PUS7-Related Neurodevelopmental Disorder

Mendelian MONDO:0032687 Pathograph 34 Show in embeddings browser Neurodevelopmental Disorder Intellectual Disability

PUS7-related neurodevelopmental disorder (intellectual developmental disorder with abnormal behavior, microcephaly, and short stature; IDDABS, MIM 618342) is an ultra-rare autosomal recessive disorder caused by biallelic variants in PUS7, which encodes the RNA-independent pseudouridine synthase 7. The core clinical picture is moderate to severe intellectual disability with delayed or absent speech, postnatal and often progressive microcephaly, poor somatic growth with short stature, and behavioural disturbance dominated by aggression that begins unusually early. Less common but more distinctive findings include sensorineural hearing loss, autistic traits, self-injurious behaviour, motor stereotypies and sleep disturbance. Mechanistically, disease alleles abolish PUS7 catalytic activity, removing pseudouridine from position 13 of at least ten cytosolic tRNAs and from PUS7-dependent mRNA and tRNA-derived-fragment substrates. Because PUS7-modified tRNA-derived fragments normally restrain translation initiation, loss of the enzyme deregulates global protein synthesis, and the developing brain appears to be the tissue least able to tolerate that perturbation.

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Classifications

Harrison's Chapter

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Inheritance

Autosomal recessive inheritance HP:0000007

Disease requires biallelic PUS7 variants. Every family reported to date has been homozygous, and most have been consanguineous; heterozygous carrier parents are unaffected. Recurrence risk for siblings of an affected proband is 25 percent, and carrier testing plus genetic counselling are indicated for at-risk relatives.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:33100873 SUPPORT Human Clinical

"Intellectual developmental disorder with abnormal behavior, microcephaly and short stature (IDDABS) is an autosomal recessive disorder is caused by homozygous mutation in the PUS7 gene (616261) that is located on chromosome 7q22."

States the autosomal recessive mode and the biallelic (homozygous) requirement at the PUS7 locus.

PMID:30778726 SUPPORT Human Clinical

"We describe two families in which two different homozygous PUS7 mutations (missense and frameshift deletion) segregate with a phenotype comprising intellectual disability and progressive microcephaly."

Documents segregation of homozygous alleles with the phenotype in two independent consanguineous families.

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Mechanistic Hypotheses

Loss of PUS7-dependent translational restraint as the disease mechanism

pus7_translational_control CANONICAL

Evidence balance 1 support

The default explanatory model. Loss of PUS7 removes pseudouridine from cytosolic tRNAs, from PUS7-dependent mRNAs, and from the tRNA-derived fragments that hold the translation initiation complex in check. The convergent consequence is loss of translational homeostasis, demonstrated directly in PUS7-deficient patient fibroblasts, and the developing brain is the tissue least able to tolerate it. Every edge in this entry that is not explicitly assigned to another hypothesis group belongs to this model.

Show evidence (1 reference)

PMID:35144859 SUPPORT In Vitro

"Patient fibroblasts demonstrated upregulation of protein synthesis, including elevated MYC protein, but did not exhibit increased rates of cell proliferation."

The human-cell demonstration on which the canonical translational model rests.

Contribution of the transcription-elongation and splicing arms of PUS7

pus7_non_translational_arms EMERGING

Evidence balance 1 support

PUS7 also pseudouridylates 7SK snRNA, controlling RNA polymerase II promoter-proximal pausing, and has reported effects on pre-mRNA splicing via U2 snRNA. Both are established for PUS7 loss in cell lines. Neither has been connected to the human neurodevelopmental phenotype in any way: no patient tissue has been assayed for 7SK pseudouridine, Pol II serine-2 phosphorylation, or splicing abnormalities. Edges opting into this group are curated because the enzymology is real, not because the disease relevance is established.

Pathograph links

Loss of Pseudouridine Synthase 7 Catalytic Activity -> Loss of 7SK snRNA Pseudouridylation and Enhanced Pol II Elongation DIRECT PUS7 also pseudouridylates the 7SK small nuclear RNA, which restrains RNA polymerase II promoter-proximal pausing. Whether this arm contributes to the human disorder is untested, so the edge belongs to an emerging rather than the canonical mechanism model.

Show evidence (1 reference)

PMID:41168165 SUPPORT In Vitro

"Whether and how Ψ may regulate transcription have not been adequately studied."

The authors' own framing of the transcription arm as newly opened rather than settled, which is why the hypothesis group status is EMERGING.

Discussions and Knowledge Gaps

Does germline Pus7 loss in the mouse reproduce the human neurodevelopmental phenotype at all, and if not, why?

HUMAN MODEL MISMATCH OPEN pus7_no_mouse_model

Attached to

pathophysiology#Impaired Neuronal Development and Function

The only in vivo evidence that PUS7 loss produces the behavioural phenotype comes from Drosophila, and the only mammalian in vivo evidence is a region-specific adult knockdown in mouse infralimbic prefrontal cortex, which models plasticity rather than development. No published Pus7-null mouse has been characterised for brain size, growth, or behaviour, even though mouse alleles exist. The mismatch matters because the two headline human features, progressive microcephaly and growth retardation, have no described animal counterpart at all: Drosophila cannot model them, and the mouse has not been asked. Without a mammalian germline model the causal step from deregulated translation to failed postnatal brain growth remains an inference.

Proposed experiments

Deep phenotyping of a germline Pus7-null mouse

exp_pus7_germline_mouse_phenotyping

Characterise a germline Pus7-null mouse for serial head and brain volume, body growth, cortical progenitor dynamics, and home-cage aggression, rather than relying on the existing high-throughput phenotyping-pipeline summary, which reports systems that do not obviously map onto the human phenotype.

Conditional Pus7 deletion to test neuron autonomy of brain growth failure

exp_pus7_conditional_neural_deletion

Delete Pus7 conditionally in neural progenitors versus post-mitotic neurons and compare brain-growth outcomes, to determine whether any mammalian brain-size phenotype is neuron-autonomous or secondary to systemic growth failure.

Show evidence (1 reference)

PMID:41094471 PARTIAL Model Organism

"Crucially, PUS7 knockdown in the ILPFC selectively impaired fear extinction memory formation without altering baseline fear expression, establishing a causal link between Ψ-dependent RNA processing and activity-dependent synaptic structural remodeling in this microcircuit."

The best available mammalian in vivo evidence, and simultaneously the demonstration of the gap: it is an adult, region-restricted knockdown, not a germline developmental model.

Why do PUS7-depleted human haematopoietic stem and progenitor cells show a severe commitment defect while PUS7-deficient patients have no reported haematological disease?

HUMAN MODEL MISMATCH OPEN pus7_haematopoietic_discrepancy

Attached to

pathophysiology#Failure of tRF-Mediated Restraint of Translation Initiation

The tRF arm of PUS7 biology was discovered in haematopoiesis, and PUS7 depletion impairs stem cell commitment and is implicated in aggressive myelodysplastic syndrome. Yet no PUS7-deficient patient has been reported with cytopenia, marrow failure, or a myeloid neoplasm. Either the human requirement is dosage- or context-dependent in a way the depletion experiments do not capture, or the haematological phenotype exists and has never been looked for because the patients present to neurology and clinical genetics. Resolving this affects how much weight the tRF arm should carry in the disease model.

Proposed experiments

Systematic haematological assessment of published PUS7 cohorts

exp_pus7_haematology_ascertainment

Report full blood counts and, where justified, marrow morphology across the existing PUS7 patient cohorts. This distinguishes a genuine absence of haematological phenotype from an absence of ascertainment, which is the first thing that must be settled before the discrepancy can be interpreted.

Tissue-specific comparison of tRF pseudouridylation and TOP mRNA translation

exp_pus7_tissue_specific_trf_compensation

Compare tRNA-derived-fragment pseudouridine levels and translation of 5-prime terminal oligopyrimidine mRNAs between patient-derived haematopoietic cells and patient fibroblasts, to test whether the haematopoietic compartment compensates for PUS7 loss in a way that fibroblasts do not.

