PUS3-Related Neurodevelopmental Disorder

Mendelian MONDO:0014886 Pathograph 20 Show in embeddings browser Neurodevelopmental Disorder Intellectual Disability

PUS3-related neurodevelopmental disorder (neurodevelopmental disorder with microcephaly and gray sclerae, NEDMIGS, MIM 617051; formerly autosomal recessive intellectual disability 55, MRT55) is an ultra-rare autosomal recessive condition caused by biallelic loss-of-function variants in PUS3, which encodes the TruA/Pus3-family tRNA pseudouridine synthase 3. The core clinical picture is global developmental delay with severe to profound intellectual disability and poor or absent speech, generalised hypotonia, microcephaly and epilepsy. A distinctive ocular and cutaneous pigmentary signature - grey sclerae together with extensive, widespread Mongolian spots (dermal melanocytosis) - was present in the founding Saudi family and supplied the descriptive Orphanet/MONDO label, but grey sclerae were subsequently found in only a minority of the pooled cohort and dermal melanocytosis has not been systematically re-reported, so neither feature is obligatory. Poor somatic growth with severe short stature or failure to thrive, coarse facial features, strabismus and variable brain MRI abnormalities (subcortical white matter signal change, atrophy or hypoplasia, corpus callosum dysgenesis) complete the syndrome. Mechanistically, disease alleles either truncate PUS3 or destabilise/aggregate the protein in cells, and in every functionally studied patient the result is the same: depletion of PUS3-dependent pseudouridine at positions 38 and 39 of the tRNA anticodon stem loop, with the developing brain the tissue least able to tolerate the resulting perturbation of translation.

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1
Inheritance
5
Pathophys.
21
Phenotypes
2
Gaps
20
Pathograph
1
Genes
5
Medical Actions
3
Differentials
10
References
1
Deep Research
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Classifications

Harrison's Chapter
NEUROLOGIC GENETICS_ENVIRONMENT_DISEASE
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Disease requires two damaging PUS3 alleles. Both homozygous genotypes, typically in consanguineous families, and compound heterozygous genotypes occur; carrier parents are unaffected. Recurrence risk for the sibling of an affected proband is 25 percent, so carrier testing and genetic counselling are indicated for at-risk relatives.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:41971559 SUPPORT Human Clinical
"Biallelic pathogenic variants cause a rare autosomal recessive neurodevelopmental disorder characterized by intellectual disability, microcephaly, hypotonia, and gray sclera."
States the autosomal recessive mode and the biallelic requirement at the PUS3 locus.
PMID:34415064 SUPPORT Human Clinical
"In conclusion, homozygous and compound heterozygous PUS3 variants lead to a rare neurodevelopmental disorder."
Documents that both homozygous and compound heterozygous biallelic genotypes cause the disorder, the defining pattern of autosomal recessive inheritance.
PMID:27055666 SUPPORT Human Clinical
"In a multiplex consanguineous family, we applied autozygosity mapping and exome sequencing and identified a novel homozygous truncating mutation in PUS3 that fully segregates with the intellectual disability phenotype."
Autozygosity mapping in a consanguineous multiplex family with full segregation of a homozygous allele is the classic demonstration of autosomal recessive inheritance.
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Discussions and Knowledge Gaps

2
Does loss of pseudouridine at tRNA positions 38 and 39 actually degrade translational fidelity or efficiency in human neural cells, and if so which transcripts or codons are most affected?
KNOWLEDGE GAP OPEN pus3_translation_step_unmeasured
Attached to
pathophysiology#Impaired Translational Fidelity and Efficiency
This is the weakest link in the causal chain. Every step from the PUS3 genotype to depleted pseudouridine at positions 38 and 39 has been measured directly in patient cells by two independent groups. The step from there to impaired translation is inferred from tRNA structural chemistry and from bacterial truA and yeast pus3 orthologue phenotypes, and the step from impaired translation to selective vulnerability of the developing brain is inferred from the pattern shared across the tRNA-modification intellectual disability disorders. No ribosome profiling, proteomics or reporter-fidelity measurement has been reported in a human PUS3-deficient neural cell. Until that measurement exists, the mechanistic explanation for why a housekeeping tRNA modification produces a brain-predominant phenotype remains a hypothesis rather than a finding.
Proposed experiments
Ribosome profiling and proteomics in patient iPSC-derived neurons
exp_pus3_ribosome_profiling_neurons
Perform ribosome profiling and quantitative proteomics in patient-derived iPSC neural progenitors and neurons versus isogenic corrected controls, testing for codon-specific ribosome pausing at codons decoded by the tRNAs that normally carry pseudouridine at positions 38 and 39.
Translational fidelity reporter assays in patient cells
exp_pus3_fidelity_reporters
Use dual-luciferase or fluorescent reporter assays of frameshifting and stop-codon readthrough in patient fibroblasts and iPSC-derived neurons, the human counterpart of the reduced minus-one frameshifting reported in yeast pus3 mutants.
Cerebral organoid model of PUS3 deficiency
exp_pus3_cerebral_organoids
Differentiate cerebral organoids from patient and isogenic corrected iPSC lines and assess progenitor proliferation and cortical layer formation, to test whether the microcephaly and developmental delay are reproducible in a human neural model.
Show evidence (1 reference)
PMID:34415064 SUPPORT Human Clinical
"Further functional studies are necessary to understand involvement of PUS3 and tRNA biogenesis in normal and abnormal brain development."
The largest cohort study states explicitly that the mechanistic link from PUS3 to brain development remains unresolved.
Is extensive dermal melanocytosis a real, mechanistically meaningful feature of PUS3 deficiency, or an ancestry-linked incidental finding in the single founding family that has been fossilised into the Orphanet and MONDO label?
KNOWLEDGE GAP OPEN pus3_dermal_melanocytosis_generalisability
Attached to
phenotypes#Extensive Dermal Melanocytosis
Extensive Mongolian spots appear in all three sisters of the founding Saudi family and are prominent enough to have named the disorder in Orphanet and MONDO. Yet the feature is absent from the abstract of the 21-individual pooled cohort, which enumerates gray sclera among pigmentary findings but not dermal melanocytosis, and it is not mentioned in the Italian, Polish or Turkish reports. Congenital dermal melanocytosis is also common in the general population of several ancestries, including the one the founding family belongs to, which makes a coincidental co-occurrence within one consanguineous sibship entirely plausible. Two things hinge on the answer. If the association is real, then PUS3 loss must perturb dermal melanocyte migration or retention and the pathograph is missing a node. If it is not, the MONDO label is actively misleading and steers curators and clinicians towards the lysosomal storage disorders. Grey sclerae, which is plausibly the ocular counterpart of the same melanocytic process, went from "characteristic" to 7/21 once a real cohort was assembled - the same deflation may await dermal melanocytosis.
Proposed experiments
Standardised re-phenotyping of the published cohort for dermal melanocytosis
exp_pus3_melanocytosis_rephenotyping
Systematically re-phenotype the existing molecularly confirmed cohort for dermal melanocytosis using standardised photographic documentation and HPO coding, with the extent and distribution recorded rather than a simple present/absent flag.
Ancestry-matched control comparison for dermal melanocytosis
exp_pus3_melanocytosis_ancestry_control
Compare dermal melanocytosis prevalence and extent between PUS3-affected individuals and ancestry-matched unaffected relatives or population controls, which is the only design that can separate a genuine disease association from an ancestry-linked background rate.
PUS3 function in dermal melanocytes
exp_pus3_melanocyte_biology
Assess PUS3 expression and pseudouridine levels in dermal melanocytes, and melanocyte migration in a PUS3-depleted model, to test whether a plausible cellular mechanism for the pigmentary phenotype exists at all.
Show evidence (2 references)
PMID:34415064 SUPPORT Human Clinical
"Gray sclera, which has previously been suggested to be a characteristic feature of PUS3-associated phenotypes, was reported in only seven individuals."
Demonstrates the precedent: a pigmentary feature considered characteristic from early reports deflated to a minority finding once a real cohort was assembled, which is the concern raised for dermal melanocytosis.
PMID:27055666 SUPPORT Human Clinical
"She has coarse facial features, bilateral strabismus, grey sclera and extensive Mongolian spots"
The single-family observation on which the whole Orphanet label rests, and therefore the observation whose generalisability is in question.
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Pathophysiology

5
Biallelic PUS3 Loss-of-Function Variants
The disorder is initiated by inheritance of two damaging PUS3 alleles. The reported allelic spectrum is broad and includes nonsense alleles that truncate the protein (the founding p.Arg435* allele), frameshift alleles, a splice-region allele, an initiation-codon substitution, and missense alleles. Critically, the missense alleles are not a milder mechanistic class: p.Tyr71Cys retains essentially normal tRNA binding and catalytic activity when the purified protein is assayed, yet behaves as a functional null in cells, so the allelic spectrum converges on one outcome rather than producing a hypomorph gradient.
PUS3 hgnc:25461
Downstream
Loss of PUS3 Pseudouridine Synthase Activity Truncating alleles remove the enzyme outright, while the studied missense alleles deplete it post-translationally, so both arms of the allelic spectrum converge on loss of available PUS3 activity in the cell.
Show evidence (2 references)
PMID:27055666 SUPPORT Human Clinical
"we identified a homozygous nonsense variant in PUS3; Chr11(GRCh37):g.125763823G>A; NM_031307.3: c.1303C>T: p.(Arg435*) that fully segregated with the phenotype in the family as confirmed by Sanger sequencing"
Establishes the founding biallelic protein-truncating allele as the initiating lesion.
PMID:36125428 SUPPORT Human Clinical
"we utilize exome sequencing to identify genomic variants that lead to a homozygous amino acid substitution"
Documents the missense arm of the allelic spectrum, identified by exome sequencing in two homozygous individuals and one compound heterozygote. The quoted fragment stops before the HGVS allele strings because their square brackets are not preserved in the cached reference text.
Loss of PUS3 Pseudouridine Synthase Activity
PUS3 is a stand-alone, guide-RNA-independent pseudouridine synthase of the TruA/Pus3 family that isomerises uridine to pseudouridine in the anticodon stem loop of cytosolic tRNAs. Cryo-EM shows it acts as a symmetric homodimer that clamps the tRNA and presents the target uridine to its active site. Two distinct routes destroy that activity in patients: outright absence of the protein from truncating alleles, and post-translational depletion from missense alleles that impair thermostability (p.Tyr71Cys) or promote aggregation (p.Ile299Thr).
tRNA pseudouridine synthase activity GO:0106029 ↓ DECREASED pseudouridine synthase activity GO:0009982 ↓ DECREASED
Downstream
Depletion of tRNA Pseudouridine at Anticodon Positions 38 and 39 Loss of the only enzyme that installs pseudouridine at these two positions leaves the corresponding uridines unmodified in patient tRNA.
Show evidence (4 references)
PMID:38996458 SUPPORT In Vitro
"Human pseudouridine synthase 3 (PUS3) catalyzes pseudouridylation of position 38/39 in tRNAs."
Identifies the enzyme and the exact catalytic reaction whose loss defines this node.
PMID:38996458 SUPPORT In Vitro
"Here, we determine single-particle cryo-EM structures of PUS3 in its apo form and bound to three tRNAs, showing how the symmetric PUS3 homodimer recognizes tRNAs and positions the target uridine next to its active site."
Supplies the structural basis for how the enzyme engages its substrate, and therefore what patient alleles disrupt.
PMID:36125428 SUPPORT In Vitro
"we find that the p.Tyr71Cys substitution neither affect tRNA binding nor pseudouridylation activity in vitro, but strongly impair the thermostability profile of PUS3, while the p.Ile299Thr mutation causes protein aggregation."
Establishes protein destabilisation and aggregation, rather than direct catalytic impairment, as the route by which missense alleles abolish activity.
+ 1 more reference
Depletion of tRNA Pseudouridine at Anticodon Positions 38 and 39
Pseudouridine at positions 38 and 39 sits in the anticodon stem loop, the part of the tRNA that pairs with the codon. Its extra imino group provides additional hydrogen bonding and rigidifies the loop, so its absence is expected to destabilise anticodon stem loop architecture. In the founding family the deficit was quantified as almost exactly one missing mole of pseudouridine per mole of tRNA-Phe, while every other measured modification of the same tRNA was unchanged, establishing that the lesion is specific to the PUS3 site rather than a general collapse of tRNA modification.
tRNA pseudouridine synthesis GO:0031119 ↓ DECREASED tRNA modification GO:0006400 ↓ DECREASED
Downstream
Impaired Translational Fidelity and Efficiency An unmodified, less rigid anticodon stem loop is the proposed proximate cause of degraded decoding at the ribosome. This step is an inference from tRNA biology and from orthologue work rather than a direct measurement in patient neurons, and it is flagged as such in the discussions section.
Show evidence (3 references)
PMID:27055666 SUPPORT In Vitro
"Since tRNAPhe from LCLs with the Arg435* allele of PUS3 had almost exactly 1 mole/mole less Ψ than control LCLs, we infer that the Arg435* allele nearly completely knocks out PUS3 function due to truncation of the conserved domain and the last 45 amino acids"
Quantifies the stoichiometric loss of one pseudouridine per tRNA molecule in patient cells.
PMID:27055666 SUPPORT In Vitro
"By contrast, the levels of the other modifications of tRNAPhe (Cm, Gm, m2G, m1A, m7G, and m5C) were all very similar in all of the LCLs including WT"
Shows the deficit is specific to the PUS3-dependent modification, excluding a generalised tRNA-modification failure.
PMID:36125428 SUPPORT In Vitro
"our results directly illustrate the link between the identified PUS3 variants and reduced Ψ levels in the patient cells, providing a molecular explanation for the observed clinical phenotypes."
Independent replication in a second patient set and with a different allele class, closing the loop from genotype to reduced pseudouridine.
Impaired Translational Fidelity and Efficiency
Reduced anticodon-loop pseudouridylation is expected to degrade the accuracy and efficiency of protein synthesis. In lower organisms loss of the orthologous enzyme is clearly consequential: bacterial truA mutants grow poorly and yeast pus3-delta mutants are slow-growing and temperature-sensitive with reduced frameshifting fidelity. The corresponding measurement has not been made in human patient neurons, so this node is the weakest link in the chain.
neuron CL:0000540
translation GO:0006412 ↓ DECREASED
Downstream
Neurodevelopmental Impairment The developing brain is disproportionately affected, which is the pattern shared across the tRNA-modification intellectual disability disorders and is attributed to a higher sensitivity of neural tissue to reduced translational efficiency.
Show evidence (3 references)
PMID:27055666 SUPPORT Model Organism
"Bacterial truA mutants have significant growth defects (Chang et al. 1971; Tsui et al. 1991), while S. cerevisiae pus3Δ mutants are slow growing and temperature-sensitive"
Orthologue evidence that loss of this specific pseudouridylation is physiologically consequential; tagged MODEL_ORGANISM because it is bacterial and yeast data, not human.
PMID:38996458 SUPPORT In Vitro
"Our work provides the molecular basis for PUS3-mediated tRNA modification in humans and explains how its tRNA modification activity is linked to intellectual disabilities."
The structural study frames the disease link as running specifically through the tRNA modification activity.
PMID:38996458 REFUTE In Vitro
"Although PUS1-dependent sites were detectable in tRNA and mRNA, we found no evidence that human PUS3 modifies mRNAs."
Refutes a direct mRNA-pseudouridylation arm of the mechanism, constraining the pathograph to the tRNA route and excluding an mRNA-substrate node.
Neurodevelopmental Impairment
The clinical endpoint. Despite wide tissue expression of PUS3, the phenotype is largely brain-predominant: global developmental delay, severe to profound intellectual disability, poor or absent speech, hypotonia, epilepsy, microcephaly and variable structural or white-matter brain abnormalities. Growth failure, pigmentary and ocular features accompany the neurological core in a subset. This places PUS3 alongside ADAT3, WDR4, NSUN2 and FTSJ1 in the family of tRNA-modification intellectual disability disorders.
central nervous system development GO:0007417 ⚠ ABNORMAL
Show evidence (3 references)
PMID:27055666 SUPPORT Human Clinical
"The phenotype we observe in the context of PUS3 deficiency is largely brain-specific."
States the brain-predominant character of the clinical endpoint.
PMID:27055666 SUPPORT Human Clinical
"Our finding adds to a growing list of intellectual disability disorders that are caused by perturbation of various tRNA modifications, which highlights the sensitivity of the brain to these highly conserved processes."
Places the disorder within the wider class of tRNA-modification intellectual disability disorders.
PMID:34415064 SUPPORT Human Clinical
"The clinical picture was dominated by global developmental delay, epilepsy, hypotonia and microcephaly."
Defines the composition of the neurodevelopmental endpoint across the largest pooled cohort.
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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 PUS3-Related Neurodevelopmental Disorder 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

