Growth Restriction Hypoplastic Kidneys Alopecia And Distinctive Facies

Mendelian MONDO:0859146 Pathograph 27 Show in embeddings browser

A lethal autosomal recessive multisystem syndrome caused by biallelic ZPR1 variants, known from six children in five families who all carry the same founder allele, with one further child reported carrying two ZPR1 variants of uncertain significance whose phase was never established. Its descriptive name is the list of the features the first report used to recognise it: pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, and hypoplastic kidneys with renal insufficiency, together with global developmental delay, severe congenital sensorineural hearing loss, hydrocephalus and genital hypoplasia. Three of the first four children died before three years of age, of uremia or sepsis. Every patient with a confirmed genotype is homozygous for the same change, ZPR1 c.587T>C (p.Ile196Thr). The 2018 report found it in four children from three families of New Mexican Hispanic heritage; the 2026 report found it again in two sisters and identified it as a founder variant of the Middle Rio Grande Valley. No second allele has been established as disease-causing. A 2026 case report does describe a thirteen-month-old with an overlapping phenotype who carries two compound heterozygous ZPR1 variants of uncertain significance - a maternally inherited frameshift, c.84del, and a missense change, p.(Leu149Ser) - but that report is explicit that phasing was never established and that both variants remain of uncertain significance, so it widens the allelic spectrum as a possibility rather than as a fact. The phenotype described here is therefore still the phenotype of one variant rather than of the gene. The mechanism is a general proliferation defect rather than an organ-specific one, which is what a syndrome touching growth, brain, kidney, hair, ear and gonad at once should look like. The missense change sits in the hydrophobic core of the protein by structural modelling, and patient fibroblasts carry no detectable ZPR1 at all - so the allele behaves as a null in the one tissue anybody has looked at. Cells lacking ZPR1 arrest in G1. Independent work on ZPR1 deficiency in other systems places that arrest downstream of disrupted subnuclear organisation, with the survival-motor-neuron protein and the histone-gene transcription factor NPAT losing their normal localisation and histone gene expression falling. That connection to the SMN protein is the strange part of this disease and is curated as an open question rather than smoothed over. Almost the entire ZPR1 literature is about spinal muscular atrophy: ZPR1 binds SMN, is downregulated in SMA patients, is a candidate SMA modifier, and Zpr1-deficient mice develop axonal pathology and neurodegeneration. None of that is what the human ZPR1 syndrome looks like. No reported patient has a motor neuron disease. The 2026 siblings added three features to the phenotype that a growth-restriction syndrome would not have predicted: abnormal glucose homeostasis, growth hormone resistance, and progressive liver disease with decompensated portal hypertension and oesophageal varices in the absence of cirrhosis. The phenotype is therefore still opening rather than closed.

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1
Mappings
1
Inheritance
5
Pathophys.
15
Phenotypes
2
Gaps
27
Pathograph
1
Genes
3
Variants
2
Medical Actions
2
Models
7
References
1
Deep Research
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Mappings

MONDO
MONDO:0859146 growth restriction, hypoplastic kidneys, alopecia, and distinctive facies
skos:exactMatch MONDO
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Inheritance

1
Autosomal recessive HP:0000007
Homozygosity for ZPR1 c.587T>C (p.Ile196Thr) in every patient with a confirmed genotype, with the heterozygous state established in the parents of one family and homozygosity excluded in her unaffected siblings. The 2026 report identifies the allele as a founder variant of the Middle Rio Grande Valley, which is consistent with the homozygosity being identity-by-descent rather than the product of separate mutational events.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:29851065 SUPPORT Human Clinical
"In a second family, the identical variant was shown to be heterozygous in the affected individual's parents and not homozygous in any of her unaffected siblings."
The segregation pattern that establishes recessive inheritance: carrier parents, no homozygous unaffected sibling.
PMID:40776660 SUPPORT Human Clinical
"Our report confirms that homozygosity for c.587 T>C in ZPR1 underlies a novel genetic syndrome with autosomal recessive inheritance and that c.587 T>C is a founder variant for ZPR1 disorder in the Middle Rio Grande Valley."
Independent confirmation of the inheritance mode, and the founder-variant finding that explains why one allele accounts for every confirmed case.
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Discussions and Knowledge Gaps

2
Nearly all ZPR1 biology comes from spinal muscular atrophy research - SMN binding, Cajal body localisation, ZPR1 as an SMA modifier, neurodegeneration in ZPR1-deficient mice. None of the reported children with the human ZPR1 syndrome has a motor neuron disease. How much of that literature applies?
HUMAN MODEL MISMATCH zpr1_smn_axis_versus_the_human_syndrome
Attached to
animal_models#Zpr1 heterozygous null mouse pathophysiology#Disrupted Subnuclear Localization of SMN and NPAT genetic#ZPR1
This is the interpretive problem the entry is built around. The mechanistic nodes between "no ZPR1 protein" and "cells stop cycling" are all imported from work whose purpose was to explain spinal muscular atrophy, and the phenotype they were developed to explain is not the phenotype these children have. What transfers cleanly is the cell-autonomous part. ZPR1 deficiency arrests the cell cycle in cultured cells, and patient fibroblasts show the same G1 arrest - that is the one place where the experimental literature and a human measurement agree, and it is why the proliferation chain is curated as the mechanism. What does not transfer is the neurological reading. The viable ZPR1-deficient mouse develops axonal pathology and neurodegeneration; the children have global developmental delay and hydrocephalus, with no reported motor neuron involvement. Three possibilities are open and nothing published distinguishes them. The mouse is heterozygous and the children have no detectable protein, so the lesions differ in dose and possibly in kind. Or the children died too early - three before age three, of renal failure - for a degenerative phenotype to declare itself. Or nobody has looked: no neuropathology, nerve conduction study or electromyogram is reported for any affected child. The consequence for this entry is deliberate. The SMN and Cajal body node is kept, because it is the best-supported account of how ZPR1 loss reaches the cell cycle, but it carries only model and cell-line evidence and its outgoing edge is INDIRECT_KNOWN_INTERMEDIATES. No neurodegeneration phenotype is curated, and the mouse link to developmental delay is recorded as FAILS_TO_RECAPITULATE rather than quietly omitted.
Show evidence (3 references)
PMID:16648254 SUPPORT Model Organism
"These data identify ZPR1 deficiency as a contributing factor in neurodegenerative disorders."
The conclusion the mouse literature reached about ZPR1, which is the frame a reader will arrive with and which this disease does not fit.
PMID:15767679 SUPPORT In Vitro
"These effects of Zpr1 gene disruption were confirmed and extended in studies of cultured motor neuron-like cells using small interfering RNA-mediated Zpr1 gene suppression; ZPR1 deficiency caused growth cone retraction, axonal defects, and apoptosis."
The neuronal phenotype of ZPR1 loss in culture. Graded IN_VITRO because the sentence reports the cultured-cell arm of that study, not the mouse arm.
PMID:29851065 SUPPORT In Vitro
"Patient fibroblast cells showed no detectable levels of ZPR1 and the cells showed a defect in cell cycle progression where a significant number of cells remained arrested in the G1 phase."
The part that does transfer: the same cell cycle arrest, measured in a patient's own cells rather than in an experimental deficiency.
Every patient with a confirmed genotype is homozygous for one founder allele in one region. Is this the phenotype of the gene, or the phenotype of p.Ile196Thr?
KNOWLEDGE GAP zpr1_single_allele_single_population
Attached to
pathophysiology#ZPR1 p.Ile196Thr Homozygous Founder Variant genetic#ZPR1 prevalence#Middle Rio Grande Valley, New Mexico (Hispanic ancestry)
Six children, five families, one variant, one region - counting only the patients whose genotype is confirmed. Nothing published separates the gene's disease from this allele's disease, and the two could differ substantially. One further genotype has been reported and it does not close the gap. A 2026 case report describes a child with an overlapping phenotype carrying two compound heterozygous ZPR1 variants of uncertain significance, one of them a maternally inherited frameshift. Its phase was never established and neither variant is classified beyond uncertain, so it is a candidate second genotype rather than a second allele. It does narrow the question usefully: the gap is no longer "has anyone ever seen another ZPR1 genotype" but "can that one be phased and classified". The specific reason to expect gene and allele might differ: p.Ile196Thr is a missense change that leaves no detectable protein in fibroblasts, but complete ZPR1 loss is embryonic lethal in mouse and these children were liveborn and lived months to years. Either the mouse and human requirements differ, or some ZPR1 remains in tissues nobody has assayed. If the latter, the syndrome is a hypomorph's phenotype and no patient carrying two complete loss-of-function alleles would survive to be found - which is consistent with the years of clinical sequencing since 2018 having produced no confirmed second pathogenic allele. Note that this predicts nothing about a single truncating allele in trans with a hypomorph, which would be viable; that is exactly what the 2026 case report would be if its variants are ever phased and reclassified, and its own authors state that ZPR1 is intolerant to complete loss of function. What would resolve it is a second independent allele established as pathogenic, or a quantitative assay of residual ZPR1 in a tissue other than skin. Neither exists. A practical consequence follows for anyone reading a ZPR1 variant in a diagnostic laboratory: outside this founder population the entire evidence base for interpreting one is a single case report of two unphased variants of uncertain significance, and the gene has no ClinGen gene-disease validity classification - it does not appear in the ClinGen Gene-Disease Validity CSV at all.
Show evidence (4 references)
PMID:40776660 SUPPORT Human Clinical
"Our report confirms that homozygosity for c.587 T>C in ZPR1 underlies a novel genetic syndrome with autosomal recessive inheritance and that c.587 T>C is a founder variant for ZPR1 disorder in the Middle Rio Grande Valley."
The founder-variant finding. It is what makes the replication meaningful and what makes it insufficient to generalise from - both families share an ancestral allele.
PMID:15767679 SUPPORT Model Organism
"We found that Zpr1-/- mice die during early embryonic development, with reduced proliferation and increased apoptosis."
The lethality that makes a true human null implausible in a liveborn child, and so makes the hypomorph reading worth stating.
PMID:42281740 SUPPORT Human Clinical
"Genetic evaluation was conducted in a stepwise approach, and with exome sequencing (ES), we identified two compound heterozygous variants of uncertain significance in the ZPR1 gene."
The candidate second genotype. It is what narrows this gap from "no other genotype has ever been seen" to "one has, and it is neither phased nor classified".
+ 1 more reference
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Pathophysiology

5
ZPR1 p.Ile196Thr Homozygous Founder Variant
ZPR1 c.587T>C (p.Ile196Thr), homozygous, in every patient with a confirmed genotype. Structural modelling places the substituted isoleucine in the hydrophobic core of the protein, which predicts a folding rather than an interaction defect. It remains the only ZPR1 allele established as disease-causing. One further genotype has been reported - a compound heterozygous pair of variants of uncertain significance, including a truncating allele, in a child with an overlapping phenotype - but its phase was never established and neither variant is classified beyond uncertain, so the genotype-phenotype relationship of the gene as a whole is still unknown. The allelic spectrum is set out in full on the ZPR1 genetic record.
ZPR1 hgnc:13051 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ZPR1 (hgnc:13051). hgnc:13051 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Absence of ZPR1 Protein
Show evidence (3 references)
PMID:29851065 SUPPORT Human Clinical
"Exome sequencing of the surviving individual identified a homozygous c.587T>C (p.Ile196Thr) mutation in ZPR1 Zinc Finger (ZPR1) that segregated appropriately in her family."
The identification of the allele in the index family.
PMID:29851065 SUPPORT Computational
"Structural modeling reveals that p.Ile196Thr disrupts the hydrophobic core of ZPR1."
The predicted structural consequence. Graded COMPUTATIONAL because it is a modelling result, not a measurement - the measured consequence is the protein's absence, recorded on the next node.
PMID:42281740 SUPPORT Human Clinical
"Genetic evaluation was conducted in a stepwise approach, and with exome sequencing (ES), we identified two compound heterozygous variants of uncertain significance in the ZPR1 gene."
The one other ZPR1 genotype ever reported, and the reason this node no longer claims p.Ile196Thr is the only allele seen in human disease. Both variants are of uncertain significance, so p.Ile196Thr remains the only established one.
Absence of ZPR1 Protein
Patient fibroblasts contain no detectable ZPR1. That is a stronger result than the missense genotype would suggest and it is the single most important fact about this disease's mechanism: a core-destabilising substitution that leaves no protein behind makes the allele functionally null, at least in fibroblasts, and licenses reading the ZPR1-deficiency literature as relevant. The caveat is that fibroblasts are the only human tissue examined. Whether kidney, hair follicle, cochlea or brain also lack the protein entirely, or retain some, has not been tested, and a residual amount somewhere would matter - complete ZPR1 loss is embryonic lethal in mouse, and these children were liveborn.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Downstream
Cell Cycle Arrest in G1
Disrupted Subnuclear Localization of SMN and NPAT
Show evidence (2 references)
PMID:29851065 SUPPORT In Vitro
"Patient fibroblast cells showed no detectable levels of ZPR1 and the cells showed a defect in cell cycle progression where a significant number of cells remained arrested in the G1 phase."
Both the absence of protein and the cellular consequence, measured in cells from an affected child.
PMID:29851065 SUPPORT Other
"ZPR1 is a ubiquitously expressed, highly conserved protein postulated to transmit proliferative signals from the cell membrane to the nucleus."
What the lost protein is for, and why losing it everywhere produces a syndrome rather than an organ-specific disease. Graded OTHER because the sentence is the report's summary of prior work, and "postulated" is the authors' own hedge.
Disrupted Subnuclear Localization of SMN and NPAT
ZPR1 moves into the nucleus during S phase and concentrates with the survival motor neurons protein and the histone gene-specific transcription factor NPAT in subnuclear foci, including Cajal bodies sitting on histone gene clusters. Without ZPR1, both proteins lose that localisation and histone gene expression falls. This node is imported from ZPR1-deficiency work in cell lines and in Zpr1-null mouse embryos, not from patients. No patient tissue has been examined for SMN or NPAT localisation, so the node describes what ZPR1 loss does rather than what was observed in this disease.
Cajal body GO:0015030 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Cajal body (GO:0015030). GO:0015030 is a cellular component from the Gene Ontology.
Animal models
Zpr1 knockout mouse Mouse recapitulates The localisation defect shown in a whole animal rather than a cell line, which is what establishes it as a property of ZPR1 loss rather than of one culture system.
Downstream
Cell Cycle Arrest in G1
Show evidence (3 references)
PMID:17068332 SUPPORT In Vitro
"In contrast, ZPR1 redistributes to the nucleus during S phase and ZPR1 exhibits prominent co-localization with the survival motor neurons protein and the histone gene-specific transcription factor NPAT in subnuclear foci, including Cajal bodies that associate with histone gene clusters."
The normal localisation that is lost, and the compartment it is lost from.
PMID:17068332 SUPPORT In Vitro
"These changes in subnuclear architecture and cell cycle progression may be caused by transcriptional defects in ZPR1-deficient cells, including decreased histone gene expression."
The proposed intermediate between the localisation defect and the arrest, which is why the outgoing edge is INDIRECT_KNOWN_INTERMEDIATES. The authors write "may be caused", and the entry does not upgrade that.
PMID:15767679 SUPPORT Model Organism
"Here we report that targeted ablation of the Zpr1 gene in mice disrupts the subcellular localization of both SMN and spliceosomal snRNPs."
The same localisation defect in a whole animal rather than a cell line, which is what makes it a property of ZPR1 loss rather than of one culture system.
Cell Cycle Arrest in G1
ZPR1-deficient cells stop cycling. In patient fibroblasts a significant fraction is arrested in G1; in experimental ZPR1 deficiency the block is broader, halting S phase progression and arresting cells in G1 and G2 both. The patient measurement is the one this entry treats as the disease phenotype; the experimental one shows the arrest is not an artefact of one cell line.
cell cycle G1/S phase transition GO:0044843 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell cycle G1/S phase transition (GO:0044843). GO:0044843 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced Cell Proliferation in Developing Tissues
Show evidence (2 references)
PMID:29851065 SUPPORT In Vitro
"Patient fibroblast cells showed no detectable levels of ZPR1 and the cells showed a defect in cell cycle progression where a significant number of cells remained arrested in the G1 phase."
The arrest as measured in cells from an affected child, which is what makes this node a finding in the disease rather than an inference from the gene.
PMID:17068332 SUPPORT In Vitro
"ZPR1 deficiency causes disruption of survival motor neurons and NPAT localization within the nucleus, blocks S phase progression, and arrests cells in both the G(1) and G(2) phases of the cell cycle."
The experimental version of the same arrest. Note it is broader than the patient finding - G2 as well as G1 - which is recorded rather than harmonised away.
Reduced Cell Proliferation in Developing Tissues
The tissue-level step, occurring in parallel across many organs: a ubiquitously expressed protein required for cell cycle progression is absent, so tissues that must proliferate in order to form do not reach their normal size or number. This is the node that accounts for the breadth of the syndrome - growth, head circumference, kidney, hair, ear and genital development are affected together because the constraint is on proliferation itself rather than on any organ's own programme. Direct evidence in humans is limited to the fibroblast arrest above; the proliferation deficit itself is demonstrated in the Zpr1-null mouse embryo, which shows reduced proliferation with increased apoptosis and dies early in development. No affected human tissue has been examined histologically.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Zpr1 knockout mouse Mouse recapitulates This is where the proliferation claim comes from. It cannot be measured in an affected child - no patient tissue has been examined histologically - so the mouse is not corroborating a human observation, it is the experiment.
Downstream
Pre- and Postnatal Growth Restriction
Microcephaly
Hypoplastic Kidneys with Renal Insufficiency
Congenital Alopecia
Distinctive Craniofacial Features
Global Developmental Delay
Severe Congenital Sensorineural Hearing Loss
Hydrocephalus
Genital Hypoplasia
Progressive Non-Cirrhotic Liver Disease with Portal Hypertension
Abnormal Glucose Homeostasis
Growth Hormone Resistance
Show evidence (2 references)
PMID:15767679 SUPPORT Model Organism
"We found that Zpr1-/- mice die during early embryonic development, with reduced proliferation and increased apoptosis."
The proliferation deficit at the level of a developing organism. The mouse is a complete null and dies before organogenesis, so it demonstrates the consequence of losing ZPR1 without modelling the human course.
PMID:29851065 SUPPORT Human Clinical
"We provide genetic and molecular evidence that a homozygous missense mutation in ZPR1 is associated with a rare and recognizable multisystem syndrome."
The authors' own summary linking the molecular finding to a multisystem clinical picture, which is the claim this node stands for.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Growth Restriction Hypoplastic Kidneys Alopecia And Distinctive Facies 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