Show evidence (1 reference)

PMID:29628141 SUPPORT In Vitro

"Remarkably, dysregulation of this posttranscriptional regulatory circuitry impairs hematopoietic stem cell commitment and is common to aggressive subtypes of human myelodysplastic syndromes."

States the haematopoietic requirement that patients do not appear to manifest.

By what cellular route does deregulated translation reduce postnatal brain growth in PUS7 deficiency?

KNOWLEDGE GAP OPEN pus7_microcephaly_causal_gap

Attached to

pathophysiology#Impaired Postnatal Brain Growth

The molecular defect and the clinical endpoint are both well established, but the step between them is entirely inferred. There is no evidence in any human or model system for neural progenitor pool depletion, altered cell cycle exit, increased apoptosis, or reduced neuronal arborisation in PUS7 deficiency. The published framing of the link is explicitly hedged, using the word "presumably". Because brain MRI architecture is normal in most patients, the deficit is one of growth rather than malformation, which narrows the candidate mechanisms but does not identify them. No iPSC-derived neural or organoid model of PUS7 deficiency exists.

Proposed experiments

PUS7-null iPSC-derived neural progenitors and cortical organoids

exp_pus7_ipsc_neural_organoid

Generate PUS7-null induced pluripotent stem cell lines and differentiate them to neural progenitors and cortical organoids, measuring progenitor proliferation, cell-cycle exit, apoptosis, and organoid size against isogenic controls. No such model currently exists, and it is the most direct test of whether the microcephaly reflects progenitor pool depletion.

Ribosome profiling in PUS7-null neural progenitors

exp_pus7_neural_ribosome_profiling

Perform ribosome profiling in PUS7-null neural progenitors to identify which transcripts change translational efficiency, and test specifically whether any are established microcephaly genes. This would convert the inferred translation-to-brain-growth link into a named set of effectors.

Show evidence (1 reference)

PMID:30778726 PARTIAL Human Clinical

"We and others have previously emphasized the predilection of Mendelian diseases caused by tRNA modification genes to CNS involvement and how this suggests the vulnerability of the brain to any perturbation of tRNA modification, presumably through its deleterious effect on protein synthesis"

The hedged wording is itself the evidence for the gap: the field states the link as a presumption, not a finding.

What is the adult course, life expectancy, and adult morbidity profile of PUS7-related neurodevelopmental disorder?

KNOWLEDGE GAP OPEN pus7_no_adult_natural_history

Attached to

pathophysiology#Cognitive and Behavioural Dysfunction

Roughly 30 patients have been published and the oldest are adolescents; one cohort states its patients ranged from 2 to 18 years. No adult patient has been described, no natural-history study or registry exists, and no deaths have been reported. Two features are documented as progressive into adolescence, head circumference and hearing, and behaviour worsens over the same period, so extrapolating a stable adult course from paediatric cross-sections is not safe. Families cannot currently be given prognostic information beyond childhood.

Proposed experiments

International PUS7 natural-history registry

exp_pus7_natural_history_registry

Establish a prospective international registry collecting longitudinal head circumference, growth, audiometry, behavioural, and adaptive-function measures on genotype-confirmed individuals, with the explicit aim of extending observation past adolescence.

Recontact of previously published PUS7 families

exp_pus7_family_recontact

Recontact the published families, several of which were reported five or more years ago, to obtain adolescent and adult follow-up. This is the fastest available route to any adult data at all and requires no new ascertainment.

Show evidence (1 reference)

PMID:33100873 SUPPORT Human Clinical

"nine patients ranged in age from 2 to 18 years old"

Documents the paediatric ceiling of the published age range.

Do PUS7 missense alleles behave as hypomorphs that spare growth and head circumference, or as complete loss of function indistinguishable from truncating alleles?

CONTROVERSY OPEN pus7_genotype_phenotype_unresolved

Attached to

pathophysiology#Biallelic PUS7 Loss-of-Function Variants

Two published positions conflict. Darvish and colleagues propose that their missense family's milder phenotype, without microcephaly or short stature, reflects a hypomorphic allele in contrast to the null truncating alleles. Against that, the missense allele in the Shaheen cohort produced severe microcephaly and behaved as a complete loss of function in yeast complementation. A truncating-versus-missense severity rule therefore cannot currently be given to families. The 13-patient, 15-variant cohort of PMID:42249560 is framed by its own authors as improving genotype-phenotype correlation and is the priority source for resolving this, but its full text was not accessible during this curation pass.

Proposed experiments

Uniform functional assay of all reported PUS7 missense alleles

exp_pus7_uniform_missense_functional_assay

Assay every reported PUS7 missense allele in the same yeast complementation and tRNA pseudouridine-13 systems, so that residual catalytic activity is measured on one scale rather than being inferred backwards from clinical severity. This is the only way to test the hypomorph hypothesis independently of the phenotype it is meant to explain.

Pooled genotype-phenotype analysis including the 2026 cohort

exp_pus7_pooled_genotype_phenotype_analysis

Extract per-variant phenotype data from the 13-patient, 15-variant cohort of PMID:42249560 once full text is accessible, pool it with the earlier cohorts, and test the missense-versus-truncating severity hypothesis across the combined series.

Show evidence (2 references)

PMID:31583274 SUPPORT Human Clinical

"The absence of highly extreme phenotypes such as short stature or microcephaly in this family might reflect genotype–phenotype correlation, since this family presented with a PUS7 missense mutation that may be hypomorphic, while previously reported families carried nonsense or frameshift..."

One side of the controversy: the hypomorphic-missense proposal.

PMID:30778726 REFUTE Model Organism

"Furthermore, the missense variant of the S. cerevisiae ortholog failed to complement the growth defect of S. cerevisiae pus7Δ trm8Δ mutants."

The other side: a patient missense allele that is a complete loss of function in a functional assay, in patients who did have severe microcephaly.

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Pathophysiology

Biallelic PUS7 Loss-of-Function Variants

The disorder is initiated by inheritance of two damaging PUS7 alleles. The reported allelic spectrum includes frameshift alleles, nonsense alleles, a deletion of the penultimate exon that escapes nonsense-mediated decay but removes the C-terminal catalytic region, and missense alleles. Missense alleles appear to behave as hypomorphs, producing a milder phenotype without microcephaly or short stature.

PUS7 hgnc:26033

Downstream

Loss of Pseudouridine Synthase 7 Catalytic Activity Damaging biallelic alleles remove or inactivate the TruD-family pseudouridine synthase encoded by PUS7.

Show evidence (2 references)

PMID:30526862 SUPPORT Human Clinical

"We describe six persons from three families with three homozygous protein truncating variants in PUS7"

Establishes biallelic protein-truncating PUS7 alleles as the initiating lesion in the founding cohort.

PMID:31583274 SUPPORT Human Clinical

Documents the allelic spectrum and the proposed hypomorph-versus-null genotype-phenotype gradient.

Loss of Pseudouridine Synthase 7 Catalytic Activity

PUS7 is an RNA-independent (stand-alone) pseudouridine synthase of the TruD family that isomerises uridine to 5-ribosyluracil without a guide snoRNA. Loss of its activity removes pseudouridine from every class of PUS7 substrate at once: cytosolic tRNAs, a defined set of mRNAs, and tRNA-derived small fragments.

Contribution of the transcription-elongation and splicing arms of PUS7

pseudouridine synthesis GO:0001522 ↓ DECREASED

pseudouridine synthase activity GO:0009982 ↓ DECREASED tRNA pseudouridine synthase activity GO:0106029 ↓ DECREASED

Downstream

Depletion of tRNA Pseudouridine at Position 13 Loss of the enzyme removes the position-13 pseudouridine it normally installs in cytosolic tRNAs.

Loss of PUS7-Dependent mRNA Pseudouridylation The same catalytic loss removes pseudouridine from PUS7-dependent mRNA substrates.

Loss of Pseudouridylation and Activation of tRNA-Derived Fragments PUS7 also pseudouridylates and thereby activates a network of tRNA-derived small fragments; loss of the enzyme leaves these fragments unmodified and inactive.