21
Cardiovascular 1
Congenital Heart Defect Abnormal heart morphology HP:0001627
Frequency omitted; a single snippet-backed individual, at the severe end of the spectrum. Term choice. The source says only "congenital heart defect" and names no specific lesion, so no more specific HPO term is defensible. HP:0001627 is the right binding rather than a mere fallback parent: OAK confirms it carries "Congenital heart defect" and "Congenital heart defects" as EXACT synonyms (alongside "Heart defect" and "Cardiac anomaly"), so the congenital semantics are present in the term even though its primary label reads "Abnormal heart morphology". Assigning a septal or valvular child term would assert a lesion the paper does not report.
Show evidence (1 reference)
PMID:34713961 SUPPORT Human Clinical
"We identified a novel homozygous PUS3 frameshift variant in a child with facial dysmorphisms, growth failure, microcephaly, retinal dystrophy, cerebellar hypoplasia, congenital heart defect, and right kidney hypoplasia."
Documents a congenital heart defect as part of the expanded severe syndromic presentation.
Eye 2
Strabismus Strabismus HP:0000486
Frequency omitted. Strabismus is 3/3 in the founding family but is not enumerated in the pooled-cohort abstract, so no defensible disease-wide band can be assigned. Other ocular findings reported in isolated individuals include nystagmus, optic disc pallor, astigmatism, abnormal visual fixation and retinal dystrophy.
Show evidence (2 references)
PMID:27055666 SUPPORT Human Clinical
"She has coarse facial features, bilateral strabismus, grey sclera and extensive Mongolian spots"
Documents bilateral strabismus in the index case.
PMID:27055666 SUPPORT Human Clinical
"She had strabismus, grey sclerae and Mongolian spots."
Documents strabismus in the third affected sister.
Retinal Dystrophy Retinal dystrophy HP:0000556
Frequency omitted; a single reported individual. Included because it materially changes ophthalmological surveillance if confirmed in further cases.
Show evidence (1 reference)
PMID:34713961 SUPPORT Human Clinical
"We identified a novel homozygous PUS3 frameshift variant in a child with facial dysmorphisms, growth failure, microcephaly, retinal dystrophy, cerebellar hypoplasia, congenital heart defect, and right kidney hypoplasia."
Documents retinal dystrophy in the expanded severe phenotype.
Head and Neck 2
Microcephaly FREQUENT Microcephaly HP:0000252
Derivation: the Nostvik full text records microcephaly in 13/18 assessed (72 percent, FREQUENT band 30-79 percent), and the pooled-cohort abstract names microcephaly among the dominant features. Microcephaly is named in the OMIM disease title (NEDMIGS) but is explicitly mild, and one of the three founding sisters had only borderline microcephaly.
Show evidence (2 references)
PMID:34415064 SUPPORT Human Clinical
"The clinical picture was dominated by global developmental delay, epilepsy, hypotonia and microcephaly."
Names microcephaly among the dominant features of the largest pooled cohort.
PMID:27055666 SUPPORT Human Clinical
"Examination revealed coarse facies but less striking compared to the sister, severe growth deficiency with borderline microcephaly"
Documents microcephaly in a second affected sister and shows it can be only borderline.
Coarse Facial Features Coarse facial features HP:0000280
Frequency omitted for the coarse-facies qualifier specifically. Non-specific facial dysmorphism is 17/18 in the Nostvik full text, but the pooled-cohort abstract states only that patients had "some dysmorphic facial features" without a recognisable gestalt, and coarse facies as such is documented only in the founding family. Coarse facies is clinically important here mainly because it is the feature that, combined with dermal melanocytosis, drives confusion with the lysosomal storage disorders.
Show evidence (2 references)
PMID:27055666 SUPPORT Human Clinical
"She has coarse facial features, bilateral strabismus, grey sclera and extensive Mongolian spots"
Documents coarse facial features in the index case.
PMID:34415064 PARTIAL Human Clinical
"The patients had some dysmorphic facial features, but a recognizable gestalt was not observed."
Confirms facial dysmorphism across the cohort while explicitly denying a recognisable gestalt, hence PARTIAL support for a specific facial phenotype.
Musculoskeletal 2
Generalized Hypotonia FREQUENT Generalized hypotonia HP:0001290
Derivation: hypotonia in 10/13 assessed (77 percent) in the Nostvik full text, within the FREQUENT band; the abstract names hypotonia among the dominant features. Three of those individuals reportedly improved, so the clinical course is not uniformly progressive and no clinical_course qualifier is asserted.
Show evidence (2 references)
PMID:34415064 SUPPORT Human Clinical
"The clinical picture was dominated by global developmental delay, epilepsy, hypotonia and microcephaly."
Names hypotonia among the dominant features of the pooled cohort.
PMID:27055666 SUPPORT Human Clinical
"Assessment at 2 years showed severe axial and appendicular hypotonia with poor interactions."
Documents the axial and appendicular distribution of the hypotonia in an individual case.
Scoliosis Scoliosis HP:0002650
Frequency omitted. Scoliosis is reported in 8/10 assessed individuals (80 percent) in the Nostvik 2021 full text, the highest rate of any non-core feature, but the denominator is not quotable from the cached abstract and scoliosis is not mentioned in the abstract at all, so no snippet-backed evidence item is possible and no band is asserted. Recorded as a phenotype rather than left buried in treatment prose because at that rate it is a real, surveillance-relevant feature of the disorder. No evidence block by design.
Nervous System 9
Global Developmental Delay FREQUENT Global developmental delay HP:0001263
Derivation: the Nostvik pooled cohort abstract states the clinical picture was "dominated by" global developmental delay, and its full text reports intellectual disability or global developmental delay in 19/19 assessed individuals; all three sisters of the founding family and the Turkish proband are additionally documented individually. The conservative FREQUENT band (30-79 percent) is assigned because the only quotable statement is the qualitative "dominated by", and the 19/19 denominator sits in full text that is not cached here.
Show evidence (2 references)
PMID:34415064 SUPPORT Human Clinical
"The clinical picture was dominated by global developmental delay, epilepsy, hypotonia and microcephaly."
Names global developmental delay first among the dominant features of the pooled 21-individual cohort.
PMID:27055666 SUPPORT Human Clinical
"Index (IV:3) is a 15 ½ year-old girl with a history of global developmental delay since infancy and failure to thrive"
Documents global developmental delay from infancy in the index case of the founding family.
Severe Intellectual Disability FREQUENT Severe intellectual disability HP:0010864
Derivation: severe in 9, moderate-to-severe in 2, moderate in 4 and unspecified in 4 of the pooled cohort per the Nostvik full text, with measured IQ from below 20 to 58. The severe-to-profound end therefore covers roughly half of graded cases, supporting FREQUENT rather than VERY_FREQUENT. Milder moderate presentations exist, so the severity qualifier is not universal even though intellectual disability itself is.
Show evidence (2 references)
PMID:34713961 SUPPORT Human Clinical
"Biallelic pathogenic variants of PUS3 have been previously associated with severe intellectual disability, microcephaly, epilepsy, and short stature."
Summarises severe intellectual disability as an established core feature of the disorder.
PMID:27055666 SUPPORT Human Clinical
"Current evaluation shows that she is in the severe range of ID (IQ 30)."
Formal IQ measurement placing the index case in the severe range.
Seizures FREQUENT Seizure HP:0001250
Derivation: epilepsy in 13/18 assessed (72 percent) in the Nostvik full text, within the FREQUENT band, and named among the dominant features in the abstract. Explicitly not universal - the eldest founding sister had seizures at 10 months but the two younger sisters had none, and the Turkish proband reached age 17 without seizures.
Show evidence (3 references)
PMID:34415064 SUPPORT Human Clinical
"The clinical picture was dominated by global developmental delay, epilepsy, hypotonia and microcephaly."
Names epilepsy among the dominant features of the pooled cohort.
PMID:27055666 SUPPORT Human Clinical
"There is a history of seizures at 10 months of age but she has been seizure-free on multiple antiepileptic medications."
Documents infantile-onset seizures and a treatment-responsive course in the index case.
PMID:41971559 PARTIAL Human Clinical
"Neurological examination revealed hyporeflexia without seizures."
Counter-example documenting a seizure-free affected individual at 17 years, supporting a non-universal frequency band.
Leukoencephalopathy Leukoencephalopathy HP:0002352
Course: STABLE
Frequency omitted. White matter abnormalities were present in 5 individuals of the Nostvik cohort with any MRI abnormality in 11/15, but the specific white-matter subset denominator is not quotable from the cached abstract. The 2019 Brazilian report (PMID:30697592) put leukoencephalopathy in its title but is a Neurology Genetics clinical note with no PubMed abstract, so it supports this phenotype only as a listed reference, not as a snippet-backed evidence item.
Show evidence (2 references)
PMID:41971559 SUPPORT Human Clinical
"Brain MRI demonstrated stable, nonprogressive, linear-nodular T2 hyperintense lesions confined to the subcortical white matter with a normal corpus callosum, an imaging pattern rarely associated with PUS3 deficiency."
Documents subcortical white matter disease and, critically, its stable non-progressive character over long follow-up.
PMID:27055666 SUPPORT Human Clinical
"there was volume loss in the frontal lobes anteriorly, and multiple T2/FLAIR white matter signal abnormalities in the subcortical white matter"
Independently documents subcortical T2/FLAIR white matter signal abnormality in the founding family.
Corpus Callosum Dysgenesis Abnormal corpus callosum morphology HP:0001273
Frequency omitted; this is a single documented individual in the founding family, with an explicit normal-corpus-callosum counter-example in PMID:41971559. Term choice. The source reports "dysgenesis of corpus callosum", i.e. a malformed but present structure. HP:0001274 Agenesis of corpus callosum was used in an earlier revision and is wrong: agenesis asserts complete absence, which is a strictly stronger and different claim than what the paper reports. HP:0001273 Abnormal corpus callosum morphology, verified with OAK as "Abnormality of the corpus callosum", is the exact concept for dysgenesis and is the parent of the agenesis term, so it is both correct and appropriately non-committal.
Show evidence (1 reference)
PMID:27055666 SUPPORT Human Clinical
"there was evidence of dysgenesis of corpus callosum, mild diffuse brain atrophy and a prominent cisterna magna"
Documents corpus callosum dysgenesis in an affected sister of the founding family.
Cerebellar Hypoplasia Cerebellar hypoplasia HP:0001321
Frequency omitted; a single reported individual at the severe end of the spectrum.
Show evidence (1 reference)
PMID:34713961 SUPPORT Human Clinical
"We identified a novel homozygous PUS3 frameshift variant in a child with facial dysmorphisms, growth failure, microcephaly, retinal dystrophy, cerebellar hypoplasia, congenital heart defect, and right kidney hypoplasia."
Documents cerebellar hypoplasia as part of the expanded severe syndromic presentation.
Delayed Speech and Language Development Delayed speech and language development HP:0000750
Frequency deliberately omitted despite a very high reported rate. Speech impairment is documented in 11/11 assessed individuals (100 percent) in the Nostvik 2021 full text, which on its face maps to VERY_FREQUENT. That denominator sits in full text that is not cached here, and the pooled-cohort abstract does not mention speech at all, so there is no quotable snippet for either the association or the band. Per the frequency-evidence guidelines the band is omitted rather than asserted from an unquotable source, and the derivation is recorded here instead. This phenotype therefore carries no evidence block by design - the entry would otherwise silently drop a near-universal feature that clears any reporting threshold.
Motor Delay Motor delay HP:0001270
Frequency omitted for the same reason as the speech phenotype: motor delay is reported in 16/18 assessed individuals (88 percent) in the Nostvik 2021 full text, but that denominator is not quotable from the cached abstract and the abstract does not name motor delay separately from global developmental delay. No evidence block by design.
Behavioral Abnormality Atypical behavior HP:0000708
Frequency omitted. Behavioural features are reported in 11 of 19 individuals and autism-spectrum features in 4/6 of those specifically assessed, per the Nostvik 2021 full text; neither denominator is quotable from the cached abstract. The broad HPO parent Atypical behavior is used deliberately because the reported behaviours are heterogeneous and no single sub-phenotype dominates. No evidence block by design.
Growth 2
Severe Short Stature and Growth Failure FREQUENT Short stature HP:0004322
Derivation: short stature in 10/17 assessed (59 percent) in the Nostvik full text, within the FREQUENT band. The severity is variable - "severe growth deficiency" in the founding family, but plain short stature or growth failure elsewhere - so the generic Short stature term is used rather than Severe short stature (HP:0003510). Note that growth was normal at birth in all three founding sisters, so this is postnatal growth failure, not intrauterine growth restriction.
Show evidence (2 references)
PMID:34713961 SUPPORT Human Clinical
"Biallelic pathogenic variants of PUS3 have been previously associated with severe intellectual disability, microcephaly, epilepsy, and short stature."
Establishes short stature as a recognised core feature of the disorder.
PMID:27055666 SUPPORT Human Clinical
"Examination revealed coarse facies but less striking compared to the sister, severe growth deficiency with borderline microcephaly"
Documents severe growth deficiency, the element of the disorder label this phenotype represents.
Failure to Thrive Failure to thrive HP:0001508
Frequency omitted. Failure to thrive is 3/3 in the founding family but is not separately enumerated from short stature in the pooled cohort, so no disease-wide band is asserted. Recorded separately from short stature because the two are distinct HPO concepts and the postnatal-onset pattern is clinically informative.
Show evidence (1 reference)
PMID:27055666 SUPPORT Human Clinical
"IV:4 is the 12-year-old sister of IV:3 who similarly presented with a history of global developmental delay, failure to thrive (birth growth parameters were normal) and severe ID."
Documents failure to thrive with explicitly normal birth growth parameters, establishing the postnatal onset.
Other 3
Grey Sclerae FREQUENT Pigmentation of the sclera HP:0007832
Derivation: 7/21 individuals in the Nostvik pooled cohort (33 percent), which sits just inside the FREQUENT band 30-79 percent. This is the one phenotype here with a directly quotable numerator and denominator. The Nostvik abstract explicitly warns that the feature is less characteristic than previously suggested, so its absence must not be used to exclude the diagnosis. The HPO term used is Pigmentation of the sclera, NOT Blue sclerae (HP:0000592) as the deep-research report suggested; blue sclerae denote the thin collagen-deficient sclerae of osteogenesis imperfecta and related connective tissue disorders, which is a mechanistically different sign from the melanocytic grey discoloration seen here.
Show evidence (2 references)
PMID:34415064 PARTIAL Human Clinical
"Gray sclera, which has previously been suggested to be a characteristic feature of PUS3-associated phenotypes, was reported in only seven individuals."
Supplies the 7/21 numerator underpinning the FREQUENT band and simultaneously qualifies the feature as non-obligatory, hence PARTIAL.
PMID:27055666 SUPPORT Human Clinical
"She has coarse facial features, bilateral strabismus, grey sclera and extensive Mongolian spots"
Documents grey sclerae in the index case of the founding family.
Extensive Dermal Melanocytosis Mongolian blue spot HP:0011369
Frequency deliberately omitted. Extensive dermal melanocytosis is documented in 3/3 individuals of the founding family but is not reported at all in the abstract of the 21-individual pooled cohort, which lists only gray sclera among pigmentary findings, nor in the 2022 Italian, 2022 Polish or 2026 Turkish reports. The honest position is that its disease-wide frequency is unknown and may be low or may reflect ascertainment in a single ancestry, so no band is asserted. This is also the feature that makes the MONDO label a named-entity-confusion hazard: extensive dermal melanocytosis with coarse facies and developmental delay is the classic presentation of GM1 gangliosidosis and the mucopolysaccharidoses, which are recorded in differential_diagnoses and which were excluded biochemically in the founding family.
Show evidence (2 references)
PMID:27055666 SUPPORT Human Clinical
"She has coarse facial features, bilateral strabismus, grey sclera and extensive Mongolian spots"
Documents extensive Mongolian spots in the index case, the observation from which the Orphanet label derives.
PMID:27055666 SUPPORT Human Clinical
"strabismus, grey sclera and widespread Mongolian spots"
Documents the same widespread distribution in a second affected sister, establishing it as a familial rather than isolated observation.
Renal Hypoplasia Renal hypoplasia HP:0000089
Frequency omitted; a single snippet-backed individual. PMID:30697592 (de Paiva et al. 2019, "PUS3 mutations are associated with intellectual disability, leukoencephalopathy, and nephropathy") independently reports nephropathy but is a Neurology Genetics clinical note with no PubMed abstract, so it appears under references only.
Show evidence (1 reference)
PMID:34713961 SUPPORT Human Clinical
"We identified a novel homozygous PUS3 frameshift variant in a child with facial dysmorphisms, growth failure, microcephaly, retinal dystrophy, cerebellar hypoplasia, congenital heart defect, and right kidney hypoplasia."
Documents right kidney hypoplasia in the expanded severe phenotype.
🧬

Genetic Associations

1
PUS3
Gene: PUS3 hgnc:25461 relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:34415064 SUPPORT Human Clinical
"Biallelic variants in PUS3 have recently been recognized as a rare cause of neurodevelopmental disorders. Pseudouridine synthase-3 encoded by PUS3 is an enzyme important for modification of various RNAs, including transfer RNA (tRNA)."
Establishes PUS3 as a recognised Mendelian disease gene and names its gene product and substrate class.
PMID:32056211 SUPPORT Human Clinical
"Our findings provide additional evidence to establish loss of PUS3 function as a cause of intellectual disability."
Independent replication in a second consanguineous population, cited by OMIM as one of the two summary sources for the disease entry.
PMID:36125428 SUPPORT Human Clinical
"Genomic mutations in the human pseudouridine synthase 3 gene (PUS3) have been identified in patients with neurodevelopmental disorders."
Confirms the gene-disease relationship from an independent group.
💊

Medical Actions

5
Antiseizure Medication
Action: anticonvulsant therapy Ontology label: Anticonvulsant Therapy NCIT:C64172
Agent: anticonvulsant agent NCIT:C264
Epilepsy is managed with standard antiseizure medication chosen by seizure type. There is no PUS3-specific drug recommendation and no evidence favouring one agent; response is variable, with some individuals achieving seizure freedom on multiple agents and others retaining breakthrough seizures.
Target Phenotypes: Seizure HP:0001250
Show evidence (1 reference)
PMID:27055666 SUPPORT Human Clinical
"There is a history of seizures at 10 months of age but she has been seizure-free on multiple antiepileptic medications."
Documents antiepileptic medication achieving seizure freedom in an affected individual.
Developmental and Rehabilitative Therapy
Action: rehabilitation Ontology label: Rehabilitation NCIT:C15315
Management is entirely supportive. Early and sustained physical, occupational and speech or augmentative-communication therapy addresses the hypotonia, motor delay and severely limited expressive language that dominate function, and physiotherapy plus orthopaedic surveillance addresses the scoliosis and contracture risk that follow from hypotonia and limited mobility.
Target Phenotypes: Generalized hypotonia HP:0001290 Global developmental delay HP:0001263 Motor delay HP:0001270 Delayed speech and language development HP:0000750 Scoliosis HP:0002650
Show evidence (1 reference)
PMID:34415064 PARTIAL Human Clinical
"The clinical picture was dominated by global developmental delay, epilepsy, hypotonia and microcephaly."
Establishes the developmental and motor targets of rehabilitation. Marked PARTIAL because the cohort study characterises the deficits rather than evaluating any rehabilitative intervention; no trial evidence for efficacy exists in this disorder.
Ophthalmological Surveillance
Action: eye examination Ontology label: Eye Examination NCIT:C38060
Baseline and periodic ophthalmological review is warranted because strabismus is common, grey sclerae are part of the diagnostic picture, and retinal dystrophy, nystagmus, optic disc pallor and abnormal visual fixation have each been reported. Untreated strabismus in a child with severe developmental delay risks amblyopia that further limits an already constrained visual and communicative repertoire. Scoped and named as surveillance to match its NCIT action term: the entry asserts case detection through formal eye examination, not any specific corrective intervention, because no strabismus or retinal treatment outcome has been reported in this disorder.
Target Phenotypes: Strabismus HP:0000486 Retinal dystrophy HP:0000556
Show evidence (2 references)
PMID:27055666 PARTIAL Human Clinical
"She has coarse facial features, bilateral strabismus, grey sclera and extensive Mongolian spots"
Documents the ocular findings that make ophthalmological surveillance appropriate. Marked PARTIAL because the paper reports the findings but does not evaluate a surveillance or treatment programme.
PMID:34713961 PARTIAL Human Clinical
"We identified a novel homozygous PUS3 frameshift variant in a child with facial dysmorphisms, growth failure, microcephaly, retinal dystrophy, cerebellar hypoplasia, congenital heart defect, and right kidney hypoplasia."
Documents retinal dystrophy, the finding that makes formal retinal assessment rather than a simple squint check appropriate. PARTIAL because it is a single case observation, not an evaluated protocol.
Genetic Counselling and Reproductive Risk Assessment
Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240
Once the biallelic PUS3 genotype is established, counselling covers the 25 percent sibling recurrence risk, carrier testing of at-risk relatives, and the availability of prenatal diagnosis and preimplantation genetic testing. This is the only intervention with a preventive rather than symptomatic role, and it is particularly relevant because many reported families are consanguineous.
Show evidence (1 reference)
PMID:41971559 SUPPORT Human Clinical
"We describe a 17-year-old girl born to second-degree consanguineous parents presenting with lifelong global developmental delay, microcephaly, gray sclera, dysmorphic features, and intellectual disability."
Documents the consanguineous family structure in which recurrence-risk counselling and carrier testing are most consequential.
Long-Term Neurological Surveillance
Action: supportive care Ontology label: Supportive Care NCIT:C15747
Because the natural history extends into adulthood and the white matter changes are stable rather than progressive, periodic rather than intensive neurological review is appropriate, with attention to emerging or evolving seizures, scoliosis and functional decline. The 2026 report makes this recommendation explicitly.
Show evidence (1 reference)
PMID:41971559 SUPPORT Human Clinical
"Her stable neurological course into late adolescence broadens the phenotypic spectrum of PUS3 deficiency and underscores the need for long-term clinical monitoring in disorders of tRNA modification."
An explicit recommendation for long-term clinical monitoring in this disorder.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from PUS3-Related Neurodevelopmental Disorder:

GM1 Gangliosidosis Type 1 MONDO:0009260
Overlapping Features The most important mimic for anyone approaching this disorder through its descriptive MONDO/Orphanet label. Infantile GM1 gangliosidosis combines congenital dermal melanocytosis (Mongolian spots), coarse facial features, developmental delay and failure to thrive - the same four-feature cluster that gives MONDO:0014886 its name. A gene-agnostic literature search on "extensive dermal melanocytosis with intellectual disability" will land on GM1 rather than on PUS3.
Distinguishing Features
  • Molecular: GLB1 beta-galactosidase deficiency versus PUS3 tRNA pseudouridine synthase deficiency. Different genes, different MONDO entities, different mechanisms entirely - lysosomal substrate storage versus a tRNA modification defect.
  • Biochemical: GM1 has a positive enzyme assay and abnormal urinary oligosaccharides/glycosaminoglycans. In PUS3 disease the entire metabolic panel is normal - urine organic acids and GAGs, tandem MS, plasma lactate and CDG screening were all negative in the founding family. The metabolic panel is the discriminator.
  • Course: infantile GM1 is a rapidly progressive neurodegenerative storage disease with hepatosplenomegaly, cherry-red spot and early death. PUS3 disease is a static encephalopathy - the white matter changes are explicitly stable and nonprogressive, individuals survive into adulthood, and there is no visceromegaly.
Show evidence (2 references)
PMID:27055666 SUPPORT Human Clinical
"Negative results include urine organic acids and GAGs, Tandem MS, plasma lactate, uric acid, lipid profile, CDG screening, and molecular karyotyping."
The negative storage-disorder workup in the founding family is precisely what separates PUS3 disease from GM1 and the mucopolysaccharidoses.
PMID:41971559 SUPPORT Human Clinical
"Her stable neurological course into late adolescence broadens the phenotypic spectrum of PUS3 deficiency and underscores the need for long-term clinical monitoring in disorders of tRNA modification."
Documents the static, non-neurodegenerative course that separates PUS3 disease from a progressive storage disorder.
PUS7-Related Neurodevelopmental Disorder MONDO:0032687
Overlapping Features The closest mechanistic relative and the sibling entry in this knowledge base. PUS7 (hgnc:26033) is another stand-alone pseudouridine synthase whose biallelic loss causes intellectual disability with microcephaly and short stature. Both disorders are described in the literature as caused by "impaired pseudouridylation", so a gene-agnostic reading of that phrase will merge them.
Distinguishing Features
  • Molecular: PUS3 (hgnc:25461) versus PUS7 (hgnc:26033). Different genes, different MONDO entities, different OMIM numbers (617051 versus 618342).
  • Substrate position: PUS3 isomerises uridine at tRNA anticodon positions 38 and 39, whereas PUS7 acts at position 13 and at position 35 of pre-tRNA-Tyr. A tRNA modification assay distinguishes them biochemically and is the cleanest functional discriminator.
  • Clinical: grey sclerae and extensive dermal melanocytosis are part of the PUS3 picture and have never been reported in PUS7 deficiency, while the PUS7 behavioural signature of very-early-onset aggression is not part of the PUS3 phenotype.
Show evidence (2 references)
PMID:27055666 SUPPORT In Vitro
"Consistent with the known role of Pus3 in isomerizing uracil to pseudouridine at positions 38 and 39 in tRNA, we found a significant reduction in this post-transcriptional modification of tRNA in patient cells."
Establishes the position-38/39 substrate specificity that biochemically separates PUS3 disease from the position-13 defect of PUS7 disease.
PMID:38996458 SUPPORT In Vitro
"Human pseudouridine synthase 3 (PUS3) catalyzes pseudouridylation of position 38/39 in tRNAs."
Confirms the PUS3-specific substrate positions from an independent structural study.
PUS1-Related Mitochondrial Myopathy and Sideroblastic Anemia Not Yet Curated MONDO:0024553
Overlapping Features The third pseudouridine synthase disease. PUS1 (hgnc:15508) is also a tRNA pseudouridylase, but its loss produces a mitochondrial muscle and marrow disease rather than a neurodevelopmental one. It is included because the shared enzyme family and shared "impaired pseudouridylation" phrasing make it a search-level confusable, and because the 2024 structural study directly contrasts PUS1 and PUS3 substrate scope.
Distinguishing Features
  • Molecular: PUS1 (hgnc:15508) versus PUS3 (hgnc:25461); PUS1 modifies both tRNA and mRNA, whereas PUS3 acts on tRNA positions 38 and 39 and has no demonstrated mRNA substrates in human cells.
  • Clinical: PUS1 disease presents with exercise intolerance, lactic acidosis and sideroblastic anaemia, without the intellectual disability, microcephaly, grey sclerae or dermal melanocytosis of PUS3 disease.
Show evidence (1 reference)
PMID:38996458 SUPPORT In Vitro
"Although PUS1-dependent sites were detectable in tRNA and mRNA, we found no evidence that human PUS3 modifies mRNAs."
Directly contrasts the substrate scope of PUS1 and PUS3 in the same experimental system, the cleanest available molecular discriminator between the two.
{ }