15
Cardiovascular 1
Progressive Non-Cirrhotic Liver Disease with Portal Hypertension HP:0001409 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Non-cirrhotic portal hypertension, annotated with Portal hypertension (HP:0001409), qualified as course progressive. HP:0001409 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Sequelae: Esophageal Varices
Show evidence (1 reference)
PMID:40776660 SUPPORT Human Clinical
"We expand our understanding of the phenotype by describing abnormal glucose homeostasis, growth hormone resistance, and progressive liver disease with decompensated portal hypertension and esophageal varices despite the absence of cirrhosis."
The phenotype expansion, including the explicit statement that cirrhosis was absent - which is why this record is bound to portal hypertension rather than to a fibrosis or cirrhosis term.
Digestive 1
Esophageal Varices Esophageal varix HP:0002040 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Esophageal varix (HP:0002040). HP:0002040 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40776660 SUPPORT Human Clinical
"We expand our understanding of the phenotype by describing abnormal glucose homeostasis, growth hormone resistance, and progressive liver disease with decompensated portal hypertension and esophageal varices despite the absence of cirrhosis."
The varices are named in the same sentence as the portal hypertension that causes them.
Ear 1
Severe Congenital Sensorineural Hearing Loss Congenital sensorineural hearing impairment HP:0008527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe congenital sensorineural hearing impairment, annotated with Congenital sensorineural hearing impairment (HP:0008527), qualified as severity severe. HP:0008527 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (1 reference)
PMID:29851065 SUPPORT Human Clinical
"A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early..."
The founding clinical description, which supplies both the congenital onset and the severity.
Genitourinary 3
Hypoplastic Kidneys with Renal Insufficiency Renal hypoplasia HP:0000089 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal hypoplasia (HP:0000089). HP:0000089 is a phenotype from the Human Phenotype Ontology.
Sequelae: Renal Insufficiency
Show evidence (2 references)
PMID:29851065 SUPPORT Human Clinical
"A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early..."
The founding clinical description, naming both the hypoplasia and the resulting insufficiency.
PMID:40776660 SUPPORT Human Clinical
"We report two female siblings, a 13-month-old and a newborn, with multiple anomalies including hypoplastic kidneys, severe growth restriction, facial dysmorphism, and alopecia, both found to be homozygous for the c.587 T>C variant in ZPR1."
Replication of the renal finding in two further children.
Renal Insufficiency HP:0000083 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal insufficiency (HP:0000083), qualified as course progressive. HP:0000083 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Sequelae: Death in Early Childhood
Show evidence (1 reference)
PMID:29851065 SUPPORT Human Clinical
"Three of the children died before 3 years of age from uremia and/or sepsis."
The outcome that makes renal insufficiency the load-bearing feature of this syndrome rather than one item on a list. Uremia is named as a cause of death.
Genital Hypoplasia External genital hypoplasia HP:0003241 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Genital hypoplasia, annotated with External genital hypoplasia (HP:0003241). HP:0003241 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29851065 SUPPORT Human Clinical
"A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early..."
The founding clinical description.
Head and Neck 2
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29851065 SUPPORT Human Clinical
"A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early..."
The founding clinical description, which lists microcephaly with the growth restriction.
Distinctive Craniofacial Features Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distinctive craniofacial features, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29851065 SUPPORT Human Clinical
"A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early..."
The founding clinical description. The features themselves are not listed in it.
PMID:40776660 SUPPORT Human Clinical
"Their clinical features are strikingly similar to those previously reported in a patient who was homozygous for the same variant."
The recognisability claim, which is what makes the facial gestalt clinically useful even though neither report decomposes it.
Integument 1
Congenital Alopecia HP:0001596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital alopecia, annotated with Alopecia (HP:0001596). HP:0001596 is a phenotype from the Human Phenotype Ontology.
HP:0005597 (Congenital alopecia totalis) would be the closer label but asserts totality, which neither abstract states. Following the ontology term contract, the specificity is carried in preferred_term instead of manufacturing a narrower ontology match.
Show evidence (2 references)
PMID:29851065 SUPPORT Human Clinical
"A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early..."
The founding clinical description, which specifies the alopecia as congenital.
PMID:40776660 SUPPORT Human Clinical
"We report two female siblings, a 13-month-old and a newborn, with multiple anomalies including hypoplastic kidneys, severe growth restriction, facial dysmorphism, and alopecia, both found to be homozygous for the c.587 T>C variant in ZPR1."
Replication of the alopecia in two further children.
Metabolism 1
Abnormal Glucose Homeostasis HP:0011014 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal glucose homeostasis (HP:0011014). HP:0011014 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40776660 SUPPORT Human Clinical
"We expand our understanding of the phenotype by describing abnormal glucose homeostasis, growth hormone resistance, and progressive liver disease with decompensated portal hypertension and esophageal varices despite the absence of cirrhosis."
One of three features the 2026 report adds to the phenotype.
Nervous System 2
Global Developmental Delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29851065 SUPPORT Human Clinical
"A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early..."
The founding clinical description.
Hydrocephalus HP:0000238 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrocephalus (HP:0000238). HP:0000238 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29851065 SUPPORT Human Clinical
"A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early..."
The founding clinical description. Note that hydrocephalus and microcephaly are reported together in the same cohort, which is unusual and is not explained in either report.
Growth 1
Pre- and Postnatal Growth Restriction 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.
Curated as one record covering both the prenatal and postnatal components because the two reports describe them together. The postnatal component is separately bindable to HP:0008897 (Postnatal growth retardation) if a later report gives it its own description.
Show evidence (2 references)
PMID:29851065 SUPPORT Human Clinical
"A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early..."
The founding clinical description. It is the source for this and for eight further phenotype records in this entry, which is why it is quoted repeatedly.
PMID:40776660 SUPPORT Human Clinical
"We report two female siblings, a 13-month-old and a newborn, with multiple anomalies including hypoplastic kidneys, severe growth restriction, facial dysmorphism, and alopecia, both found to be homozygous for the c.587 T>C variant in ZPR1."
Independent replication in two further children, with the severity qualifier the first report does not give.
Other 2
Death in Early Childhood
Left unbound deliberately. HP:0003819 (Death in childhood) is the right concept, but it sits in the HPO Mortality/Aging branch rather than under HP:0000118 (Phenotypic abnormality), so it is not a member of the PhenotypeTerm dynamic enum and binding it fails term validation. The same is true of HP:0001522 (Death in infancy). Other entries in this repository handle it the same way - see Autosomal_Recessive_Spondylometaphyseal_Dysplasia_Megarbane_Type. The mortality is also recorded in `progression`. Numerator and denominator: 3 of the 4 children in the founding cohort, before age 3. The two children in the 2026 report were alive at publication and are not counted either way, so no frequency band is recorded.
Show evidence (1 reference)
PMID:29851065 SUPPORT Human Clinical
"Three of the children died before 3 years of age from uremia and/or sepsis."
The mortality observation, with both stated causes.
Growth Hormone Resistance
Deliberately left unbound. HPO has no term for growth hormone resistance or growth hormone insensitivity: a search of the ontology returned 52 terms matching "growth hormone", none of which describes resistance, and targeted searches for "resistance", "insensitivity" and "Laron" returned nothing applicable either. HP:0000845 (Elevated circulating growth hormone concentration) and HP:0030353 (Decreased circulating insulin-like growth factor 1 concentration) are the laboratory findings that would normally establish resistance, but the abstract reports neither value, so binding either would assert a measurement that was not published. No term beats a wrong one.
Show evidence (1 reference)
PMID:40776660 SUPPORT Human Clinical
"We expand our understanding of the phenotype by describing abnormal glucose homeostasis, growth hormone resistance, and progressive liver disease with decompensated portal hypertension and esophageal varices despite the absence of cirrhosis."
The report of growth hormone resistance, in the sentence that adds it to the phenotype.
🧬

Genetic Associations

1
ZPR1
Gene: ZPR1 hgnc:13051 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ZPR1 (hgnc:13051). hgnc:13051 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (8 references)
PMID:29851065 SUPPORT Other
"ZPR1 is a ubiquitously expressed, highly conserved protein postulated to transmit proliferative signals from the cell membrane to the nucleus."
What the gene product does, as summarised by the report that tied it to this disease.
PMID:40776660 SUPPORT Human Clinical
"Our report confirms that homozygosity for c.587 T>C in ZPR1 underlies a novel genetic syndrome with autosomal recessive inheritance and that c.587 T>C is a founder variant for ZPR1 disorder in the Middle Rio Grande Valley."
The gene-disease confirmation from an independent group, and the founder-variant finding that explains why one allele accounts for every confirmed case.
PMID:9852145 SUPPORT In Vitro
"The zinc finger protein ZPR1 is present in the cytoplasm of quiescent mammalian cells and translocates to the nucleus upon treatment with mitogens, including epidermal growth factor (EGF)."
The mitogen-responsive shuttling that the "proliferative signal" description rests on, measured in mammalian cells.
+ 5 more references
Variants (3)
ZPR1 c.587T>C (p.Ile196Thr) Pathogenic
Gene: ZPR1 hgnc:13051 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in ZPR1 (hgnc:13051). hgnc:13051 is a gene from the HUGO Gene Nomenclature Committee. missense variant
The founder allele of the Middle Rio Grande Valley, homozygous in all six patients with a confirmed genotype. Structural modelling places the substituted isoleucine in the hydrophobic core of the protein, and patient fibroblasts contain no detectable ZPR1, so it behaves as a null in the one human tissue anybody has assayed.
Show evidence (2 references)
PMID:40776660 SUPPORT Human Clinical
"Our report confirms that homozygosity for c.587 T>C in ZPR1 underlies a novel genetic syndrome with autosomal recessive inheritance and that c.587 T>C is a founder variant for ZPR1 disorder in the Middle Rio Grande Valley."
The independent confirmation that this allele underlies the syndrome, which is the basis for classifying it PATHOGENIC rather than of uncertain significance.
PMID:42281740 SUPPORT Other
"These variants resembled previously reported pathogenic ZPR1 variants associated with a syndrome characterized by growth restriction, craniofacial abnormalities, alopecia, and hypoplastic kidneys."
A third group describing the previously reported ZPR1 variants as pathogenic. Graded OTHER because the sentence is that report's characterisation of prior work rather than a result it generated.
ZPR1 c.84del Uncertain Significance
Gene: ZPR1 hgnc:13051 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in ZPR1 (hgnc:13051). hgnc:13051 is a gene from the HUGO Gene Nomenclature Committee. frameshift variant
A maternally inherited frameshift, reported once, in a thirteen-month-old with a phenotype overlapping this syndrome and presumed - not shown - to be in trans with p.(Leu149Ser). The reporting authors predict it produces a null protein lacking all characterised functional domains. It is the only truncating ZPR1 allele reported in a patient, and it is classified as of uncertain significance in that report.
Show evidence (1 reference)
PMID:42281740 SUPPORT Human Clinical
"The c.84del variant, maternally inherited, results in an early frameshift predicted to produce a null protein lacking all characterized functional domains"
The variant and its maternal origin are the clinical genetic finding; the null protein is the reporting authors' inference from the frameshift position, not a measurement, and is not treated here as demonstrated.
ZPR1 p.(Leu149Ser) Uncertain Significance
Gene: ZPR1 hgnc:13051 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in ZPR1 (hgnc:13051). hgnc:13051 is a gene from the HUGO Gene Nomenclature Committee. missense variant
A missense change of unknown parental origin reported in the same child, placed by the reporting authors in the eEF1-alpha binding domain and compared by them with p.Ile196Thr as a hydrophobic-to-polar substitution in the same pocket. Classified as of uncertain significance in that report.
Show evidence (1 reference)
PMID:42281740 SUPPORT Other
"The missense variant p.(Leu149Ser), of unknown inheritance, occurs within the eEF1α binding domain and resembles the previously reported p.Ile196Thr variant"
Where the variant sits and why its reporters compared it with the founder allele. Graded OTHER because the sentence is a domain annotation and an interpretive comparison rather than an experimental or in-silico result.
💊

Medical Actions

2
Renal Supportive Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
Management of the renal insufficiency arising from hypoplastic kidneys is the intervention that would change the course, since uremia is a named cause of death in this disease. No treatment of any kind is described in either published report - no dialysis, no transplantation, no outcome - so this record states the target rather than an experience, and no treatment_effect is claimed.
Mechanism Target:
Renal Insufficiency — Addresses the functional renal failure rather than the hypoplasia that causes it or the ZPR1 loss upstream of both. No treatment_effect value is recorded because every value in that enum asserts a change to the mechanism, and supportive management of uremia makes no such claim.
Show evidence (1 reference)
PMID:29851065 SUPPORT Human Clinical
"Three of the children died before 3 years of age from uremia and/or sepsis."
The reason renal management is the priority in this disease: uremia is one of the two named causes of death.
Genetic Counselling
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
Platform: Other
Recessive counselling with a 25 percent recurrence risk for a carrier couple. What is specific here is that a single founder allele explains every published case with a confirmed genotype in a defined region, which makes targeted carrier testing of extended family and of the wider Middle Rio Grande Valley population a coherent proposition rather than a theoretical one. It also means prenatal or preimplantation testing is a single-variant assay for that population. Outside it, the one further reported ZPR1 genotype is two variants of uncertain significance whose phase was never established, so there is nothing there to counsel from.
Show evidence (1 reference)
PMID:40776660 SUPPORT Human Clinical
"Our report confirms that homozygosity for c.587 T>C in ZPR1 underlies a novel genetic syndrome with autosomal recessive inheritance and that c.587 T>C is a founder variant for ZPR1 disorder in the Middle Rio Grande Valley."
The founder finding that makes population-level carrier testing worth raising in the counselling room.
🔬

Diagnosis

1
Exome or genome sequencing, with ZPR1 c.587T>C prioritised by ancestry
Both reported families reached the diagnosis by exome sequencing. The practical point is narrower than "sequence the child": a single founder allele accounts for every published case with a confirmed genotype, so in an infant of Middle Rio Grande Valley or New Mexican Hispanic ancestry presenting with congenital alopecia and hypoplastic kidneys, ZPR1 c.587T>C is a targeted test rather than a discovery exercise. Congenital alopecia together with renal hypoplasia is the pairing that should raise it; neither feature alone is specific. Outside that ancestry there is no such shortcut, and a targeted founder-allele assay would have missed the one further reported ZPR1 genotype, which was found by untargeted exome sequencing - see the ZPR1 genetic record.
Show evidence (2 references)
PMID:29851065 SUPPORT Human Clinical
"Exome sequencing of the surviving individual identified a homozygous c.587T>C (p.Ile196Thr) mutation in ZPR1 Zinc Finger (ZPR1) that segregated appropriately in her family."
The diagnostic route used in the index family.
PMID:40776660 SUPPORT Human Clinical
"Our report confirms that homozygosity for c.587 T>C in ZPR1 underlies a novel genetic syndrome with autosomal recessive inheritance and that c.587 T>C is a founder variant for ZPR1 disorder in the Middle Rio Grande Valley."
The founder-variant finding is what turns a broad sequencing question into a targeted one for a defined population.
📈

