT1b double-knockout mice reproduced the anemia. Thus the same angiotensin II deficiency that drives renal maldevelopment independently impairs red-cell production, explaining why anemia in ACE-RTD is worse than renal EPO deficiency alone would predict.

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

1. Biallelic loss-of-function variant in ACE (missense/frameshift/nonsense/splice)
       | results in
2. Absent/deficient angiotensin I–converting enzyme catalytic activity
       | results in
3. Failure to convert angiotensin I -> angiotensin II (fetal RAS inactive)
       | leads to
4. Loss of AT1-receptor signaling + chronically low fetal renal perfusion pressure
       | branches into three downstream arms:

   ARM A (renal development — demonstrated histologically):
   5a. Impaired proximal-tubule differentiation (from ~18 wk gestation)
+ impaired ureteric-bud branching morphogenesis (inferred from mouse/dev studies)
-> medullary/papillary hypoplasia, thickened preglomerular vasculature
-> fetal anuria -> oligohydramnios/anhydramnios
-> Potter sequence (pulmonary hypoplasia, limb/facial deformation)
-> neonatal respiratory failure   <- major cause of perinatal death

   ARM B (hemodynamic):
   5b. Loss of angiotensin II vasopressor tone
-> refractory neonatal hypotension (vasopressor-resistant)
-> compensatory renin hypersecretion (feedback, no downstream effect)
-> skull ossification defect (large fontanelles, wide sutures; perfusion-linked, inferred)

   ARM C (hematologic — manifest mainly in survivors):
   5c. Loss of angiotensin II pro-erythropoietic action (EPO secretagogue + direct AT1 growth factor)
-> impaired erythropoiesis
-> anemia disproportionate to renal failure

Upstream vs downstream

The upstream node is unambiguous: ACE LoF → angiotensin II deficiency. Everything else is downstream and convergent. The human genetic evidence (gene-independent severity across AGT/REN/ACE/AGTR1; PMID: 22095942) and the mouse genetic evidence (phenotypic equivalence of Ace−/−, Agt−/−, and Agtr1a/1b−/−; PMID: 9860997) jointly establish that the pathology is a readout of the final common endpoint — absent angiotensin II / AT1 signaling and renal hypoperfusion — not of any ACE-specific moonlighting function.

Cell types, tissues, and processes

Level Structure / process Ontology suggestion
Organ (primary) Kidney UBERON:0002113
Organ (secondary) Lung (hypoplasia via oligohydramnios) UBERON:0002048
Organ (secondary) Skull / cranial bones (ossification defect) UBERON:0003129
Organ (rare assoc.) Colon (microcolon; novel RTD assoc., PMID 30071301) UBERON:0001155
Tissue Renal tubular epithelium UBERON:0004135
Cell Proximal tubule epithelial cell CL:1000838
Cell Juxtaglomerular (renin-producing) cell CL:1000697
Cell Erythroid progenitor cell CL:0000038
Process Proximal tubule / nephron differentiation GO:0072014 / GO:0072006
Process Ureteric bud branching morphogenesis GO:0060676
Process Renin–angiotensin regulation of blood pressure GO:0002018
Process Regulation of erythropoiesis GO:0045646
Pathway Renin–angiotensin system KEGG hsa04614
Chemical Angiotensin II CHEBI:2719