Loss of 7SK snRNA Pseudouridylation and Enhanced Pol II Elongation PUS7 also pseudouridylates the 7SK small nuclear RNA, which restrains RNA polymerase II promoter-proximal pausing. Whether this arm contributes to the human disorder is untested, so the edge belongs to an emerging rather than the canonical mechanism model.

Show evidence (2 references)

PMID:30526862 SUPPORT Human Clinical

"PUS7 encodes the RNA-independent pseudouridylate synthase 7."

Identifies the gene product whose activity is lost, and its RNA-independent (guide-RNA-free) mode of substrate recognition.

PMID:30778726 SUPPORT Model Organism

"Furthermore, the missense variant of the S. cerevisiae ortholog failed to complement the growth defect of S. cerevisiae pus7Δ trm8Δ mutants."

Yeast complementation shows that a patient missense allele is a complete loss-of-function at the level of enzyme activity, not merely a destabilising substitution.

Loss of 7SK snRNA Pseudouridylation and Enhanced Pol II Elongation

Loss of PUS7 leaves 7SK snRNA hypo-pseudouridylated, which releases the positive transcription elongation factor b complex from 7SK, raises serine-2 phosphorylation of the RNA polymerase II C-terminal domain, and enhances transcription elongation. This is a transcription-level rather than a translation-level consequence of the same enzymatic deficit. It is included because it is mechanistically established for PUS7 loss, but its relevance to the neurodevelopmental phenotype is entirely untested: the work was done in colorectal cancer cells, and no patient tissue has been examined.

regulation of transcription elongation by RNA polymerase II GO:0034243 ↑ INCREASED

Show evidence (1 reference)

PMID:41168165 SUPPORT In Vitro

"PUS7 loss leads to hypo-pseudouridylation of 7SK, which promotes dissociation of the positive transcription elongation factor b (P-TEFb) complex from 7SK. The release of P-TEFb from 7SK increases serine 2 phosphorylation (Ser2P) in the RNA Pol II C-terminal domain and enhances transcription elongation."

The full molecular chain from PUS7 loss to enhanced Pol II elongation, demonstrated in cell lines.

Depletion of tRNA Pseudouridine at Position 13

Patient cells lose pseudouridine specifically at position 13 of at least ten different cytosolic tRNAs, with other pseudouridine positions in the same tRNAs preserved. The defect is therefore a clean, position-specific ablation of one modification rather than a general collapse of tRNA maturation.

tRNA pseudouridine synthesis GO:0031119 ↓ DECREASED tRNA modification GO:0006400 ↓ DECREASED

Downstream

Deregulated Global Protein Synthesis Loss of a conserved tRNA body modification perturbs the translational apparatus. The authors of the founding cohorts attribute the disease to a deleterious effect on protein synthesis, but the quantitative step from missing Psi-13 to altered translation output has not been measured directly in neurons.

Loss of Codon-Specific Translational Control PUS7-dependent tRNA pseudouridine is required for codon-biased regulation of translation, so losing it releases codon-specific control over which transcripts are efficiently translated.

Show evidence (2 references)

PMID:33100873 SUPPORT In Vitro

"Patient-derived cells showed decreased pseudouridylation signals specifically for PUS7 substrates at position 13 of at least 10 different cytosolic tRNAs, but not at other positions."

States both the breadth (at least ten tRNAs) and the specificity (position 13 only) of the modification loss in patient cells.

PMID:31583274 SUPPORT In Vitro

"All identified PUS7 variants resulted in aberrant pseudouridylation of at least 10 cytosolic tRNAs at position 13."

Independent confirmation that the position-13 defect is common to the whole reported allelic series.

Loss of Codon-Specific Translational Control

PUS7-dependent tRNA pseudouridylation biases translation toward or away from particular codons, so its loss changes which transcripts are efficiently decoded. This is the most satisfying available answer to the central puzzle of the disorder: how the loss of a broadly expressed housekeeping RNA writer produces a selective, largely neurological phenotype rather than uniform cellular failure. The mapping was performed in glioblastoma stem cells, and the equivalent codon-level analysis has never been done in neurons or neural progenitors.

regulation of translation GO:0006417 ↓ DECREASED

Downstream

Deregulated Global Protein Synthesis Loss of codon-level control contributes to the overall derangement of translational output.

Show evidence (1 reference)

PMID:35121864 SUPPORT In Vitro

"Mechanistically, we identify PUS7 targets in GSCs through small RNA pseudouridine sequencing and show that pseudouridylation of PUS7-regulated transfer RNA is critical for codon-specific translational control of key regulators of GSCs."

The direct demonstration that PUS7-dependent tRNA pseudouridine controls translation in a codon-specific rather than a global manner.

Loss of PUS7-Dependent mRNA Pseudouridylation

PUS7 recognises a UNPsiAR-type sequence motif and pseudouridylates a defined set of mRNAs. Patient cells show reduced mRNA pseudouridylation, although the functional consequence of this arm has not been established as disease-relevant.

mRNA modification GO:0016556 ↓ DECREASED

Downstream

Deregulated Global Protein Synthesis Loss of mRNA pseudouridylation is a candidate contributor to the translational phenotype, but its functional weight is explicitly undetermined in the source literature.

Show evidence (1 reference)

PMID:30526862 SUPPORT In Vitro

"We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates."

Establishes mRNA as a genuine second substrate class lost in patients, not only tRNA.

Loss of Pseudouridylation and Activation of tRNA-Derived Fragments

PUS7 pseudouridylates a network of tRNA-derived small fragments (tRFs). The modification is what activates them; unmodified tRFs cannot engage the translation initiation complex.

Downstream

Failure of tRF-Mediated Restraint of Translation Initiation Without the activating pseudouridine, the tRF network can no longer repress translation initiation.

Show evidence (1 reference)

PMID:29628141 SUPPORT In Vitro

"Mechanistically, the Ψ "writer" PUS7 modifies and activates a novel network of tRNA-derived small fragments (tRFs) targeting the translation initiation complex."

Identifies the tRF arm and its molecular target, the translation initiation complex.

Failure of tRF-Mediated Restraint of Translation Initiation

PUS7-modified tRFs act as brakes on the translation initiation complex. The best-resolved arm is the mini-tRF carrying a 5-prime terminal oligoguanine (mTOG): its pseudouridine engages the RNA-recognition-motif domains of PABPC1, which blocks recruitment of the translational co-activator PAIP1 and represses translation of transcripts carrying pyrimidine-enriched and 5-prime terminal oligopyrimidine sequences, many of which encode components of the protein-synthesis machinery itself. Removing the brake therefore releases initiation from its normal ceiling, and does so in a feed-forward way because the derepressed transcripts build more translational machinery.

regulation of translational initiation GO:0006446 ↓ DECREASED negative regulation of translation GO:0017148 ↓ DECREASED

Downstream

Deregulated Global Protein Synthesis Release of the initiation brake increases global protein biosynthesis.

Show evidence (3 references)

PMID:29628141 SUPPORT In Vitro

"PUS7 inactivation in embryonic stem cells impairs tRF-mediated translation regulation, leading to increased protein biosynthesis and defective germ layer specification."

Directly names the loss of tRF-mediated translation regulation as the consequence of PUS7 inactivation.

PMID:35292784 SUPPORT In Vitro

"Building on evidence that mTOG-Ψ targets polyadenylate-binding protein cytoplasmic 1 (PABPC1), we employed isotope exchange proteomics to reveal critical interactions between mTOG and functional RNA-recognition motif (RRM) domains of PABPC1."

Identifies PABPC1 as the direct molecular target of the pseudouridylated tRF, which is what makes this the mechanistically best-resolved arm.

PMID:35292784 SUPPORT In Vitro

"Mechanistically, this hinders the recruitment of translational co-activator PABPC1-interacting protein 1 (PAIP1)3 and strongly represses the translation of transcripts sharing pyrimidine-enriched sequences (PES) at the 5' untranslated region (UTR), including 5' terminal oligopyrimidine tracts..."