Progression

1
Infancy and early childhood
Age: birth to 3 years
The disease is present at birth - growth restriction, alopecia, hearing loss and renal hypoplasia are all congenital - and the course is dominated by renal failure. Three of the four children in the founding cohort died before three years of age, of uremia and/or sepsis. The 2026 siblings, aged 13 months and newborn at report, extend the phenotype into liver and endocrine involvement without yet extending the known survival.
Show evidence (1 reference)
PMID:29851065 SUPPORT Human Clinical
"Three of the children died before 3 years of age from uremia and/or sepsis."
The only survival data published for this disease.
📊

Prevalence

1
Middle Rio Grande Valley, New Mexico (Hispanic ancestry)
Cases In Literature Ultra Rare
Six children in five families across two reports: four children from three families of New Mexican Hispanic heritage in 2018, and two sisters in 2026. All are homozygous for the same founder allele and all trace to the same region, so the disease is geographically concentrated rather than uniformly ultra-rare. No carrier frequency has been published, and none of the reports estimates a prevalence, so ULTRA_RARE is a qualitative band and no rate_per_100000 is recorded. A seventh child, reported in 2026 with two ZPR1 variants of uncertain significance rather than the founder allele, is deliberately not counted in this population record. The genotype is unconfirmed, and that report gives no ancestry or geography that would place the child inside or outside the founder population, so counting the case would attribute it to a population on no evidence.
Show evidence (2 references)
PMID:40776660 SUPPORT Human Clinical
"Our report confirms that homozygosity for c.587 T>C in ZPR1 underlies a novel genetic syndrome with autosomal recessive inheritance and that c.587 T>C is a founder variant for ZPR1 disorder in the Middle Rio Grande Valley."
The founder-variant finding, which is what makes ancestry and geography the right population stratifier here rather than "worldwide".
PMID:29851065 SUPPORT Human Clinical
"A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early..."
The founding cohort's size and ancestry, which is four of the six reported children.
🐁

Animal Models

2
Zpr1 knockout mouse
The complete null, and the reason ZPR1 is described as essential. Zpr1-/- embryos die early in development with reduced proliferation and increased apoptosis, and they lose the normal subnuclear localisation of SMN and of spliceosomal snRNPs. Its relationship to the human disease is asymmetric: it demonstrates that losing ZPR1 stops cells proliferating in a developing organism, which is the mechanism this entry curates, while dying too early to model any of the syndrome's organ features.
Species
Mouse
Genotype
Zpr1 -/- (complete null)
Genes
ZPR1 hgnc:13051 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns ZPR1 (hgnc:13051). hgnc:13051 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:15767679
Pathograph links
Reduced Cell Proliferation in Developing Tissues recapitulates fidelity: moderate This is where the proliferation claim comes from. It cannot be measured in an affected child - no patient tissue has been examined histologically - so the mouse is not corroborating a human observation, it is the experiment.
Limitations: The mouse is a complete germline null and dies during early embryonic development; the human allele is a homozygous missense change and the children were liveborn and lived months to years. So the mouse establishes the direction of the effect while necessarily overstating its degree, and it cannot speak to any organ phenotype because it dies before organogenesis. Fidelity is MODERATE rather than HIGH for that reason.
Readouts
Embryonic cell proliferation and apoptosis
Direction: DECREASED
Interpretation: Proliferation falls and apoptosis rises in the null embryo, which is the cellular deficit this node stands for.
Show evidence (1 reference)
PMID:15767679 SUPPORT Model Organism
"We found that Zpr1-/- mice die during early embryonic development, with reduced proliferation and increased apoptosis."
The measurement behind this readout, and the lethality that bounds what the model can show.
Show evidence (1 reference)
PMID:15767679 SUPPORT Model Organism
"We found that Zpr1-/- mice die during early embryonic development, with reduced proliferation and increased apoptosis."
Why this line is informative for a node about proliferation in developing tissue.
Disrupted Subnuclear Localization of SMN and NPAT recapitulates fidelity: moderate The localisation defect shown in a whole animal rather than a cell line, which is what establishes it as a property of ZPR1 loss rather than of one culture system.
Limitations: Measured for SMN and spliceosomal snRNPs in the mouse; NPAT localisation was shown separately in cultured cells, so no single system has shown both. And no patient tissue has been examined for either, so the node has no human observation behind it at all.
Readouts
Subcellular localization of SMN and spliceosomal snRNPs
Direction: ALTERED
Interpretation: SMN fails to reach Cajal bodies and gems, and cytoplasmic snRNP is reduced, in cells from null embryos.
Show evidence (1 reference)
PMID:15767679 SUPPORT Model Organism
"Here we report that targeted ablation of the Zpr1 gene in mice disrupts the subcellular localization of both SMN and spliceosomal snRNPs."
The localisation measurement behind this readout.
Show evidence (1 reference)
PMID:15767679 SUPPORT Model Organism
"Here we report that targeted ablation of the Zpr1 gene in mice disrupts the subcellular localization of both SMN and spliceosomal snRNPs."
Why this line is informative for the localisation node.
Zpr1 heterozygous null mouse
The viable ZPR1-deficient mouse, and the one that produces a postnatal phenotype. It develops axonal pathology and neurodegeneration, and it was made and studied to test ZPR1 as a modifier of spinal muscular atrophy rather than as a model of any human ZPR1 syndrome. It is included here precisely because its phenotype does not match the human disease. A curator reaching for "the ZPR1 mouse" will find a neurodegeneration model, and no reported patient with this syndrome - confirmed genotype or not - has a motor neuron disease.
Species
Mouse
Genotype
Zpr1 +/- (ZPR1-deficient, viable)
Genes
ZPR1 hgnc:13051 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns ZPR1 (hgnc:13051). hgnc:13051 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:16648254
{ }

Source YAML

click to show 
name: Growth Restriction Hypoplastic Kidneys Alopecia And Distinctive Facies
category: Mendelian
creation_date: "2026-09-04T00:00:00Z"
synonyms:
- GKAF
- ZPR1-related multisystem syndrome
- growth restriction, hypoplastic kidneys, alopecia, and distinctive facies
description: >-
  A lethal autosomal recessive multisystem syndrome caused by biallelic ZPR1 variants, known
  from six children in five families who all carry the same founder allele, with one further
  child reported carrying two ZPR1 variants of uncertain significance whose phase was never
  established. Its descriptive name is the list of the features the first report used to
  recognise it: pre- and postnatal growth restriction with microcephaly, distinctive
  craniofacial features, congenital alopecia, and
  hypoplastic kidneys with renal insufficiency, together with global developmental delay,
  severe congenital sensorineural hearing loss, hydrocephalus and genital hypoplasia. Three
  of the first four children died before three years of age, of uremia or sepsis.

  Every patient with a confirmed genotype is homozygous for the same change, ZPR1 c.587T>C
  (p.Ile196Thr). The 2018 report found it in four children from three families of New
  Mexican Hispanic heritage; the 2026 report found it again in two sisters and identified it
  as a founder variant of the Middle Rio Grande Valley. No second allele has been
  established as disease-causing. A 2026 case report does describe a thirteen-month-old with
  an overlapping phenotype who carries two compound heterozygous ZPR1 variants of uncertain
  significance - a maternally inherited frameshift, c.84del, and a missense change,
  p.(Leu149Ser) - but that report is explicit that phasing was never established and that
  both variants remain of uncertain significance, so it widens the allelic spectrum as a
  possibility rather than as a fact. The phenotype described here is therefore still the
  phenotype of one variant rather than of the gene.

  The mechanism is a general proliferation defect rather than an organ-specific one, which
  is what a syndrome touching growth, brain, kidney, hair, ear and gonad at once should
  look like. The missense change sits in the hydrophobic core of the protein by structural
  modelling, and patient fibroblasts carry no detectable ZPR1 at all - so the allele
  behaves as a null in the one tissue anybody has looked at. Cells lacking ZPR1 arrest in
  G1. Independent work on ZPR1 deficiency in other systems places that arrest downstream of
  disrupted subnuclear organisation, with the survival-motor-neuron protein and the
  histone-gene transcription factor NPAT losing their normal localisation and histone gene
  expression falling.

  That connection to the SMN protein is the strange part of this disease and is curated as
  an open question rather than smoothed over. Almost the entire ZPR1 literature is about
  spinal muscular atrophy: ZPR1 binds SMN, is downregulated in SMA patients, is a candidate
  SMA modifier, and Zpr1-deficient mice develop axonal pathology and neurodegeneration.
  None of that is what the human ZPR1 syndrome looks like. No reported patient has a motor
  neuron disease.

  The 2026 siblings added three features to the phenotype that a growth-restriction syndrome
  would not have predicted: abnormal glucose homeostasis, growth hormone resistance, and
  progressive liver disease with decompensated portal hypertension and oesophageal varices
  in the absence of cirrhosis. The phenotype is therefore still opening rather than closed.
disease_term:
  preferred_term: growth restriction, hypoplastic kidneys, alopecia, and distinctive facies
  term:
    id: MONDO:0859146
    label: growth restriction, hypoplastic kidneys, alopecia, and distinctive facies
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0859146
      label: growth restriction, hypoplastic kidneys, alopecia, and distinctive facies
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
references:
- reference: PMID:29851065
  title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
- reference: PMID:40776660
  title: "Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1."
- reference: PMID:17068332
  title: "Deficiency of the zinc finger protein ZPR1 causes defects in transcription and cell cycle progression."
- reference: PMID:15767679
  title: "ZPR1 is essential for survival and is required for localization of the survival motor neurons (SMN) protein to Cajal bodies."
- reference: PMID:16648254
  title: "Deficiency of the zinc finger protein ZPR1 causes neurodegeneration."
- reference: PMID:9852145
  title: "Interaction of ZPR1 with translation elongation factor-1alpha in proliferating cells."
- reference: PMID:42281740
  title: "Understanding the Role of Genetic Testing in Diagnosing a Complex Pediatric Case."
inheritance:
- name: Autosomal recessive
  description: >-
    Homozygosity for ZPR1 c.587T>C (p.Ile196Thr) in every patient with a confirmed genotype,
    with the heterozygous state established in the parents of one family and homozygosity
    excluded in her unaffected siblings. The 2026 report identifies the allele as a founder variant of
    the Middle Rio Grande Valley, which is consistent with the homozygosity being
    identity-by-descent rather than the product of separate mutational events.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a second family, the identical variant was shown to be heterozygous in the affected individual's parents and not homozygous in any of her unaffected siblings."
    explanation: >-
      The segregation pattern that establishes recessive inheritance: carrier parents,
      no homozygous unaffected sibling.
  - reference: PMID:40776660
    reference_title: "Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our report confirms that homozygosity for c.587 T>C in ZPR1 underlies a novel genetic syndrome with autosomal recessive inheritance and that c.587 T>C is a founder variant for ZPR1 disorder in the Middle Rio Grande Valley."
    explanation: >-
      Independent confirmation of the inheritance mode, and the founder-variant finding that
      explains why one allele accounts for every confirmed case.
pathophysiology:
- name: ZPR1 p.Ile196Thr Homozygous Founder Variant
  description: >-
    ZPR1 c.587T>C (p.Ile196Thr), homozygous, in every patient with a confirmed genotype.
    Structural modelling places the substituted isoleucine in the hydrophobic core of the
    protein, which predicts a folding rather than an interaction defect. It remains the only
    ZPR1 allele established as disease-causing. One further genotype has been reported - a
    compound heterozygous pair of variants of uncertain significance, including a truncating
    allele, in a child with an overlapping phenotype - but its phase was never established
    and neither variant is classified beyond uncertain, so the genotype-phenotype
    relationship of the gene as a whole is still unknown. The allelic spectrum is set out in
    full on the ZPR1 genetic record.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ZPR1
    term:
      id: hgnc:13051
      label: ZPR1
  downstream:
  - target: Absence of ZPR1 Protein
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing of the surviving individual identified a homozygous c.587T>C (p.Ile196Thr) mutation in ZPR1 Zinc Finger (ZPR1) that segregated appropriately in her family."
    explanation: The identification of the allele in the index family.
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Structural modeling reveals that p.Ile196Thr disrupts the hydrophobic core of ZPR1."
    explanation: >-
      The predicted structural consequence. Graded COMPUTATIONAL because it is a modelling
      result, not a measurement - the measured consequence is the protein's absence,
      recorded on the next node.
  - reference: PMID:42281740
    reference_title: "Understanding the Role of Genetic Testing in Diagnosing a Complex Pediatric Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic evaluation was conducted in a stepwise approach, and with exome sequencing (ES), we identified two compound heterozygous variants of uncertain significance in the ZPR1 gene."
    explanation: >-
      The one other ZPR1 genotype ever reported, and the reason this node no longer claims
      p.Ile196Thr is the only allele seen in human disease. Both variants are of uncertain
      significance, so p.Ile196Thr remains the only established one.
- name: Absence of ZPR1 Protein
  description: >-
    Patient fibroblasts contain no detectable ZPR1. That is a stronger result than the
    missense genotype would suggest and it is the single most important fact about this
    disease's mechanism: a core-destabilising substitution that leaves no protein behind
    makes the allele functionally null, at least in fibroblasts, and licenses reading the
    ZPR1-deficiency literature as relevant.

    The caveat is that fibroblasts are the only human tissue examined. Whether kidney, hair
    follicle, cochlea or brain also lack the protein entirely, or retain some, has not been
    tested, and a residual amount somewhere would matter - complete ZPR1 loss is embryonic
    lethal in mouse, and these children were liveborn.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  downstream:
  - target: Cell Cycle Arrest in G1
    causal_link_type: DIRECT
  - target: Disrupted Subnuclear Localization of SMN and NPAT
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient fibroblast cells showed no detectable levels of ZPR1 and the cells showed a defect in cell cycle progression where a significant number of cells remained arrested in the G1 phase."
    explanation: >-
      Both the absence of protein and the cellular consequence, measured in cells from an
      affected child.
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ZPR1 is a ubiquitously expressed, highly conserved protein postulated to transmit proliferative signals from the cell membrane to the nucleus."
    explanation: >-
      What the lost protein is for, and why losing it everywhere produces a syndrome rather
      than an organ-specific disease. Graded OTHER because the sentence is the report's
      summary of prior work, and "postulated" is the authors' own hedge.
- name: Disrupted Subnuclear Localization of SMN and NPAT
  description: >-
    ZPR1 moves into the nucleus during S phase and concentrates with the survival motor
    neurons protein and the histone gene-specific transcription factor NPAT in subnuclear
    foci, including Cajal bodies sitting on histone gene clusters. Without ZPR1, both
    proteins lose that localisation and histone gene expression falls.

    This node is imported from ZPR1-deficiency work in cell lines and in Zpr1-null mouse
    embryos, not from patients. No patient tissue has been examined for SMN or NPAT
    localisation, so the node describes what ZPR1 loss does rather than what was observed in
    this disease.
  biological_scale: CELLULAR
  cellular_components:
  - preferred_term: Cajal body
    term:
      id: GO:0015030
      label: Cajal body
  downstream:
  - target: Cell Cycle Arrest in G1
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:17068332
    reference_title: "Deficiency of the zinc finger protein ZPR1 causes defects in transcription and cell cycle progression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast, ZPR1 redistributes to the nucleus during S phase and ZPR1 exhibits prominent co-localization with the survival motor neurons protein and the histone gene-specific transcription factor NPAT in subnuclear foci, including Cajal bodies that associate with histone gene clusters."
    explanation: The normal localisation that is lost, and the compartment it is lost from.
  - reference: PMID:17068332
    reference_title: "Deficiency of the zinc finger protein ZPR1 causes defects in transcription and cell cycle progression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These changes in subnuclear architecture and cell cycle progression may be caused by transcriptional defects in ZPR1-deficient cells, including decreased histone gene expression."
    explanation: >-
      The proposed intermediate between the localisation defect and the arrest, which is why
      the outgoing edge is INDIRECT_KNOWN_INTERMEDIATES. The authors write "may be caused",
      and the entry does not upgrade that.
  - reference: PMID:15767679
    reference_title: "ZPR1 is essential for survival and is required for localization of the survival motor neurons (SMN) protein to Cajal bodies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we report that targeted ablation of the Zpr1 gene in mice disrupts the subcellular localization of both SMN and spliceosomal snRNPs."
    explanation: >-
      The same localisation defect in a whole animal rather than a cell line, which is what
      makes it a property of ZPR1 loss rather than of one culture system.
- name: Cell Cycle Arrest in G1
  description: >-
    ZPR1-deficient cells stop cycling. In patient fibroblasts a significant fraction is
    arrested in G1; in experimental ZPR1 deficiency the block is broader, halting S phase
    progression and arresting cells in G1 and G2 both. The patient measurement is the one
    this entry treats as the disease phenotype; the experimental one shows the arrest is not
    an artefact of one cell line.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: cell cycle G1/S phase transition
    term:
      id: GO:0044843
      label: cell cycle G1/S phase transition
    modifier: DECREASED
  downstream:
  - target: Reduced Cell Proliferation in Developing Tissues
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient fibroblast cells showed no detectable levels of ZPR1 and the cells showed a defect in cell cycle progression where a significant number of cells remained arrested in the G1 phase."
    explanation: >-
      The arrest as measured in cells from an affected child, which is what makes this node
      a finding in the disease rather than an inference from the gene.
  - reference: PMID:17068332
    reference_title: "Deficiency of the zinc finger protein ZPR1 causes defects in transcription and cell cycle progression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ZPR1 deficiency causes disruption of survival motor neurons and NPAT localization within the nucleus, blocks S phase progression, and arrests cells in both the G(1) and G(2) phases of the cell cycle."
    explanation: >-
      The experimental version of the same arrest. Note it is broader than the patient
      finding - G2 as well as G1 - which is recorded rather than harmonised away.
- name: Reduced Cell Proliferation in Developing Tissues
  description: >-
    The tissue-level step, occurring in parallel across many organs: a ubiquitously
    expressed protein required for cell cycle progression is absent, so tissues that must
    proliferate in order to form do not reach their normal size or number. This is the node
    that accounts for the breadth of the syndrome - growth, head circumference, kidney, hair,
    ear and genital development are affected together because the constraint is on
    proliferation itself rather than on any organ's own programme.