Evidence Base

PMID Study (abbrev.) Evidence type Supports
16116425 Mutations in RAS genes cause AR-RTD (Gribouval 2005) Human genetic F1, F2 — ACE as one of 4 RAS genes; hypoperfusion mechanism
16790508 RTD, role of RAS (Lacoste 2006) Human histopathology F2, F3 — proximal-tubule defect from 18 wk; renin↑; perinatal death
22095942 Spectrum of RAS mutations in AR-RTD (Gribouval 2012) Human genetic cohort F5 — ACE = 64.6% of families; gene-independent severity
32198635 Biallelic RAS mutations can present as progressive CKD (Fila 2020) Human clinical F1, F3, F6 — atypical CKD; disproportionate anemia; polyuro-polydipsia
34957720 RTD secondary to RAS mutations (Schreiber 2021) Human clinical F3 — survivors 5–20 yr with variable CKD
9860997 AT1A/AT1B double-KO mice Mouse model F4 — phenotype "virtually identical" to Ace−/−, Agt−/−
18406804 Role of ACE (review) Mouse model F4 — Ace−/− low BP + renal developmental defects
11096065 Lethality in Agt−/− mice Mouse model F4 — systemic AGT loss → perinatal death, renal lesions
18158355 ACE C-domain main cleavage site Mouse model F4 — urinary concentrating defect
26107632 Erythropoiesis/BP via AT1 (Kato 2015) Mouse model F6 — Ang II deficiency → anemia, rescued by Ang II
20400218 RAS in regulation of erythropoiesis Review F6 — Ang II is a physiological erythropoiesis regulator
24061643 / 21359618 RAS in ureteric-bud branching Developmental F5 — Ang II loss impairs UB branching → medullary hypoplasia
30071301 RTD + microcolon Human clinical F1 — ACE variants; novel gut association
30058238 / 32329243 Novel ACE splice/compound-het variants Human genetic F1 — variant spectrum (splice, frameshift, missense)
33768328 Adult AGTR1 LoF survivor Human clinical F3 — survival with managed tubular/glomerular dysfunction
35848000 / 42831903 / 40930738 / 40709124 ACE-RTD neonatal survivors Human clinical F3 — survival with dialysis/ventilation

Section-by-Section Characterization

1. Disease Information

RTD-ACE is a severe, prenatally-onset autosomal recessive disorder of kidney development characterized by poor differentiation of renal proximal tubules with a grossly normal kidney architecture, leading to fetal anuria, oligohydramnios, and Potter sequence. Identifiers: MONDO:0700337; OMIM 267430 (RTD phenotype); gene ACE OMIM 106180; Orphanet ORPHA:97369; ICD-10 Q63.8 (other specified congenital malformations of kidney). Synonyms: autosomal recessive renal tubular dysgenesis (AR-RTD); RTD; primary/hereditary RTD; RTD-ACE (ACE-related RTD). The knowledge base is derived from aggregated disease-level resources (OMIM, Orphanet) plus individual-patient case reports and small case series.

2. Etiology

Primary cause: biallelic (homozygous or compound heterozygous) loss-of-function variants in ACE. Genetic risk factors: consanguinity markedly increases risk (many reported families are consanguineous, e.g., PMID: 30058238, PMID: 38649831); carrier parents are typically asymptomatic. Environmental phenocopy: acquired RTD occurs with in-utero exposure to RAS-blocking drugs (ACE inhibitors, ARBs) and NSAIDs (PMID: 35848000), and with any cause of severe fetal renal hypoperfusion (e.g., twin-twin transfusion), demonstrating a true gene–environment convergence on the same angiotensin II–deficiency / hypoperfusion endpoint (PMID: 22095942). Protective factors: none genetically established; postnatally, intensive supportive care is "protective" against early death.

3. Phenotypes

Phenotype Type HPO term Onset Frequency
Oligohydramnios/anhydramnios Prenatal sign HP:0001562 Prenatal Near-universal
Fetal/neonatal anuria/oliguria Clinical sign HP:0100519 / HP:0100520 Fetal/neonatal Near-universal
Refractory arterial hypotension Clinical sign HP:0002615 Neonatal Very frequent
Pulmonary hypoplasia Physical HP:0002089 Prenatal/neonatal Very frequent
Large fontanelles / delayed skull ossification Physical HP:0000239 / HP:0010656 Neonatal Frequent
Renal tubular dysgenesis (proximal tubule paucity) Lab/path HP:0000107 context Prenatal Defining
Chronic kidney disease / ESKD (survivors) Lab HP:0012622 / HP:0003774 Childhood Survivors
Anemia (disproportionate) Lab HP:0001903 Childhood Survivors (atypical)
Polyuria–polydipsia / concentrating defect Clinical HP:0000103 / HP:0001959 Childhood Survivors (atypical)

Severity is classically severe/lethal; the course in survivors is progressive toward CKD/ESKD. Quality-of-life impact in survivors is substantial (dialysis dependence, growth impairment, transplantation need).