Source YAML

click to show 
name: PUS3-Related Neurodevelopmental Disorder
creation_date: "2026-08-01T18:40:00Z"
category: Mendelian
description: >-
  PUS3-related neurodevelopmental disorder (neurodevelopmental disorder with
  microcephaly and gray sclerae, NEDMIGS, MIM 617051; formerly autosomal recessive
  intellectual disability 55, MRT55) is an ultra-rare autosomal recessive condition
  caused by biallelic loss-of-function variants in PUS3, which encodes the
  TruA/Pus3-family tRNA pseudouridine synthase 3. The core clinical picture is
  global developmental delay with severe to profound intellectual disability and
  poor or absent speech, generalised hypotonia, microcephaly and epilepsy. A
  distinctive ocular and cutaneous pigmentary signature - grey sclerae together
  with extensive, widespread Mongolian spots (dermal melanocytosis) - was present
  in the founding Saudi family and supplied the descriptive Orphanet/MONDO label,
  but grey sclerae were subsequently found in only a minority of the pooled cohort
  and dermal melanocytosis has not been systematically re-reported, so neither
  feature is obligatory. Poor somatic growth with severe short stature or failure
  to thrive, coarse facial features, strabismus and variable brain MRI
  abnormalities (subcortical white matter signal change, atrophy or hypoplasia,
  corpus callosum dysgenesis) complete the syndrome. Mechanistically, disease
  alleles either truncate PUS3 or destabilise/aggregate the protein in cells, and
  in every functionally studied patient the result is the same: depletion of
  PUS3-dependent pseudouridine at positions 38 and 39 of the tRNA anticodon stem
  loop, with the developing brain the tissue least able to tolerate the resulting
  perturbation of translation.
notes: >-
  Named-entity-confusion guardrail and label caveat. This entry is anchored strictly
  on MONDO:0014886 / OMIM:617051 / PUS3 (hgnc:25461). The anchor was established
  BEFORE any deep research by running `runoak -i sqlite:obo:mondo info MONDO:0014886
  -O obo`, which returns no textual definition but does carry an unambiguous gene
  association line, `relationship: RO:0004003 HGNC:25461 ! PUS3`, together with
  `xref: OMIM:617051` and `xref: Orphanet:488627`. The gene was independently
  confirmed against the NCBI MedGen record for the same concept (MEDGEN:934712 /
  UMLS:C4310745), whose OMIM-sourced definition reads "Neurodevelopmental disorder
  with microcephaly and gray sclerae (NEDMIGS) ... (summary by Shaheen et al., 2016
  and Froukh et al., 2020)" - the two PUS3 papers curated here as PMID:27055666 and
  PMID:32056211.

  The MONDO/Orphanet label is descriptive, not mechanistic. "Severe growth
  deficiency-strabismus-extensive dermal melanocytosis-intellectual disability
  syndrome" is the ORDO (Orphanet:488627) preferred term and enumerates four
  features of the three affected sisters in the single founding family
  (PMID:27055666); OMIM instead names the same entity after two different features
  (microcephaly and gray sclerae). Because the ORDO label reads like a clinical
  gestalt rather than a gene-based name, and because extensive dermal melanocytosis
  plus coarse facies plus developmental delay is the classic presentation of the
  lysosomal storage disorders, this label is a high named-entity-confusion risk: a
  gene-agnostic literature search on the label alone will drift onto GM1
  gangliosidosis and the mucopolysaccharidoses/mucolipidoses. Those are recorded in
  `differential_diagnoses`. The entry `name` therefore uses the gene-anchored form
  used throughout the clinical literature ("PUS3-related disorder", "PUS3-associated
  neurodevelopmental disorders", "PUS3 deficiency"), and the full ORDO label is
  retained verbatim as the bound `disease_term.term.label` and as a synonym. Note
  that in the founding paper the sisters were explicitly negative for urine organic
  acids and GAGs, tandem MS, plasma lactate and CDG screening, which is exactly the
  workup that excludes the storage-disorder mimics.

  Deep-research provenance and NEC preflight outcome. One deep-research run was
  performed, Edison/Falcon (`just research-disorder falcon
  PUS3-Related_Neurodevelopmental_Disorder`), and it PASSED the NEC preflight: the
  report's dominant gene is PUS3, it asserts OMIM #617051 / NEDMIGS, and it did not
  drift onto any lysosomal storage disorder. It was nevertheless used only as a
  lead-generator. Its one genuinely new lead, the Fang et al. Chinese infant with
  severe epileptic encephalopathy (resolved to PMID:31444731 via the DOI it
  supplied), turned out to be a letter with no PubMed abstract and therefore carries
  no snippet-backed evidence item here; it is listed under `references:` only. The
  report's detailed per-feature denominators (ID 19/19, speech 11/11, motor delay
  16/18, hypotonia 10/13, epilepsy 13/18, microcephaly 13/18, facial dysmorphism
  17/18, short stature 10/17, scoliosis 8/10, MRI abnormal 11/15) come from the
  Nostvik 2021 full text, of which only the abstract is cached; those numbers are
  recorded in phenotype `notes` as derivation reasoning and are NOT quoted as
  evidence snippets. The report also stated it could not verify a MONDO identifier;
  that gap is closed here by the OAK lookup above.

  Two things the report asserted that are deliberately NOT carried into this entry.
  (1) It reports mitochondrial localisation of PUS3 and a possible mitochondrial
  contribution to pathogenesis; it flags this itself as "plausible but unproven",
  and the 2024 cryo-EM/Pseudo-seq study (PMID:38996458) found no evidence that human
  PUS3 modifies mRNAs, so no mitochondrial or mRNA-substrate node is asserted in the
  pathograph. (2) It suggests "Blue sclerae, HP:0000592" for grey sclerae; that term
  denotes the blue sclerae of collagen disorders such as osteogenesis imperfecta and
  is a different sign, so `HP:0007832 Pigmentation of the sclera` is used instead.

  No GeneReviews chapter exists for PUS3. This was checked with the PubMed
  E-utilities search `PUS3 GeneReviews[All Fields]`, which returns zero records, so
  the mandatory GeneReviews phenotype baseline does not apply. The largest available
  substitute baseline, the 21-individual multicentre delineation of Nostvik et al.
  2021 (PMID:34415064), was used in its place and every feature named in its
  abstract is represented in `phenotypes`.

  Orphanet epidemiology was not adopted. `just refresh-orphadata` currently fails a
  manifest checksum against upstream, no `references_cache/ORPHA_488627.md` exists,
  and the entry therefore records a qualitative `prevalence_class: ULTRA_RARE`
  backed by a published case-count quotation rather than an Orphanet prevalence
  band.