    Direct evidence in humans is limited to the fibroblast arrest above; the proliferation
    deficit itself is demonstrated in the Zpr1-null mouse embryo, which shows reduced
    proliferation with increased apoptosis and dies early in development. No affected human
    tissue has been examined histologically.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: cell population proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: DECREASED
  downstream:
  - target: Pre- and Postnatal Growth Restriction
    causal_link_type: DIRECT
  - target: Microcephaly
    causal_link_type: DIRECT
  - target: Hypoplastic Kidneys with Renal Insufficiency
    causal_link_type: DIRECT
  - target: Congenital Alopecia
    causal_link_type: DIRECT
  - target: Distinctive Craniofacial Features
    causal_link_type: DIRECT
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Severe Congenital Sensorineural Hearing Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hydrocephalus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Genital Hypoplasia
    causal_link_type: DIRECT
  - target: Progressive Non-Cirrhotic Liver Disease with Portal Hypertension
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal Glucose Homeostasis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Growth Hormone Resistance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:15767679
    reference_title: "ZPR1 is essential for survival and is required for localization of the survival motor neurons (SMN) protein to Cajal bodies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found that Zpr1-/- mice die during early embryonic development, with reduced proliferation and increased apoptosis."
    explanation: >-
      The proliferation deficit at the level of a developing organism. The mouse is a
      complete null and dies before organogenesis, so it demonstrates the consequence of
      losing ZPR1 without modelling the human course.
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We provide genetic and molecular evidence that a homozygous missense mutation in ZPR1 is associated with a rare and recognizable multisystem syndrome."
    explanation: >-
      The authors' own summary linking the molecular finding to a multisystem clinical
      picture, which is the claim this node stands for.
phenotypes:
- name: Pre- and Postnatal Growth Restriction
  category: Growth
  description: >-
    Growth restriction beginning before birth and continuing after it, in every patient with
    a confirmed genotype. The 2026 siblings are described as severely growth restricted. No
    centiles or measurements are given in either abstract, and with six confirmed children in
    total no frequency band is recorded.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  notes: >-
    Curated as one record covering both the prenatal and postnatal components because the
    two reports describe them together. The postnatal component is separately bindable to
    HP:0008897 (Postnatal growth retardation) if a later report gives it its own
    description.
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage."
    explanation: >-
      The founding clinical description. It is the source for this and for eight further
      phenotype records in this entry, which is why it is quoted repeatedly.
  - reference: PMID:40776660
    reference_title: "Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two female siblings, a 13-month-old and a newborn, with multiple anomalies including hypoplastic kidneys, severe growth restriction, facial dysmorphism, and alopecia, both found to be homozygous for the c.587 T>C variant in ZPR1."
    explanation: >-
      Independent replication in two further children, with the severity qualifier the first
      report does not give.
- name: Microcephaly
  category: Neurological
  description: >-
    Small head circumference, reported as part of the growth restriction in the founding
    cohort. Whether it is congenital or acquired, and whether head circumference falls
    faster than length and weight, is not stated.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage."
    explanation: The founding clinical description, which lists microcephaly with the growth restriction.
- name: Hypoplastic Kidneys with Renal Insufficiency
  category: Renal
  description: >-
    Small kidneys with impaired function, present in the founding cohort and again in the
    2026 siblings - the one feature both reports place first. It is also the feature that
    kills: three of the first four children died before three years of age, of uremia and
    or sepsis.
  phenotype_term:
    preferred_term: Renal hypoplasia
    term:
      id: HP:0000089
      label: Renal hypoplasia
  sequelae:
  - target: Renal Insufficiency
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage."
    explanation: The founding clinical description, naming both the hypoplasia and the resulting insufficiency.
  - reference: PMID:40776660
    reference_title: "Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two female siblings, a 13-month-old and a newborn, with multiple anomalies including hypoplastic kidneys, severe growth restriction, facial dysmorphism, and alopecia, both found to be homozygous for the c.587 T>C variant in ZPR1."
    explanation: Replication of the renal finding in two further children.
- name: Renal Insufficiency
  category: Renal
  description: >-
    Impaired kidney function arising from the hypoplastic kidneys, and the proximate cause
    of death in the children who died of uremia. Curated as its own record so that the
    hypoplasia can be distinguished from its functional consequence, and so that mortality
    hangs off the functional record rather than off the structural one.
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
    clinical_course: PROGRESSIVE
  sequelae:
  - target: Death in Early Childhood
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three of the children died before 3 years of age from uremia and/or sepsis."
    explanation: >-
      The outcome that makes renal insufficiency the load-bearing feature of this syndrome
      rather than one item on a list. Uremia is named as a cause of death.
- name: Death in Early Childhood
  category: Outcome
  description: >-
    Three of the first four reported children died before three years of age, of uremia
    and/or sepsis. The 2026 siblings were 13 months old and a newborn at report, so they
    contribute no survival information. Six children with a confirmed genotype is far too
    small a denominator for a mortality rate and none is recorded. The one further reported
    child, whose ZPR1 genotype is unconfirmed, was alive at report and does not change that
    denominator either way.
  phenotype_term:
    preferred_term: Death in early childhood
  notes: >-
    Left unbound deliberately. HP:0003819 (Death in childhood) is the right concept, but it
    sits in the HPO Mortality/Aging branch rather than under HP:0000118 (Phenotypic
    abnormality), so it is not a member of the PhenotypeTerm dynamic enum and binding it
    fails term validation. The same is true of HP:0001522 (Death in infancy). Other entries
    in this repository handle it the same way - see
    Autosomal_Recessive_Spondylometaphyseal_Dysplasia_Megarbane_Type. The mortality is also
    recorded in `progression`.

    Numerator and denominator: 3 of the 4 children in the founding cohort, before age 3. The
    two children in the 2026 report were alive at publication and are not counted either
    way, so no frequency band is recorded.
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three of the children died before 3 years of age from uremia and/or sepsis."
    explanation: The mortality observation, with both stated causes.
- name: Congenital Alopecia
  category: Dermatological
  description: >-
    Absence of hair from birth, present in the founding cohort and in both 2026 siblings.
    Neither report describes whether eyebrows and lashes are involved, or whether the
    follicles are absent or present but inactive, so the record is bound to the general
    HPO term rather than to a congenital-total subtype the sources do not establish.
  phenotype_term:
    preferred_term: Congenital alopecia
    term:
      id: HP:0001596
      label: Alopecia
  notes: >-
    HP:0005597 (Congenital alopecia totalis) would be the closer label but asserts totality,
    which neither abstract states. Following the ontology term contract, the specificity is
    carried in preferred_term instead of manufacturing a narrower ontology match.
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage."
    explanation: The founding clinical description, which specifies the alopecia as congenital.
  - reference: PMID:40776660
    reference_title: "Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two female siblings, a 13-month-old and a newborn, with multiple anomalies including hypoplastic kidneys, severe growth restriction, facial dysmorphism, and alopecia, both found to be homozygous for the c.587 T>C variant in ZPR1."
    explanation: Replication of the alopecia in two further children.
- name: Distinctive Craniofacial Features
  category: Craniofacial
  description: >-
    A recognisable facial appearance, called distinctive craniofacial features in the
    founding report and facial dysmorphism in the 2026 report. Neither abstract enumerates
    the individual features, so no specific dysmorphology is curated - and a gestalt that
    cannot be decomposed is exactly the kind of claim this entry should not manufacture
    detail for.
  phenotype_term:
    preferred_term: Distinctive craniofacial features
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage."
    explanation: The founding clinical description. The features themselves are not listed in it.
  - reference: PMID:40776660
    reference_title: "Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their clinical features are strikingly similar to those previously reported in a patient who was homozygous for the same variant."
    explanation: >-
      The recognisability claim, which is what makes the facial gestalt clinically useful
      even though neither report decomposes it.
- name: Global Developmental Delay
  category: Neurological
  description: >-
    Delay across developmental domains in the founding cohort. Given that three of those
    four children died before three years of age, the delay is characterised over a very
    short observation window and no developmental trajectory can be described.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage."
    explanation: The founding clinical description.
- name: Severe Congenital Sensorineural Hearing Loss
  category: Auditory
  description: >-
    Sensorineural hearing loss, severe and present from birth. No audiometric detail,
    laterality or configuration is reported, and no temporal bone imaging is described.
  phenotype_term:
    preferred_term: Severe congenital sensorineural hearing impairment
    term:
      id: HP:0008527
      label: Congenital sensorineural hearing impairment
    severity: SEVERE
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage."
    explanation: The founding clinical description, which supplies both the congenital onset and the severity.
- name: Hydrocephalus
  category: Neurological
  description: >-
    Hydrocephalus in the founding cohort. Whether it is communicating or obstructive, and
    whether any child was shunted, is not reported.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage."
    explanation: >-
      The founding clinical description. Note that hydrocephalus and microcephaly are
      reported together in the same cohort, which is unusual and is not explained in either
      report.
- name: Genital Hypoplasia
  category: Genitourinary
  description: >-
    Underdeveloped external genitalia in the founding cohort. The sex of the affected
    children and whether the finding was present in both sexes is not stated in the
    abstract; the two children in the 2026 report are female and no genital finding is
    described for them.
  phenotype_term:
    preferred_term: Genital hypoplasia
    term:
      id: HP:0003241
      label: External genital hypoplasia
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage."
    explanation: The founding clinical description.
- name: Progressive Non-Cirrhotic Liver Disease with Portal Hypertension
  category: Hepatic
  description: >-
    Progressive liver disease reaching decompensated portal hypertension, and doing so
    without cirrhosis. That combination is unusual and is the most mechanistically
    suggestive of the newly described features - non-cirrhotic portal hypertension points
    at the portal vasculature or at portal tract architecture rather than at hepatocyte
    injury, which is consistent with a developmental proliferation defect but has not been
    investigated.

    Reported only in the 2026 siblings. Whether it was absent in the founding cohort or
    simply not looked for is unknown; three of those children died before three years of
    age.
  phenotype_term:
    preferred_term: Non-cirrhotic portal hypertension
    term:
      id: HP:0001409
      label: Portal hypertension
    clinical_course: PROGRESSIVE
  sequelae:
  - target: Esophageal Varices
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:40776660
    reference_title: "Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We expand our understanding of the phenotype by describing abnormal glucose homeostasis, growth hormone resistance, and progressive liver disease with decompensated portal hypertension and esophageal varices despite the absence of cirrhosis."
    explanation: >-
      The phenotype expansion, including the explicit statement that cirrhosis was absent -
      which is why this record is bound to portal hypertension rather than to a fibrosis or
      cirrhosis term.
- name: Esophageal Varices
  category: Gastrointestinal
  description: >-
    Oesophageal varices as the consequence of the portal hypertension, reported in the 2026
    siblings. No bleeding episode is described in the abstract.
  phenotype_term:
    preferred_term: Esophageal varix
    term:
      id: HP:0002040
      label: Esophageal varix
  evidence:
  - reference: PMID:40776660
    reference_title: "Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We expand our understanding of the phenotype by describing abnormal glucose homeostasis, growth hormone resistance, and progressive liver disease with decompensated portal hypertension and esophageal varices despite the absence of cirrhosis."
    explanation: The varices are named in the same sentence as the portal hypertension that causes them.
- name: Abnormal Glucose Homeostasis
  category: Endocrine
  description: >-
    Disordered glucose handling in the 2026 siblings. The direction is not specified in the
    abstract - neither hypoglycaemia nor hyperglycaemia is named - so the record is bound at
    the level the source actually supports.
  phenotype_term:
    preferred_term: Abnormal glucose homeostasis
    term:
      id: HP:0011014
      label: Abnormal glucose homeostasis
  evidence:
  - reference: PMID:40776660
    reference_title: "Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We expand our understanding of the phenotype by describing abnormal glucose homeostasis, growth hormone resistance, and progressive liver disease with decompensated portal hypertension and esophageal varices despite the absence of cirrhosis."
    explanation: One of three features the 2026 report adds to the phenotype.
- name: Growth Hormone Resistance
  category: Endocrine
  description: >-
    Growth hormone resistance in the 2026 siblings - growth failure that does not respond to
    growth hormone as expected. This matters clinically out of proportion to how briefly it
    is reported: it predicts that growth hormone therapy, an obvious thing to try in a child
    with severe growth restriction, will not work, and it suggests the growth failure is
    cell-autonomous rather than endocrine.
  phenotype_term:
    preferred_term: growth hormone resistance
  notes: >-
    Deliberately left unbound. HPO has no term for growth hormone resistance or growth
    hormone insensitivity: a search of the ontology returned 52 terms matching "growth
    hormone", none of which describes resistance, and targeted searches for "resistance",
    "insensitivity" and "Laron" returned nothing applicable either. HP:0000845 (Elevated
    circulating growth hormone concentration) and HP:0030353 (Decreased circulating
    insulin-like growth factor 1 concentration) are the laboratory findings that would
    normally establish resistance, but the abstract reports neither value, so binding
    either would assert a measurement that was not published. No term beats a wrong one.
  evidence:
  - reference: PMID:40776660
    reference_title: "Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We expand our understanding of the phenotype by describing abnormal glucose homeostasis, growth hormone resistance, and progressive liver disease with decompensated portal hypertension and esophageal varices despite the absence of cirrhosis."
    explanation: The report of growth hormone resistance, in the sentence that adds it to the phenotype.
genetic:
- name: ZPR1
  notes: >-
    ZPR1 encodes a ubiquitously expressed, highly conserved zinc finger protein that
    shuttles between cytoplasm and nucleus with the cell cycle, entering the nucleus in S
    phase and concentrating with the survival motor neurons protein and NPAT in Cajal
    bodies. It sits in the cytoplasm of quiescent cells and moves to the nucleus on mitogen
    stimulation, and its interaction with translation elongation factor 1-alpha was shown -
    in yeast genetics and in mammalian cells - to contribute to normal proliferation. That
    is the basis for the long-standing description of ZPR1 as transmitting proliferative
    signals from the cell membrane to the nucleus.

    One human disease allele is established: c.587T>C (p.Ile196Thr), homozygous in all six
    patients with a confirmed genotype and a founder variant of the Middle Rio Grande
    Valley. It is a missense change that behaves as a null in patient fibroblasts, where no
    ZPR1 protein is detectable.

    A second genotype has been reported once, and it is why the single-allele statement
    throughout this entry is a qualified one rather than an absolute. A 2026 case report
    describes a thirteen-month-old with microcephaly, generalized hypotonia, sensorineural
    hearing loss, visual impairment, alopecia, hypoplastic kidneys with chronic kidney
    disease and dysmorphic craniofacial features - a picture its authors read as resembling
    this syndrome - carrying two compound heterozygous ZPR1 variants of uncertain
    significance: a maternally inherited frameshift, c.84del, which those authors predict
    produces a null protein, and a missense change, p.(Leu149Ser), which they place in the
    eEF1-alpha binding domain and compare with p.Ile196Thr. Two things stop it counting as a
    second disease allele. Phasing was never established, because parental DNA was
    incomplete, so the two changes are inferred rather than shown to be in trans; and both
    remain of uncertain significance. For the same reasons no phenotype from that child is
    curated in this entry, and the case counts are stated as counts of confirmed genotypes.

    It does bear on the hypomorph question raised in the knowledge gap below. That report's
    authors state that ZPR1 is intolerant to complete loss of function, and the truncating
    allele they describe is in a liveborn child - which fits their own statement only if the
    other allele retains some function.