4. Genetic/Molecular Information

Causal gene: ACE (gene OMIM 106180; HGNC:2707; 17q23.3). Variant types: missense, nonsense, frameshift, canonical splice-site; all loss-of-function. Examples: c.1454_1455insC p.(S486Ffs29); c.1037C>G p.(Ser346Trp); c.1465A>G p.(Asn489Asp) (PMID: 32329243); c.2642-1G>A splice (PMID: 30058238). Origin: germline, biallelic. Functional consequence: loss of ACE enzymatic activity → no angiotensin II. Allele frequency: pathogenic alleles are rare/absent in gnomAD. Modifier genes: the other RAS genes act as a functional network; no formal modifier established, though gene-independent severity (PMID: 22095942) argues the pathway endpoint dominates. Epigenetic/chromosomal:* no recurrent abnormalities reported.

5. Environmental Information

Non-genetic phenocopies: maternal ACE inhibitors/ARBs and NSAIDs in pregnancy; severe fetal renal hypoperfusion of any cause (PMID: 35848000, PMID: 22095942). No infectious agents implicated. Relevant chemical entities: captopril/enalapril (ACE inhibitors), NSAIDs.

6. Mechanism / Pathophysiology

See the ordered causal chain above. Core pathway: renin–angiotensin system (KEGG hsa04614). Upstream lesion = ACE LoF → angiotensin II deficiency; downstream = failed proximal-tubule differentiation and ureteric-bud branching (renal), loss of vasopressor tone (hemodynamic), and impaired erythropoiesis (hematologic). Compensatory renin hypersecretion is a diagnostic feedback signature (PMID: 16790508, PMID: 7994002).

7. Anatomical Structures Affected

Primary: kidney (UBERON:0002113), specifically renal cortex proximal tubules and preglomerular vasculature. Secondary: lung (pulmonary hypoplasia, UBERON:0002048), cranial bones (UBERON:0003129), and rarely colon (microcolon, PMID: 30071301). Body systems: urinary, cardiovascular (hemodynamic), respiratory, skeletal, and hematopoietic. Lateralization: bilateral renal involvement.

8. Temporal Development

Onset is congenital/prenatal (proximal-tubule defect from ~18 gestational weeks; PMID: 16790508). Course: historically lethal in the perinatal period; in survivors, chronic and progressive toward ESKD over years (PMID: 34957720). Critical intervention window is the immediate neonatal period (BP support, ventilation, dialysis); prenatal diagnosis enables counseling and planning.

9. Inheritance and Population

Inheritance: autosomal recessive. Penetrance: high/complete for biallelic LoF, though with variable expressivity (lethal vs survivor-CKD vs atypical late CKD). Consanguinity is a major contributor. Carrier frequency: low; founder effects not firmly established. Epidemiology: very rare (Orphanet class <1/1,000,000); exact prevalence/incidence not well quantified. Sex ratio: approximately equal (autosomal). ACE accounts for ≈65% of genetically solved families (PMID: 22095942).

10. Diagnostics

Prenatal: oligohydramnios/anhydramnios on ultrasound; enlarged echogenic kidneys with poor corticomedullary differentiation. Postnatal labs: anuria, refractory hypotension, markedly elevated plasma renin activity with undetectable/low ACE (PMID: 32808512). Imaging: skull X-ray showing large fontanelles/wide sutures; renal ultrasound. Histopathology (definitive morphology): absent/paucal differentiated proximal tubules with increased renin immunostaining. Genetic testing (definitive): WES/WGS or RAS-gene panels (ACE, AGT, REN, AGTR1) — WES identified ACE variants in multiple cases (PMID: 30058238, PMID: 35848000). Differential diagnosis: ARPKD, bilateral renal agenesis/dysplasia, other CAKUT, and acquired (drug-induced) RTD. Prenatal diagnosis is available for at-risk pregnancies after family variant identification.