Spells out the repressive step that is lost in PUS7 deficiency and names the class of transcripts derepressed, including those encoding the translational machinery itself.

Deregulated Global Protein Synthesis

The convergent cellular consequence of losing PUS7 across all three substrate classes is loss of translational homeostasis. Fibroblasts from PUS7-deficient patients show upregulated protein synthesis with elevated MYC protein, and notably this occurs without a corresponding increase in proliferation rate, which distinguishes the neurodevelopmental consequence from the proliferative consequence of upregulated translation in cancer.

patient dermal fibroblast CL:0000057

cytoplasmic translation GO:0002181 ↑ INCREASED positive regulation of translation GO:0045727 ↑ INCREASED

Downstream

Impaired Neuronal Development and Function Neurons appear to be the cell type least tolerant of deregulated translation, which is the proposed reason the phenotype is dominated by brain involvement.

Secondary Reduction of HPRT1 Protein In the two NIH Undiagnosed Diseases Program siblings, deregulated translation was accompanied by a mild reduction in HPRT1 protein despite normal HPRT1 sequence.

Impaired Somatic Growth Poor pre- and postnatal growth with short stature is a consistent feature of the loss-of-function cohorts, plausibly reflecting the same translational defect in non-neural tissue, though this has not been demonstrated experimentally.

Show evidence (2 references)

PMID:35144859 SUPPORT In Vitro

"Patient fibroblasts demonstrated upregulation of protein synthesis, including elevated MYC protein, but did not exhibit increased rates of cell proliferation."

The primary human-cell evidence for the translational phenotype, including the dissociation from proliferation.

PMID:35144859 SUPPORT Human Clinical

"These findings strengthen the correlation between neurodevelopmental disease, particularly autism spectrum disorders, and the rate of protein translation."

Links the translational phenotype to the neurodevelopmental outcome in the authors' own framing.

Secondary Reduction of HPRT1 Protein

A translation-level, sequence-independent reduction in hypoxanthine-guanine phosphoribosyltransferase protein. This is a proposed explanation for the Lesch-Nyhan-like hyperuricaemia and self-injurious behaviour observed in one sibling pair, and it has not been replicated in other PUS7 cohorts.

Downstream

Purine Metabolic Derangement and Lesch-Nyhan-Like Features Reduced HPRT1 protein is proposed to underlie the hyperuricaemia and self-injurious behaviour seen without any HPRT1 sequence variant.

Show evidence (1 reference)

PMID:35144859 SUPPORT In Vitro

"Interestingly, the dysregulation of protein translation also resulted in mildly decreased levels of HPRT1 protein suggesting an association between dysregulated protein translation and the LNS-like phenotypic findings."

Reports the reduced HPRT1 protein level and the authors' proposed link to the Lesch-Nyhan-like features.

Purine Metabolic Derangement and Lesch-Nyhan-Like Features

Hyperuricaemia with self-injurious behaviour resembling Lesch-Nyhan syndrome, observed in PUS7-deficient siblings with a normal HPRT1 gene. This branch of the graph is reported in a single family and should not be treated as a core feature of the disorder.

Show evidence (1 reference)

PMID:35144859 SUPPORT Human Clinical

"Both patients also had features of Lesch-Nyhan syndrome, including hyperuricemia and self-injurious behavior, but without pathogenic variants in HPRT1."

The clinical observation defining this node.

Impaired Neuronal Development and Function

The convergent neural consequence. Human evidence is the invariant cognitive and behavioural phenotype; experimental support comes from pus7 knockout in Drosophila, which reproduces increased activity, disorientation and aggressiveness, and from mouse infralimbic prefrontal cortex knockdown, which selectively impairs an activity-dependent synaptic plasticity behaviour.

neuron CL:0000540

neuron development GO:0048666 ⚠ ABNORMAL

Downstream

Impaired Postnatal Brain Growth Defective neuronal development and function translates into failure of postnatal head growth.

Cognitive and Behavioural Dysfunction The dominant clinical output: intellectual disability, speech delay and early-onset aggression.

Impaired Activity-Dependent Synaptic Remodelling Beyond the developmental deficit, PUS7 is required in mature mammalian cortex for the pseudouridine-dependent RNA processing that supports experience-driven synaptic change.

Show evidence (3 references)

PMID:30526862 SUPPORT Model Organism

"Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused by PUS7 variants."

Animal loss-of-function evidence that the neurological and specifically aggressive phenotype follows from loss of the enzyme.

PMID:41094471 SUPPORT Model Organism

Region-specific mouse knockdown showing that PUS7 is required for activity-dependent synaptic remodelling, a plausible cellular substrate for the cognitive phenotype.

PMID:33100873 SUPPORT In Vitro

"The findings indicated that RNA pseudouridylation, along with tRNA modification is important for proper neural development"

Independent restatement that the pseudouridylation defect converges on neural development.

Impaired Activity-Dependent Synaptic Remodelling

A distinct, more disease-proximal neuronal mechanism than the developmental one. In mouse infralimbic prefrontal cortex, learning drives pseudouridine deposition on exons of synaptic regulatory genes and upregulation of synaptogenic transcripts, and PUS7 is required for this. Knocking PUS7 down in that region selectively blocks extinction learning while leaving baseline behaviour intact, which shows the requirement is for plasticity rather than for maintenance. This provides a candidate substrate for the cognitive and behavioural phenotype that is separable from the growth phenotype. It is mouse knockdown in adult cortex, not a germline model of the human disorder, so it is a mechanistic analogy and not a demonstration.

neuron CL:0000540

regulation of synapse structure or activity GO:0050803 ↓ DECREASED learning GO:0007612 ↓ DECREASED

Downstream

Cognitive and Behavioural Dysfunction Failure of activity-dependent synaptic remodelling is a candidate contributor to the learning and behavioural phenotype, in addition to the developmental deficit.

Show evidence (1 reference)

PMID:41094471 SUPPORT Model Organism

Region-specific mouse knockdown establishing a causal, plasticity-specific requirement for PUS7.

Impaired Postnatal Brain Growth

Head circumference is typically normal or near-normal at birth and falls progressively across childhood, which is why the microcephaly is described as progressive or acquired rather than congenital. Brain MRI architecture is normal in most reported patients.

brain development GO:0007420 ⚠ ABNORMAL

Show evidence (1 reference)

PMID:37067188 SUPPORT Human Clinical

"PUS7 gene pathogenic variants cause a deficiency in an RNA-independent pseudouridine synthase, which results in a neurodevelopmental phenotype characterized by various degrees of psychomotor delay, acquired microcephaly, aggressive behavior, and intellectual disability."

Explicitly characterises the microcephaly as acquired rather than congenital.

Impaired Somatic Growth

Poor overall growth with short stature and low weight, described as marked growth retardation in the larger cohorts. Growth failure is a feature of the truncating-allele families and was absent in the one reported missense (hypomorphic) family.

Show evidence (1 reference)

PMID:42249560 SUPPORT Human Clinical

"Recently, papers reported that variants in PUS7 in 16 patients were involved in marked growth retardation with microcephaly, associated with intellectual disability and behavioral issues such as self-injurious and aggressive behavior."

Summarises growth retardation as a defining feature of the previously published cohort.

Cognitive and Behavioural Dysfunction

Moderate to severe intellectual disability with delayed or absent speech, plus a behavioural signature dominated by aggression of unusually early onset, and in a minority autistic traits, self-injury, stereotypies and sleep disturbance. The 2026 review argues that the core features are non-specific but that the very early onset of aggressiveness is the discriminating clue.

Show evidence (1 reference)

PMID:42226002 SUPPORT Human Clinical

"These features are common but non-specific, with the exception of aggressiveness that manifests at a very early age."