    Nearly all published ZPR1 biology comes from spinal muscular atrophy research rather
    than from this syndrome: ZPR1 interacts with SMN complexes, is downregulated in SMA
    patients, and has been proposed as an SMA modifier. Whether any of that mechanism is
    what makes these children ill is unresolved, and is curated as a knowledge gap rather
    than assumed.
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: ZPR1
    term:
      id: hgnc:13051
      label: ZPR1
  variants:
  - name: ZPR1 c.587T>C (p.Ile196Thr)
    description: >-
      The founder allele of the Middle Rio Grande Valley, homozygous in all six patients with
      a confirmed genotype. Structural modelling places the substituted isoleucine in the
      hydrophobic core of the protein, and patient fibroblasts contain no detectable ZPR1, so
      it behaves as a null in the one human tissue anybody has assayed.
    type: missense variant
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: ZPR1
      term:
        id: hgnc:13051
        label: ZPR1
    evidence:
    - reference: PMID:40776660
      reference_title: "Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our report confirms that homozygosity for c.587 T>C in ZPR1 underlies a novel genetic syndrome with autosomal recessive inheritance and that c.587 T>C is a founder variant for ZPR1 disorder in the Middle Rio Grande Valley."
      explanation: >-
        The independent confirmation that this allele underlies the syndrome, which is the
        basis for classifying it PATHOGENIC rather than of uncertain significance.
    - reference: PMID:42281740
      reference_title: "Understanding the Role of Genetic Testing in Diagnosing a Complex Pediatric Case."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "These variants resembled previously reported pathogenic ZPR1 variants associated with a syndrome characterized by growth restriction, craniofacial abnormalities, alopecia, and hypoplastic kidneys."
      explanation: >-
        A third group describing the previously reported ZPR1 variants as pathogenic. Graded
        OTHER because the sentence is that report's characterisation of prior work rather
        than a result it generated.
  - name: ZPR1 c.84del
    description: >-
      A maternally inherited frameshift, reported once, in a thirteen-month-old with a
      phenotype overlapping this syndrome and presumed - not shown - to be in trans with
      p.(Leu149Ser). The reporting authors predict it produces a null protein lacking all
      characterised functional domains. It is the only truncating ZPR1 allele reported in a
      patient, and it is classified as of uncertain significance in that report.
    type: frameshift variant
    clinical_significance: UNCERTAIN_SIGNIFICANCE
    gene:
      preferred_term: ZPR1
      term:
        id: hgnc:13051
        label: ZPR1
    evidence:
    - reference: PMID:42281740
      reference_title: "Understanding the Role of Genetic Testing in Diagnosing a Complex Pediatric Case."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The c.84del variant, maternally inherited, results in an early frameshift predicted to produce a null protein lacking all characterized functional domains"
      explanation: >-
        The variant and its maternal origin are the clinical genetic finding; the null
        protein is the reporting authors' inference from the frameshift position, not a
        measurement, and is not treated here as demonstrated.
  - name: ZPR1 p.(Leu149Ser)
    description: >-
      A missense change of unknown parental origin reported in the same child, placed by the
      reporting authors in the eEF1-alpha binding domain and compared by them with
      p.Ile196Thr as a hydrophobic-to-polar substitution in the same pocket. Classified as of
      uncertain significance in that report.
    type: missense variant
    clinical_significance: UNCERTAIN_SIGNIFICANCE
    gene:
      preferred_term: ZPR1
      term:
        id: hgnc:13051
        label: ZPR1
    evidence:
    - reference: PMID:42281740
      reference_title: "Understanding the Role of Genetic Testing in Diagnosing a Complex Pediatric Case."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The missense variant p.(Leu149Ser), of unknown inheritance, occurs within the eEF1α binding domain and resembles the previously reported p.Ile196Thr variant"
      explanation: >-
        Where the variant sits and why its reporters compared it with the founder allele.
        Graded OTHER because the sentence is a domain annotation and an interpretive
        comparison rather than an experimental or in-silico result.
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ZPR1 is a ubiquitously expressed, highly conserved protein postulated to transmit proliferative signals from the cell membrane to the nucleus."
    explanation: What the gene product does, as summarised by the report that tied it to this disease.
  - reference: PMID:40776660
    reference_title: "Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our report confirms that homozygosity for c.587 T>C in ZPR1 underlies a novel genetic syndrome with autosomal recessive inheritance and that c.587 T>C is a founder variant for ZPR1 disorder in the Middle Rio Grande Valley."
    explanation: >-
      The gene-disease confirmation from an independent group, and the founder-variant
      finding that explains why one allele accounts for every confirmed case.
  - reference: PMID:9852145
    reference_title: "Interaction of ZPR1 with translation elongation factor-1alpha in proliferating cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The zinc finger protein ZPR1 is present in the cytoplasm of quiescent mammalian cells and translocates to the nucleus upon treatment with mitogens, including epidermal growth factor (EGF)."
    explanation: >-
      The mitogen-responsive shuttling that the "proliferative signal" description rests on,
      measured in mammalian cells.
  - reference: PMID:9852145
    reference_title: "Interaction of ZPR1 with translation elongation factor-1alpha in proliferating cells."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We conclude that ZPR1 is essential for cell viability and that its interaction with eEF-1alpha contributes to normal cellular proliferation."
    explanation: >-
      The essentiality and proliferation conclusion, from the study that identified the
      eEF-1alpha interaction. Graded OTHER because the sentence concludes across a yeast
      genetic arm and a mammalian cell arm, and yeast genetics fits neither MODEL_ORGANISM
      (no animal) nor IN_VITRO (a whole organism) cleanly.
  - reference: PMID:16648254
    reference_title: "Deficiency of the zinc finger protein ZPR1 causes neurodegeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "One potential modifier gene is represented by ZPR1, which is down-regulated in patients with SMA and encodes a zinc finger protein that interacts with complexes formed by SMN."
    explanation: >-
      The SMA framing that dominates the ZPR1 literature, stated by that literature itself.
      Graded OTHER because the sentence is this paper's summary of prior work rather than a
      result it reports.
  - reference: PMID:42281740
    reference_title: "Understanding the Role of Genetic Testing in Diagnosing a Complex Pediatric Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic evaluation was conducted in a stepwise approach, and with exome sequencing (ES), we identified two compound heterozygous variants of uncertain significance in the ZPR1 gene."
    explanation: >-
      The second reported ZPR1 genotype, and the finding that turns every absolute
      single-allele statement in this entry into a qualified one.
  - reference: PMID:42281740
    reference_title: "Understanding the Role of Genetic Testing in Diagnosing a Complex Pediatric Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the case of a 13-month-old female with multiple congenital anomalies including microcephaly, generalized hypotonia, sensorineural hearing loss, visual impairment, alopecia, and hypoplastic kidneys with chronic kidney disease, and dysmorphic craniofacial features."
    explanation: >-
      That child's phenotype, which is why the report is relevant to this entry at all: it
      overlaps the alopecia, hypoplastic kidney, microcephaly and craniofacial core of the
      syndrome.
  - reference: PMID:42281740
    reference_title: "Understanding the Role of Genetic Testing in Diagnosing a Complex Pediatric Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, phasing of the two variants is unknown, as parental DNA was incomplete."
    explanation: >-
      The limitation that keeps the second genotype a candidate rather than a second disease
      allele: the two variants are inferred to be in trans, not shown to be.
prevalence:
- population: Middle Rio Grande Valley, New Mexico (Hispanic ancestry)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Six children in five families across two reports: four children from three families of
    New Mexican Hispanic heritage in 2018, and two sisters in 2026. All are homozygous for
    the same founder allele and all trace to the same region, so the disease is
    geographically concentrated rather than uniformly ultra-rare. No carrier frequency has
    been published, and none of the reports estimates a prevalence, so ULTRA_RARE is a
    qualitative band and no rate_per_100000 is recorded.

    A seventh child, reported in 2026 with two ZPR1 variants of uncertain significance rather
    than the founder allele, is deliberately not counted in this population record. The
    genotype is unconfirmed, and that report gives no ancestry or geography that would place
    the child inside or outside the founder population, so counting the case would attribute
    it to a population on no evidence.
  evidence:
  - reference: PMID:40776660
    reference_title: "Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our report confirms that homozygosity for c.587 T>C in ZPR1 underlies a novel genetic syndrome with autosomal recessive inheritance and that c.587 T>C is a founder variant for ZPR1 disorder in the Middle Rio Grande Valley."
    explanation: >-
      The founder-variant finding, which is what makes ancestry and geography the right
      population stratifier here rather than "worldwide".
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage."
    explanation: The founding cohort's size and ancestry, which is four of the six reported children.
progression:
- phase: Infancy and early childhood
  age_range: birth to 3 years
  notes: >-
    The disease is present at birth - growth restriction, alopecia, hearing loss and renal
    hypoplasia are all congenital - and the course is dominated by renal failure. Three of
    the four children in the founding cohort died before three years of age, of uremia
    and/or sepsis. The 2026 siblings, aged 13 months and newborn at report, extend the
    phenotype into liver and endocrine involvement without yet extending the known survival.
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three of the children died before 3 years of age from uremia and/or sepsis."
    explanation: The only survival data published for this disease.
diagnosis:
- name: Exome or genome sequencing, with ZPR1 c.587T>C prioritised by ancestry
  description: >-
    Both reported families reached the diagnosis by exome sequencing. The practical point is
    narrower than "sequence the child": a single founder allele accounts for every published
    case with a confirmed genotype, so in an infant of Middle Rio Grande Valley or New
    Mexican Hispanic ancestry presenting with congenital alopecia and hypoplastic kidneys,
    ZPR1 c.587T>C is a targeted test rather than a discovery exercise. Congenital alopecia
    together with renal hypoplasia is the pairing that should raise it; neither feature alone
    is specific.

    Outside that ancestry there is no such shortcut, and a targeted founder-allele assay
    would have missed the one further reported ZPR1 genotype, which was found by untargeted
    exome sequencing - see the ZPR1 genetic record.
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing of the surviving individual identified a homozygous c.587T>C (p.Ile196Thr) mutation in ZPR1 Zinc Finger (ZPR1) that segregated appropriately in her family."
    explanation: The diagnostic route used in the index family.
  - reference: PMID:40776660
    reference_title: "Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our report confirms that homozygosity for c.587 T>C in ZPR1 underlies a novel genetic syndrome with autosomal recessive inheritance and that c.587 T>C is a founder variant for ZPR1 disorder in the Middle Rio Grande Valley."
    explanation: >-
      The founder-variant finding is what turns a broad sequencing question into a targeted
      one for a defined population.
treatments:
- name: Renal Supportive Care
  description: >-
    Management of the renal insufficiency arising from hypoplastic kidneys is the
    intervention that would change the course, since uremia is a named cause of death in
    this disease. No treatment of any kind is described in either published report - no
    dialysis, no transplantation, no outcome - so this record states the target rather than
    an experience, and no treatment_effect is claimed.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Renal Insufficiency
    description: >-
      Addresses the functional renal failure rather than the hypoplasia that causes it or
      the ZPR1 loss upstream of both. No treatment_effect value is recorded because every
      value in that enum asserts a change to the mechanism, and supportive management of
      uremia makes no such claim.
  evidence:
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three of the children died before 3 years of age from uremia and/or sepsis."
    explanation: >-
      The reason renal management is the priority in this disease: uremia is one of the two
      named causes of death.
- name: Genetic Counselling
  description: >-
    Recessive counselling with a 25 percent recurrence risk for a carrier couple. What is
    specific here is that a single founder allele explains every published case with a
    confirmed genotype in a defined region, which makes targeted carrier testing of extended
    family and of the wider Middle Rio Grande Valley population a coherent proposition rather
    than a theoretical one. It also means prenatal or preimplantation testing is a
    single-variant assay for that population. Outside it, the one further reported ZPR1
    genotype is two variants of uncertain significance whose phase was never established, so
    there is nothing there to counsel from.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  notes: >-
    No target_mechanisms link is recorded: counselling does not act on a pathograph node and
    every TreatmentEffectEnum value asserts a change to a mechanism. No ZPR1-directed
    therapy and no clinical trial for this disease has been reported.
  evidence:
  - reference: PMID:40776660
    reference_title: "Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our report confirms that homozygosity for c.587 T>C in ZPR1 underlies a novel genetic syndrome with autosomal recessive inheritance and that c.587 T>C is a founder variant for ZPR1 disorder in the Middle Rio Grande Valley."
    explanation: >-
      The founder finding that makes population-level carrier testing worth raising in the
      counselling room.
animal_models:
- name: Zpr1 knockout mouse
  species: Mouse
  genotype: Zpr1 -/- (complete null)
  publication: PMID:15767679
  description: >-
    The complete null, and the reason ZPR1 is described as essential. Zpr1-/- embryos die
    early in development with reduced proliferation and increased apoptosis, and they lose
    the normal subnuclear localisation of SMN and of spliceosomal snRNPs.

    Its relationship to the human disease is asymmetric: it demonstrates that losing ZPR1
    stops cells proliferating in a developing organism, which is the mechanism this entry
    curates, while dying too early to model any of the syndrome's organ features.
  genes:
  - preferred_term: ZPR1
    term:
      id: hgnc:13051
      label: ZPR1
  modeled_mechanisms:
  - target: Reduced Cell Proliferation in Developing Tissues
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      This is where the proliferation claim comes from. It cannot be measured in an affected
      child - no patient tissue has been examined histologically - so the mouse is not
      corroborating a human observation, it is the experiment.
    limitations: >-
      The mouse is a complete germline null and dies during early embryonic development;
      the human allele is a homozygous missense change and the children were liveborn and
      lived months to years. So the mouse establishes the direction of the effect while
      necessarily overstating its degree, and it cannot speak to any organ phenotype because
      it dies before organogenesis. Fidelity is MODERATE rather than HIGH for that reason.
    readouts:
    - name: Embryonic cell proliferation and apoptosis
      target: Reduced Cell Proliferation in Developing Tissues
      direction: DECREASED
      interpretation: >-
        Proliferation falls and apoptosis rises in the null embryo, which is the cellular
        deficit this node stands for.
      evidence:
      - reference: PMID:15767679
        reference_title: "ZPR1 is essential for survival and is required for localization of the survival motor neurons (SMN) protein to Cajal bodies."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "We found that Zpr1-/- mice die during early embryonic development, with reduced proliferation and increased apoptosis."
        explanation: The measurement behind this readout, and the lethality that bounds what the model can show.
    evidence:
    - reference: PMID:15767679
      reference_title: "ZPR1 is essential for survival and is required for localization of the survival motor neurons (SMN) protein to Cajal bodies."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We found that Zpr1-/- mice die during early embryonic development, with reduced proliferation and increased apoptosis."
      explanation: Why this line is informative for a node about proliferation in developing tissue.
  - target: Disrupted Subnuclear Localization of SMN and NPAT
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The localisation defect shown in a whole animal rather than a cell line, which is what
      establishes it as a property of ZPR1 loss rather than of one culture system.
    limitations: >-
      Measured for SMN and spliceosomal snRNPs in the mouse; NPAT localisation was shown
      separately in cultured cells, so no single system has shown both. And no patient tissue
      has been examined for either, so the node has no human observation behind it at all.
    readouts:
    - name: Subcellular localization of SMN and spliceosomal snRNPs
      target: Disrupted Subnuclear Localization of SMN and NPAT
      direction: ALTERED
      interpretation: >-
        SMN fails to reach Cajal bodies and gems, and cytoplasmic snRNP is reduced, in cells
        from null embryos.
      evidence:
      - reference: PMID:15767679
        reference_title: "ZPR1 is essential for survival and is required for localization of the survival motor neurons (SMN) protein to Cajal bodies."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Here we report that targeted ablation of the Zpr1 gene in mice disrupts the subcellular localization of both SMN and spliceosomal snRNPs."
        explanation: The localisation measurement behind this readout.
    evidence:
    - reference: PMID:15767679
      reference_title: "ZPR1 is essential for survival and is required for localization of the survival motor neurons (SMN) protein to Cajal bodies."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here we report that targeted ablation of the Zpr1 gene in mice disrupts the subcellular localization of both SMN and spliceosomal snRNPs."
      explanation: Why this line is informative for the localisation node.
- name: Zpr1 heterozygous null mouse
  species: Mouse
  genotype: Zpr1 +/- (ZPR1-deficient, viable)
  publication: PMID:16648254
  description: >-
    The viable ZPR1-deficient mouse, and the one that produces a postnatal phenotype. It
    develops axonal pathology and neurodegeneration, and it was made and studied to test
    ZPR1 as a modifier of spinal muscular atrophy rather than as a model of any human ZPR1
    syndrome.