11. Outcome/Prognosis

Historically very poor — near-universal perinatal death (PMID: 16790508). With modern intensive care and dialysis, survivors reach 5–20 years with variable CKD/ESKD (PMID: 34957720); an adult AGTR1 survivor retained GFR ~30 mL/min with managed tubular/glomerular dysfunction (PMID: 33768328). Complications: pulmonary hypoplasia, ESKD, growth impairment, disproportionate anemia. Prognostic factors: degree of pulmonary hypoplasia, postnatal urine-output trajectory, and feasibility of dialysis.

12. Treatment

No curative therapy; management is supportive. Neonatal: mechanical ventilation, aggressive vasopressor/blood-pressure support, early peritoneal dialysis (PMID: 42831903, PMID: 40930738). Longer-term: renal replacement therapy and eventual kidney transplantation; fludrocortisone has been used to treat hyperkalemia/salt-wasting in a RAS-LoF survivor (PMID: 33768328); erythropoiesis-stimulating agents for the anemia. RAS-blocking drugs are contraindicated (would worsen the deficiency). No gene/cell/RNA therapies exist. NCIT terms: Dialysis (NCIT:C15248), Kidney Transplantation (NCIT:C15366), Supportive Care (NCIT:C15285).

13. Prevention

No primary prevention of the genetic form. Secondary/tertiary: avoid RAS inhibitors and NSAIDs in pregnancy (prevents acquired phenocopy); prenatal and preimplantation genetic diagnosis for at-risk couples after variant identification; genetic counseling for consanguineous and previously affected families; cascade carrier testing. Early prenatal detection enables planned delivery at a tertiary center with neonatal dialysis capability.

14. Other Species / Natural Disease

No naturally occurring companion-animal RTD-ACE is well documented; the disease is primarily defined in humans. Orthologous genes are conserved — mouse Ace (NCBI Gene 11421), Agt, Ren, Agtr1a/Agtr1b. The renal mechanism is evolutionarily conserved across mammals, as evidenced by matching mouse knockout phenotypes. Experimental species: Mus musculus (NCBI:txid10090), Rattus norvegicus.

15. Model Organisms

The mouse is the primary model. Relevant genetic models: Ace−/− (low BP, renal developmental defects; PMID: 18406804); Agt−/− (perinatal lethal, renal vascular/tubular lesions; PMID: 11096065); Agtr1a−/−Agtr1b−/− double knockout (renal vascular thickening, medullary atrophy; PMID: 9860997); ACE C-domain–inactive knock-in (urinary concentrating defect; PMID: 18158355). Phenotype recapitulation: high — these models reproduce the renal vascular/tubular pathology, hypotension, concentrating defect, and anemia. Limitations: mouse models capture the renal and hemodynamic lesions but the human Potter-sequence/pulmonary-hypoplasia context differs, and the atypical human progressive-CKD phenotype is less directly modeled.

Limitations and Knowledge Gaps

  1. Rarity and small cohorts. Most evidence derives from single case reports and modest series; precise prevalence, incidence, penetrance, and survival statistics are not firmly established.
  2. Genotype–phenotype resolution. Although severity appears gene-independent, it remains unclear what determines whether a given biallelic ACE LoF produces lethal neonatal disease versus the atypical progressive-CKD phenotype — residual ACE activity, modifier genes, or environmental factors are all plausible but untested.
  3. Inferred steps in the causal chain. The link from angiotensin II deficiency to skull ossification defects, and the ureteric-bud branching contribution in humans, is extrapolated largely from mouse/developmental data rather than demonstrated directly in human RTD-ACE tissue.
  4. Survivor natural history. Long-term outcomes (renal, neurocognitive, cardiovascular) in the growing survivor population are incompletely characterized; the oldest well-documented survivors are only ~20 years old.
  5. No disease-specific therapeutics. No treatment restores fetal angiotensin II signaling during the critical developmental window; management is entirely supportive.