Identifies the discriminating behavioural feature within the otherwise non-specific phenotype.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Ear 1

Sensorineural Hearing Impairment OCCASIONAL Sensorineural hearing impairment HP:0000407

Derivation: reported in 2 of the 3 patients in PMID:30778726 and in both brothers in PMID:33100873, i.e. 4 individuals in total. Against the roughly 17 cases enumerated in the PMID:42226002 review that is approximately 24 percent, which lies in the OCCASIONAL band (5-29 percent). This agrees with that review's own classification of sensorineural hearing loss as one of the "less common" findings, which the curation SOP maps to OCCASIONAL. Note that PMID:30778726 warns that de Brouwer's cohort did not specifically comment on hearing, so the true rate may be higher than the published counts suggest.

Show evidence (2 references)

PMID:30778726 SUPPORT Human Clinical

"In addition, we note the presence of sensorineural hearing loss in two of our patients."

Explicit count of affected individuals within a defined three-patient cohort.

PMID:42226002 SUPPORT Human Clinical

"Less common but more peculiar findings included sensorineural hearing loss, autistic traits, self-injurious behavior, and motor stereotypies."

Places sensorineural hearing loss in the less common but more specific category across the whole published series.

Head and Neck 1

Abnormal Facial Shape Abnormal facial shape HP:0001999

Severity: MILD

No frequency band is asserted. The PMID:42226002 review lists mild facial dysmorphisms among the most frequent features across 17 cases but gives no count, and the individual features vary between families.

Show evidence (2 references)

PMID:33100873 SUPPORT Human Clinical

"behavioral abnormalities, including aggression and short temper with variable dysmorphic features, including smooth philtrum, epicanthal folds, down slanting palpebral fissures, broad nasal root, full lips, everted lower lip, hypodontia, and misaligned or conical shaped teeth"

Enumerates the reported dysmorphic features and states their variability.

PMID:42226002 SUPPORT Human Clinical

"Across 17 cases, the most frequent features were moderate/severe intellectual disability, delayed/absent speech, aggressive behavior, microcephaly, mild facial dysmorphisms, motor delay, and short stature."

Confirms that facial dysmorphism is common but mild across the published series.

Metabolism 1

Hyperuricemia Hyperuricemia HP:0002149

No frequency band is asserted. Hyperuricaemia has been reported in exactly one family (two siblings) out of the roughly 30 published patients, and no other cohort reports urate measurements at all, so there is no denominator for a population estimate and the observation may be family-specific.

Show evidence (1 reference)

PMID:35144859 SUPPORT Human Clinical

"Both patients also had features of Lesch-Nyhan syndrome, including hyperuricemia and self-injurious behavior, but without pathogenic variants in HPRT1."

The only published observation of hyperuricaemia in PUS7 deficiency, with the HPRT1 differential explicitly excluded.

Musculoskeletal 1

Hypotonia Hypotonia HP:0001252

Attribution caveat, not a frequency claim. Both brothers in PMID:33100873 also carry a splice-acceptor variant in AASS, and that same paper states that hyperlysinaemia type I (the AASS phenotype) itself presents with "nonspecific seizure, hypotonia, mildly delayed psychomotor development". The hypotonia in those two boys therefore cannot be attributed to PUS7 alone, which is why the evidence is curated as PARTIAL and no frequency band is given. See the hyperlysinaemia entry in differential_diagnoses.

Show evidence (1 reference)

PMID:33100873 PARTIAL Human Clinical

"He had ID, gross motor delay along with hypotonia."

Documents hypotonia in a PUS7 patient who also carries an AASS variant, so the attribution to PUS7 is partial.

Nervous System 11

Intellectual Disability VERY_FREQUENT Intellectual disability HP:0001249

Derivation: 6/6 in PMID:30526862, 3/3 in PMID:30778726, 2/2 in PMID:31583274, 2/2 in PMID:33100873 and 1/1 in PMID:37067188, i.e. 14/14 individuals in the cohorts that report individual-level data (100 percent, VERY_FREQUENT band 80-100 percent). The PMID:42226002 review independently lists moderate/severe intellectual disability first among the most frequent features across 17 cases.

Show evidence (2 references)

PMID:30526862 SUPPORT Human Clinical

"All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior."

Documents intellectual disability in all six individuals of the founding cohort.

PMID:42226002 SUPPORT Human Clinical

Confirms moderate to severe intellectual disability as the leading feature across the whole published series.

Delayed Speech and Language Development VERY_FREQUENT Delayed speech and language development HP:0000750

Derivation: 6/6 in PMID:30526862 (speech delay named in the title and in the all-individuals sentence), plus both siblings in PMID:31583274 and both brothers in PMID:33100873, i.e. at least 10/10 of the individuals for whom the feature is reported. The PMID:42226002 review lists delayed/absent speech second among the most frequent features across 17 cases.

Show evidence (2 references)

PMID:30526862 SUPPORT Human Clinical

"All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior."

Speech delay in all six individuals of the founding cohort.

PMID:30778726 SUPPORT Human Clinical

"He showed a severe speech delay and his expressive vocabulary was limited to about 30 words."

Illustrates the severity of the expressive language deficit at age 16 in one proband.

Absent or Near-Absent Speech Absent speech HP:0001344

No frequency band is asserted. The distinction between severely delayed and truly absent speech is not separately counted in any cohort abstract; the PMID:42226002 review groups the two together as "delayed/absent speech", and PMID:33100873 reports two brothers who cannot speak. That is not a usable denominator for absent speech alone.

Show evidence (1 reference)

PMID:33100873 SUPPORT Human Clinical

"described as developmental delay, poor or absent speech, intellectual disability, short stature, mild to progressive microcephaly"

Names poor or absent speech as part of the defining IDDABS description.

Aggressive Behavior VERY_FREQUENT Aggressive behavior HP:0000718

Derivation: 6/6 in PMID:30526862, 2/3 in PMID:30778726 (index 3 was described as an obedient child and explicitly did not show aggressiveness like his brother), 2/2 in PMID:31583274 and 1/1 in PMID:37067188 = 11/12, i.e. 92 percent, in the VERY_FREQUENT band (80-100 percent).

Show evidence (3 references)

PMID:30526862 SUPPORT Human Clinical

"All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior."

Aggressive behaviour in all six individuals of the founding cohort.

PMID:42226002 SUPPORT Human Clinical

"These features are common but non-specific, with the exception of aggressiveness that manifests at a very early age."

Establishes the early age of onset that makes aggression the discriminating feature of this disorder.

PMID:30778726 PARTIAL Human Clinical

"Psychological evaluation indicated attention deficit hyperactivity but he did not show aggressiveness like his brother."

Recorded as PARTIAL because it is the one documented affected sibling without aggression, and it is the case that keeps the derived band at 11/12 rather than 12/12.

Global Developmental Delay Global developmental delay HP:0001263

No frequency band is asserted. The PMID:42226002 review lists motor delay among the most frequent features across 17 cases but gives no count, and the individual cohorts describe motor development inconsistently (some children walked at a normal age, others at 20 to 24 months). Rather than convert a qualitative list position into a band, the band is omitted.

Show evidence (1 reference)

PMID:37067188 SUPPORT Human Clinical

"which results in a neurodevelopmental phenotype characterized by various degrees of psychomotor delay, acquired microcephaly, aggressive behavior, and intellectual disability"

Names variable psychomotor delay as a defining component of the phenotype.

Motor Delay Motor delay HP:0001270

No frequency band is asserted, for the same reason as global developmental delay: the PMID:42226002 review names motor delay among the most frequent features across 17 cases but publishes no per-feature count, and no cohort abstract supplies a usable denominator.

Show evidence (2 references)

PMID:42226002 SUPPORT Human Clinical

Lists motor delay among the most frequent features of the published series.

PMID:33100873 SUPPORT Human Clinical

"He had ID, gross motor delay along with hypotonia."

Individual-level documentation of gross motor delay in one affected brother.

Self-Injurious Behavior OCCASIONAL Self-injurious behavior HP:0100716

Derivation: 1/1 in PMID:37067188 and 2/2 in PMID:35144859, i.e. 3 individuals against the roughly 17 enumerated in the PMID:42226002 review, approximately 18 percent, in the OCCASIONAL band (5-29 percent). That review independently classifies self-injurious behaviour as one of the "less common" findings.