    It is included here precisely because its phenotype does not match the human disease.
    A curator reaching for "the ZPR1 mouse" will find a neurodegeneration model, and no
    reported patient with this syndrome - confirmed genotype or not - has a motor neuron
    disease.
  genes:
  - preferred_term: ZPR1
    term:
      id: hgnc:13051
      label: ZPR1
  modeled_mechanisms:
  - target: Global Developmental Delay
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The only neurological phenotype reported in patients with a confirmed genotype is
      global developmental delay, characterised over a few months to a few years of life. The
      mouse's phenotype is axonal pathology and neurodegeneration - a different kind of
      neurological disease, and one that no report of this syndrome describes.
    limitations: >-
      The mismatch may be about dose rather than about biology: the mouse is heterozygous
      and retains one working allele, while the patients have no detectable protein in the
      tissue examined, so the two are not the same lesion and the comparison is not
      controlled. It may equally be that early death from renal failure precludes a
      neurodegenerative phenotype ever being observed in patients, or that nobody has looked
      - no neuropathology, nerve conduction study or electromyogram is reported for any
      affected child. The one further reported child, whose ZPR1 genotype is unconfirmed (see
      the ZPR1 genetic record), had generalized hypotonia and brainstem and internal-capsule
      T2 signal change; neither is motor neuron disease, and the genotype is not established,
      so the mismatch stands. Recorded as FAILS_TO_RECAPITULATE because the published
      phenotypes do not correspond, not because degeneration has been excluded in patients.
    evidence:
    - reference: PMID:16648254
      reference_title: "Deficiency of the zinc finger protein ZPR1 causes neurodegeneration."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We report that ZPR1-deficient mice exhibit axonal pathology and neurodegeneration."
      explanation: The mouse phenotype, which is what does not correspond to the human one.
    - reference: PMID:29851065
      reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A novel autosomal recessive disorder characterized by pre- and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage."
      explanation: >-
        The human side of the mismatch: the full published phenotype list, in which the
        neurological findings are developmental delay and hydrocephalus, not degeneration.
discussions:
- discussion_id: zpr1_smn_axis_versus_the_human_syndrome
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Nearly all ZPR1 biology comes from spinal muscular atrophy research - SMN binding, Cajal
    body localisation, ZPR1 as an SMA modifier, neurodegeneration in ZPR1-deficient mice.
    None of the reported children with the human ZPR1 syndrome has a motor neuron
    disease. How much of that literature applies?
  attaches_to:
  - animal_models#Zpr1 heterozygous null mouse
  - pathophysiology#Disrupted Subnuclear Localization of SMN and NPAT
  - genetic#ZPR1
  rationale: >-
    This is the interpretive problem the entry is built around. The mechanistic nodes
    between "no ZPR1 protein" and "cells stop cycling" are all imported from work whose
    purpose was to explain spinal muscular atrophy, and the phenotype they were developed to
    explain is not the phenotype these children have.

    What transfers cleanly is the cell-autonomous part. ZPR1 deficiency arrests the cell
    cycle in cultured cells, and patient fibroblasts show the same G1 arrest - that is the
    one place where the experimental literature and a human measurement agree, and it is why
    the proliferation chain is curated as the mechanism.

    What does not transfer is the neurological reading. The viable ZPR1-deficient mouse
    develops axonal pathology and neurodegeneration; the children have global developmental
    delay and hydrocephalus, with no reported motor neuron involvement. Three possibilities
    are open and nothing published distinguishes them. The mouse is heterozygous and the
    children have no detectable protein, so the lesions differ in dose and possibly in kind.
    Or the children died too early - three before age three, of renal failure - for a
    degenerative phenotype to declare itself. Or nobody has looked: no neuropathology, nerve
    conduction study or electromyogram is reported for any affected child.

    The consequence for this entry is deliberate. The SMN and Cajal body node is kept,
    because it is the best-supported account of how ZPR1 loss reaches the cell cycle, but it
    carries only model and cell-line evidence and its outgoing edge is
    INDIRECT_KNOWN_INTERMEDIATES. No neurodegeneration phenotype is curated, and the mouse
    link to developmental delay is recorded as FAILS_TO_RECAPITULATE rather than quietly
    omitted.
  evidence:
  - reference: PMID:16648254
    reference_title: "Deficiency of the zinc finger protein ZPR1 causes neurodegeneration."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These data identify ZPR1 deficiency as a contributing factor in neurodegenerative disorders."
    explanation: >-
      The conclusion the mouse literature reached about ZPR1, which is the frame a reader
      will arrive with and which this disease does not fit.
  - reference: PMID:15767679
    reference_title: "ZPR1 is essential for survival and is required for localization of the survival motor neurons (SMN) protein to Cajal bodies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These effects of Zpr1 gene disruption were confirmed and extended in studies of cultured motor neuron-like cells using small interfering RNA-mediated Zpr1 gene suppression; ZPR1 deficiency caused growth cone retraction, axonal defects, and apoptosis."
    explanation: >-
      The neuronal phenotype of ZPR1 loss in culture. Graded IN_VITRO because the sentence
      reports the cultured-cell arm of that study, not the mouse arm.
  - reference: PMID:29851065
    reference_title: "A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient fibroblast cells showed no detectable levels of ZPR1 and the cells showed a defect in cell cycle progression where a significant number of cells remained arrested in the G1 phase."
    explanation: >-
      The part that does transfer: the same cell cycle arrest, measured in a patient's own
      cells rather than in an experimental deficiency.
- discussion_id: zpr1_single_allele_single_population
  kind: KNOWLEDGE_GAP
  prompt: >-
    Every patient with a confirmed genotype is homozygous for one founder allele in one
    region. Is this the phenotype of the gene, or the phenotype of p.Ile196Thr?
  attaches_to:
  - pathophysiology#ZPR1 p.Ile196Thr Homozygous Founder Variant
  - genetic#ZPR1
  - prevalence#Middle Rio Grande Valley, New Mexico (Hispanic ancestry)
  rationale: >-
    Six children, five families, one variant, one region - counting only the patients whose
    genotype is confirmed. Nothing published separates the gene's disease from this allele's
    disease, and the two could differ substantially.

    One further genotype has been reported and it does not close the gap. A 2026 case report
    describes a child with an overlapping phenotype carrying two compound heterozygous ZPR1
    variants of uncertain significance, one of them a maternally inherited frameshift. Its
    phase was never established and neither variant is classified beyond uncertain, so it is
    a candidate second genotype rather than a second allele. It does narrow the question
    usefully: the gap is no longer "has anyone ever seen another ZPR1 genotype" but "can that
    one be phased and classified".

    The specific reason to expect gene and allele might differ: p.Ile196Thr is a missense
    change that leaves no detectable protein in fibroblasts, but complete ZPR1 loss is
    embryonic lethal in mouse and these children were liveborn and lived months to years.
    Either the mouse and human requirements differ, or some ZPR1 remains in tissues nobody
    has assayed. If the latter, the syndrome is a hypomorph's phenotype and no patient
    carrying two complete loss-of-function alleles would survive to be found - which is
    consistent with the years of clinical sequencing since 2018 having produced no confirmed
    second pathogenic allele. Note that this predicts nothing about a single truncating
    allele in trans with a hypomorph, which would be viable; that is exactly what the 2026
    case report would be if its variants are ever phased and reclassified, and its own
    authors state that ZPR1 is intolerant to complete loss of function.

    What would resolve it is a second independent allele established as pathogenic, or a
    quantitative assay of residual ZPR1 in a tissue other than skin. Neither exists.

    A practical consequence follows for anyone reading a ZPR1 variant in a diagnostic
    laboratory: outside this founder population the entire evidence base for interpreting
    one is a single case report of two unphased variants of uncertain significance, and the
    gene has no ClinGen gene-disease validity classification - it does not appear in the
    ClinGen Gene-Disease Validity CSV at all.
  evidence:
  - reference: PMID:40776660
    reference_title: "Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our report confirms that homozygosity for c.587 T>C in ZPR1 underlies a novel genetic syndrome with autosomal recessive inheritance and that c.587 T>C is a founder variant for ZPR1 disorder in the Middle Rio Grande Valley."
    explanation: >-
      The founder-variant finding. It is what makes the replication meaningful and what makes
      it insufficient to generalise from - both families share an ancestral allele.
  - reference: PMID:15767679
    reference_title: "ZPR1 is essential for survival and is required for localization of the survival motor neurons (SMN) protein to Cajal bodies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found that Zpr1-/- mice die during early embryonic development, with reduced proliferation and increased apoptosis."
    explanation: >-
      The lethality that makes a true human null implausible in a liveborn child, and so
      makes the hypomorph reading worth stating.
  - reference: PMID:42281740
    reference_title: "Understanding the Role of Genetic Testing in Diagnosing a Complex Pediatric Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic evaluation was conducted in a stepwise approach, and with exome sequencing (ES), we identified two compound heterozygous variants of uncertain significance in the ZPR1 gene."
    explanation: >-
      The candidate second genotype. It is what narrows this gap from "no other genotype has
      ever been seen" to "one has, and it is neither phased nor classified".
  - reference: PMID:42281740
    reference_title: "Understanding the Role of Genetic Testing in Diagnosing a Complex Pediatric Case."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ZPR1 is intolerant to complete loss of function, consistent with embryonic lethality in mouse models"
    explanation: >-
      An independent group reaching the same intolerance-to-complete-loss conclusion that the
      hypomorph reading rests on. Graded OTHER because the sentence is that report's summary
      of the mouse literature rather than a result it produced.
📚

References & Deep Research

References

7
PMID:29851065
A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys.
No top-level findings curated for this source.
PMID:40776660
Congenital Alopecia, Hypoplastic Kidneys, Growth Restriction, Growth Hormone Resistance, and Liver Fibrosis: Confirmation of a New Syndrome Caused by Biallelic Variants in ZPR1.
No top-level findings curated for this source.
PMID:17068332
Deficiency of the zinc finger protein ZPR1 causes defects in transcription and cell cycle progression.
No top-level findings curated for this source.
PMID:15767679
ZPR1 is essential for survival and is required for localization of the survival motor neurons (SMN) protein to Cajal bodies.
No top-level findings curated for this source.
PMID:16648254
Deficiency of the zinc finger protein ZPR1 causes neurodegeneration.
No top-level findings curated for this source.
PMID:9852145
Interaction of ZPR1 with translation elongation factor-1alpha in proliferating cells.
No top-level findings curated for this source.
PMID:42281740
Understanding the Role of Genetic Testing in Diagnosing a Complex Pediatric Case.
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: Growth Restriction, Hypoplastic Kidneys, Alopecia and Distinctive Facies (GKAF, ZPR1) · 2026-09-04T22:28:38Z · View source

Identity resolved from the stub's MONDO xref chain, since MONDO records no causal gene for MONDO:0859146: OLS gave OMIM:619321, NCBI mim2gene_medgen mapped that MIM to GeneID 8882, and NCBI Gene resolved it to ZPR1 (11q23.3). Coverage recheck by gene against origin/main found no kb/ entry for ZPR1 (the only matches were an unrelated Wilson's-disease Biomni expression table), so this is a new Disease rather than a fold-in. Evidence base: two clinical reports totalling six children in five families (PMID:29851065 Ito 2018, four children from three New Mexican Hispanic families; PMID:40776660 2026, two sisters, identifying c.587T>C as a Middle Rio Grande Valley founder variant), plus three ZPR1-deficiency mechanism papers (PMID:17068332 cell cycle and transcription, PMID:15767679 Zpr1-null mouse, PMID:16648254 Zpr1-deficient mouse neurodegeneration). Both clinical papers are abstract-only in the cache; the abstracts are unusually complete and carry the whole phenotype list, the mortality, the variant, the structural modelling and the fibroblast result. Mechanism curated as a general proliferation defect: p.Ile196Thr (predicted to disrupt the hydrophobic core, COMPUTATIONAL) -> no detectable ZPR1 protein in patient fibroblasts -> G1 cell cycle arrest, and in parallel disrupted subnuclear localisation of SMN and NPAT -> reduced proliferation in developing tissues -> the twelve organ phenotypes. That breadth is the point: the constraint is on proliferation itself, which is why one lesion touches growth, brain, kidney, hair, ear, gonad, liver and endocrine axis. The interpretive problem is recorded rather than smoothed over. Almost all ZPR1 biology comes from spinal muscular atrophy research, and the viable Zpr1+/- mouse develops axonal pathology and neurodegeneration, which no reported patient has. The Zpr1+/- model link to Global Developmental Delay is therefore curated as FAILS_TO_RECAPITULATE with both required limitations and evidence, and a HUMAN_MODEL_MISMATCH discussion sets out the three open explanations (dose difference, early renal death, or nobody looked). A second KNOWLEDGE_GAP records that one allele in one founder population cannot separate the gene's phenotype from p.Ile196Thr's, and notes the tension that a true ZPR1 null is embryonic lethal in mouse while these children were liveborn. Two phenotypes are deliberately left with preferred_term and no term:. Growth Hormone Resistance - HPO has no term for growth hormone resistance or insensitivity (52 'growth hormone' matches searched, plus targeted searches for resistance, insensitivity and Laron), and binding the laboratory findings that would establish it would assert measurements the abstract does not report. Death in Early Childhood - HP:0003819 and HP:0001522 sit in the HPO Mortality/Aging branch, outside the PhenotypeTerm dynamic enum; this follows the precedent in Autosomal_Recessive_Spondylometaphyseal_Dysplasia_Megarbane_Type, and the mortality is also recorded under progression. Deep research: falcon, on topic (ZPR1 50 mentions, p.Ile196Thr 15, no substituted disease; preflight-dr SKIPs because MONDO records no canonical gene, so substitution was checked by manual gene grep). Nothing was bound from the report; its own term validation flagged two mislabelled CURIEs. Validation: just validate (schema + terms + references) passed; 52/52 snippets verified, no prefix skips; check-entity-refs, check-duplicate-keys, check-causal-targets, check-enum-values, check-qualifier-terms all clean. Every phenotype is wired; the only node with no incoming edge is the variant, which is the root.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 18 citations 2026-09-04T15:26:37.099709

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Growth Restriction Hypoplastic Kidneys Alopecia And Distinctive Facies
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Growth Restriction Hypoplastic Kidneys Alopecia And Distinctive Facies covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
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Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Growth Restriction, Hypoplastic Kidneys, Alopecia, and Distinctive Facies

Executive summary

Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies is an exceptionally rare, congenital, autosomal-recessive multisystem disorder caused by biallelic ZPR1 variants. The disease is indexed as MONDO:0859146. The defining report described only four affected children from three New Mexican Hispanic families, all associated with homozygous ZPR1 c.587T>C (p.Ile196Thr), rs368697578. Consequently, phenotype frequencies, penetrance, survival, and treatment effects cannot yet be estimated reliably. Open Targets independently maps the disorder to ZPR1 (ENSG00000109917) and specifies a biallelic allelic requirement. (OpenTargets Search: Growth Restriction Hypoplastic Kidneys Alopecia And Distinctive Facies, abok2024bioinformaticanalysisof pages 1-4)

The principal primary publication is Ito et al., Clinical Genetics, published online June 2018, volume 94, pages 303–312, PMID: 29851065, DOI: 10.1111/cge.13388. The most recent disease-focused analysis located was a March 1, 2024 bioRxiv preprint, DOI: 10.1101/2024.02.27.582196; it is computational, not peer reviewed, and must not be treated as an expanded clinical cohort. (abok2024bioinformaticanalysisof pages 1-4, abok2024bioinformaticanalysisof pages 15-19)