  Citation-string quirk. PubMed records the title of PMID:41971559 with a missing
  space ("Expandingthe Phenotypic Spectrum ..."). The top-level `references:` entry
  reproduces that string verbatim because the reference validator compares it
  against the cached record; the inline `reference_title:` fields use the corrected
  spacing for readability. This is an upstream PubMed typo, not a curation error.
disease_term:
  preferred_term: PUS3-related neurodevelopmental disorder (NEDMIGS)
  term:
    id: MONDO:0014886
    label: severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome
parents:
- Neurodevelopmental Disorder
- Intellectual Disability
synonyms:
- severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome
- neurodevelopmental disorder with microcephaly and gray sclerae
- NEDMIGS
- MRT55
- intellectual disability, autosomal recessive 55
- PUS3 deficiency
- PUS3-associated neurodevelopmental disorder
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      The clinical burden is overwhelmingly neurodevelopmental: global developmental
      delay, severe to profound intellectual disability, absent or poor speech,
      hypotonia, epilepsy and microcephaly. The pigmentary, growth, ocular and
      skeletal findings are additional syndromic features rather than the dominant
      morbidity.
    evidence:
    - reference: PMID:34415064
      reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The clinical picture was dominated by global developmental delay, epilepsy,
        hypotonia and microcephaly.
      explanation: >-
        The largest published cohort states directly that the phenotype is dominated
        by neurological features, supporting a neurologic chapter assignment.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A monogenic autosomal recessive Mendelian disorder recognised and diagnosed
      through exome or genome sequencing rather than through a clinical gestalt.
    evidence:
    - reference: PMID:34415064
      reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In conclusion, homozygous and compound heterozygous PUS3 variants lead to a
        rare neurodevelopmental disorder.
      explanation: >-
        States the monogenic biallelic genetic basis of the disorder.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Disease requires two damaging PUS3 alleles. Both homozygous genotypes, typically
    in consanguineous families, and compound heterozygous genotypes occur; carrier
    parents are unaffected. Recurrence risk for the sibling of an affected proband is
    25 percent, so carrier testing and genetic counselling are indicated for at-risk
    relatives.
  evidence:
  - reference: PMID:41971559
    reference_title: "Expanding the Phenotypic Spectrum of PUS3 Deficiency: A p.Tyr71Cys Case Demonstrating a Stable, Nonprogressive Leukoencephalopathy Pattern."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic pathogenic variants cause a rare autosomal recessive
      neurodevelopmental disorder characterized by intellectual disability,
      microcephaly, hypotonia, and gray sclera.
    explanation: >-
      States the autosomal recessive mode and the biallelic requirement at the PUS3
      locus.
  - reference: PMID:34415064
    reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, homozygous and compound heterozygous PUS3 variants lead to a
      rare neurodevelopmental disorder.
    explanation: >-
      Documents that both homozygous and compound heterozygous biallelic genotypes
      cause the disorder, the defining pattern of autosomal recessive inheritance.
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a multiplex consanguineous family, we applied autozygosity mapping and exome
      sequencing and identified a novel homozygous truncating mutation in PUS3 that
      fully segregates with the intellectual disability phenotype.
    explanation: >-
      Autozygosity mapping in a consanguineous multiplex family with full segregation
      of a homozygous allele is the classic demonstration of autosomal recessive
      inheritance.
prevalence:
- population: Worldwide reported literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based prevalence or incidence study exists for this disorder, and
    no Orphanet prevalence band is adopted here because the Orphadata bulk refresh is
    currently failing its manifest checksum and no ORPHA_488627 cache record exists to
    quote. The published case count is therefore the only defensible measure. The
    2021 multicentre delineation pooled 21 individuals; the 2026 Turkish case report
    states that fewer than thirty individuals have been reported in total. Cases have
    come from Saudi, Jordanian, Emirati, Brazilian, Chinese, Italian, Turkish,
    Ukrainian and other European families, so there is no established founder
    population.
  evidence:
  - reference: PMID:41971559
    reference_title: "Expanding the Phenotypic Spectrum of PUS3 Deficiency: A p.Tyr71Cys Case Demonstrating a Stable, Nonprogressive Leukoencephalopathy Pattern."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fewer than thirty individuals have been reported, including only five carrying
      the recurrent c.212A>G (p.Tyr71Cys) variant.
    explanation: >-
      Gives the cumulative worldwide published case count as of 2026, which places
      the disorder in the ultra-rare band.
  - reference: PMID:34415064
    reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we present the clinical and genetic features of 21 individuals with
      biallelic PUS3 variants: seven new and 14 previously reported individuals,
      where clinical features of two were updated.
    explanation: >-
      Supplies the intermediate published case count from the largest pooled cohort.
pathophysiology:
- name: Biallelic PUS3 Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    The disorder is initiated by inheritance of two damaging PUS3 alleles. The
    reported allelic spectrum is broad and includes nonsense alleles that truncate
    the protein (the founding p.Arg435* allele), frameshift alleles, a splice-region
    allele, an initiation-codon substitution, and missense alleles. Critically, the
    missense alleles are not a milder mechanistic class: p.Tyr71Cys retains
    essentially normal tRNA binding and catalytic activity when the purified protein
    is assayed, yet behaves as a functional null in cells, so the allelic spectrum
    converges on one outcome rather than producing a hypomorph gradient.
  genes:
  - preferred_term: PUS3
    term:
      id: hgnc:25461
      label: PUS3
  evidence:
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified a homozygous nonsense variant in PUS3; Chr11(GRCh37):g.125763823G>A;
      NM_031307.3: c.1303C>T: p.(Arg435*) that fully segregated with the phenotype in
      the family as confirmed by Sanger sequencing
    explanation: >-
      Establishes the founding biallelic protein-truncating allele as the initiating
      lesion.
  - reference: PMID:36125428
    reference_title: "Destabilization of mutated human PUS3 protein causes intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we utilize exome sequencing to identify genomic variants that lead to a
      homozygous amino acid substitution
    explanation: >-
      Documents the missense arm of the allelic spectrum, identified by exome
      sequencing in two homozygous individuals and one compound heterozygote. The
      quoted fragment stops before the HGVS allele strings because their square
      brackets are not preserved in the cached reference text.
  downstream:
  - target: Loss of PUS3 Pseudouridine Synthase Activity
    description: >-
      Truncating alleles remove the enzyme outright, while the studied missense
      alleles deplete it post-translationally, so both arms of the allelic spectrum
      converge on loss of available PUS3 activity in the cell.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36125428
      reference_title: "Destabilization of mutated human PUS3 protein causes intellectual disability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we observe that the PUS3 protein levels as well as the level of
        PUS3-dependent Ψ levels are strongly reduced in fibroblasts derived from all
        three patients.
      explanation: >-
        Directly links patient PUS3 alleles to depletion of the enzyme and of its
        catalytic product in patient-derived cells.
- name: Loss of PUS3 Pseudouridine Synthase Activity
  biological_scale: MOLECULAR
  description: >-
    PUS3 is a stand-alone, guide-RNA-independent pseudouridine synthase of the
    TruA/Pus3 family that isomerises uridine to pseudouridine in the anticodon stem
    loop of cytosolic tRNAs. Cryo-EM shows it acts as a symmetric homodimer that
    clamps the tRNA and presents the target uridine to its active site. Two distinct
    routes destroy that activity in patients: outright absence of the protein from
    truncating alleles, and post-translational depletion from missense alleles that
    impair thermostability (p.Tyr71Cys) or promote aggregation (p.Ile299Thr).
  molecular_functions:
  - preferred_term: tRNA pseudouridine synthase activity
    term:
      id: GO:0106029
      label: tRNA pseudouridine synthase activity
    modifier: DECREASED
  - preferred_term: pseudouridine synthase activity
    term:
      id: GO:0009982
      label: pseudouridine synthase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:38996458
    reference_title: "The molecular basis of tRNA selectivity by human pseudouridine synthase 3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Human pseudouridine synthase 3 (PUS3) catalyzes pseudouridylation of position
      38/39 in tRNAs.
    explanation: >-
      Identifies the enzyme and the exact catalytic reaction whose loss defines this
      node.
  - reference: PMID:38996458
    reference_title: "The molecular basis of tRNA selectivity by human pseudouridine synthase 3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we determine single-particle cryo-EM structures of PUS3 in its apo form
      and bound to three tRNAs, showing how the symmetric PUS3 homodimer recognizes
      tRNAs and positions the target uridine next to its active site.
    explanation: >-
      Supplies the structural basis for how the enzyme engages its substrate, and
      therefore what patient alleles disrupt.
  - reference: PMID:36125428
    reference_title: "Destabilization of mutated human PUS3 protein causes intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we find that the p.Tyr71Cys substitution neither affect tRNA binding nor
      pseudouridylation activity in vitro, but strongly impair the thermostability
      profile of PUS3, while the p.Ile299Thr mutation causes protein aggregation.
    explanation: >-
      Establishes protein destabilisation and aggregation, rather than direct
      catalytic impairment, as the route by which missense alleles abolish activity.
  - reference: PMID:34713961
    reference_title: "PUS3-related disorder: Report of a novel patient and delineation of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PUS3 encodes the pseudouridylate synthase 3, an enzyme catalyzing the formation
      of tRNA pseudouridine, which plays a critical role in tRNA structure, function,
      and stability.
    explanation: >-
      States the gene product's enzymatic role and why its loss matters for tRNA.
  downstream:
  - target: Depletion of tRNA Pseudouridine at Anticodon Positions 38 and 39
    description: >-
      Loss of the only enzyme that installs pseudouridine at these two positions
      leaves the corresponding uridines unmodified in patient tRNA.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27055666
      reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Consistent with the known role of Pus3 in isomerizing uracil to pseudouridine
        at positions 38 and 39 in tRNA, we found a significant reduction in this
        post-transcriptional modification of tRNA in patient cells.
      explanation: >-
        Measures the loss of the specific modification directly in patient-derived
        cells carrying the disease allele.
- name: Depletion of tRNA Pseudouridine at Anticodon Positions 38 and 39
  biological_scale: MOLECULAR
  description: >-
    Pseudouridine at positions 38 and 39 sits in the anticodon stem loop, the part of
    the tRNA that pairs with the codon. Its extra imino group provides additional
    hydrogen bonding and rigidifies the loop, so its absence is expected to
    destabilise anticodon stem loop architecture. In the founding family the deficit
    was quantified as almost exactly one missing mole of pseudouridine per mole of
    tRNA-Phe, while every other measured modification of the same tRNA was unchanged,
    establishing that the lesion is specific to the PUS3 site rather than a general
    collapse of tRNA modification.
  biological_processes:
  - preferred_term: tRNA pseudouridine synthesis
    term:
      id: GO:0031119
      label: tRNA pseudouridine synthesis
    modifier: DECREASED
  - preferred_term: tRNA modification
    term:
      id: GO:0006400
      label: tRNA modification
    modifier: DECREASED
  evidence:
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Since tRNAPhe from LCLs with the Arg435* allele of PUS3 had almost exactly 1
      mole/mole less Ψ than control LCLs, we infer that the Arg435* allele nearly
      completely knocks out PUS3 function due to truncation of the conserved domain
      and the last 45 amino acids
    explanation: >-
      Quantifies the stoichiometric loss of one pseudouridine per tRNA molecule in
      patient cells.
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      By contrast, the levels of the other modifications of tRNAPhe (Cm, Gm, m2G,
      m1A, m7G, and m5C) were all very similar in all of the LCLs including WT
    explanation: >-
      Shows the deficit is specific to the PUS3-dependent modification, excluding a
      generalised tRNA-modification failure.
  - reference: PMID:36125428
    reference_title: "Destabilization of mutated human PUS3 protein causes intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      our results directly illustrate the link between the identified PUS3 variants
      and reduced Ψ levels in the patient cells, providing a molecular explanation
      for the observed clinical phenotypes.
    explanation: >-
      Independent replication in a second patient set and with a different allele
      class, closing the loop from genotype to reduced pseudouridine.
  downstream:
  - target: Impaired Translational Fidelity and Efficiency
    description: >-
      An unmodified, less rigid anticodon stem loop is the proposed proximate cause of
      degraded decoding at the ribosome. This step is an inference from tRNA biology
      and from orthologue work rather than a direct measurement in patient neurons,
      and it is flagged as such in the discussions section.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41971559
      reference_title: "Expanding the Phenotypic Spectrum of PUS3 Deficiency: A p.Tyr71Cys Case Demonstrating a Stable, Nonprogressive Leukoencephalopathy Pattern."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        PUS3 encodes a transfer RNA (tRNA) pseudouridine synthase essential for
        translational fidelity.
      explanation: >-
        States the accepted functional role of the enzyme in translational fidelity;
        marked PARTIAL because the statement is a review assertion rather than a
        measurement of translation in patient cells.
- name: Impaired Translational Fidelity and Efficiency
  biological_scale: CELLULAR
  description: >-
    Reduced anticodon-loop pseudouridylation is expected to degrade the accuracy and
    efficiency of protein synthesis. In lower organisms loss of the orthologous
    enzyme is clearly consequential: bacterial truA mutants grow poorly and yeast
    pus3-delta mutants are slow-growing and temperature-sensitive with reduced
    frameshifting fidelity. The corresponding measurement has not been made in human
    patient neurons, so this node is the weakest link in the chain.
  biological_processes:
  - preferred_term: translation
    term:
      id: GO:0006412
      label: translation
    modifier: DECREASED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Bacterial truA mutants have significant growth defects (Chang et al. 1971; Tsui
      et al. 1991), while S. cerevisiae pus3Δ mutants are slow growing and
      temperature-sensitive
    explanation: >-
      Orthologue evidence that loss of this specific pseudouridylation is
      physiologically consequential; tagged MODEL_ORGANISM because it is bacterial
      and yeast data, not human.
  - reference: PMID:38996458
    reference_title: "The molecular basis of tRNA selectivity by human pseudouridine synthase 3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our work provides the molecular basis for PUS3-mediated tRNA modification in
      humans and explains how its tRNA modification activity is linked to
      intellectual disabilities.
    explanation: >-
      The structural study frames the disease link as running specifically through
      the tRNA modification activity.
  - reference: PMID:38996458
    reference_title: "The molecular basis of tRNA selectivity by human pseudouridine synthase 3."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      Although PUS1-dependent sites were detectable in tRNA and mRNA, we found no
      evidence that human PUS3 modifies mRNAs.
    explanation: >-
      Refutes a direct mRNA-pseudouridylation arm of the mechanism, constraining the
      pathograph to the tRNA route and excluding an mRNA-substrate node.
  downstream:
  - target: Neurodevelopmental Impairment
    description: >-
      The developing brain is disproportionately affected, which is the pattern shared
      across the tRNA-modification intellectual disability disorders and is attributed
      to a higher sensitivity of neural tissue to reduced translational efficiency.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27055666
      reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        it is possible that brain-specific phenotype reflects a higher sensitivity to
        reduced translational efficiency by the brain compared to other organs
      explanation: >-
        States the proposed reason the phenotype is brain-predominant despite wide
        tissue expression of PUS3.
- name: Neurodevelopmental Impairment
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint. Despite wide tissue expression of PUS3, the phenotype is
    largely brain-predominant: global developmental delay, severe to profound
    intellectual disability, poor or absent speech, hypotonia, epilepsy, microcephaly
    and variable structural or white-matter brain abnormalities. Growth failure,
    pigmentary and ocular features accompany the neurological core in a subset. This
    places PUS3 alongside ADAT3, WDR4, NSUN2 and FTSJ1 in the family of
    tRNA-modification intellectual disability disorders.
  biological_processes:
  - preferred_term: central nervous system development
    term:
      id: GO:0007417
      label: central nervous system development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotype we observe in the context of PUS3 deficiency is largely
      brain-specific.
    explanation: >-
      States the brain-predominant character of the clinical endpoint.
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our finding adds to a growing list of intellectual disability disorders that are
      caused by perturbation of various tRNA modifications, which highlights the
      sensitivity of the brain to these highly conserved processes.
    explanation: >-
      Places the disorder within the wider class of tRNA-modification intellectual
      disability disorders.
  - reference: PMID:34415064
    reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical picture was dominated by global developmental delay, epilepsy,
      hypotonia and microcephaly.
    explanation: >-
      Defines the composition of the neurodevelopmental endpoint across the largest
      pooled cohort.
phenotypes:
- name: Global Developmental Delay
  category: Neurologic
  description: >-
    Global developmental delay from infancy is the presenting feature in essentially
    every reported individual, affecting motor, language and cognitive domains
    together. Independent ambulation is often not achieved, or is achieved only with
    assistance.
  frequency: FREQUENT
  notes: >-
    Derivation: the Nostvik pooled cohort abstract states the clinical picture was
    "dominated by" global developmental delay, and its full text reports intellectual
    disability or global developmental delay in 19/19 assessed individuals; all three
    sisters of the founding family and the Turkish proband are additionally
    documented individually. The conservative FREQUENT band (30-79 percent) is
    assigned because the only quotable statement is the qualitative "dominated by",
    and the 19/19 denominator sits in full text that is not cached here.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:34415064
    reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical picture was dominated by global developmental delay, epilepsy,
      hypotonia and microcephaly.
    explanation: >-
      Names global developmental delay first among the dominant features of the
      pooled 21-individual cohort.
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Index (IV:3) is a 15 ½ year-old girl with a history of global developmental
      delay since infancy and failure to thrive
    explanation: >-
      Documents global developmental delay from infancy in the index case of the
      founding family.
- name: Severe Intellectual Disability
  category: Neurologic
  description: >-
    Intellectual disability is severe to profound in most reported individuals, with
    poor or absent expressive language. Formal testing in the founding family gave an
    IQ of 30 in the eldest sister and a profound range score below 20 in the youngest.
  frequency: FREQUENT
  notes: >-
    Derivation: severe in 9, moderate-to-severe in 2, moderate in 4 and unspecified in
    4 of the pooled cohort per the Nostvik full text, with measured IQ from below 20
    to 58. The severe-to-profound end therefore covers roughly half of graded cases,
    supporting FREQUENT rather than VERY_FREQUENT. Milder moderate presentations
    exist, so the severity qualifier is not universal even though intellectual
    disability itself is.
  phenotype_term:
    preferred_term: Severe intellectual disability
    term:
      id: HP:0010864
      label: Severe intellectual disability
  evidence:
  - reference: PMID:34713961
    reference_title: "PUS3-related disorder: Report of a novel patient and delineation of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic pathogenic variants of PUS3 have been previously associated with
      severe intellectual disability, microcephaly, epilepsy, and short stature.
    explanation: >-
      Summarises severe intellectual disability as an established core feature of the
      disorder.
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Current evaluation shows that she is in the severe range of ID (IQ 30).
    explanation: >-
      Formal IQ measurement placing the index case in the severe range.
- name: Microcephaly
  category: Neurologic
  description: >-
    Head circumference is reduced, usually mildly, and is not always present at birth
    - the founding sisters had normal birth growth parameters and developed
    microcephaly postnatally, with occipitofrontal circumference between -2.1 and -3.3
    standard deviations at later evaluation.
  frequency: FREQUENT
  notes: >-
    Derivation: the Nostvik full text records microcephaly in 13/18 assessed (72
    percent, FREQUENT band 30-79 percent), and the pooled-cohort abstract names
    microcephaly among the dominant features. Microcephaly is named in the OMIM
    disease title (NEDMIGS) but is explicitly mild, and one of the three founding
    sisters had only borderline microcephaly.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:34415064
    reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical picture was dominated by global developmental delay, epilepsy,
      hypotonia and microcephaly.
    explanation: >-
      Names microcephaly among the dominant features of the largest pooled cohort.
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Examination revealed coarse facies but less striking compared to the sister,
      severe growth deficiency with borderline microcephaly
    explanation: >-
      Documents microcephaly in a second affected sister and shows it can be only
      borderline.
- name: Generalized Hypotonia
  category: Neurologic
  description: >-
    Axial and appendicular hypotonia is present from infancy and is often severe
    enough to preclude independent ambulation. It is not invariably progressive; some
    individuals improve with age.
  frequency: FREQUENT
  notes: >-
    Derivation: hypotonia in 10/13 assessed (77 percent) in the Nostvik full text,
    within the FREQUENT band; the abstract names hypotonia among the dominant
    features. Three of those individuals reportedly improved, so the clinical course
    is not uniformly progressive and no clinical_course qualifier is asserted.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:34415064
    reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical picture was dominated by global developmental delay, epilepsy,
      hypotonia and microcephaly.
    explanation: >-
      Names hypotonia among the dominant features of the pooled cohort.
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Assessment at 2 years showed severe axial and appendicular hypotonia with poor
      interactions.
    explanation: >-
      Documents the axial and appendicular distribution of the hypotonia in an
      individual case.
- name: Seizures
  category: Neurologic
  description: >-
    Epilepsy affects most but not all individuals. Onset ranges from early infancy to
    adolescence and the seizure semiology is heterogeneous, including tonic,
    generalised tonic-clonic, focal, atypical absence, infantile spasms, myoclonic and
    atonic seizures. Seizure control is variable; some individuals become seizure-free
    on antiseizure medication and others do not.
  frequency: FREQUENT
  notes: >-
    Derivation: epilepsy in 13/18 assessed (72 percent) in the Nostvik full text,
    within the FREQUENT band, and named among the dominant features in the abstract.
    Explicitly not universal - the eldest founding sister had seizures at 10 months
    but the two younger sisters had none, and the Turkish proband reached age 17
    without seizures.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:34415064
    reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical picture was dominated by global developmental delay, epilepsy,
      hypotonia and microcephaly.
    explanation: >-
      Names epilepsy among the dominant features of the pooled cohort.
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is a history of seizures at 10 months of age but she has been seizure-free
      on multiple antiepileptic medications.
    explanation: >-
      Documents infantile-onset seizures and a treatment-responsive course in the
      index case.
  - reference: PMID:41971559
    reference_title: "Expanding the Phenotypic Spectrum of PUS3 Deficiency: A p.Tyr71Cys Case Demonstrating a Stable, Nonprogressive Leukoencephalopathy Pattern."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological examination revealed hyporeflexia without seizures.
    explanation: >-
      Counter-example documenting a seizure-free affected individual at 17 years,
      supporting a non-universal frequency band.
- name: Grey Sclerae
  category: Ophthalmologic
  description: >-
    Grey discoloration of the sclerae is the feature that gives the OMIM disease its
    name (neurodevelopmental disorder with microcephaly and gray sclerae). It was
    present in all three sisters of the founding family and is a genuinely useful
    diagnostic pointer, but the pooled cohort showed it is far from obligatory.
  frequency: FREQUENT
  notes: >-
    Derivation: 7/21 individuals in the Nostvik pooled cohort (33 percent), which sits
    just inside the FREQUENT band 30-79 percent. This is the one phenotype here with a
    directly quotable numerator and denominator. The Nostvik abstract explicitly warns
    that the feature is less characteristic than previously suggested, so its absence
    must not be used to exclude the diagnosis. The HPO term used is Pigmentation of
    the sclera, NOT Blue sclerae (HP:0000592) as the deep-research report suggested;
    blue sclerae denote the thin collagen-deficient sclerae of osteogenesis imperfecta
    and related connective tissue disorders, which is a mechanistically different
    sign from the melanocytic grey discoloration seen here.
  phenotype_term:
    preferred_term: Grey sclerae
    term:
      id: HP:0007832
      label: Pigmentation of the sclera
  evidence:
  - reference: PMID:34415064
    reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gray sclera, which has previously been suggested to be a characteristic feature
      of PUS3-associated phenotypes, was reported in only seven individuals.
    explanation: >-
      Supplies the 7/21 numerator underpinning the FREQUENT band and simultaneously
      qualifies the feature as non-obligatory, hence PARTIAL.
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She has coarse facial features, bilateral strabismus, grey sclera and extensive
      Mongolian spots
    explanation: >-
      Documents grey sclerae in the index case of the founding family.
- name: Extensive Dermal Melanocytosis
  category: Dermatologic
  description: >-
    Widespread, extensive Mongolian spots - congenital deep dermal melanocytosis
    extending well beyond the usual sacral distribution - were present in all three
    sisters of the founding Saudi family and supply the "extensive dermal
    melanocytosis" element of the Orphanet and MONDO label for this disorder. This is
    the single most distinctive external sign of the founding phenotype and is the
    handle by which the descriptive label can be recognised.
  notes: >-
    Frequency deliberately omitted. Extensive dermal melanocytosis is documented in
    3/3 individuals of the founding family but is not reported at all in the abstract
    of the 21-individual pooled cohort, which lists only gray sclera among pigmentary
    findings, nor in the 2022 Italian, 2022 Polish or 2026 Turkish reports. The honest
    position is that its disease-wide frequency is unknown and may be low or may
    reflect ascertainment in a single ancestry, so no band is asserted. This is also
    the feature that makes the MONDO label a named-entity-confusion hazard: extensive
    dermal melanocytosis with coarse facies and developmental delay is the classic
    presentation of GM1 gangliosidosis and the mucopolysaccharidoses, which are
    recorded in differential_diagnoses and which were excluded biochemically in the
    founding family.
  phenotype_term:
    preferred_term: Extensive Mongolian spots (dermal melanocytosis)
    term:
      id: HP:0011369
      label: Mongolian blue spot
  evidence:
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She has coarse facial features, bilateral strabismus, grey sclera and extensive
      Mongolian spots
    explanation: >-
      Documents extensive Mongolian spots in the index case, the observation from
      which the Orphanet label derives.
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      strabismus, grey sclera and widespread Mongolian spots
    explanation: >-
      Documents the same widespread distribution in a second affected sister,
      establishing it as a familial rather than isolated observation.
- name: Strabismus
  category: Ophthalmologic
  description: >-
    Strabismus, bilateral in the index case, is the third element of the descriptive
    Orphanet label and was present in all three sisters of the founding family.
  notes: >-
    Frequency omitted. Strabismus is 3/3 in the founding family but is not enumerated
    in the pooled-cohort abstract, so no defensible disease-wide band can be assigned.
    Other ocular findings reported in isolated individuals include nystagmus, optic
    disc pallor, astigmatism, abnormal visual fixation and retinal dystrophy.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She has coarse facial features, bilateral strabismus, grey sclera and extensive
      Mongolian spots
    explanation: >-
      Documents bilateral strabismus in the index case.
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had strabismus, grey sclerae and Mongolian spots.
    explanation: >-
      Documents strabismus in the third affected sister.
- name: Severe Short Stature and Growth Failure
  category: Growth
  description: >-
    Growth parameters are normal at birth and then fall away postnatally. In the
    founding family height was -4.3 to -5.9 standard deviations and weight -4.1 to
    -7.5 standard deviations, giving the "severe growth deficiency" element of the
    Orphanet label. Growth failure is also a recurrent feature outside that family.
  frequency: FREQUENT
  notes: >-
    Derivation: short stature in 10/17 assessed (59 percent) in the Nostvik full text,
    within the FREQUENT band. The severity is variable - "severe growth deficiency" in
    the founding family, but plain short stature or growth failure elsewhere - so the
    generic Short stature term is used rather than Severe short stature (HP:0003510).
    Note that growth was normal at birth in all three founding sisters, so this is
    postnatal growth failure, not intrauterine growth restriction.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:34713961
    reference_title: "PUS3-related disorder: Report of a novel patient and delineation of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic pathogenic variants of PUS3 have been previously associated with
      severe intellectual disability, microcephaly, epilepsy, and short stature.
    explanation: >-
      Establishes short stature as a recognised core feature of the disorder.
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Examination revealed coarse facies but less striking compared to the sister,
      severe growth deficiency with borderline microcephaly
    explanation: >-
      Documents severe growth deficiency, the element of the disorder label this
      phenotype represents.
- name: Failure to Thrive
  category: Growth
  description: >-
    Poor weight gain from infancy, with normal birth growth parameters, was documented
    in all three sisters of the founding family and accompanies the later short
    stature.
  notes: >-
    Frequency omitted. Failure to thrive is 3/3 in the founding family but is not
    separately enumerated from short stature in the pooled cohort, so no disease-wide
    band is asserted. Recorded separately from short stature because the two are
    distinct HPO concepts and the postnatal-onset pattern is clinically informative.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IV:4 is the 12-year-old sister of IV:3 who similarly presented with a history of
      global developmental delay, failure to thrive (birth growth parameters were
      normal) and severe ID.
    explanation: >-
      Documents failure to thrive with explicitly normal birth growth parameters,
      establishing the postnatal onset.
- name: Coarse Facial Features
  category: Craniofacial
  description: >-
    Coarse facial features were present in the founding sisters, varying in degree
    between them. Facial dysmorphism of some kind is near-universal across the wider
    cohort, but no recognisable gestalt exists, so the face supports rather than
    establishes the diagnosis.
  notes: >-
    Frequency omitted for the coarse-facies qualifier specifically. Non-specific
    facial dysmorphism is 17/18 in the Nostvik full text, but the pooled-cohort
    abstract states only that patients had "some dysmorphic facial features" without a
    recognisable gestalt, and coarse facies as such is documented only in the founding
    family. Coarse facies is clinically important here mainly because it is the
    feature that, combined with dermal melanocytosis, drives confusion with the
    lysosomal storage disorders.
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence:
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She has coarse facial features, bilateral strabismus, grey sclera and extensive
      Mongolian spots
    explanation: >-
      Documents coarse facial features in the index case.
  - reference: PMID:34415064
    reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients had some dysmorphic facial features, but a recognizable gestalt was
      not observed.
    explanation: >-
      Confirms facial dysmorphism across the cohort while explicitly denying a
      recognisable gestalt, hence PARTIAL support for a specific facial phenotype.
- name: Leukoencephalopathy
  category: Neurologic
  description: >-
    Subcortical white matter signal abnormality on T2/FLAIR is a recurrent
    neuroimaging finding, seen in the founding sisters and forming the whole
    neuroimaging phenotype of the 2026 Turkish proband. Importantly the pattern
    appears stable and non-progressive on long-term follow-up rather than
    representing a leukodystrophy, and brain MRI can also be entirely normal.
  notes: >-
    Frequency omitted. White matter abnormalities were present in 5 individuals of the
    Nostvik cohort with any MRI abnormality in 11/15, but the specific white-matter
    subset denominator is not quotable from the cached abstract. The 2019 Brazilian
    report (PMID:30697592) put leukoencephalopathy in its title but is a Neurology
    Genetics clinical note with no PubMed abstract, so it supports this phenotype only
    as a listed reference, not as a snippet-backed evidence item.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
    clinical_course: STABLE
  evidence:
  - reference: PMID:41971559
    reference_title: "Expanding the Phenotypic Spectrum of PUS3 Deficiency: A p.Tyr71Cys Case Demonstrating a Stable, Nonprogressive Leukoencephalopathy Pattern."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI demonstrated stable, nonprogressive, linear-nodular T2 hyperintense
      lesions confined to the subcortical white matter with a normal corpus callosum,
      an imaging pattern rarely associated with PUS3 deficiency.
    explanation: >-
      Documents subcortical white matter disease and, critically, its stable
      non-progressive character over long follow-up.
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there was volume loss in the frontal lobes anteriorly, and multiple T2/FLAIR
      white matter signal abnormalities in the subcortical white matter
    explanation: >-
      Independently documents subcortical T2/FLAIR white matter signal abnormality in
      the founding family.
- name: Corpus Callosum Dysgenesis
  category: Neurologic
  description: >-
    Corpus callosum dysgenesis with diffuse brain atrophy and a prominent cisterna
    magna was documented in one of the founding sisters. It is not a constant feature
    - the corpus callosum was explicitly normal in the 2026 Turkish proband - so it
    belongs to the variable structural spectrum rather than the core phenotype.
  notes: >-
    Frequency omitted; this is a single documented individual in the founding family,
    with an explicit normal-corpus-callosum counter-example in PMID:41971559.