Show evidence (2 references)

PMID:37067188 SUPPORT Human Clinical

"We describe the case of a male infant with a homozygous truncating pathogenic variant in the PUS7 gene (c.329_332delCTGA; p.Thr110Argfs*4) who, in addition to the previously mentioned features, displays self-injurious behavior, sleep disturbances and motor stereotypies."

First dedicated report of self-injurious behaviour in a genetically confirmed PUS7 patient.

PMID:35144859 SUPPORT Human Clinical

"Both patients also had features of Lesch-Nyhan syndrome, including hyperuricemia and self-injurious behavior, but without pathogenic variants in HPRT1."

Independent replication in two further PUS7-deficient siblings, with the HPRT1 genotype excluded.

Autistic Behavior OCCASIONAL Autistic behavior HP:0000729

Derivation: autistic features in both siblings of PMID:31583274 and a formal autism spectrum disorder diagnosis in the proband of PMID:35144859, i.e. 3 individuals against roughly 17 enumerated in the PMID:42226002 review, approximately 18 percent, in the OCCASIONAL band (5-29 percent). That review independently classifies autistic traits as one of the "less common" findings.

Show evidence (2 references)

PMID:31583274 SUPPORT Human Clinical

"further confirming the pathogenic role of PUS7 in ID syndromes with autistic features, speech delays, and aggressive behaviors"

Documents autistic features in a genetically confirmed PUS7 family.

PMID:35144859 SUPPORT Human Clinical

"These patients exhibited a neurodevelopmental phenotype including autism spectrum disorder in the proband."

Formal autism spectrum disorder diagnosis in an independent PUS7-deficient proband.

Sleep Disturbance Sleep disturbance HP:0002360

No frequency band is asserted. Sleep disturbance is documented in the single patient of PMID:37067188 and is not enumerated in any cohort with a denominator; a single case is below the 1 percent threshold at which the curation SOP directs the band to be omitted entirely.

Show evidence (1 reference)

PMID:37067188 SUPPORT Human Clinical

"displays self-injurious behavior, sleep disturbances and motor stereotypies"

The single-case report that introduced sleep disturbance into the phenotype.

Hyperactivity Hyperactivity HP:0000752

No frequency band is asserted; no cohort reports a count for hyperactivity against a stated denominator.

Show evidence (2 references)

PMID:33100873 SUPPORT Human Clinical

"delayed psychomotor development, hyperactivity, seizure, along with mild to swear aggressive behavior"

Hyperactivity is part of the published clinical description of IDDABS.

PMID:30778726 SUPPORT Human Clinical

"Psychological evaluation indicated attention deficit hyperactivity but he did not show aggressiveness like his brother."

Individual-level documentation of attention deficit hyperactivity in an affected sibling.

Seizure Seizure HP:0001250

Deliberately curated with a REFUTE item alongside the report. The IDDABS description in PMID:33100873 lists seizure, but the only individual-level seizure in that paper is in a proband with a second pathogenic locus (AASS), and PMID:30778726 states positively that its three patients lacked epilepsy. No frequency band is asserted, and clinicians should not expect epilepsy in this disorder.

Show evidence (2 references)

PMID:33100873 PARTIAL Human Clinical

"He was also reported difficulties in swallowing with nonspecific seizure, hypotonia, mildly delayed psychomotor development."

The only individual-level seizure report in the PUS7 literature, in a proband who also carries an AASS splice-acceptor variant, hence PARTIAL.

PMID:30778726 REFUTE Human Clinical

"While the phenotype we present in the three study patients supports the consistent involvement of cognition and postnatal brain growth and lack of epilepsy in PUS7 deficiency, it also suggests that other aspects are more variable."

Positively asserts the absence of epilepsy as a consistent feature of PUS7 deficiency, refuting seizures as a core phenotype.

Growth 1

Short Stature FREQUENT Short stature HP:0004322

Derivation: 6/6 in PMID:30526862, 2/3 in PMID:30778726 (index 1 had normal height at the 33rd centile; the two Egyptian siblings had heights of minus 4 and minus 6.6 standard deviations) and 0/2 in PMID:31583274 = 8/11, i.e. 73 percent, in the FREQUENT band (30-79 percent). PMID:33100873, PMID:35144859 and PMID:37067188 do not give per-individual stature data in their abstracts and are excluded from the denominator.

Show evidence (2 references)

PMID:30526862 SUPPORT Human Clinical

"All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior."

Short stature in all six individuals of the founding cohort.

PMID:30778726 PARTIAL Human Clinical

"Short stature and hearing loss were variable in these patients."

Recorded as PARTIAL because it documents the variability that keeps the band below VERY_FREQUENT.

Other 4

Progressive Microcephaly FREQUENT Progressive microcephaly HP:0000253

Course: PROGRESSIVE

Derivation: 6/6 in PMID:30526862, 3/3 in PMID:30778726, 0/2 in PMID:31583274 (the missense family explicitly lacks microcephaly), 1/2 in PMID:33100873 (microcephaly documented for patient IV-1 only) and 1/1 in PMID:37067188 = 11/14, i.e. 79 percent, which falls in the FREQUENT band (30-79 percent). The band is deliberately not raised to VERY_FREQUENT because the hypomorphic missense genotype spares head growth.

Show evidence (2 references)

PMID:30778726 SUPPORT Human Clinical

Establishes the progressive character of the microcephaly in three individuals from two families.

PMID:31583274 PARTIAL Human Clinical

"We report a novel PUS7 homozygous mutation resulting in p.Gly128Arg amino-acid translation in a consanguineous Afghani family presenting with similar but milder clinical features without microcephaly and short stature"

Recorded as PARTIAL because it documents the exception: a PUS7 family with no microcephaly at all. This is the observation that keeps the band at FREQUENT rather than VERY_FREQUENT.

Motor Stereotypy OCCASIONAL Motor stereotypy HP:0000733

Derivation: motor stereotypies in 1/1 in PMID:37067188 and inappropriate stereotypic movements with head nodding in 1 of the 3 patients in PMID:30778726, i.e. 2 individuals against roughly 17 enumerated in the PMID:42226002 review, approximately 12 percent, in the OCCASIONAL band (5-29 percent). That review independently classifies motor stereotypies as one of the "less common" findings.

Show evidence (2 references)

PMID:30778726 SUPPORT Human Clinical

"He also had behavioral problems including inappropriate stereotypic movements, head nodding, bruxism and sometimes tantrums."

Individual-level documentation of stereotyped movements in an affected proband.

PMID:42226002 SUPPORT Human Clinical

"Less common but more peculiar findings included sensorineural hearing loss, autistic traits, self-injurious behavior, and motor stereotypies."

Places motor stereotypies among the less common but diagnostically suggestive findings.

Smooth Philtrum Smooth philtrum HP:0000319

No frequency band is asserted; the feature is described qualitatively as one of several variable dysmorphic findings without a denominator.

Show evidence (1 reference)

PMID:33100873 SUPPORT Human Clinical

"variable dysmorphic features, including smooth philtrum, epicanthal folds, down slanting palpebral fissures"

Names smooth philtrum among the recurrent dysmorphic features.

Everted Lower Lip Vermilion Everted lower lip vermilion HP:0000232

No frequency band is asserted; the feature is described qualitatively without a denominator.

Show evidence (1 reference)

PMID:33100873 SUPPORT Human Clinical

"full lips, everted lower lip, hypodontia, and misaligned or conical shaped teeth"

Names the everted lower lip among the recurrent oro-facial features.

🧬

Genetic Associations

PUS7

Gene: PUS7 hgnc:26033 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:30778726 SUPPORT Human Clinical

"Our results confirm that PUS7 is a bona fide Mendelian disease gene and expand the list of human diseases caused by impaired pseudouridylation."

Independent replication establishing PUS7 as a definitive Mendelian disease gene.

PMID:31583274 SUPPORT Human Clinical

"PUS7 encodes for a pseudouridine synthase 7 that catalyzes the isomerization of RNA uridine to RNA pseudouridine (Psi), which is the most abundant modified nucleotide found in all cellular RNAs and which may function as an RNA chaperone."