Domain Established finding Suggested ontology term(s) Evidence type/strength Key source
Disease identity Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies is an ultra-rare congenital multisystem Mendelian syndrome associated with ZPR1 deficiency. MONDO:0859146; suggested synonym: ZPR1-associated growth-restriction syndrome Authoritative disease-level association supported by one small human case series Open Targets maps the exact disease label to MONDO:0859146 and ZPR1 (OpenTargets Search: Growth Restriction Hypoplastic Kidneys Alopecia And Distinctive Facies)
Causal gene and inheritance Biallelic ZPR1 variation causes the syndrome; segregation in reported families supports autosomal-recessive inheritance. Parents and unaffected siblings were heterozygous carriers. Suggested: ZPR1; autosomal recessive inheritance (HP:0000007) Strong human genetic evidence, but based on four affected children from three families Ito et al., 2018, PMID 29851065; summarized in the 2024 analysis (abok2024bioinformaticanalysisof pages 1-4)
Pathogenic variant Reported causal variant: homozygous ZPR1 c.587T>C (p.Ile196Thr), dbSNP rs368697578; germline missense variant in the A-domain involved in eEF1A interaction. Suggested: sequence variant; missense variant (SO:0001583); germline variant Strong segregation plus patient-cell functional evidence; ClinVar-listed, although current laboratory classification should be verified directly Ito et al., 2018; variant/domain data (abok2024bioinformaticanalysisof pages 1-4, abok2024bioinformaticanalysisof pages 8-11)
Growth phenotype Prenatal and postnatal growth restriction is a defining manifestation; the cellular phenotype resembles mechanisms implicated in primordial dwarfism. Suggested HPO: intrauterine growth restriction (HP:0001511), postnatal growth retardation (HP:0008897), short stature (HP:0004322) Human clinical evidence; exact patient-level frequencies and longitudinal growth curves unavailable in retrieved evidence Four-child case series summarized in 2024 (abok2024bioinformaticanalysisof pages 1-4)
Renal phenotype Hypoplastic kidneys and kidney dysfunction are core manifestations. Detailed laterality, nephron pathology, laboratory values, chronic-kidney-disease stages, and progression rates were not available. Suggested HPO: renal hypoplasia (HP:0000089), abnormal renal function (exact term to validate); suggested UBERON: kidney Human clinical evidence; small cohort and incomplete natural history Ito et al., 2018 title and subsequent summary (abok2024bioinformaticanalysisof pages 1-4)
Hair/ectodermal phenotype Congenital or inborn alopecia is characteristic. Hair-follicle histopathology and progression were not reported in the retrieved evidence. Suggested HPO: alopecia (HP:0001596), congenital alopecia (exact child term to validate); suggested UBERON: hair follicle Human clinical evidence; frequency not independently quantifiable beyond the defining case-series phenotype Ito et al., 2018; 2024 summary (abok2024bioinformaticanalysisof pages 1-4)
Craniofacial and neurologic phenotype Distinctive craniofacial features occur; reported associated findings include microcephaly, moderate intellectual disability, developmental delay, optic-nerve atrophy, and sensorineural hearing loss. Suggested HPO: abnormal facial shape (HP:0001999), microcephaly (HP:0000252), intellectual disability (HP:0001249), global developmental delay (HP:0001263), optic atrophy (HP:0000648), sensorineural hearing impairment (HP:0000407) Human clinical evidence, but individual-feature denominators are unavailable Human syndrome findings summarized from Ito et al. (chittilla2021highfatdietassociatedcognitive pages 4-5, abok2024bioinformaticanalysisof pages 1-4)
Protein dysfunction p.Ile196Thr lies in the hydrophobic core/A-domain and destabilizes ZPR1; patient fibroblasts reportedly contained little or no detectable ZPR1 because the misfolded protein was degraded by the proteasome. A 2024 FoldX analysis predicted a destabilizing ΔΔG of approximately 2.3 kcal/mol. Suggested GO: protein folding, proteasomal protein catabolic process, regulation of protein stability; suggested cellular components: cytoplasm, nucleus, nucleolus Patient-cell evidence plus computational structural support; degradation mechanism is stronger than purely in-silico predictions but needs replication Ito et al. functional findings and 2024 modeling (abok2024bioinformaticanalysisof pages 11-15, chittilla2021highfatdietassociatedcognitive pages 4-5, abok2024bioinformaticanalysisof pages 8-11)
Cell-cycle mechanism Mutant patient fibroblasts showed impaired progression beyond G1, with very few cells reaching late S or G2/M. Reduced proliferative capacity is the most direct demonstrated mechanism linking ZPR1 deficiency to generalized developmental growth failure. Suggested GO: cell-cycle progression (GO:0007049), G1/S transition of mitotic cell cycle (GO:0000082), cell proliferation (GO:0008283); suggested CL: fibroblast (CL:0000057) Direct patient-derived-cell functional evidence; organ-specific causal links remain inferred Ito et al. findings summarized in the 2024 analysis (abok2024bioinformaticanalysisof pages 11-15, abok2024bioinformaticanalysisof pages 1-4)
Molecular pathway ZPR1 normally participates in eEF1A-, EGFR-, SMN-, and RNA-polymerase-II-related complexes, translocating from cytoplasm to nucleus/nucleolus in proliferating cells. Disruption of ZPR1–eEF1A interaction by p.Ile196Thr is plausible but not directly demonstrated for every affected tissue. Suggested GO: protein binding, nucleolar localization, transcription regulation, ribonucleoprotein-complex assembly; suggested cellular components: nucleolus (GO:0005730), nucleus (GO:0005634), cytoplasm (GO:0005737) Established general ZPR1 biology; syndrome-specific pathway assignment remains partly inferred Structural and localization literature summarized in 2024 (abok2024bioinformaticanalysisof pages 1-4, abok2024bioinformaticanalysisof pages 15-19)
Diagnosis Diagnosis rests on recognition of the congenital phenotype plus molecular confirmation of biallelic ZPR1 variants. Exome or genome sequencing is preferable when the phenotype is nonspecific; targeted familial testing can confirm segregation. Renal ultrasound/function tests, audiology, ophthalmology, growth, and developmental assessments define organ involvement. Suggested NCIT: Whole Exome Sequencing, Whole Genome Sequencing, Genetic Testing, Ultrasonography, Audiologic Test; suggested HPO-driven phenotyping Genetic-testing strategy is a rational implementation based on discovery by exome sequencing; no formal syndrome-specific diagnostic criteria or guideline Proband exome and segregation evidence (abok2024bioinformaticanalysisof pages 1-4); limited formal characterization acknowledged in 2024 (abok2024bioinformaticanalysisof pages 11-15)
Epidemiology and population data Only four affected children from three New Mexican Hispanic ancestral families were initially reported; a Rio Grande Valley founder effect/endogamy was suggested but not proven. A 2024 preprint reported predicted damaging heterozygous ZPR1 variants in 0.04%–0.34% of ancestry groups, but these figures are not disease prevalence or validated carrier frequency for p.Ile196Thr. Suggested epidemiology annotation: ultra-rare disease; founder variant hypothesis Very limited human ascertainment; population estimates are computational and should not be used as clinical penetrance estimates Human families and founder hypothesis (abok2024bioinformaticanalysisof pages 1-4); gnomAD-based computational statistics (abok2024bioinformaticanalysisof pages 8-11, abok2024bioinformaticanalysisof pages 21-27)
Management and trials No disease-modifying therapy, syndrome-specific management guideline, or relevant clinical trial was identified. Care is supportive and organ-directed, with renal, growth/nutrition, hearing, vision, neurodevelopmental, and genetic-counseling follow-up. ZPR1 overexpression studies in spinal muscular atrophy are not treatment evidence for this syndrome. Suggested NCIT: Supportive Care, Genetic Counseling, Audiologic Rehabilitation, Physical Therapy, Occupational Therapy; exact NCIT identifiers to validate Expert extrapolation from manifestations; no syndrome-specific intervention evidence Literature and trial-gap assessment (chittilla2021highfatdietassociatedcognitive pages 1-2, abok2024bioinformaticanalysisof pages 1-4, abok2024bioinformaticanalysisof pages 15-19, abok2024bioinformaticanalysisof pages 4-8)
Prognosis The published phenotype includes increased early mortality, but survival rates, causes of death, renal-failure risk, and life expectancy have not been quantified. Lifelong multisystem morbidity is likely, but the course cannot be reliably estimated from four reported patients. Suggested HPO/course annotations: congenital onset, chronic course, early mortality (exact terms to validate) Weak-to-moderate natural-history evidence because of extremely small sample and absent longitudinal cohort Clinical summary of the original families (abok2024bioinformaticanalysisof pages 1-4)
Models and comparative evidence No natural veterinary disease or p.Ile196Thr syndrome-specific knock-in model was identified. Zpr1-deficient mice show neurodegeneration, facial and spinal motor-neuron loss, axon retraction, and microtubule disruption; these models establish biological necessity but incompletely reproduce the human renal–hair–growth syndrome. Suggested taxa: Mus musculus (NCBI Taxon:10090); suggested CL: motor neuron (CL:0000100); suggested GO: neuron death, axon maintenance, microtubule organization Experimental mouse evidence, indirect for this syndrome; SMA rescue models are mechanistic comparators only ZPR1-deficient mouse findings and limitations (chittilla2021highfatdietassociatedcognitive pages 1-2)

Table: Compact ontology-ready summary of established findings, evidence strength, and major knowledge gaps for MONDO:0859146. Ontology mappings marked “suggested” require curator validation before database ingestion.

1. Disease information

The disorder is a developmental syndrome combining prenatal and postnatal growth failure, congenital alopecia, renal hypoplasia/dysfunction, and recognizable craniofacial features. Reported additional manifestations include developmental delay, moderate intellectual disability, microcephaly, sensorineural hearing loss, and optic atrophy. Evidence comes principally from a small published family cohort, not from EHR-scale aggregation or a disease registry. (abok2024bioinformaticanalysisof pages 1-4, chittilla2021highfatdietassociatedcognitive pages 4-5)

Identifiers and nomenclature

  • MONDO: MONDO:0859146.
  • Gene: ZPR1, “ZPR1 zinc finger”; Ensembl ENSG00000109917; cytogenetic location 11q23.3.
  • Synonyms suitable for indexing: ZPR1-associated growth-restriction syndrome; growth restriction–hypoplastic kidneys–alopecia–distinctive facies syndrome; and the descriptive title alopecia–primordial dwarfism–renal syndrome used in earlier conference literature.
  • OMIM, Orphanet, MeSH, ICD-10, and ICD-11: no disease-specific identifiers were established in the retrieved authoritative evidence. A 2024 source stated that ZPR1-associated disease was absent from Orphanet at the time assessed. Generic congenital-malformation or genetic-disease codes should not be presented as disease-specific identifiers. (OpenTargets Search: Growth Restriction Hypoplastic Kidneys Alopecia And Distinctive Facies, abok2024bioinformaticanalysisof pages 1-4, abok2024bioinformaticanalysisof pages 11-15)

2. Etiology, risk, and protective factors

Causal factor

The demonstrated cause is a germline homozygous missense variant in ZPR1, c.587T>C, p.Ile196Thr. Parents and unaffected siblings were heterozygous, supporting autosomal-recessive segregation. The affected families’ shared Rio Grande Valley ancestry suggested—but did not prove—a founder variant combined with endogamy. (abok2024bioinformaticanalysisof pages 1-4)

Risk factors

The principal risk is inheriting two pathogenic ZPR1 alleles. For two confirmed heterozygous parents, standard autosomal-recessive counseling predicts, for each pregnancy, a 25% probability of an affected child, 50% probability of an unaffected carrier, and 25% probability of an unaffected non-carrier. Consanguinity or shared founder ancestry may increase the chance that partners carry the same rare allele, although consanguinity itself was not established as causal in the reported families.

No sex-, age-, infectious-, occupational-, toxin-, smoking-, dietary-, or lifestyle-related cause of this congenital syndrome has been demonstrated. Common ZPR1-region variants associated with lipids or diabetes, and experiments linking high-fat diets to altered ZPR1 expression, concern complex metabolic traits or experimental neurobiology—not this recessive syndrome. They should not be imported as syndrome risk factors. (chittilla2021highfatdietassociatedcognitive pages 2-3, chittilla2021highfatdietassociatedcognitive pages 1-2, abok2024bioinformaticanalysisof pages 4-8)

Protective factors and gene–environment interaction

No protective allele, modifier gene, diet, medication, or environmental exposure has been validated. EGF-regulated nuclear translocation, high-fat-diet models, and n-3 PUFA observations concern general ZPR1 biology and do not establish clinically actionable gene–environment interaction in affected children. (chittilla2021highfatdietassociatedcognitive pages 1-2, abok2024bioinformaticanalysisof pages 1-4)

3. Phenotypes

Because only four original patients were reported and individual-level denominators were not available in the retrieved text, the defining manifestations should be recorded as observed/core, not assigned precise percentages.

Manifestation Type, onset, and course Suggested HPO term
Prenatal growth restriction Physical sign; prenatal onset; apparently persistent Intrauterine growth retardation, HP:0001511
Postnatal growth failure/short stature Physical sign; infancy/childhood; chronic Postnatal growth retardation, HP:0008897; short stature, HP:0004322
Congenital alopecia Ectodermal manifestation; present from birth Alopecia, HP:0001596; validate a congenital-alopecia child term
Hypoplastic kidneys Structural congenital anomaly; likely bilateral status should be verified patient by patient Renal hypoplasia, HP:0000089
Kidney dysfunction Laboratory/functional abnormality; severity and progression unavailable Abnormal renal physiology; curator should select the most specific term from patient data
Distinctive facies Dysmorphic sign; congenital Abnormal facial shape, HP:0001999
Microcephaly Growth/neurodevelopmental sign Microcephaly, HP:0000252
Developmental delay/intellectual disability Neurodevelopmental; childhood; at least one patient described as moderately affected Global developmental delay, HP:0001263; intellectual disability, HP:0001249
Sensorineural hearing impairment Sensory manifestation; onset details unavailable HP:0000407
Optic atrophy Ophthalmologic sign HP:0000648

The 2024 summary characterizes the syndrome as including prenatal/postnatal growth restriction, congenital hair loss, kidney dysfunction, developmental delay, hearing impairment, and increased early mortality. A later review quotes the original patient description as including “moderate intellectual disability.” (chittilla2021highfatdietassociatedcognitive pages 4-5, abok2024bioinformaticanalysisof pages 1-4)

No validated EQ-5D, SF-36, PROMIS, behavioral, or disease-specific quality-of-life data exist. Nevertheless, chronic renal monitoring, marked short stature, sensory impairment, alopecia, and developmental disability plausibly impose substantial educational, medical, communication, and psychosocial burdens; this is clinical inference rather than measured outcome evidence.

4. Genetic and molecular information

ZPR1 encodes a 459-amino-acid, ubiquitously expressed C4-type zinc-finger protein. It is normally cytoplasmic in quiescent cells and relocates to the nucleus/nucleolus during growth-factor-stimulated proliferation. It interacts with eEF1A, EGFR, SMN, and RNA polymerase II-associated machinery. (chittilla2021highfatdietassociatedcognitive pages 1-2, abok2024bioinformaticanalysisof pages 1-4)

The syndrome-associated allele is:

  • ZPR1 c.587T>C; p.Ile196Thr; rs368697578.
  • Germline, homozygous in affected individuals and heterozygous in available unaffected relatives.
  • Missense variant in the A-domain involved in eEF1A interaction.
  • Patient-cell evidence supports protein destabilization and loss of functional abundance; the mutant protein was described as misfolded and proteasomally degraded.
  • A 2024 FoldX analysis estimated ΔΔG ≈2.3 kcal/mol, consistent with destabilization, but that result is computational support rather than an independent functional assay. (abok2024bioinformaticanalysisof pages 11-15, chittilla2021highfatdietassociatedcognitive pages 4-5, abok2024bioinformaticanalysisof pages 8-11)

Open Targets reports ClinVar/EVA support and a biallelic requirement, but the current ClinVar review status and ACMG criteria should be checked directly before clinical reporting. The 2024 preprint’s classification of 60 predicted variants as “pathogenic” using in-silico consensus is not equivalent to expert-panel ACMG classification. No validated modifier gene, disease-associated methylation signature, somatic mechanism, repeat expansion, mitochondrial variant, or pathogenic chromosomal rearrangement has been reported. (OpenTargets Search: Growth Restriction Hypoplastic Kidneys Alopecia And Distinctive Facies, abok2024bioinformaticanalysisof pages 8-11, abok2024bioinformaticanalysisof pages 15-19)

5. Environmental information

No environmental, lifestyle, toxicological, infectious, or nutritional cause is known. The disorder is Mendelian and congenital. High-fat-diet studies show altered hippocampal ZPR1 expression and neurobiological effects in rodents, but these do not demonstrate that diet causes, prevents, or changes the pediatric ZPR1 syndrome. There is no evidence for zoonotic or infectious transmission. (chittilla2021highfatdietassociatedcognitive pages 1-2, chittilla2021highfatdietassociatedcognitive pages 5-6)

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic ZPR1 p.Ile196Thr leads to substitution of a buried hydrophobic-core/A-domain residue.
  2. The substitution leads to ZPR1 destabilization and misfolding, followed by proteasomal degradation in patient fibroblasts.
  3. Reduced functional ZPR1 results in defective proliferative-cell ZPR1 activity and abnormal subcellular/cell-cycle behavior.
  4. This dysfunction leads to failure of efficient G1-to-S progression; very few patient fibroblasts reached late S or G2/M.
  5. Reduced cell proliferation during development is inferred to lead to prenatal/postnatal growth restriction and microcephaly.
  6. Branch A: impaired proliferation/differentiation in renal developmental lineages is inferred to result in hypoplastic kidneys and renal dysfunction.
  7. Branch B: impaired epithelial/hair-follicle development is inferred to result in congenital alopecia.
  8. Branch C: disturbed neural and sensory development, potentially compounded by ZPR1’s roles in SMN/RNA processing and genome maintenance, is inferred to result in developmental disability, hearing impairment, and optic atrophy.
  9. Multiorgan developmental disease and renal dysfunction may lead to increased early mortality, but causes of death have not been quantified. (abok2024bioinformaticanalysisof pages 11-15, chittilla2021highfatdietassociatedcognitive pages 4-5, abok2024bioinformaticanalysisof pages 1-4)

The strongest syndrome-specific functional evidence is therefore protein loss plus cell-cycle arrest in patient fibroblasts. Disruption of the ZPR1–eEF1A interaction is mechanistically plausible because Ile196 lies in the eEF1A-binding A-domain, but direct disruption by p.Ile196Thr was not established in every affected lineage. (abok2024bioinformaticanalysisof pages 11-15)

General ZPR1 studies connect deficiency with altered SMN localization/transcription, R-loop accumulation, impaired DNA repair, MLK3–MKK7–JNK signaling, caspase-3 activation, and neurodegeneration. These pathways provide biological hypotheses for neurologic disease but were primarily demonstrated in SMA or other experimental contexts, not in renal or hair tissue from these patients. (chittilla2021highfatdietassociatedcognitive pages 1-2, chittilla2021highfatdietassociatedcognitive pages 2-3)

Suggested annotations: GO:0007049 cell cycle; GO:0000082 G1/S transition of mitotic cell cycle; GO:0008283 cell population proliferation; proteasomal protein catabolic process; protein folding; RNA processing; DNA repair; GO:0005634 nucleus; GO:0005730 nucleolus; GO:0005737 cytoplasm. Suggested cell types include fibroblast (CL:0000057), renal epithelial/progenitor cells, hair-follicle epithelial cells, sensory neurons, and motor neurons; only fibroblasts were directly examined in syndrome-specific functional work.