    Term choice. The source reports "dysgenesis of corpus callosum", i.e. a
    malformed but present structure. HP:0001274 Agenesis of corpus callosum was
    used in an earlier revision and is wrong: agenesis asserts complete absence,
    which is a strictly stronger and different claim than what the paper reports.
    HP:0001273 Abnormal corpus callosum morphology, verified with OAK as
    "Abnormality of the corpus callosum", is the exact concept for dysgenesis and
    is the parent of the agenesis term, so it is both correct and appropriately
    non-committal.
  phenotype_term:
    preferred_term: Dysgenesis of the corpus callosum
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there was evidence of dysgenesis of corpus callosum, mild diffuse brain atrophy
      and a prominent cisterna magna
    explanation: >-
      Documents corpus callosum dysgenesis in an affected sister of the founding
      family.
- name: Cerebellar Hypoplasia
  category: Neurologic
  description: >-
    Cerebellar hypoplasia was reported in the Italian child whose case defined the
    severe end of the syndromic spectrum, together with retinal dystrophy, a
    congenital heart defect and renal hypoplasia.
  notes: >-
    Frequency omitted; a single reported individual at the severe end of the spectrum.
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  evidence:
  - reference: PMID:34713961
    reference_title: "PUS3-related disorder: Report of a novel patient and delineation of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a novel homozygous PUS3 frameshift variant in a child with facial
      dysmorphisms, growth failure, microcephaly, retinal dystrophy, cerebellar
      hypoplasia, congenital heart defect, and right kidney hypoplasia.
    explanation: >-
      Documents cerebellar hypoplasia as part of the expanded severe syndromic
      presentation.
- name: Retinal Dystrophy
  category: Ophthalmologic
  description: >-
    Retinal dystrophy has been reported once, in the same severely affected Italian
    child, and represents an expansion of the ocular phenotype beyond the strabismus
    and grey sclerae of the founding description.
  notes: >-
    Frequency omitted; a single reported individual. Included because it materially
    changes ophthalmological surveillance if confirmed in further cases.
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:34713961
    reference_title: "PUS3-related disorder: Report of a novel patient and delineation of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a novel homozygous PUS3 frameshift variant in a child with facial
      dysmorphisms, growth failure, microcephaly, retinal dystrophy, cerebellar
      hypoplasia, congenital heart defect, and right kidney hypoplasia.
    explanation: >-
      Documents retinal dystrophy in the expanded severe phenotype.
- name: Renal Hypoplasia
  category: Renal
  description: >-
    Unilateral kidney hypoplasia was reported in the severely affected Italian child.
    A separate Brazilian report placed nephropathy in its title, so renal involvement
    is a recurring if uncommon element of the syndrome.
  notes: >-
    Frequency omitted; a single snippet-backed individual. PMID:30697592 (de Paiva et
    al. 2019, "PUS3 mutations are associated with intellectual disability,
    leukoencephalopathy, and nephropathy") independently reports nephropathy but is a
    Neurology Genetics clinical note with no PubMed abstract, so it appears under
    references only.
  phenotype_term:
    preferred_term: Renal hypoplasia
    term:
      id: HP:0000089
      label: Renal hypoplasia
  evidence:
  - reference: PMID:34713961
    reference_title: "PUS3-related disorder: Report of a novel patient and delineation of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a novel homozygous PUS3 frameshift variant in a child with facial
      dysmorphisms, growth failure, microcephaly, retinal dystrophy, cerebellar
      hypoplasia, congenital heart defect, and right kidney hypoplasia.
    explanation: >-
      Documents right kidney hypoplasia in the expanded severe phenotype.
- name: Congenital Heart Defect
  category: Cardiovascular
  description: >-
    A congenital heart defect was reported in the severely affected Italian child,
    in the same sentence that records the retinal dystrophy, cerebellar hypoplasia
    and renal hypoplasia of that expanded phenotype. The specific cardiac lesion is
    not named in the abstract. Atrial septal defect and patent foramen ovale have
    each been noted in isolated individuals elsewhere in the literature.
  notes: >-
    Frequency omitted; a single snippet-backed individual, at the severe end of the
    spectrum.

    Term choice. The source says only "congenital heart defect" and names no
    specific lesion, so no more specific HPO term is defensible. HP:0001627 is the
    right binding rather than a mere fallback parent: OAK confirms it carries
    "Congenital heart defect" and "Congenital heart defects" as EXACT synonyms
    (alongside "Heart defect" and "Cardiac anomaly"), so the congenital semantics
    are present in the term even though its primary label reads "Abnormal heart
    morphology". Assigning a septal or valvular child term would assert a lesion the
    paper does not report.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:34713961
    reference_title: "PUS3-related disorder: Report of a novel patient and delineation of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a novel homozygous PUS3 frameshift variant in a child with facial
      dysmorphisms, growth failure, microcephaly, retinal dystrophy, cerebellar
      hypoplasia, congenital heart defect, and right kidney hypoplasia.
    explanation: >-
      Documents a congenital heart defect as part of the expanded severe syndromic
      presentation.
- name: Delayed Speech and Language Development
  category: Neurologic
  description: >-
    Speech is poor or absent in every individual for whom it has been assessed, and
    is disproportionately affected even against the background of global
    developmental delay. One child spoke first single words only at age eight.
  notes: >-
    Frequency deliberately omitted despite a very high reported rate. Speech
    impairment is documented in 11/11 assessed individuals (100 percent) in the
    Nostvik 2021 full text, which on its face maps to VERY_FREQUENT. That
    denominator sits in full text that is not cached here, and the pooled-cohort
    abstract does not mention speech at all, so there is no quotable snippet for
    either the association or the band. Per the frequency-evidence guidelines the
    band is omitted rather than asserted from an unquotable source, and the
    derivation is recorded here instead. This phenotype therefore carries no
    evidence block by design - the entry would otherwise silently drop a
    near-universal feature that clears any reporting threshold.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
- name: Motor Delay
  category: Neurologic
  description: >-
    Gross and fine motor milestones are delayed, and many individuals never achieve
    independent ambulation or achieve it only with assistance. Motor delay is closely
    tied to the generalised hypotonia and is part of the global developmental delay
    rather than a separable regression.
  notes: >-
    Frequency omitted for the same reason as the speech phenotype: motor delay is
    reported in 16/18 assessed individuals (88 percent) in the Nostvik 2021 full
    text, but that denominator is not quotable from the cached abstract and the
    abstract does not name motor delay separately from global developmental delay.
    No evidence block by design.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
- name: Scoliosis
  category: Skeletal
  description: >-
    Scoliosis, ranging from mild to severe, is a frequent finding and is the main
    reason orthopaedic surveillance belongs in the management plan. Whether it is a
    primary skeletal feature or secondary to hypotonia, neurological impairment and
    limited mobility is unresolved.
  notes: >-
    Frequency omitted. Scoliosis is reported in 8/10 assessed individuals (80
    percent) in the Nostvik 2021 full text, the highest rate of any non-core feature,
    but the denominator is not quotable from the cached abstract and scoliosis is not
    mentioned in the abstract at all, so no snippet-backed evidence item is possible
    and no band is asserted. Recorded as a phenotype rather than left buried in
    treatment prose because at that rate it is a real, surveillance-relevant feature
    of the disorder. No evidence block by design.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
- name: Behavioral Abnormality
  category: Behavioral
  description: >-
    Behavioural disturbance is common and heterogeneous, reported as anxiety,
    attention disorder or aggression; autistic features have been noted in a subset
    of those formally assessed. There is no single characteristic behavioural
    signature, which distinguishes this disorder from the very-early-onset aggression
    that characterises PUS7 deficiency.
  notes: >-
    Frequency omitted. Behavioural features are reported in 11 of 19 individuals and
    autism-spectrum features in 4/6 of those specifically assessed, per the Nostvik
    2021 full text; neither denominator is quotable from the cached abstract. The
    broad HPO parent Atypical behavior is used deliberately because the reported
    behaviours are heterogeneous and no single sub-phenotype dominates. No evidence
    block by design.
  phenotype_term:
    preferred_term: Behavioral abnormality
    term:
      id: HP:0000708
      label: Atypical behavior
genetic:
- name: PUS3
  gene_term:
    preferred_term: PUS3
    term:
      id: hgnc:25461
      label: PUS3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    PUS3 (11q24.2, gene MIM 616283) encodes a 481-amino-acid, guide-RNA-independent
    pseudouridine synthase of the TruA/Pus3 family that isomerises uridine to
    pseudouridine at positions 38 and 39 of the tRNA anticodon stem loop. The
    orthologous enzyme acts at U38/U39/U40 in bacteria (TruA), at U38 and U39 in
    S. cerevisiae, and preferentially at U39 in mouse. The reference transcript used
    in the clinical literature is NM_031307.

    Gene identity was verified against the MONDO gene-association relation
    (`RO:0004003 HGNC:25461 ! PUS3`) and against the HGNC record `hgnc:25461`, whose
    definition "pseudouridine synthase 3" cites PMID:27055666. This is deliberately
    distinct from the family members PUS1 (hgnc:15508), which causes myopathy with
    lactic acidosis and sideroblastic anaemia, and PUS7 (hgnc:26033), which causes a
    separate intellectual disability syndrome already curated in this knowledge base;
    see differential_diagnoses. Note also that MIM 616283 is the PUS3 GENE entry
    whereas MIM 617051 is the DISEASE entry that MONDO:0014886 cross-references.