Describes the gene product and its enzymatic function.

💊

Medical Actions

Special Education and Developmental Support

Action: special education Ontology label: Supportive Care NCIT:C15747

There is no disease-modifying therapy. Management is entirely supportive and is built around structured special education, which affected children in the published cohorts have received.

Target Phenotypes: Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:30778726 SUPPORT Human Clinical

"He was admitted in a school for special education."

Documents special-education placement as the management actually applied to an affected proband.

Speech and Language Therapy

Action: Speech Language Therapy NCIT:C159273

Speech delay is near-universal and is often the presenting complaint, so speech and language therapy is a core component of supportive management. Expressive vocabulary can remain very limited into adolescence, and augmentative communication should be considered where speech is absent.

Target Phenotypes: Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:30778726 PARTIAL Human Clinical

"He showed a severe speech delay and his expressive vocabulary was limited to about 30 words."

Establishes the indication for speech and language therapy; no efficacy data exist, so support is PARTIAL.

Risperidone for Aggressive Behavior

Action: Pharmacotherapy NCIT:C15986

Agent: risperidone CHEBI:8871

Aggression is the most burdensome behavioural feature and has been managed pharmacologically. Risperidone was introduced in a 16-year-old proband who presented with aggressive behaviour.

Target Phenotypes: Aggressive behavior HP:0000718

Show evidence (1 reference)

PMID:30778726 PARTIAL Human Clinical

"We re-evaluated him at age 16 yrs, he presented with aggressive behavior and Risperidone treatment was introduced."

Documents that risperidone was used for the aggression, without reporting response.

Hearing Amplification

Action: hearing aid provision Ontology label: Supportive Care NCIT:C15747

Sensorineural hearing loss can be progressive and severe, and can be masked early on by coexisting middle-ear effusion. Formal audiological assessment is warranted in every affected child, and hearing aids have been fitted in at least one reported patient.

Target Phenotypes: Sensorineural hearing impairment HP:0000407

Show evidence (1 reference)

PMID:30778726 SUPPORT Human Clinical

"Further, he developed severe sensorineural hearing loss and hearing aid was used."

Documents hearing-aid use in an affected proband with progressive sensorineural hearing loss.

Allopurinol for Hyperuricemia

Action: Pharmacotherapy NCIT:C15986

Agent: allopurinol CHEBI:40279

Where hyperuricaemia is present it is treatable and its complications (urate nephropathy, nephrolithiasis, gout) are preventable, which makes measuring serum urate one of the few actionable investigations in this disorder. The two siblings in whom hyperuricaemia was documented were treated with allopurinol.

Target Phenotypes: Hyperuricemia HP:0002149

Show evidence (1 reference)

PMID:35144859 PARTIAL Human Clinical

"Both patients also had features of Lesch-Nyhan syndrome, including hyperuricemia and self-injurious behavior, but without pathogenic variants in HPRT1."

Establishes the treatable indication. Support is PARTIAL because the cached abstract documents the hyperuricaemia but not the allopurinol prescription or its outcome.

Genetic Counselling and Carrier Testing

Action: Genetic Counseling NCIT:C15240

Because inheritance is autosomal recessive and most reported families are consanguineous, carrier testing and counselling with a 25 percent sibling recurrence risk follow directly from a molecular diagnosis. The diagnostic testing itself is modelled in the diagnosis: section rather than here.

Show evidence (1 reference)

PMID:42226002 SUPPORT Human Clinical

"We recommend looking for PUS7 pathological variants when performing whole exome sequencing in children with this constellation of neurodevelopmental and behavioral signs."

An explicit diagnostic recommendation from the most recent review of the disorder.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from PUS7-Related Neurodevelopmental Disorder:

PUS3-related intellectual disability and microcephaly syndrome MONDO:0014886

Overlapping Features The single most confusable entity. PUS3 (hgnc:25461) is another stand-alone pseudouridine synthase whose loss causes an autosomal recessive intellectual disability and microcephaly syndrome (MONDO:0014886, OMIM:617051, also known as MRT55). Both disorders are described in the literature as caused by "impaired pseudouridylation" and both were characterised by overlapping author groups, so 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 positions 38 and 39, whereas PUS7 acts at position 13 (and at position 35 of pre-tRNA-Tyr). A tRNA modification assay therefore distinguishes them biochemically, and this is the cleanest functional discriminator.
Clinical: the PUS3 MONDO entity carries severe growth deficiency, strabismus and extensive dermal melanocytosis as label-level features. Dermal melanocytosis has never been reported in PUS7 deficiency, and the PUS7 behavioural signature of very-early-onset aggression is not part of the PUS3 label.

Show evidence (2 references)

PMID:27055666 SUPPORT Human Clinical

"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:30778726 SUPPORT Human Clinical

"In 2016, we described a novel intellectual disability and microcephaly syndrome in three affected siblings who all shared a homozygous truncating variant in PUS3 (Shaheen et al. 2016)."

The PUS7 paper itself distinguishes the PUS3 syndrome as a separate entity, in the same authors' words.

PUS1-related myopathy, lactic acidosis and sideroblastic anaemia (MLASA1) Not Yet Curated MONDO:0024553

Overlapping Features The first pseudouridine synthase disease described in humans, caused by biallelic PUS1 variants (hgnc:15508). Despite sharing the "deficient pseudouridylation" mechanism language with PUS7 disease, the phenotype is almost disjoint: a mitochondrial oxidative-phosphorylation disorder restricted to skeletal muscle and bone marrow.

Distinguishing Features

Molecular: PUS1 (hgnc:15508) versus PUS7 (hgnc:26033); MONDO:0024553 versus MONDO:0032687.
Compartment: PUS1 deficiency is proposed to act through deficient pseudouridylation of MITOCHONDRIAL tRNAs, whereas PUS7 acts on cytosolic tRNAs, mRNAs and tRNA-derived fragments. This is the mechanistic reason the two phenotypes barely overlap.
Clinical: MLASA1 presents with exercise intolerance, myopathy, lactic acidosis and sideroblastic anaemia. Intellectual disability, microcephaly and aggression are not part of it, and conversely myopathy, lactic acidosis and sideroblastic anaemia have never been reported in PUS7 deficiency. A patient with anaemia and a raised lactate is not a PUS7 candidate.

Show evidence (2 references)

PMID:15108122 SUPPORT Human Clinical

"Mitochondrial myopathy and sideroblastic anemia (MLASA) is a rare, autosomal recessive oxidative phosphorylation disorder specific to skeletal muscle and bone marrow."

Defines the MLASA phenotype as tissue-restricted to muscle and marrow, which is the clinical discriminator from the CNS-dominated PUS7 disorder.

PMID:15108122 SUPPORT Human Clinical

"We propose deficient pseudouridylation of mitochondrial tRNAs as an etiology of MLASA."

States the mitochondrial-tRNA compartment that separates the PUS1 mechanism from the cytosolic PUS7 mechanism, while showing exactly why the shared "deficient pseudouridylation" phrasing is a confusion hazard.

PUS7L-related neurodevelopmental disorder

Overlapping Features PUS7L (hgnc:25276) is the paralogue of PUS7 and is a separate gene. A patient with severe global developmental delay and epilepsy carrying a homozygous truncating PUS7L variant was noted in passing by the same group that characterised PUS7 disease. Because the gene symbols differ by a single trailing character, this is a high-risk symbol-level confusion, distinct from the mechanism-level confusion posed by PUS1 and PUS3.

Distinguishing Features

Molecular: PUS7L is hgnc:25276, PUS7 is hgnc:26033. They are distinct paralogous genes at distinct loci, and PUS7L has its own tRNA targets, mapped in PMID:41136621.
Clinical: the reported PUS7L phenotype prominently included epilepsy, whereas PMID:30778726 positively asserts the LACK of epilepsy as a consistent feature of PUS7 deficiency. Seizures should therefore push a differential toward PUS7L, not PUS7.