Proposed Follow-up Experiments / Actions

  1. International RTD-ACE registry to quantify prevalence, survival with modern care, and long-term survivor outcomes, enabling evidence-based prognostic counseling.
  2. Systematic ACE genotype–residual-activity correlation (functional assays of patient variants) to test whether partial/hypomorphic activity predicts the atypical progressive-CKD phenotype versus lethal disease.
  3. Kidney-organoid and iPSC models carrying patient ACE variants to dissect the human proximal-tubule differentiation defect and test whether exogenous angiotensin II (or AT1 agonism) during a developmental window rescues tubulogenesis.
  4. Prospective anemia characterization in survivors — measure EPO, reticulocyte response, and ESA responsiveness to confirm the angiotensin II–erythropoiesis mechanism clinically and optimize anemia management.
  5. Standardized neonatal management protocol (BP targets, timing of dialysis, ventilation strategy) evaluated prospectively, given the expanding survivor spectrum.
  6. Pharmacovigilance / public-health messaging reinforcing avoidance of RAS inhibitors and NSAIDs in pregnancy to prevent acquired phenocopies.

Report compiled from 6 confirmed findings and 42 reviewed papers over 5 investigation iterations. Evidence types are distinguished throughout as human clinical, human genetic/histopathology, mouse model, or review.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 24
Resolved 22
Unresolved (possible confabulation) 2
Unverifiable 0
References weighed for topical relevance 22
On topic 19
Off topic 0

Unresolved references

These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:

  • PMID:32808512 (5 mentions) - Identifier did not resolve to a record
  • PMID:18406804 (6 mentions) - Identifier did not resolve to a record

Term Validation

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

Outcome Count
Terms checked 33
Resolved 31
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 16
Terms named correctly 2
Terms named as a different term 7
Terms whose name is worth a second look 7

Terms the report names something else

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

  • UBERON:0002048 (2 mentions) - the report calls it "Lung (hypoplasia via oligohydramnios)"; UBERON calls it lung
  • UBERON:0003129 (2 mentions) - the report calls it "Skull / cranial bones (ossification defect)"; UBERON calls it skull
  • UBERON:0001155 (1 mention) - the report calls it "Colon (microcolon; novel RTD assoc., PMID 30071301)"; UBERON calls it colon
  • CL:1000697 (1 mention) - the report calls it "Juxtaglomerular (renin-producing) cell"; CL calls it kidney interstitial suppressor macrophage
  • HP:0001562 (1 mention) - the report calls it "Prenatal sign"; HP calls it Oligohydramnios
  • HP:0002615 (1 mention) - the report calls it "Clinical sign"; HP calls it Hypotension
  • HP:0001903 (1 mention) - the report calls it "Lab"; HP calls it Anemia

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:

  • UBERON:0004135 (1 mention) - the report calls it "Renal tubular epithelium"; UBERON calls it distal tubule, and lists "renal distal tubule" among its other names
  • CL:1000838 (1 mention) - the report calls it "Proximal tubule epithelial cell"; CL calls it kidney proximal convoluted tubule epithelial cell
  • GO:0060676 (1 mention) - the report calls it "Ureteric bud branching morphogenesis"; GO calls it ureteric bud formation
  • GO:0002018 (1 mention) - the report calls it "Renin–angiotensin regulation of blood pressure"; GO calls it renin-angiotensin regulation of aldosterone production
  • GO:0045646 (1 mention) - the report calls it "Regulation of erythropoiesis"; GO calls it regulation of erythrocyte differentiation
  • CHEBI:2719 (1 mention) - the report calls it "Angiotensin II"; CHEBI calls it Ile(5)-angiotensin II, and lists "Angiotensin II" among its other names
  • HP:0002089 (1 mention) - the report calls it "Physical"; HP calls it Pulmonary hypoplasia, and lists "Hypoplastic lung" among its other names

Terms named inconsistently

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

  • HGNC:2707 - called "ACE", "Gene:* ACE"

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.