    Reported allelic spectrum comprises roughly 17 distinct variants across the
    published cohort: eight missense, seven protein-truncating (three nonsense, two
    single-base deletions, two single-base duplications), one splice-region variant
    and one initiation-codon substitution. Both homozygous and compound heterozygous
    genotypes occur in approximately equal numbers.
  evidence:
  - reference: PMID:34415064
    reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic variants in PUS3 have recently been recognized as a rare cause of
      neurodevelopmental disorders. Pseudouridine synthase-3 encoded by PUS3 is an
      enzyme important for modification of various RNAs, including transfer RNA
      (tRNA).
    explanation: >-
      Establishes PUS3 as a recognised Mendelian disease gene and names its gene
      product and substrate class.
  - reference: PMID:32056211
    reference_title: "Genetic basis of neurodevelopmental disorders in 103 Jordanian families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings provide additional evidence to establish loss of PUS3 function as a
      cause of intellectual disability.
    explanation: >-
      Independent replication in a second consanguineous population, cited by OMIM as
      one of the two summary sources for the disease entry.
  - reference: PMID:36125428
    reference_title: "Destabilization of mutated human PUS3 protein causes intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genomic mutations in the human pseudouridine synthase 3 gene (PUS3) have been
      identified in patients with neurodevelopmental disorders.
    explanation: >-
      Confirms the gene-disease relationship from an independent group.
  variants:
  - name: c.1303C>T (p.Arg435*)
    type: NONSENSE
    clinical_significance: PATHOGENIC
    description: >-
      The founding allele, homozygous in three affected Saudi sisters. It truncates
      the final 46 residues plus the end of a conserved region and behaves as a
      near-complete null in patient lymphoblastoid cells.
    evidence:
    - reference: PMID:27055666
      reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we identified a homozygous nonsense variant in PUS3; Chr11(GRCh37):g.125763823G>A;
        NM_031307.3: c.1303C>T: p.(Arg435*) that fully segregated with the phenotype in
        the family as confirmed by Sanger sequencing
      explanation: >-
        Names the allele, its genomic and cDNA coordinates, and its full segregation
        with disease.
    - reference: PMID:27055666
      reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This variant is absent in 1,500 Saudi exomes as well as in the ExAC Browser.
      explanation: >-
        Population-frequency evidence supporting pathogenicity.
  - name: c.212A>G (p.Tyr71Cys)
    type: MISSENSE
    clinical_significance: LIKELY_PATHOGENIC
    description: >-
      A recurrent missense allele, found homozygous or in trans with p.Ile299Thr, and
      carried by five of the fewer than thirty reported individuals. Mechanistically
      instructive: the purified protein retains normal tRNA binding and
      pseudouridylation activity, but its thermostability is strongly impaired and it
      is nearly absent from patient fibroblasts, so it is a functional null despite
      normal in vitro catalysis.
    evidence:
    - reference: PMID:36125428
      reference_title: "Destabilization of mutated human PUS3 protein causes intellectual disability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we find that the p.Tyr71Cys substitution neither affect tRNA binding nor
        pseudouridylation activity in vitro, but strongly impair the thermostability
        profile of PUS3, while the p.Ile299Thr mutation causes protein aggregation.
      explanation: >-
        Establishes the destabilisation mechanism that makes this missense allele a
        functional null.
    - reference: PMID:41971559
      reference_title: "Expanding the Phenotypic Spectrum of PUS3 Deficiency: A p.Tyr71Cys Case Demonstrating a Stable, Nonprogressive Leukoencephalopathy Pattern."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Whole-exome sequencing identified a homozygous PUS3 c.212A>G (p.Tyr71Cys)
        variant, classified as likely pathogenic based on ACMG criteria (PM2, PM3, PP3,
        PP5).
      explanation: >-
        Supplies the ACMG classification and confirms recurrence of the allele in an
        unrelated population.
  - name: c.896T>C (p.Ile299Thr)
    type: MISSENSE
    clinical_significance: LIKELY_PATHOGENIC
    description: >-
      Found in trans with p.Tyr71Cys in a compound heterozygous patient. Unlike
      p.Tyr71Cys it acts by promoting aggregation of the recombinant protein, a second
      distinct route to loss of available enzyme.
    evidence:
    - reference: PMID:36125428
      reference_title: "Destabilization of mutated human PUS3 protein causes intellectual disability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we find that the p.Tyr71Cys substitution neither affect tRNA binding nor
        pseudouridylation activity in vitro, but strongly impair the thermostability
        profile of PUS3, while the p.Ile299Thr mutation causes protein aggregation.
      explanation: >-
        Names the aggregation mechanism specific to this allele.
diagnosis:
- name: Molecular diagnosis by exome or genome sequencing
  description: >-
    There is no pathognomonic clinical gestalt, so molecular testing establishes the
    diagnosis. Trio exome or genome sequencing, or a comprehensive intellectual
    disability / epilepsy panel that includes PUS3, is the appropriate route, followed
    by parental segregation testing to confirm that the two alleles are in trans.
    Grey sclerae and extensive dermal melanocytosis can raise suspicion but their
    absence does not exclude the diagnosis.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:41971559
    reference_title: "Expanding the Phenotypic Spectrum of PUS3 Deficiency: A p.Tyr71Cys Case Demonstrating a Stable, Nonprogressive Leukoencephalopathy Pattern."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing identified a homozygous PUS3 c.212A>G (p.Tyr71Cys)
      variant, classified as likely pathogenic based on ACMG criteria (PM2, PM3, PP3,
      PP5).
    explanation: >-
      Documents whole-exome sequencing as the diagnostic method actually used, with
      ACMG-based variant classification.
  - reference: PMID:34415064
    reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals were characterized by the local clinicians and the gene variants
      were identified by next generation sequencing (NGS) based methodologies.
    explanation: >-
      Confirms next-generation sequencing as the diagnostic route across the whole
      published cohort.
  - reference: PMID:34415064
    reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients had some dysmorphic facial features, but a recognizable gestalt was
      not observed.
    explanation: >-
      Supports the claim that molecular testing rather than clinical recognition
      establishes the diagnosis.
- name: tRNA pseudouridine assay for variant interpretation
  description: >-
    Measuring PUS3-dependent pseudouridine in patient-derived cells is the direct
    functional readout of the enzyme defect and is the assay that resolves a PUS3
    variant of uncertain significance. It is essential for missense alleles, because
    p.Tyr71Cys demonstrates that a variant can look catalytically normal in a purified
    enzyme assay while being a functional null in the cell - so protein-level and
    pseudouridine-level measurement in patient cells, not in vitro catalysis, is the
    informative test. This remains a research-level assay rather than routine
    diagnostics.
  diagnosis_term:
    preferred_term: molecular analysis
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:36125428
    reference_title: "Destabilization of mutated human PUS3 protein causes intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we observe that the PUS3 protein levels as well as the level of PUS3-dependent Ψ
      levels are strongly reduced in fibroblasts derived from all three patients.
    explanation: >-
      Establishes reduced PUS3 protein and pseudouridine in patient fibroblasts as the
      functional readout the assay measures.
  - reference: PMID:36125428
    reference_title: "Destabilization of mutated human PUS3 protein causes intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we find that the p.Tyr71Cys substitution neither affect tRNA binding nor
      pseudouridylation activity in vitro, but strongly impair the thermostability
      profile of PUS3
    explanation: >-
      Demonstrates why an in vitro catalytic assay alone is insufficient for variant
      interpretation and cell-based measurement is required.
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consistent with the known role of Pus3 in isomerizing uracil to pseudouridine at
      positions 38 and 39 in tRNA, we found a significant reduction in this
      post-transcriptional modification of tRNA in patient cells.
    explanation: >-
      The original demonstration of the assay applied to patient-derived cells.
- name: Metabolic screening to exclude storage-disorder mimics
  description: >-
    Because extensive dermal melanocytosis with coarse facies and developmental delay
    is the classic presentation of GM1 gangliosidosis and the
    mucopolysaccharidoses/mucolipidoses, the diagnostic workup should include urine
    glycosaminoglycans and organic acids, tandem mass spectrometry, plasma lactate and
    congenital disorders of glycosylation screening. In the founding family all of
    these were negative, and that negative panel is what separated this disorder from
    the storage mimics before the gene was known.
  notes: >-
    Term choice. An earlier revision bound this to NCIT:C19770 Molecular Analysis,
    which is wrong: urine glycosaminoglycans and organic acids, tandem mass
    spectrometry and plasma lactate are biochemical assays on body fluids, not
    molecular-genetic analysis. NCIT:C25294 Laboratory Procedure, verified with OAK
    as "Any procedure that involves testing or manipulating a sample of blood,
    urine, or other body substance in a laboratory setting", is the correct action
    term. The genuinely molecular assay in this entry - the tRNA pseudouridine
    measurement - correctly keeps NCIT:C19770.
  diagnosis_term:
    preferred_term: biochemical laboratory screening
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Negative results include urine organic acids and GAGs, Tandem MS, plasma lactate,
      uric acid, lipid profile, CDG screening, and molecular karyotyping.
    explanation: >-
      Documents the exact exclusionary metabolic panel performed in the founding
      family and its negative result.
- name: Brain MRI
  description: >-
    Brain MRI is informative but neither sensitive nor specific. Findings range from
    entirely normal through subcortical white matter T2/FLAIR signal change, frontal
    volume loss, ventriculomegaly, arachnoid cysts and corpus callosum dysgenesis to
    cerebellar hypoplasia. A normal MRI does not exclude the diagnosis, and where
    white matter change is present it appears stable rather than progressive, which
    argues against a leukodystrophy.
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:41971559
    reference_title: "Expanding the Phenotypic Spectrum of PUS3 Deficiency: A p.Tyr71Cys Case Demonstrating a Stable, Nonprogressive Leukoencephalopathy Pattern."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI demonstrated stable, nonprogressive, linear-nodular T2 hyperintense
      lesions confined to the subcortical white matter with a normal corpus callosum,
      an imaging pattern rarely associated with PUS3 deficiency.
    explanation: >-
      Documents both the white-matter pattern and the explicit statement that it is
      only rarely associated with the disorder, supporting low specificity.
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI at 2 years was unremarkable apart from small arachnoid cyst seen along
      the anterolateral surface of the left cerebellar hemisphere in the posterior
      fossa.
    explanation: >-
      Shows that an affected individual can have essentially unremarkable imaging,
      supporting the low sensitivity of MRI.
treatments:
- name: Antiseizure Medication
  description: >-
    Epilepsy is managed with standard antiseizure medication chosen by seizure type.
    There is no PUS3-specific drug recommendation and no evidence favouring one agent;
    response is variable, with some individuals achieving seizure freedom on multiple
    agents and others retaining breakthrough seizures.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: anticonvulsant therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
    therapeutic_agent:
    - preferred_term: anticonvulsant agent
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is a history of seizures at 10 months of age but she has been seizure-free
      on multiple antiepileptic medications.
    explanation: >-
      Documents antiepileptic medication achieving seizure freedom in an affected
      individual.
- name: Developmental and Rehabilitative Therapy
  description: >-
    Management is entirely supportive. Early and sustained physical, occupational and
    speech or augmentative-communication therapy addresses the hypotonia, motor delay
    and severely limited expressive language that dominate function, and physiotherapy
    plus orthopaedic surveillance addresses the scoliosis and contracture risk that
    follow from hypotonia and limited mobility.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  target_phenotypes:
  - preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:34415064
    reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical picture was dominated by global developmental delay, epilepsy,
      hypotonia and microcephaly.
    explanation: >-
      Establishes the developmental and motor targets of rehabilitation. Marked PARTIAL
      because the cohort study characterises the deficits rather than evaluating any
      rehabilitative intervention; no trial evidence for efficacy exists in this
      disorder.
- name: Ophthalmological Surveillance
  description: >-
    Baseline and periodic ophthalmological review is warranted because strabismus is
    common, grey sclerae are part of the diagnostic picture, and retinal dystrophy,
    nystagmus, optic disc pallor and abnormal visual fixation have each been reported.
    Untreated strabismus in a child with severe developmental delay risks amblyopia
    that further limits an already constrained visual and communicative repertoire.
    Scoped and named as surveillance to match its NCIT action term: the entry asserts
    case detection through formal eye examination, not any specific corrective
    intervention, because no strabismus or retinal treatment outcome has been reported
    in this disorder.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: eye examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  target_phenotypes:
  - preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  - preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She has coarse facial features, bilateral strabismus, grey sclera and extensive
      Mongolian spots
    explanation: >-
      Documents the ocular findings that make ophthalmological surveillance
      appropriate. Marked PARTIAL because the paper reports the findings but does not
      evaluate a surveillance or treatment programme.
  - reference: PMID:34713961
    reference_title: "PUS3-related disorder: Report of a novel patient and delineation of the phenotypic spectrum."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a novel homozygous PUS3 frameshift variant in a child with facial
      dysmorphisms, growth failure, microcephaly, retinal dystrophy, cerebellar
      hypoplasia, congenital heart defect, and right kidney hypoplasia.
    explanation: >-
      Documents retinal dystrophy, the finding that makes formal retinal assessment
      rather than a simple squint check appropriate. PARTIAL because it is a single
      case observation, not an evaluated protocol.
- name: Genetic Counselling and Reproductive Risk Assessment
  description: >-
    Once the biallelic PUS3 genotype is established, counselling covers the 25 percent
    sibling recurrence risk, carrier testing of at-risk relatives, and the availability
    of prenatal diagnosis and preimplantation genetic testing. This is the only
    intervention with a preventive rather than symptomatic role, and it is
    particularly relevant because many reported families are consanguineous.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:41971559
    reference_title: "Expanding the Phenotypic Spectrum of PUS3 Deficiency: A p.Tyr71Cys Case Demonstrating a Stable, Nonprogressive Leukoencephalopathy Pattern."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a 17-year-old girl born to second-degree consanguineous parents
      presenting with lifelong global developmental delay, microcephaly, gray sclera,
      dysmorphic features, and intellectual disability.
    explanation: >-
      Documents the consanguineous family structure in which recurrence-risk
      counselling and carrier testing are most consequential.
- name: Long-Term Neurological Surveillance
  description: >-
    Because the natural history extends into adulthood and the white matter changes
    are stable rather than progressive, periodic rather than intensive neurological
    review is appropriate, with attention to emerging or evolving seizures, scoliosis
    and functional decline. The 2026 report makes this recommendation explicitly.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:41971559
    reference_title: "Expanding the Phenotypic Spectrum of PUS3 Deficiency: A p.Tyr71Cys Case Demonstrating a Stable, Nonprogressive Leukoencephalopathy Pattern."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her stable neurological course into late adolescence broadens the phenotypic
      spectrum of PUS3 deficiency and underscores the need for long-term clinical
      monitoring in disorders of tRNA modification.
    explanation: >-
      An explicit recommendation for long-term clinical monitoring in this disorder.
differential_diagnoses:
- name: GM1 Gangliosidosis Type 1
  disease_term:
    preferred_term: GM1 gangliosidosis type 1
    term:
      id: MONDO:0009260
      label: GM1 gangliosidosis type 1
  description: >-
    The most important mimic for anyone approaching this disorder through its
    descriptive MONDO/Orphanet label. Infantile GM1 gangliosidosis combines congenital
    dermal melanocytosis (Mongolian spots), coarse facial features, developmental
    delay and failure to thrive - the same four-feature cluster that gives
    MONDO:0014886 its name. A gene-agnostic literature search on "extensive dermal
    melanocytosis with intellectual disability" will land on GM1 rather than on PUS3.
  distinguishing_features:
  - >-
    Molecular: GLB1 beta-galactosidase deficiency versus PUS3 tRNA pseudouridine
    synthase deficiency. Different genes, different MONDO entities, different
    mechanisms entirely - lysosomal substrate storage versus a tRNA modification
    defect.
  - >-
    Biochemical: GM1 has a positive enzyme assay and abnormal urinary
    oligosaccharides/glycosaminoglycans. In PUS3 disease the entire metabolic panel is
    normal - urine organic acids and GAGs, tandem MS, plasma lactate and CDG screening
    were all negative in the founding family. The metabolic panel is the discriminator.
  - >-
    Course: infantile GM1 is a rapidly progressive neurodegenerative storage disease
    with hepatosplenomegaly, cherry-red spot and early death. PUS3 disease is a static
    encephalopathy - the white matter changes are explicitly stable and nonprogressive,
    individuals survive into adulthood, and there is no visceromegaly.
  evidence:
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Negative results include urine organic acids and GAGs, Tandem MS, plasma lactate,
      uric acid, lipid profile, CDG screening, and molecular karyotyping.
    explanation: >-
      The negative storage-disorder workup in the founding family is precisely what
      separates PUS3 disease from GM1 and the mucopolysaccharidoses.
  - reference: PMID:41971559
    reference_title: "Expanding the Phenotypic Spectrum of PUS3 Deficiency: A p.Tyr71Cys Case Demonstrating a Stable, Nonprogressive Leukoencephalopathy Pattern."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her stable neurological course into late adolescence broadens the phenotypic
      spectrum of PUS3 deficiency and underscores the need for long-term clinical
      monitoring in disorders of tRNA modification.
    explanation: >-
      Documents the static, non-neurodegenerative course that separates PUS3 disease
      from a progressive storage disorder.
- name: PUS7-Related Neurodevelopmental Disorder
  disease_term:
    preferred_term: PUS7-related neurodevelopmental disorder (IDDABS)
    term:
      id: MONDO:0032687
      label: intellectual developmental disorder with abnormal behavior, microcephaly, and short stature
  description: >-
    The closest mechanistic relative and the sibling entry in this knowledge base.
    PUS7 (hgnc:26033) is another stand-alone pseudouridine synthase whose biallelic
    loss causes intellectual disability with microcephaly and short stature. Both
    disorders are described in the literature as caused by "impaired
    pseudouridylation", so a gene-agnostic reading of that phrase will merge them.
  distinguishing_features:
  - >-
    Molecular: PUS3 (hgnc:25461) versus PUS7 (hgnc:26033). Different genes, different
    MONDO entities, different OMIM numbers (617051 versus 618342).
  - >-
    Substrate position: PUS3 isomerises uridine at tRNA anticodon positions 38 and 39,
    whereas PUS7 acts at position 13 and at position 35 of pre-tRNA-Tyr. A tRNA
    modification assay distinguishes them biochemically and is the cleanest functional
    discriminator.
  - >-
    Clinical: grey sclerae and extensive dermal melanocytosis are part of the PUS3
    picture and have never been reported in PUS7 deficiency, while the PUS7
    behavioural signature of very-early-onset aggression is not part of the PUS3
    phenotype.
  evidence:
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consistent with the known role of Pus3 in isomerizing uracil to pseudouridine at
      positions 38 and 39 in tRNA, we found a significant reduction in this
      post-transcriptional modification of tRNA in patient cells.
    explanation: >-
      Establishes the position-38/39 substrate specificity that biochemically separates
      PUS3 disease from the position-13 defect of PUS7 disease.
  - reference: PMID:38996458
    reference_title: "The molecular basis of tRNA selectivity by human pseudouridine synthase 3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Human pseudouridine synthase 3 (PUS3) catalyzes pseudouridylation of position
      38/39 in tRNAs.
    explanation: >-
      Confirms the PUS3-specific substrate positions from an independent structural
      study.
- name: PUS1-Related Mitochondrial Myopathy and Sideroblastic Anemia
  disease_term:
    preferred_term: myopathy, lactic acidosis, and sideroblastic anemia 1
    term:
      id: MONDO:0024553
      label: myopathy, lactic acidosis, and sideroblastic anemia 1
  description: >-
    The third pseudouridine synthase disease. PUS1 (hgnc:15508) is also a tRNA
    pseudouridylase, but its loss produces a mitochondrial muscle and marrow disease
    rather than a neurodevelopmental one. It is included because the shared enzyme
    family and shared "impaired pseudouridylation" phrasing make it a search-level
    confusable, and because the 2024 structural study directly contrasts PUS1 and PUS3
    substrate scope.
  distinguishing_features:
  - >-
    Molecular: PUS1 (hgnc:15508) versus PUS3 (hgnc:25461); PUS1 modifies both tRNA and
    mRNA, whereas PUS3 acts on tRNA positions 38 and 39 and has no demonstrated mRNA
    substrates in human cells.
  - >-
    Clinical: PUS1 disease presents with exercise intolerance, lactic acidosis and
    sideroblastic anaemia, without the intellectual disability, microcephaly, grey
    sclerae or dermal melanocytosis of PUS3 disease.
  evidence:
  - reference: PMID:38996458
    reference_title: "The molecular basis of tRNA selectivity by human pseudouridine synthase 3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Although PUS1-dependent sites were detectable in tRNA and mRNA, we found no
      evidence that human PUS3 modifies mRNAs.
    explanation: >-
      Directly contrasts the substrate scope of PUS1 and PUS3 in the same experimental
      system, the cleanest available molecular discriminator between the two.
discussions:
- discussion_id: pus3_translation_step_unmeasured
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does loss of pseudouridine at tRNA positions 38 and 39 actually degrade
    translational fidelity or efficiency in human neural cells, and if so which
    transcripts or codons are most affected?
  attaches_to:
  - pathophysiology#Impaired Translational Fidelity and Efficiency
  rationale: >-
    This is the weakest link in the causal chain. Every step from the PUS3 genotype to
    depleted pseudouridine at positions 38 and 39 has been measured directly in patient
    cells by two independent groups. The step from there to impaired translation is
    inferred from tRNA structural chemistry and from bacterial truA and yeast pus3
    orthologue phenotypes, and the step from impaired translation to selective
    vulnerability of the developing brain is inferred from the pattern shared across
    the tRNA-modification intellectual disability disorders. No ribosome profiling,
    proteomics or reporter-fidelity measurement has been reported in a human
    PUS3-deficient neural cell. Until that measurement exists, the mechanistic
    explanation for why a housekeeping tRNA modification produces a brain-predominant
    phenotype remains a hypothesis rather than a finding.
  proposed_experiments:
  - experiment_id: exp_pus3_ribosome_profiling_neurons
    name: Ribosome profiling and proteomics in patient iPSC-derived neurons
    description: >-
      Perform ribosome profiling and quantitative proteomics in patient-derived iPSC
      neural progenitors and neurons versus isogenic corrected controls, testing for
      codon-specific ribosome pausing at codons decoded by the tRNAs that normally
      carry pseudouridine at positions 38 and 39.
  - experiment_id: exp_pus3_fidelity_reporters
    name: Translational fidelity reporter assays in patient cells
    description: >-
      Use dual-luciferase or fluorescent reporter assays of frameshifting and
      stop-codon readthrough in patient fibroblasts and iPSC-derived neurons, the
      human counterpart of the reduced minus-one frameshifting reported in yeast pus3
      mutants.
  - experiment_id: exp_pus3_cerebral_organoids
    name: Cerebral organoid model of PUS3 deficiency
    description: >-
      Differentiate cerebral organoids from patient and isogenic corrected iPSC lines
      and assess progenitor proliferation and cortical layer formation, to test
      whether the microcephaly and developmental delay are reproducible in a human
      neural model.
  evidence:
  - reference: PMID:34415064
    reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further functional studies are necessary to understand involvement of PUS3 and
      tRNA biogenesis in normal and abnormal brain development.
    explanation: >-
      The largest cohort study states explicitly that the mechanistic link from PUS3 to
      brain development remains unresolved.
- discussion_id: pus3_dermal_melanocytosis_generalisability
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is extensive dermal melanocytosis a real, mechanistically meaningful feature of
    PUS3 deficiency, or an ancestry-linked incidental finding in the single founding
    family that has been fossilised into the Orphanet and MONDO label?
  attaches_to:
  - phenotypes#Extensive Dermal Melanocytosis
  rationale: >-
    Extensive Mongolian spots appear in all three sisters of the founding Saudi family
    and are prominent enough to have named the disorder in Orphanet and MONDO. Yet the
    feature is absent from the abstract of the 21-individual pooled cohort, which
    enumerates gray sclera among pigmentary findings but not dermal melanocytosis, and
    it is not mentioned in the Italian, Polish or Turkish reports. Congenital dermal
    melanocytosis is also common in the general population of several ancestries,
    including the one the founding family belongs to, which makes a coincidental
    co-occurrence within one consanguineous sibship entirely plausible. Two things
    hinge on the answer. If the association is real, then PUS3 loss must perturb
    dermal melanocyte migration or retention and the pathograph is missing a node. If
    it is not, the MONDO label is actively misleading and steers curators and
    clinicians towards the lysosomal storage disorders. Grey sclerae, which is
    plausibly the ocular counterpart of the same melanocytic process, went from
    "characteristic" to 7/21 once a real cohort was assembled - the same deflation may
    await dermal melanocytosis.
  proposed_experiments:
  - experiment_id: exp_pus3_melanocytosis_rephenotyping
    name: Standardised re-phenotyping of the published cohort for dermal melanocytosis
    description: >-
      Systematically re-phenotype the existing molecularly confirmed cohort for dermal
      melanocytosis using standardised photographic documentation and HPO coding, with
      the extent and distribution recorded rather than a simple present/absent flag.
  - experiment_id: exp_pus3_melanocytosis_ancestry_control
    name: Ancestry-matched control comparison for dermal melanocytosis
    description: >-
      Compare dermal melanocytosis prevalence and extent between PUS3-affected
      individuals and ancestry-matched unaffected relatives or population controls,
      which is the only design that can separate a genuine disease association from an
      ancestry-linked background rate.
  - experiment_id: exp_pus3_melanocyte_biology
    name: PUS3 function in dermal melanocytes
    description: >-
      Assess PUS3 expression and pseudouridine levels in dermal melanocytes, and
      melanocyte migration in a PUS3-depleted model, to test whether a plausible
      cellular mechanism for the pigmentary phenotype exists at all.
  evidence:
  - reference: PMID:34415064
    reference_title: "Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gray sclera, which has previously been suggested to be a characteristic feature
      of PUS3-associated phenotypes, was reported in only seven individuals.
    explanation: >-
      Demonstrates the precedent: a pigmentary feature considered characteristic from
      early reports deflated to a minority finding once a real cohort was assembled,
      which is the concern raised for dermal melanocytosis.
  - reference: PMID:27055666
    reference_title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She has coarse facial features, bilateral strabismus, grey sclera and extensive
      Mongolian spots
    explanation: >-
      The single-family observation on which the whole Orphanet label rests, and
      therefore the observation whose generalisability is in question.
references:
- reference: PMID:27055666
  title: A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition.
- reference: PMID:34415064
  title: Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders.
- reference: PMID:36125428
  title: Destabilization of mutated human PUS3 protein causes intellectual disability.
- reference: PMID:38996458
  title: The molecular basis of tRNA selectivity by human pseudouridine synthase 3.
- reference: PMID:34713961
  title: "PUS3-related disorder: Report of a novel patient and delineation of the phenotypic spectrum."
- reference: PMID:41971559
  title: "Expandingthe Phenotypic Spectrum of PUS3 Deficiency: A p.Tyr71Cys Case Demonstrating a Stable, Nonprogressive Leukoencephalopathy Pattern."
- reference: PMID:32056211
  title: Genetic basis of neurodevelopmental disorders in 103 Jordanian families.
- reference: PMID:30697592
  title: "PUS3 mutations are associated with intellectual disability, leukoencephalopathy, and nephropathy."
- reference: PMID:30308082
  title: A null variant in PUS3 confirms its involvement in intellectual disability and further delineates the associated neurodevelopmental disease.
- reference: PMID:31444731
  title: Compound heterozygous mutations in PUS3 gene identified in a Chinese infant with severe epileptic encephalopathy and multiple malformations.
📚

References & Deep Research

References

10
PMID:27055666
A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition.
No top-level findings curated for this source.
PMID:34415064
Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders.
No top-level findings curated for this source.
PMID:36125428
Destabilization of mutated human PUS3 protein causes intellectual disability.
No top-level findings curated for this source.
PMID:38996458
The molecular basis of tRNA selectivity by human pseudouridine synthase 3.
No top-level findings curated for this source.
PMID:34713961
PUS3-related disorder: Report of a novel patient and delineation of the phenotypic spectrum.
No top-level findings curated for this source.
PMID:41971559
Expandingthe Phenotypic Spectrum of PUS3 Deficiency: A p.Tyr71Cys Case Demonstrating a Stable, Nonprogressive Leukoencephalopathy Pattern.
No top-level findings curated for this source.
PMID:32056211
Genetic basis of neurodevelopmental disorders in 103 Jordanian families.
No top-level findings curated for this source.
PMID:30697592
PUS3 mutations are associated with intellectual disability, leukoencephalopathy, and nephropathy.
No top-level findings curated for this source.
PMID:30308082
A null variant in PUS3 confirms its involvement in intellectual disability and further delineates the associated neurodevelopmental disease.
No top-level findings curated for this source.
PMID:31444731
Compound heterozygous mutations in PUS3 gene identified in a Chinese infant with severe epileptic encephalopathy and multiple malformations.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
PUS3-Related Neurodevelopmental Disorder: Disease-Characteristics Report
Edison Scientific Literature 15 citations 2026-08-01T18:30:42.988906

PUS3-Related Neurodevelopmental Disorder: Disease-Characteristics Report

Executive summary

PUS3-related neurodevelopmental disorder is an ultra-rare autosomal-recessive Mendelian condition caused by biallelic pathogenic or likely pathogenic variants in PUS3, which encodes pseudouridine synthase 3. The established phenotype comprises developmental delay/intellectual disability, severe speech impairment, motor delay, hypotonia, epilepsy, microcephaly, variable brain MRI abnormalities, growth restriction, scoliosis, behavioral abnormalities, and nonspecific facial dysmorphism. The OMIM name is neurodevelopmental disorder with microcephaly and gray sclera (NEDMIGS), OMIM #617051, although gray sclera occurs in only a minority and should not be required for diagnosis. The largest disease-specific synthesis included 21 individuals from 15 families; thus, frequencies below are provisional and vulnerable to ascertainment and missing-data bias. (nøstvik2021clinicalandmolecular pages 2-3, nøstvik2021clinicalandmolecular pages 1-2)

The strongest mechanistic evidence comes from patient fibroblasts and recombinant-protein experiments. PUS3 normally installs pseudouridine at positions 38–39 in the tRNA anticodon loop. The recurrent p.Tyr71Cys substitution retained near-normal catalytic activity in purified-protein assays but destabilized the protein in cells, whereas p.Ile299Thr promoted aggregation. Both were associated with markedly reduced PUS3 protein and PUS3-dependent tRNA pseudouridylation in patient fibroblasts. (lin2022destabilizationofmutated pages 13-13, lin2022destabilizationofmutated pages 2-3, lin2022destabilizationofmutated pages 1-2)

No disease-specific therapy, validated biomarker, natural-history study, prevalence estimate, management guideline, or relevant registered interventional trial was identified. Current practice is molecular diagnosis, individualized symptomatic treatment, developmental rehabilitation, surveillance, and genetic counseling.