No disease-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, organoid, CRISPR-screen, or multi-omics profile was identified.

7. Anatomical structures affected

Primary organs are the kidneys, skin appendages/hair follicles, craniofacial structures, and the growth axis/skeleton. Secondary or associated involvement includes brain/head growth, auditory structures, and optic nerves. Suggested anatomical mappings are kidney (UBERON:0002113), hair follicle (UBERON:0002073, curator validation advised), skin, brain, optic nerve, and inner ear. Available evidence does not establish renal laterality, nephron-segment specificity, histopathology, or a single targeted kidney cell population. (chittilla2021highfatdietassociatedcognitive pages 4-5, abok2024bioinformaticanalysisof pages 1-4)

At the subcellular level, ZPR1 biology implicates the cytoplasm, nucleus, and nucleolus. Misfolded p.Ile196Thr also implicates cytosolic protein-quality-control/proteasomal machinery. (chittilla2021highfatdietassociatedcognitive pages 1-2, abok2024bioinformaticanalysisof pages 1-4)

8. Temporal development

Onset is prenatal/congenital: fetal growth restriction, renal hypoplasia, dysmorphism, and alopecia arise during development. Postnatal growth failure and neurodevelopmental disability persist. The syndrome should be considered chronic and lifelong, but no validated staging system, progression rate, remission pattern, or critical treatment window exists. Early childhood appears to be a vulnerable period because increased early mortality was reported, although the number and causes of deaths were not recovered. (abok2024bioinformaticanalysisof pages 1-4)

9. Inheritance and population

Inheritance is autosomal recessive. The original evidence comprises four affected children in three families of New Mexican Hispanic ancestry. The suggested Rio Grande Valley founder effect remains unconfirmed by haplotype dating or broad population screening. Penetrance for true biallelic loss-of-function genotypes is unknown; expressivity appears multisystemic, but its range cannot be defined from four patients. Anticipation has not been reported. Germline mosaicism is theoretically possible for any Mendelian variant but has not been demonstrated. (abok2024bioinformaticanalysisof pages 1-4)

No incidence, prevalence per 100,000, sex ratio, or validated disease-carrier frequency is available. A 2024 preprint screened 122,678 gnomAD individuals and computationally labeled 60 of 223 ZPR1 missense variants as damaging. It reported 330 heterozygous carriers (0.27%) and three homozygotes for this pooled predicted-variant set, with heterozygote proportions from 0.04% in Ashkenazi Jewish to 0.34% in African/African American groups. These values are neither prevalence estimates for MONDO:0859146 nor carrier frequencies for p.Ile196Thr; prediction-based classifications and apparently healthy homozygotes demand cautious interpretation. (abok2024bioinformaticanalysisof pages 8-11, abok2024bioinformaticanalysisof pages 21-27)

10. Diagnostics

Diagnosis should combine the congenital phenotype with molecular confirmation:

  1. Document prenatal/postnatal growth, head circumference, alopecia, dysmorphology, renal anatomy/function, development, hearing, and vision.
  2. Perform renal ultrasonography; serum creatinine/eGFR, electrolytes, urinalysis, urine protein/albumin, and blood pressure should characterize renal involvement.
  3. Conduct audiology, ophthalmology, neurodevelopmental assessment, and nutritional/endocrine evaluation tailored to growth failure.
  4. Use a growth-disorder, CAKUT, alopecia/ectodermal-dysplasia, or developmental-disorder panel containing ZPR1, or preferably trio WES/WGS when the presentation is nonspecific.
  5. Confirm candidate variants by an orthogonal method and test parental segregation. Targeted familial testing is appropriate once the allele is known.

Exome sequencing identified the causal allele in the original proband, supporting real-world use of WES. WGS may detect noncoding or structural variants missed by WES, but no syndrome-specific WGS yield has been reported. CMA is reasonable when multiple congenital anomalies remain unexplained but will not detect an ordinary single-nucleotide ZPR1 variant. Karyotyping, FISH, mitochondrial sequencing, repeat-expansion testing, liquid biopsy, proteomics, and metabolomics are not first-line tests for this phenotype unless independently indicated. (abok2024bioinformaticanalysisof pages 1-4)

There are no standardized clinical diagnostic criteria. Differential diagnoses include other primordial dwarfism/cell-cycle disorders, syndromic CAKUT, ectodermal dysplasias, renal–retinal ciliopathies, progeroid disorders, and BRESEK/BRESHECK-like syndromes. Molecular confirmation is decisive because phenotypic overlap is substantial.

11. Outcome and prognosis

The available literature indicates increased early mortality, but provides no five- or ten-year survival, life expectancy, cause-specific mortality, renal-failure probability, or prognostic biomarker. Potential morbidity includes chronic kidney disease, severe growth impairment, hearing/vision disability, developmental disability, and psychosocial effects of alopecia. Prognosis should therefore be individualized according to renal function, growth/nutrition, neurodevelopment, and sensory involvement. (abok2024bioinformaticanalysisof pages 1-4)

Recovery from congenital structural abnormalities is not expected, although functional outcomes may improve with early supportive interventions. No molecular marker has been validated to predict severity.

12. Treatment and current implementation

No approved disease-modifying treatment, genotype-directed drug, gene therapy, RNA therapy, cell therapy, immunotherapy, or disease-specific clinical trial was identified. No response-rate or adverse-event dataset exists. (chittilla2021highfatdietassociatedcognitive pages 1-2, abok2024bioinformaticanalysisof pages 1-4, abok2024bioinformaticanalysisof pages 15-19)

Current care is necessarily multidisciplinary and organ directed:

  • Pediatric nephrology: avoid nephrotoxins and dehydration; manage hypertension, proteinuria, electrolyte disturbance, anemia, CKD-mineral/bone disease, and renal failure according to standard pediatric nephrology practice.
  • Growth/nutrition: dietitian assessment and evaluation for treatable nutritional or endocrine contributors. Evidence is insufficient to recommend growth hormone specifically for ZPR1 deficiency.
  • Audiology/ENT: hearing aids, cochlear-implant assessment, and communication support when indicated.
  • Ophthalmology: monitor optic and visual function and provide low-vision services.
  • Development: early-intervention services, physical, occupational, speech/language, and educational therapies.
  • Dermatology and psychosocial care: scalp protection and optional cosmetic hair prostheses.
  • Clinical genetics: family testing, recurrence-risk counseling, and variant reinterpretation.

Suggested NCIT concepts include Genetic Counseling, Supportive Care, Whole Exome Sequencing, Whole Genome Sequencing, Ultrasonography, Audiologic Testing, Physical Therapy, Occupational Therapy, and Speech Therapy; exact NCIT identifiers should be validated by a terminology curator.

ZPR1 overexpression increased SMN and rescued SMA-model phenotypes, but this is not evidence that ZPR1 augmentation is safe or effective for children with biallelic ZPR1 deficiency. It remains a conceptual research direction only. (abok2024bioinformaticanalysisof pages 4-8)

13. Prevention

There is no lifestyle, vaccine, medication, or public-health intervention that prevents a child with a biallelic pathogenic genotype from developing the syndrome.

Primary genetic prevention options include carrier testing for adult relatives, partner testing, preimplantation genetic testing for monogenic disease, prenatal diagnosis by chorionic-villus sampling or amniocentesis, and use of donor gametes. Secondary prevention consists of early molecular diagnosis and prompt renal, hearing, visual, nutritional, and developmental evaluation. Tertiary prevention targets CKD progression, sensory disability, nutritional complications, and developmental loss. Population-wide newborn or carrier screening is not currently justified by the extremely limited natural-history and variant-classification evidence. (abok2024bioinformaticanalysisof pages 15-19)

14. Other species and natural disease

No naturally occurring veterinary counterpart, breed predisposition, zoonotic potential, or cross-species transmission was identified. ZPR1 is evolutionarily conserved, and mouse structural data were used to model the human protein. Relevant taxonomy is Homo sapiens (NCBI Taxon:9606) and Mus musculus (NCBI Taxon:10090). (abok2024bioinformaticanalysisof pages 4-8)

15. Model organisms

No p.Ile196Thr knock-in mouse, zebrafish, organoid, or patient-derived iPSC model that reproduces the combined renal–hair–growth phenotype was identified. Zpr1-deficient mice show facial and spinal motor-neuron degeneration, axon retraction, microtubule disruption, and other neurodegenerative abnormalities. These experiments demonstrate that ZPR1 is required for neuronal maintenance but do not fully model the human syndrome. (chittilla2021highfatdietassociatedcognitive pages 1-2)

Patient fibroblasts remain the most disease-specific experimental model: they show markedly depleted ZPR1 and impaired cell-cycle progression. Future priority models should include isogenic p.Ile196Thr iPSCs differentiated into nephron progenitors, hair-follicle organoids, neural lineages, and a knock-in animal model to distinguish developmental cell-proliferation failure from tissue-specific RNA-processing or genome-maintenance defects. (abok2024bioinformaticanalysisof pages 11-15)

Evidence appraisal and research priorities

The present understanding rests on one four-patient clinical report, patient fibroblast experiments, general ZPR1 biology, and a 2024 computational preprint. Major unresolved questions are the full phenotypic spectrum, renal natural history, causes of early mortality, penetrance of other biallelic alleles, founder-variant frequency, genotype–phenotype relationships, growth-hormone biology, and therapeutic reversibility. The most authoritative conclusion is therefore narrow: biallelic ZPR1 p.Ile196Thr causes a congenital growth–renal–hair–craniofacial syndrome through ZPR1 protein deficiency with defective cellular proliferation; most organ-specific mechanistic links and all treatment claims remain unproven. (OpenTargets Search: Growth Restriction Hypoplastic Kidneys Alopecia And Distinctive Facies, abok2024bioinformaticanalysisof pages 11-15, abok2024bioinformaticanalysisof pages 1-4)

Key references

  1. Ito YA, Smith AC, Kernohan KD, et al. “A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys.” Clinical Genetics. 2018;94:303–312. PMID: 29851065. DOI: 10.1111/cge.13388. (abok2024bioinformaticanalysisof pages 15-19)
  2. Abok JI, Garver WS, Edwards JS. “Bioinformatic analysis of human ZPR1 gene pathogenic exome mutations.” bioRxiv. Posted March 1, 2024. DOI: 10.1101/2024.02.27.582196. The abstract states: “We examined 223 germline ZPR1 exome variants” and reports predicted heterozygous harmful-variant frequencies of 0.04%–0.34%; these remain computational findings. (abok2024bioinformaticanalysisof pages 1-4)
  3. Chittilla M, Akimbekov NS, Razzaque MS. “High-fat diet-associated cognitive decline: Is zinc finger protein 1 (ZPR1) the molecular connection?” Current Research in Physiology. Available online October 2, 2021. DOI: 10.1016/j.crphys.2021.09.004. This is supporting general ZPR1 biology, not syndrome-specific clinical evidence. (chittilla2021highfatdietassociatedcognitive pages 1-2)

References

  1. (OpenTargets Search: Growth Restriction Hypoplastic Kidneys Alopecia And Distinctive Facies): Open Targets Query (Growth Restriction Hypoplastic Kidneys Alopecia And Distinctive Facies, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (abok2024bioinformaticanalysisof pages 1-4): Jeremiah I. Abok, William S. Garver, and Jeremy S. Edwards. Bioinformatic analysis of human zpr1 gene pathogenic exome mutations. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.02.27.582196, doi:10.1101/2024.02.27.582196. This article has 0 citations.

  3. (abok2024bioinformaticanalysisof pages 15-19): Jeremiah I. Abok, William S. Garver, and Jeremy S. Edwards. Bioinformatic analysis of human zpr1 gene pathogenic exome mutations. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.02.27.582196, doi:10.1101/2024.02.27.582196. This article has 0 citations.

  4. (abok2024bioinformaticanalysisof pages 8-11): Jeremiah I. Abok, William S. Garver, and Jeremy S. Edwards. Bioinformatic analysis of human zpr1 gene pathogenic exome mutations. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.02.27.582196, doi:10.1101/2024.02.27.582196. This article has 0 citations.

  5. (chittilla2021highfatdietassociatedcognitive pages 4-5): Mythri Chittilla, Nuraly S. Akimbekov, and Mohammed S. Razzaque. High-fat diet-associated cognitive decline: is zinc finger protein 1 (zpr1) the molecular connection? Current Research in Physiology, 4:223-228, Oct 2021. URL: https://doi.org/10.1016/j.crphys.2021.09.004, doi:10.1016/j.crphys.2021.09.004. This article has 5 citations and is from a peer-reviewed journal.

  6. (abok2024bioinformaticanalysisof pages 11-15): Jeremiah I. Abok, William S. Garver, and Jeremy S. Edwards. Bioinformatic analysis of human zpr1 gene pathogenic exome mutations. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.02.27.582196, doi:10.1101/2024.02.27.582196. This article has 0 citations.

  7. (abok2024bioinformaticanalysisof pages 21-27): Jeremiah I. Abok, William S. Garver, and Jeremy S. Edwards. Bioinformatic analysis of human zpr1 gene pathogenic exome mutations. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.02.27.582196, doi:10.1101/2024.02.27.582196. This article has 0 citations.

  8. (chittilla2021highfatdietassociatedcognitive pages 1-2): Mythri Chittilla, Nuraly S. Akimbekov, and Mohammed S. Razzaque. High-fat diet-associated cognitive decline: is zinc finger protein 1 (zpr1) the molecular connection? Current Research in Physiology, 4:223-228, Oct 2021. URL: https://doi.org/10.1016/j.crphys.2021.09.004, doi:10.1016/j.crphys.2021.09.004. This article has 5 citations and is from a peer-reviewed journal.

  9. (abok2024bioinformaticanalysisof pages 4-8): Jeremiah I. Abok, William S. Garver, and Jeremy S. Edwards. Bioinformatic analysis of human zpr1 gene pathogenic exome mutations. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.02.27.582196, doi:10.1101/2024.02.27.582196. This article has 0 citations.

  10. (chittilla2021highfatdietassociatedcognitive pages 2-3): Mythri Chittilla, Nuraly S. Akimbekov, and Mohammed S. Razzaque. High-fat diet-associated cognitive decline: is zinc finger protein 1 (zpr1) the molecular connection? Current Research in Physiology, 4:223-228, Oct 2021. URL: https://doi.org/10.1016/j.crphys.2021.09.004, doi:10.1016/j.crphys.2021.09.004. This article has 5 citations and is from a peer-reviewed journal.

  11. (chittilla2021highfatdietassociatedcognitive pages 5-6): Mythri Chittilla, Nuraly S. Akimbekov, and Mohammed S. Razzaque. High-fat diet-associated cognitive decline: is zinc finger protein 1 (zpr1) the molecular connection? Current Research in Physiology, 4:223-228, Oct 2021. URL: https://doi.org/10.1016/j.crphys.2021.09.004, doi:10.1016/j.crphys.2021.09.004. This article has 5 citations and is from a peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 4
Resolved 4
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 4
On topic 2
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 26
Resolved 24
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 2
Terms named correctly 0
Terms named as a different term 2

Terms the report names something else

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

  • HP:0000648 (2 mentions) - the report calls it "Ophthalmologic sign"; HP calls it Optic atrophy
  • HP:0000407 (2 mentions) - the report calls it "Sensory manifestation; onset details unavailable"; HP calls it Sensorineural hearing impairment

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: Taxon.