Domain Best current finding Quantitative detail Evidence type/strength
Disease identity PUS3-related neurodevelopmental disorder is the same entity referred to in OMIM as NEDMIGS: neurodevelopmental disorder with microcephaly and gray sclera (OMIM #617051); gray sclera is not consistently present 21 reported individuals from 15 families in the main aggregate cohort; gray/blue sclera in 7 individuals overall Human clinical aggregate cohort; strongest disease-level summary currently available (nøstvik2021clinicalandmolecular pages 2-3, nøstvik2021clinicalandmolecular pages 1-2)
Gene and inheritance Caused by biallelic PUS3 variants; autosomal recessive pattern supported by homozygous and compound-heterozygous cases with unaffected parents 10/21 homozygous; 11/21 compound heterozygous Human genetic evidence from multiple families; strong (nøstvik2021clinicalandmolecular pages 3-5, lin2022destabilizationofmutated pages 7-8)
Cohort size/demographics Largest delineation collected published and new cases internationally Age at evaluation 8 months-44 years; median 13 years; no sex difference Human clinical cohort; moderate-strong for phenotype frequencies, limited by retrospective aggregation (nøstvik2021clinicalandmolecular pages 2-3)
Core neurodevelopmental phenotype Disorder is dominated by intellectual disability/global developmental delay, speech impairment, motor delay, hypotonia, microcephaly, and facial dysmorphism ID 19/19 (100% among assessed); impaired speech 11/11 (100%); motor delay 16/18 (88%); hypotonia 10/13 (77%); microcephaly/anencephaly 13/18 (72%); facial dysmorphism 17/18 (94%) Human clinical aggregate evidence; strong for recurrent features, but denominators vary by reported assessment (nøstvik2021clinicalandmolecular pages 1-2, nøstvik2021clinicalandmolecular pages 2-3)
Epilepsy Epilepsy is common but variable in onset, seizure type, and treatment response 13/18 (72%); onset 1.5 months-18 years, median 22.5 months; 3/7 with available data achieved seizure freedom on treatment; EEG documented in 9, epileptiform discharges in 3 Human clinical evidence; moderate due to incomplete ascertainment and heterogeneous follow-up (nøstvik2021clinicalandmolecular pages 2-3)
Neuroimaging and ancillary findings Brain MRI may be normal or abnormal; common reported abnormalities include atrophy/hypoplasia and white-matter changes; growth/skeletal/behavioral issues are frequent MRI abnormal 11/15 (73%), normal 4/15; short stature 10/17 (59%); scoliosis 8/10 (80%); behavioral features in 11/19; autism features in 4/6 assessed Human clinical aggregate evidence; moderate (nøstvik2021clinicalandmolecular pages 3-5, nøstvik2021clinicalandmolecular pages 2-3)
Severe infant presentation One reported Chinese infant had a severe epileptic encephalopathy/malformation presentation that broadens severity spectrum Male infant, 8 months; compound heterozygous c.55C>T (p.Arg19*) and c.620dupT (p.Thr208fs); MRI with dilated cisterna magna and bilateral frontotemporal extracerebral space; metabolic screens normal Single-patient case report; useful for edge phenotype, lower generalizability (fang2020compoundheterozygousmutations pages 1-3)
Variant spectrum Broad allelic heterogeneity with missense and loss-of-function alleles; several recurrent variants exist 17 distinct PUS3 variants in 21 individuals: 8 missense, 7 protein-truncating, 1 splice, 1 initiation-codon substitution Human aggregate genetics; strong descriptive evidence (nøstvik2021clinicalandmolecular pages 3-5, nøstvik2021clinicalandmolecular pages 5-6)
Direct functional mechanism Pathogenic variants can reduce PUS3 function by destabilizing or aggregating the protein, causing depletion of cellular PUS3 and reduced PUS3-dependent pseudouridylation in patient fibroblasts despite near-normal in vitro catalytic behavior for Y71C In 3 patients, p.Tyr71Cys and p.Ile299Thr were linked to strongly reduced PUS3 protein and reduced PUS3-dependent Ψ levels in fibroblasts; Y71C preserved in vitro tRNA binding/activity but impaired thermostability; I299T promoted aggregation Patient fibroblasts + recombinant protein assays; strongest direct mechanistic evidence available (lin2022destabilizationofmutated pages 13-13, lin2022destabilizationofmutated pages 2-3, lin2022destabilizationofmutated pages 10-10, lin2022destabilizationofmutated pages 1-2)
Molecular function/pathophysiology PUS3 is a TruA/Pus3-family pseudouridine synthase that modifies tRNA anticodon-loop uridines (positions 38-39); deficiency likely impairs tRNA stabilization/biogenesis and downstream translation important for brain development; mitochondrial contribution remains plausible but unproven PUS3 modifies U38/U39 of tRNA; localized in cytoplasm and mitochondria according to disease review/case synthesis Integrated human genetics + biochemical inference; moderate, with some steps still inferential (nøstvik2021clinicalandmolecular pages 1-2, nøstvik2021clinicalandmolecular pages 3-5)
Diagnosis Diagnosis currently depends on molecular testing rather than a pathognomonic clinical signature Identified by exome sequencing, whole-genome sequencing, or virtual gene panels; parental testing performed in reported families Human real-world diagnostic implementation; strong for current practice (nøstvik2021clinicalandmolecular pages 1-2, nøstvik2021clinicalandmolecular pages 2-3)
Treatment and real-world management No disease-specific therapy exists; care is supportive and symptom-directed, especially antiseizure therapy and rehabilitation In the severe infant case, sodium valproate gave incomplete control with seizures about every 3 months; in the pooled cohort, seizure control was variable and 3/7 achieved seizure freedom Human case-based management evidence only; weak for treatment efficacy (fang2020compoundheterozygousmutations pages 1-3, nøstvik2021clinicalandmolecular pages 2-3)
Trials and translational pipeline No relevant interventional clinical trials were identified for PUS3-related disorder 0 relevant PUS3-specific trials found in tool search Trial search evidence; strong for current absence of registered disease-specific trials in searched sources (tool search result summarized in conversation; no context ID available for citation, so omitted from citation field)
Major evidence gaps No robust prevalence/incidence estimates, natural-history cohorts, validated biomarkers, genotype-specific management guidelines, or established disease animal models were identified; newer 2023-2024 literature is mostly broad RNA-modification review rather than disease-specific clinical advance Epidemiology unknown; no disease-modifying therapy; no validated single-cell/spatial/multi-omics disease datasets identified in reviewed evidence Evidence-gap synthesis from available human/mechanistic literature; moderate confidence in absence from searched sources (nøstvik2021clinicalandmolecular pages 2-3, nøstvik2021clinicalandmolecular pages 3-5, nøstvik2021clinicalandmolecular pages 1-2)

Table: This table summarizes the strongest currently available evidence for PUS3-related neurodevelopmental disorder across identity, genetics, phenotype, mechanism, diagnosis, treatment, and gaps. It is useful as a compact knowledge-base scaffold because the literature is sparse and distributed across a few key reports.

1. Disease information

Definition and nomenclature

The preferred descriptive name is PUS3-related neurodevelopmental disorder or PUS3-associated neurodevelopmental disorder. Synonyms include:

  • Neurodevelopmental disorder with microcephaly and gray sclera
  • NEDMIGS
  • PUS3-related intellectual disability
  • Autosomal-recessive intellectual disability due to PUS3 deficiency

The 2021 aggregate study states directly: “Biallelic variants in PUS3 have recently been recognized as a rare cause of neurodevelopmental disorders.” It also concluded that “homozygous and compound heterozygous PUS3 variants lead to a rare neurodevelopmental disorder.” (nøstvik2021clinicalandmolecular pages 1-2)

Identifiers

  • OMIM: #617051, NEDMIGS.
  • Causal gene: PUS3; reference transcript used by the principal cohort was NM_031307.4 and protein NP_112597.4. (lin2022destabilizationofmutated pages 2-3, nøstvik2021clinicalandmolecular pages 2-3)
  • MONDO: A disease-specific MONDO identifier could not be verified from the retrieved authoritative evidence; use an exact MONDO term only after direct MONDO validation.
  • Orphanet: No dedicated identifier was established in the retrieved literature.
  • ICD-10/ICD-11/MeSH: No PUS3-specific code or heading was identified. In clinical systems, manifestations may be coded under developmental disorder/intellectual disability, epilepsy, microcephaly, or genetic syndrome categories rather than a disease-specific code.

Evidence provenance

The evidence is primarily aggregated disease-level literature assembled from individually evaluated patients, not an EHR-derived population dataset. The largest study combined seven new and 14 previously reported individuals; local clinicians performed phenotyping, and genetic findings came from clinical or research next-generation sequencing. Some data arose through routine clinical care, whereas other cases were recruited through collaborations and GeneMatcher. (nøstvik2021clinicalandmolecular pages 1-2, nøstvik2021clinicalandmolecular pages 2-3)

2. Etiology, risk, and protective factors

Causal factor

The primary and currently sufficient cause is biallelic germline PUS3 dysfunction. Both homozygous and compound-heterozygous genotypes occur, establishing autosomal-recessive inheritance. In the 21-person cohort, 10 individuals were homozygous and 11 were compound heterozygous. (nøstvik2021clinicalandmolecular pages 3-5)

The pathogenic mechanism is predominantly loss of effective PUS3 function through truncation, altered initiation/splicing, protein destabilization, or aggregation. Direct cellular evidence shows that some missense alleles can behave as loss-of-function variants through protein instability even when purified enzyme activity appears preserved. (lin2022destabilizationofmutated pages 2-3, lin2022destabilizationofmutated pages 1-2)

Genetic risk factors

  • Two pathogenic/likely pathogenic alleles in trans constitute the principal risk.
  • Consanguinity can increase the probability of homozygous disease alleles, as expected for an autosomal-recessive disorder, but it is not required because compound-heterozygous patients are common.
  • A recurrent c.212A>G, p.Tyr71Cys allele was reported at approximately 0.0001 in Europeans in gnomAD; the 2021 cohort found all disease-associated variants absent or extremely rare and none homozygous in gnomAD. (lin2022destabilizationofmutated pages 13-13, nøstvik2021clinicalandmolecular pages 3-5)
  • No validated modifier gene, susceptibility locus, protective allele, founder effect, or penetrance-reducing allele has been demonstrated.

Environmental, lifestyle, infectious, and protective factors

No environmental toxin, infection, diet, activity pattern, parental age effect, or lifestyle exposure is known to cause or materially modify PUS3-related disorder. Fever triggered seizures in one severely affected infant, but this represents a seizure precipitant rather than disease causation. No genetic or environmental protective factors have been established. (fang2020compoundheterozygousmutations pages 1-3)

There is no demonstrated gene–environment interaction. The report of anencephaly in four affected fetuses was explicitly interpreted cautiously because other genetic or environmental contributors could not be excluded. (nøstvik2021clinicalandmolecular pages 2-3)

3. Phenotypes

The following frequencies derive mainly from the heterogeneous 21-person cohort and use the number actually assessed as denominator. They should not be treated as population prevalence estimates. (nøstvik2021clinicalandmolecular pages 1-2, nøstvik2021clinicalandmolecular pages 2-3)

Neurodevelopment and behavior

  • Intellectual disability/global developmental delay: 19/19 assessed (100%). Severity was severe in 9, moderate–severe in 2, moderate in 4, and unspecified in 4; measured IQ in seven ranged from <20 to 58. Suggested HPO: Intellectual disability, HP:0001249; Global developmental delay, HP:0001263. (nøstvik2021clinicalandmolecular pages 3-5, nøstvik2021clinicalandmolecular pages 2-3)
  • Speech impairment: 11/11 documented (100%), often severe; one child spoke first single words at age eight. Suggested HPO: Delayed speech and language development, HP:0000750; absent or severely limited speech where applicable. (lin2022destabilizationofmutated pages 7-8, nøstvik2021clinicalandmolecular pages 1-2)
  • Motor delay: 16/18 (88%). Suggested HPO: Motor delay, HP:0001270. (nøstvik2021clinicalandmolecular pages 2-3)
  • Behavioral abnormalities: anxiety, attention disorder, or aggression in 11 individuals; autism-spectrum features in 4/6 specifically assessed. Suggested HPO: Abnormality of behavior, HP:0000708, Autistic behavior, HP:0000729, anxiety, attention deficit, and aggressive behavior terms. These findings affect education, social participation, supervision needs, and family burden, although no formal EQ-5D, SF-36, PROMIS, or caregiver-burden study exists. (nøstvik2021clinicalandmolecular pages 3-5)

Neurologic features

  • Hypotonia: 10/13 (77%); three patients reportedly improved, indicating that hypotonia need not be relentlessly progressive. One individual had upper-extremity hypertonia. Suggested HPO: Hypotonia, HP:0001252. (nøstvik2021clinicalandmolecular pages 3-5, nøstvik2021clinicalandmolecular pages 1-2)
  • Epilepsy: 13/18 (72%). Onset ranged from 1.5 months to 18 years, with reported median 22.5 months. Tonic, generalized tonic-clonic, focal, atypical absence, infantile spasms, myoclonic, and atonic seizures occurred. Frequency ranged from multiple daily events to monthly seizures. Suggested HPO: Seizure, HP:0001250, with seizure-subtype terms assigned patient by patient. (nøstvik2021clinicalandmolecular pages 2-3)
  • EEG: Nine had documented EEGs; three showed epileptiform discharges, including multifocal abnormalities or generalized spike-and-slow-wave activity. A severely affected infant had slow background rhythm. (fang2020compoundheterozygousmutations pages 1-3, nøstvik2021clinicalandmolecular pages 2-3)
  • Microcephaly: 12 individuals had head circumference at or below the third percentile; the aggregate microcephaly/anencephaly count was 13/18 (72%). Suggested HPO: Microcephaly, HP:0000252. Four fetuses classified as one study individual had anencephaly, but causation by PUS3 alone remains uncertain. (nøstvik2021clinicalandmolecular pages 2-3)

Imaging, growth, skeletal, ocular, and other findings

  • Brain MRI abnormality: 11/15 (73%), versus four normal scans. Hypoplasia or atrophy occurred in seven and white-matter abnormalities in five. Other isolated findings included dilated cisterna magna and enlarged frontotemporal extracerebral spaces. Normal MRI does not exclude the disorder. Suggested HPO: cerebral atrophy, white-matter abnormality, and mega cisterna magna terms as appropriate. (fang2020compoundheterozygousmutations pages 1-3, nøstvik2021clinicalandmolecular pages 2-3)
  • Short stature: 10/17 (59%); eight had height at or below the third percentile. Suggested HPO: Short stature, HP:0004322. (nøstvik2021clinicalandmolecular pages 2-3)
  • Scoliosis: 8/10 (80%), ranging from mild to severe. Whether primary or secondary to hypotonia, neurologic impairment, and immobility is unresolved. Suggested HPO: Scoliosis, HP:0002650. (nøstvik2021clinicalandmolecular pages 2-3)
  • Facial dysmorphism: 17/18 (94%), but without a recognizable gestalt. Suggested HPO: Abnormal facial shape, HP:0001999, followed by patient-specific features such as depressed nasal bridge or micrognathia. (fang2020compoundheterozygousmutations pages 1-3, nøstvik2021clinicalandmolecular pages 2-3)
  • Gray/blue sclera: only seven individuals overall, making it neither sensitive nor obligatory despite inclusion in NEDMIGS. Suggested HPO: Blue sclerae, HP:0000592. (nøstvik2021clinicalandmolecular pages 2-3, nøstvik2021clinicalandmolecular pages 1-2)
  • Reported additional findings include nystagmus, optic-disc pallor, astigmatism, hearing loss, excessive drooling, incontinence, atrial septal defect, patent foramen ovale, delayed bone age, and nephropathy in isolated reports. Evidence is insufficient to define their disease-wide frequencies. (fang2020compoundheterozygousmutations pages 1-3, lin2022destabilizationofmutated pages 7-8, nøstvik2021clinicalandmolecular pages 5-6)

4. Genetic and molecular information

Gene and protein

PUS3 encodes a highly conserved, 481-amino-acid TruA/Pus3-family pseudouridine synthase. It is reported in cytoplasmic and mitochondrial compartments and modifies tRNA anticodon-loop uridines, particularly positions 38 and 39. (nøstvik2021clinicalandmolecular pages 1-2)

Suggested annotations include:

  • Gene: PUS3; verify current HGNC identifier directly in HGNC before database loading.
  • GO molecular function: pseudouridine synthase activity; RNA binding; tRNA binding.
  • GO biological process: tRNA pseudouridine synthesis, tRNA modification, tRNA stabilization, translation.
  • GO cellular component: cytoplasm and mitochondrion, noting that disease-specific compartmental effects remain incompletely tested.

Variant spectrum

The 2021 series contained 17 distinct variants: eight missense, seven protein-truncating variants—three nonsense, two single-base deletions, and two single-base duplications—one splice-region variant, and one initiation-codon substitution. Eight families carried at least one null allele; seven families carried two missense alleles. (nøstvik2021clinicalandmolecular pages 3-5)

Documented examples include:

  • c.1303C>T, p.Arg435Ter, homozygous, foundational Saudi-family truncating allele.
  • c.55C>T, p.Arg19Ter and c.620dupT, p.Thr208AsnfsTer14, compound heterozygous in a severely affected Chinese infant. (fang2020compoundheterozygousmutations pages 1-3)
  • c.212A>G, p.Tyr71Cys, homozygous or in trans with c.896T>C, p.Ile299Thr. (lin2022destabilizationofmutated pages 13-13, lin2022destabilizationofmutated pages 2-3)
  • Additional reported alleles include p.Tyr160Ter, p.Arg280Ter, p.Arg193Gln, p.Leu21Arg, p.Cys190Tyr, p.Val279Phe, p.Leu366Pro, and p.Ser394CysfsTer18. (nøstvik2021clinicalandmolecular pages 3-5, nøstvik2021clinicalandmolecular pages 5-6)

Variants are germline. No disease-causing somatic PUS3 mechanism, chromosomal rearrangement, aneuploidy, repeat expansion, or mitochondrial-DNA variant has been established. ACMG/AMP classifications should be assigned per variant and laboratory evidence; the cohort used ACMG/AMP interpretation, gnomAD, CADD, SpliceAI, segregation testing, and HGVS nomenclature. (nøstvik2021clinicalandmolecular pages 2-3)

Functional consequences

For p.Tyr71Cys, purified PUS3 showed similar tRNA binding and pseudouridylation to wild type, but reduced thermostability and near-complete depletion in patient fibroblasts. p.Ile299Thr promoted aggregation. Patient cells had markedly reduced PUS3-dependent pseudouridine, providing direct functional support for loss of effective enzyme activity. Structural modeling placed residues 71–88 and 227–238 in predicted tRNA-binding finger loops analogous to bacterial TruA. (lin2022destabilizationofmutated pages 10-10, lin2022destabilizationofmutated pages 2-3, lin2022destabilizationofmutated pages 7-8, lin2022destabilizationofmutated pages 1-2)

No validated modifier genes, disease-associated methylation signature, chromatin abnormality, or recurrent large PUS3-containing copy-number alteration was identified.

5. Environmental information

PUS3-related disorder is genetic, not infectious, toxic, occupational, nutritional, or lifestyle-mediated. No smoking, alcohol, exercise, diet, pollution, radiation, or infectious-agent relationship has been demonstrated. Standard healthy-lifestyle measures remain appropriate for general health but are not primary prevention of the molecular disorder.

6. Mechanism and pathophysiology

Supported causal chain

  1. Upstream trigger: biallelic pathogenic PUS3 variants.
  2. Protein-level defect: absent/truncated protein or missense-induced instability/aggregation.
  3. Biochemical defect: deficient PUS3-mediated conversion of uridine to pseudouridine in tRNA, especially anticodon-loop U38/U39.
  4. RNA-level consequence: impaired tRNA stabilization, maturation/biogenesis, anticodon-loop function, and translational efficiency or accuracy.
  5. Cellular consequence: altered protein synthesis and cellular homeostasis during development; mitochondrial dysfunction has been proposed because PUS3 is also localized to mitochondria, but it has not been directly demonstrated in disease cells.
  6. Tissue consequence: disproportionate impairment of developing nervous-system function, producing developmental delay, intellectual disability, epilepsy, hypotonia, microcephaly, and variable structural brain abnormalities. (lin2022destabilizationofmutated pages 2-3, nøstvik2021clinicalandmolecular pages 3-5, nøstvik2021clinicalandmolecular pages 1-2)

The 2021 paper concluded that biallelic variants likely cause “inefficient post-transcriptional modification of tRNA resulting in an impaired tRNA biogenesis,” followed by abnormal brain development. The 2022 study provided the missing direct bridge by showing reduced PUS3 protein and pseudouridine in patient cells. (lin2022destabilizationofmutated pages 1-2, nøstvik2021clinicalandmolecular pages 3-5)

What remains inferential

No PUS3-specific evidence establishes activation of Wnt, MAPK, mTOR, PI3K–AKT, apoptosis, autophagy, inflammation, oxidative stress, fibrosis, or immune pathways. Likewise, no disease-specific metabolomic, lipidomic, proteomic, transcriptomic, single-cell, spatial-transcriptomic, organoid, or integrated multi-omic signature has been validated. Human mRNA targets of PUS3 were explicitly described as still requiring investigation. (lin2022destabilizationofmutated pages 13-14)

Suggested GO processes include tRNA pseudouridylation, tRNA modification, RNA stabilization, translation, nervous-system development, and cognition. Candidate cell-type annotations should be conservative: neuron (CL:0000540) and neural progenitor cell are biologically plausible, but no patient single-cell study identifies a selectively vulnerable cell population.

7. Anatomical structures affected

The central nervous system is primary. Suggested anatomy terms include brain (UBERON:0000955), cerebral cortex, cerebral white matter, and cerebellum only when supported by individual imaging. The abnormalities can be diffuse or region-specific, and no consistent lateralization is reported. (nøstvik2021clinicalandmolecular pages 2-3)

Secondary systems may include skeletal muscle/tone regulation, axial skeleton, growth, eye, hearing, and—rarely—heart or kidney. Evidence does not establish a single primary non-neural target organ. At the subcellular level, the relevant compartments are cytoplasm and mitochondria; the direct biochemical substrate is tRNA. (nøstvik2021clinicalandmolecular pages 1-2, fang2020compoundheterozygousmutations pages 1-3, nøstvik2021clinicalandmolecular pages 5-6)

8. Temporal development

The disorder is congenital in molecular origin, with clinical recognition usually in infancy or childhood through delayed milestones, hypotonia, growth abnormalities, microcephaly, or seizures. Epilepsy onset is highly variable, from 1.5 months to 18 years. (nøstvik2021clinicalandmolecular pages 2-3)

The available age range—8 months to 44 years—shows survival into adulthood but is insufficient for life-expectancy estimates. Developmental disability is chronic and likely lifelong. Hypotonia improved in three patients, whereas developmental gains may continue slowly; there is no evidence of remission of the underlying disorder. White-matter abnormalities or atrophy do not yet establish a progressive neurodegenerative course. (nøstvik2021clinicalandmolecular pages 3-5, nøstvik2021clinicalandmolecular pages 2-3)

No validated disease stages, progression rate, critical therapeutic window, or longitudinal natural-history trajectory exists.

9. Inheritance and population

Inheritance is autosomal recessive. For two heterozygous carrier parents, standard Mendelian counseling gives a 25% affected, 50% carrier, and 25% non-carrier probability for each pregnancy, assuming both familial alleles are confirmed and no unusual mechanism intervenes.

Penetrance among individuals with clearly deleterious biallelic variants appears high, but the dataset is too small and clinically ascertained to quantify penetrance. Expressivity is variable, ranging from moderate intellectual disability to severe epileptic encephalopathy with multiple anomalies. Anticipation is not expected and has not been reported. Germline mosaicism has not been documented but cannot be excluded in apparently de novo situations.

No incidence or prevalence per 100,000 is available. At least 21 individuals from 15 families were synthesized in 2021, but this is a literature count, not epidemiology. Ages ranged from 8 months to 44 years, with no observed sex difference. Cases originated from multiple geographic and ancestral backgrounds, including Saudi, Ukrainian/European, Chinese, and other international families; no robust ethnic risk or founder distribution is established. (nøstvik2021clinicalandmolecular pages 2-3)

10. Diagnostics

Clinical suspicion

Consider PUS3 testing in unexplained developmental delay/intellectual disability—especially severe speech delay—with any combination of epilepsy, hypotonia, microcephaly, short stature, scoliosis, behavioral abnormalities, or nonspecific dysmorphism. Gray sclera can support suspicion but its absence is not exclusionary. Normal MRI and a non-epileptiform routine EEG also do not exclude the condition. (lin2022destabilizationofmutated pages 7-8, nøstvik2021clinicalandmolecular pages 1-2, nøstvik2021clinicalandmolecular pages 2-3)

Recommended molecular approach

  1. Trio exome or genome sequencing is the most efficient approach because the phenotype is nonspecific and genetically heterogeneous.
  2. A comprehensive neurodevelopmental-disorder/intellectual-disability/epilepsy panel should include PUS3 and detect single-nucleotide and small insertion/deletion variants.
  3. Confirm candidate variants by an orthogonal method where required and perform parental segregation/phasing to establish biallelic inheritance in trans.
  4. Ensure copy-number calling or deletion/duplication analysis if only one pathogenic allele is found.
  5. RNA studies may clarify suspected splice variants; patient fibroblast protein or pseudouridine assays remain research-level functional tests rather than routine diagnostics.

The principal cohort used exome sequencing, whole-genome sequencing, or virtual gene panels, followed by family testing. (nøstvik2021clinicalandmolecular pages 2-3)

CMA can detect alternative diagnoses and large deletions but will miss most PUS3 sequence variants. Karyotype, FISH, mitochondrial DNA analysis, and repeat-expansion assays are not disease-specific tests. No blood metabolite, enzyme assay, biopsy, proteomic, epigenomic, or liquid-biopsy biomarker is validated; one severe infant had normal blood and urine metabolic screening. (fang2020compoundheterozygousmutations pages 1-3)

Differential diagnosis

The differential includes other tRNA-modification and RNA-processing disorders, PUS7-related neurodevelopmental disorder, PUS1-associated MLASA, aminoacyl-tRNA synthetase disorders, mitochondrial disease, developmental and epileptic encephalopathies, pontocerebellar hypoplasias, and syndromic microcephaly. Distinction requires molecular testing because the clinical gestalt is not specific.

11. Outcome and prognosis

No survival curves, mortality rate, life-expectancy estimate, or five-/ten-year outcome data exist. Survival to age 44 years was represented in the aggregate cohort, but this does not establish normal longevity. (nøstvik2021clinicalandmolecular pages 2-3)

Long-term morbidity is principally neurodevelopmental: intellectual disability, limited communication, epilepsy, motor impairment, behavioral difficulties, scoliosis, and dependence in activities of daily living. Some individuals require continence support and intensive rehabilitation. Formal quality-of-life instruments have not been reported. (lin2022destabilizationofmutated pages 7-8, nøstvik2021clinicalandmolecular pages 3-5)

Seizure outcome is variable: only 3/7 individuals with available treatment-response data achieved seizure freedom. Prognostic biomarkers and reliable genotype–phenotype rules are unavailable. Null alleles and very early epileptic encephalopathy may indicate greater severity, but available numbers do not justify a definitive prediction. (fang2020compoundheterozygousmutations pages 1-3, nøstvik2021clinicalandmolecular pages 2-3)

12. Treatment

No therapy corrects PUS3 deficiency or restores tRNA pseudouridylation in patients. No gene replacement, gene editing, RNA therapy, cell therapy, targeted small molecule, or immunotherapy has entered disease-specific clinical testing.

Current management is multidisciplinary and symptom-directed:

  • Epilepsy: antiseizure medication selected by seizure type and standard pediatric/adult epilepsy practice; EEG follow-up when clinically indicated. Sodium valproate produced incomplete control in one infant, while aggregate response varied and 3/7 became seizure-free. This is insufficient to recommend one preferred drug. Suggested NCIT concepts: anticonvulsant therapy and seizure management. (fang2020compoundheterozygousmutations pages 1-3, nøstvik2021clinicalandmolecular pages 2-3)
  • Development: early physical, occupational, speech/language, augmentative-communication, behavioral, and educational intervention. One reported child received intensive rehabilitation. Suggested NCIT concepts: physical therapy, occupational therapy, speech therapy, rehabilitation therapy. (lin2022destabilizationofmutated pages 7-8)
  • Nutrition/growth: monitor feeding, weight, stature, and bone health; intervene for dysphagia or inadequate intake.
  • Musculoskeletal: serial examination for scoliosis and contractures, with physiotherapy, orthotics, and orthopedic referral as needed.
  • Vision/hearing: baseline and symptom-driven ophthalmologic and audiologic assessment.
  • Cardiac/renal: evaluate when clinically indicated rather than assuming universal involvement.
  • Behavior/sleep: standard neurodevelopmental behavioral assessment and individualized interventions.

No PUS3-specific pharmacogenomic recommendation or treatment-response rate exists beyond sparse case data.

13. Prevention

Primary prevention by lifestyle change, vaccination, toxin avoidance, or prophylactic medication is not applicable. The principal preventive strategy is genetic counseling and reproductive risk assessment.

Once familial variants are known, options include carrier testing of adult relatives, cascade testing, prenatal diagnosis, and preimplantation genetic testing for monogenic disease. Early molecular diagnosis is secondary prevention in the sense that it can prompt epilepsy surveillance, developmental therapy, hearing/vision assessment, and scoliosis monitoring before avoidable complications accumulate. Tertiary prevention consists of seizure control, mobility support, communication intervention, nutritional management, and orthopedic surveillance.

Population newborn screening is not available or justified by current evidence. Routine population carrier screening has not been established; targeted testing is most appropriate in known families.

14. Other species and natural disease

PUS3/TruA-family enzymes are evolutionarily conserved across bacteria, yeast, plants, invertebrates, and mammals. Comparative proteins referenced in structural analyses include mouse Pus3, Drosophila Pus3, yeast Deg1, bacterial TruA, Arabidopsis Pus, and archaeal homologs. (lin2022destabilizationofmutated pages 7-8)

No naturally occurring veterinary PUS3 neurodevelopmental syndrome, breed association, zoonotic transmission, or cross-species infectious susceptibility was identified. Zoonosis is not applicable.

15. Model organisms and experimental models

No validated Pus3 knockout or knock-in animal model that demonstrably recapitulates the human syndrome was identified in the reviewed evidence. Consequently, there are no established mouse, zebrafish, Drosophila, organoid, or iPSC resources for therapeutic efficacy testing specific to this disorder.

Existing experimental systems include:

  • Patient-derived fibroblasts for PUS3 protein abundance, mRNA expression, and PUS3-dependent pseudouridine measurements.
  • Recombinant wild-type and mutant human PUS3 expressed in insect cells.
  • In-vitro-transcribed human and yeast tRNA substrates.
  • EMSA and microscale thermophoresis for tRNA binding, pseudouridylation assays, gel filtration, nanoDSF/DLS for stability and aggregation, western blotting, quantitative PCR, and AlphaFold2-guided structural interpretation. (lin2022destabilizationofmutated pages 10-10, lin2022destabilizationofmutated pages 5-6, lin2022destabilizationofmutated pages 1-2)

These systems establish biochemical pathogenicity but cannot model brain development, circuit dysfunction, seizures, cognition, or whole-organism treatment response. Priority models are patient iPSC-derived neural progenitors and neurons, cerebral organoids, and a viable conditional Pus3 loss-of-function mouse or zebrafish model.

Recent developments and evidence gaps

The most important disease-specific advances remain the 2021 clinical delineation and the 2022 patient-cell mechanism study. The latter’s key abstract conclusion was that the results “directly illustrate the link between the identified PUS3 variants and reduced Ψ levels in the patient cells.” (lin2022destabilizationofmutated pages 1-2)

Recent 2023–2024 work in the broader field has emphasized RNA modification as a developmental and neurologic regulatory layer, but no comparably large 2023–2024 PUS3 clinical cohort, natural-history study, trial, or therapeutic implementation was identified. The highest priorities are prospective international registry development; standardized HPO phenotyping; longitudinal epilepsy, MRI, growth, and functional outcomes; functional classification of all missense/splice alleles; direct mapping of PUS3-dependent RNA targets in neural cells; mitochondrial studies; and disease-relevant animal and iPSC models.

Key publications and URLs

  1. Nøstvik et al. Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders. Clinical Genetics. Published online August 2021; 100:628–633. DOI/URL: https://doi.org/10.1111/cge.14051. This is the principal 21-individual clinical synthesis. (nøstvik2021clinicalandmolecular pages 1-2)
  2. Lin et al. Destabilization of mutated human PUS3 protein causes intellectual disability. Human Mutation. Published October 2022; 43:2063–2078. DOI/URL: https://doi.org/10.1002/humu.24471. This provides the strongest patient-cell and recombinant-protein mechanism evidence. (lin2022destabilizationofmutated pages 13-13, lin2022destabilizationofmutated pages 1-2)
  3. Fang et al. Compound heterozygous mutations in PUS3 gene identified in a Chinese infant with severe epileptic encephalopathy and multiple malformations. Neurological Sciences. 2020;41:465–467. DOI/URL: https://doi.org/10.1007/s10072-019-04049-1. (fang2020compoundheterozygousmutations pages 1-3)
  4. Shaheen et al. A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition. Human Genetics. 2016;135:707–713. DOI/URL: https://doi.org/10.1007/s00439-016-1665-7. The report introduced the homozygous p.Arg435Ter association and demonstrated reduced post-transcriptional tRNA modification, as summarized in the later cohort. (nøstvik2021clinicalandmolecular pages 3-5, nøstvik2021clinicalandmolecular pages 5-6)

PMIDs were not present in the retrieved full-text evidence and therefore are not supplied rather than risk introducing unverified identifiers.

References

  1. (nøstvik2021clinicalandmolecular pages 2-3): Miriam Nøstvik, Sarah M. Kateta, Bitten Schönewolf‐Greulich, Alexandra Afenjar, Magalie Barth, Felix Boschann, Diane Doummar, Tobias B. Haack, Boris Keren, Ludmila A. Livshits, Davide Mei, Joohyun Park, Tiziana Pisano, Clement Prouteau, Muhammad Umair, Ahmed Waqas, Alban Ziegler, Renzo Guerrini, Rikke S. Møller, and Zeynep Tümer. Clinical and molecular delineation of pus3‐associated neurodevelopmental disorders. Clinical Genetics, 100:628-633, Aug 2021. URL: https://doi.org/10.1111/cge.14051, doi:10.1111/cge.14051. This article has 40 citations and is from a peer-reviewed journal.

  2. (nøstvik2021clinicalandmolecular pages 1-2): Miriam Nøstvik, Sarah M. Kateta, Bitten Schönewolf‐Greulich, Alexandra Afenjar, Magalie Barth, Felix Boschann, Diane Doummar, Tobias B. Haack, Boris Keren, Ludmila A. Livshits, Davide Mei, Joohyun Park, Tiziana Pisano, Clement Prouteau, Muhammad Umair, Ahmed Waqas, Alban Ziegler, Renzo Guerrini, Rikke S. Møller, and Zeynep Tümer. Clinical and molecular delineation of pus3‐associated neurodevelopmental disorders. Clinical Genetics, 100:628-633, Aug 2021. URL: https://doi.org/10.1111/cge.14051, doi:10.1111/cge.14051. This article has 40 citations and is from a peer-reviewed journal.

  3. (lin2022destabilizationofmutated pages 13-13): Ting‐Yu Lin, Robert Smigiel, Bozena Kuzniewska, Joanna J. Chmielewska, Joanna Kosińska, Mateusz Biela, Anna Biela, Anna Kościelniak, Dominika Dobosz, Izabela Laczmanska, Andrzej Chramiec‐Głąbik, Jakub Jeżowski, Jakub Nowak, Monika Gos, Sylwia Rzonca‐Niewczas, Magdalena Dziembowska, Rafał Ploski, and Sebastian Glatt. Destabilization of mutated human pus3 protein causes intellectual disability. Human Mutation, 43:2063-2078, Oct 2022. URL: https://doi.org/10.1002/humu.24471, doi:10.1002/humu.24471. This article has 30 citations and is from a domain leading peer-reviewed journal.

  4. (lin2022destabilizationofmutated pages 2-3): Ting‐Yu Lin, Robert Smigiel, Bozena Kuzniewska, Joanna J. Chmielewska, Joanna Kosińska, Mateusz Biela, Anna Biela, Anna Kościelniak, Dominika Dobosz, Izabela Laczmanska, Andrzej Chramiec‐Głąbik, Jakub Jeżowski, Jakub Nowak, Monika Gos, Sylwia Rzonca‐Niewczas, Magdalena Dziembowska, Rafał Ploski, and Sebastian Glatt. Destabilization of mutated human pus3 protein causes intellectual disability. Human Mutation, 43:2063-2078, Oct 2022. URL: https://doi.org/10.1002/humu.24471, doi:10.1002/humu.24471. This article has 30 citations and is from a domain leading peer-reviewed journal.

  5. (lin2022destabilizationofmutated pages 1-2): Ting‐Yu Lin, Robert Smigiel, Bozena Kuzniewska, Joanna J. Chmielewska, Joanna Kosińska, Mateusz Biela, Anna Biela, Anna Kościelniak, Dominika Dobosz, Izabela Laczmanska, Andrzej Chramiec‐Głąbik, Jakub Jeżowski, Jakub Nowak, Monika Gos, Sylwia Rzonca‐Niewczas, Magdalena Dziembowska, Rafał Ploski, and Sebastian Glatt. Destabilization of mutated human pus3 protein causes intellectual disability. Human Mutation, 43:2063-2078, Oct 2022. URL: https://doi.org/10.1002/humu.24471, doi:10.1002/humu.24471. This article has 30 citations and is from a domain leading peer-reviewed journal.

  6. (nøstvik2021clinicalandmolecular pages 3-5): Miriam Nøstvik, Sarah M. Kateta, Bitten Schönewolf‐Greulich, Alexandra Afenjar, Magalie Barth, Felix Boschann, Diane Doummar, Tobias B. Haack, Boris Keren, Ludmila A. Livshits, Davide Mei, Joohyun Park, Tiziana Pisano, Clement Prouteau, Muhammad Umair, Ahmed Waqas, Alban Ziegler, Renzo Guerrini, Rikke S. Møller, and Zeynep Tümer. Clinical and molecular delineation of pus3‐associated neurodevelopmental disorders. Clinical Genetics, 100:628-633, Aug 2021. URL: https://doi.org/10.1111/cge.14051, doi:10.1111/cge.14051. This article has 40 citations and is from a peer-reviewed journal.

  7. (lin2022destabilizationofmutated pages 7-8): Ting‐Yu Lin, Robert Smigiel, Bozena Kuzniewska, Joanna J. Chmielewska, Joanna Kosińska, Mateusz Biela, Anna Biela, Anna Kościelniak, Dominika Dobosz, Izabela Laczmanska, Andrzej Chramiec‐Głąbik, Jakub Jeżowski, Jakub Nowak, Monika Gos, Sylwia Rzonca‐Niewczas, Magdalena Dziembowska, Rafał Ploski, and Sebastian Glatt. Destabilization of mutated human pus3 protein causes intellectual disability. Human Mutation, 43:2063-2078, Oct 2022. URL: https://doi.org/10.1002/humu.24471, doi:10.1002/humu.24471. This article has 30 citations and is from a domain leading peer-reviewed journal.

  8. (fang2020compoundheterozygousmutations pages 1-3): Hongjun Fang, Lily Zhang, Bo Xiao, Hongyu Long, and Liming Yang. Compound heterozygous mutations in pus3 gene identified in a chinese infant with severe epileptic encephalopathy and multiple malformations. Neurological Sciences, 41:465-467, Aug 2020. URL: https://doi.org/10.1007/s10072-019-04049-1, doi:10.1007/s10072-019-04049-1. This article has 11 citations and is from a peer-reviewed journal.

  9. (nøstvik2021clinicalandmolecular pages 5-6): Miriam Nøstvik, Sarah M. Kateta, Bitten Schönewolf‐Greulich, Alexandra Afenjar, Magalie Barth, Felix Boschann, Diane Doummar, Tobias B. Haack, Boris Keren, Ludmila A. Livshits, Davide Mei, Joohyun Park, Tiziana Pisano, Clement Prouteau, Muhammad Umair, Ahmed Waqas, Alban Ziegler, Renzo Guerrini, Rikke S. Møller, and Zeynep Tümer. Clinical and molecular delineation of pus3‐associated neurodevelopmental disorders. Clinical Genetics, 100:628-633, Aug 2021. URL: https://doi.org/10.1111/cge.14051, doi:10.1111/cge.14051. This article has 40 citations and is from a peer-reviewed journal.

  10. (lin2022destabilizationofmutated pages 10-10): Ting‐Yu Lin, Robert Smigiel, Bozena Kuzniewska, Joanna J. Chmielewska, Joanna Kosińska, Mateusz Biela, Anna Biela, Anna Kościelniak, Dominika Dobosz, Izabela Laczmanska, Andrzej Chramiec‐Głąbik, Jakub Jeżowski, Jakub Nowak, Monika Gos, Sylwia Rzonca‐Niewczas, Magdalena Dziembowska, Rafał Ploski, and Sebastian Glatt. Destabilization of mutated human pus3 protein causes intellectual disability. Human Mutation, 43:2063-2078, Oct 2022. URL: https://doi.org/10.1002/humu.24471, doi:10.1002/humu.24471. This article has 30 citations and is from a domain leading peer-reviewed journal.

  11. (lin2022destabilizationofmutated pages 13-14): Ting‐Yu Lin, Robert Smigiel, Bozena Kuzniewska, Joanna J. Chmielewska, Joanna Kosińska, Mateusz Biela, Anna Biela, Anna Kościelniak, Dominika Dobosz, Izabela Laczmanska, Andrzej Chramiec‐Głąbik, Jakub Jeżowski, Jakub Nowak, Monika Gos, Sylwia Rzonca‐Niewczas, Magdalena Dziembowska, Rafał Ploski, and Sebastian Glatt. Destabilization of mutated human pus3 protein causes intellectual disability. Human Mutation, 43:2063-2078, Oct 2022. URL: https://doi.org/10.1002/humu.24471, doi:10.1002/humu.24471. This article has 30 citations and is from a domain leading peer-reviewed journal.

  12. (lin2022destabilizationofmutated pages 5-6): Ting‐Yu Lin, Robert Smigiel, Bozena Kuzniewska, Joanna J. Chmielewska, Joanna Kosińska, Mateusz Biela, Anna Biela, Anna Kościelniak, Dominika Dobosz, Izabela Laczmanska, Andrzej Chramiec‐Głąbik, Jakub Jeżowski, Jakub Nowak, Monika Gos, Sylwia Rzonca‐Niewczas, Magdalena Dziembowska, Rafał Ploski, and Sebastian Glatt. Destabilization of mutated human pus3 protein causes intellectual disability. Human Mutation, 43:2063-2078, Oct 2022. URL: https://doi.org/10.1002/humu.24471, doi:10.1002/humu.24471. This article has 30 citations and is from a domain leading peer-reviewed journal.

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