Show evidence (2 references)

PMID:30778726 SUPPORT Human Clinical

"In addition, we recently encountered a patient with severe global developmental delay and epilepsy with a homozygous truncating variant in PUS7L (manuscript under review)."

The only clinical description of a PUS7L patient in the cited literature, written by the PUS7 authors themselves, and the source of the epilepsy-versus-no-epilepsy discriminator.

PMID:41136621 SUPPORT In Vitro

"Through this approach, we uncovered previously unknown targets of several PUS enzymes, including RPUSD1, RPUSD2, PUS3, PUSL1 and PUS7L."

Confirms PUS7L as an enzymatically distinct family member with its own substrate set, not a synonym or isoform of PUS7.

Lesch-Nyhan syndrome MONDO:0010298

Overlapping Features An X-linked disorder of purine metabolism caused by HPRT deficiency, presenting with hyperuricaemia, intellectual disability and severe self-injurious behaviour. Two PUS7-deficient siblings were investigated for Lesch-Nyhan syndrome because they had exactly this combination, and no HPRT1 variant was found. This is therefore a real, documented diagnostic trap, not a theoretical one.

Distinguishing Features

Molecular: Lesch-Nyhan is X-linked and caused by HPRT1 variants; PUS7 disease is autosomal recessive with biallelic PUS7 variants and a NORMAL HPRT1 sequence. Sequencing resolves it.
Biochemical nuance: HPRT1 protein was mildly REDUCED in the PUS7 siblings despite a normal HPRT1 gene, attributed to deregulated translation. A protein-level or enzyme-activity assay may therefore be mildly abnormal in PUS7 disease and should not be read as confirming Lesch-Nyhan.
Clinical: microcephaly, short stature and early-onset aggression point to PUS7; the dystonia, choreoathetosis and gouty arthropathy of classic Lesch-Nyhan have not been reported in PUS7 deficiency.

Show evidence (2 references)

PMID:35144859 SUPPORT Human Clinical

"Both patients also had features of Lesch-Nyhan syndrome, including hyperuricemia and self-injurious behavior, but without pathogenic variants in HPRT1."

Documents the actual clinical confusion and its genetic resolution.

PMID:35144859 SUPPORT In Vitro

Explains why an HPRT1 protein assay can be misleading in PUS7 deficiency.

Hyperlysinaemia type I (AASS-related) Not Yet Curated MONDO:0009388

Overlapping Features Not a phenotypic mimic so much as a documented co-occurring second diagnosis. The two Saudi brothers reported in PMID:33100873 carry both a homozygous PUS7 frameshift and a splice-acceptor variant in AASS, the hyperlysinaemia type I gene (OMIM:238700, the OMIM xref of MONDO:0009388). Any curator importing that paper's phenotype list must decide which findings belong to which locus.

Distinguishing Features

Attribution, not exclusion: the two diagnoses coexist in the same children, so finding one does not exclude the other. That paper itself states that hyperlysinaemia type I presents with nonspecific seizure, hypotonia and mildly delayed psychomotor development, all of which are also recorded for those brothers.
Biochemical: hyperlysinaemia is confirmed by elevated plasma lysine and saccharopinuria, which are not features of PUS7 deficiency and have never been measured in any other PUS7 cohort.

Show evidence (1 reference)

PMID:33100873 SUPPORT Human Clinical

"Patient with hyperlysinemia Type 1 (OMIM# 238700) having nonspecific seizure, hypotonia, mildly delayed psychomotor development, while patients with Saccharopinuria (OMIM# 268700) show mild developmental delay, hyperactivity and speech delay."

The dual-locus paper's own statement that the AASS phenotype includes seizure, hypotonia and psychomotor delay, which is exactly why those findings in its probands cannot be attributed to PUS7 alone.

Smith-Magenis syndrome MONDO:0008434

Overlapping Features The closest non-genetic-family phenocopy on behavioural grounds. Smith-Magenis syndrome, caused by the recurrent 17p11.2 deletion or by intragenic RAI1 variants, combines intellectual disability, sleep disturbance, aggression, self-injurious behaviour, motor stereotypies and short stature. That is a near-complete overlap with the "less common but more peculiar" cluster that PMID:42226002 proposes as the discriminating signature of PUS7 deficiency, which means the very features that are supposed to raise suspicion of PUS7 disease also describe Smith-Magenis. This differential exists because the behavioural gestalt collides, not because the genes or mechanisms are related.

Distinguishing Features

Molecular: a 17p11.2 microdeletion or heterozygous RAI1 variant, autosomal dominant and usually de novo, versus biallelic recessive PUS7. Chromosomal microarray detects the common deletion and will be normal in PUS7 disease.
Sleep: Smith-Magenis has a characteristic inverted circadian melatonin rhythm with the classic phenotype of daytime sleepiness and night waking. The sleep disturbance reported in PUS7 deficiency is a single-case observation with no described circadian signature.
Head size: progressive postnatal microcephaly is a core PUS7 feature and is not characteristic of Smith-Magenis, so serial head-circumference plotting is a cheap discriminator.
Visceral involvement: Smith-Magenis includes craniofacial, skeletal and visceral anomalies. PUS7 deficiency has mild non-specific facial dysmorphism and no visceral anomalies.

Show evidence (2 references)

PMID:20932317 SUPPORT Human Clinical

"Smith-Magenis syndrome (SMS) is a complex syndrome involving intellectual disabilities, sleep disturbance, behavioural problems, and a variety of craniofacial, skeletal, and visceral anomalies."

States the overlapping triad of intellectual disability, sleep disturbance and behavioural problems that makes this a genuine clinical differential, and the visceral involvement that separates it.

PMID:20932317 SUPPORT Human Clinical

"While the majority of SMS cases harbor an ~3.5 Mb common deletion on 17p11.2 that encompasses the retinoic acid induced-1 (RAI1) gene, some patients carry small intragenic deletions or point mutations in RAI1."

Gives the molecular discriminator and, importantly, the reason a normal microarray does not exclude Smith-Magenis; RAI1 sequencing is still needed.

Other tRNA-modification intellectual disability syndromes Not Yet Curated MONDO:0014119

Overlapping Features PUS7 disease sits inside a growing class of autosomal recessive intellectual disability syndromes caused by loss of a single tRNA modification, all of which share intellectual disability with variable microcephaly and short stature and are therefore clinically indistinguishable without sequencing. The record is bound to the ADAT3 entity (MONDO:0014119, adenosine-to-inosine editing at wobble position 34), which is the most common cause of autosomal recessive intellectual disability in Arabia and is therefore the highest-prior alternative in the very populations where PUS7 families have been ascertained.

Distinguishing Features

Molecular: ADAT3 (hgnc:25151) wobble-position inosine editing, NSUN2 (hgnc:25994, MONDO:0012613) 5-methylcytosine, TRMT10A 1-methylguanosine at position 9, WDR4 7-methylguanosine at position 46, THUMPD1 tRNA acetylation. None of these is a pseudouridine synthase, and none produces a position-13 pseudouridine defect.
Assay: the discriminating test is which modification is missing. PUS7 disease shows loss of pseudouridine at tRNA position 13 with other pseudouridine positions in the same tRNAs intact.
Clinical: strabismus is a label-level feature of the ADAT3 entity and is not reported in PUS7 deficiency; conversely very-early-onset aggression is the PUS7 signature.

Show evidence (2 references)

PMID:27055666 SUPPORT Human Clinical

"For example, the most common form of autosomal recessive ID in Arabia was found to be due to mutation of ADAT3, which edits adenosine to inosine at the wobble position 34 of mature tRNA"

Establishes ADAT3 disease as the highest-prior alternative diagnosis in the populations where PUS7 families have been ascertained, and names its distinct modification chemistry.

PMID:30778726 SUPPORT Human Clinical

"Additional Mendelian disorders include TRM10A- and NSUN2-related syndromes of intellectual disability, microcephaly and short stature"

Names two further tRNA-modification syndromes whose stated triad (intellectual disability, microcephaly, short stature) is the same as this disorder's, which is precisely why sequencing rather than phenotyping is the discriminator.

{ }

Source YAML

click to show

name: PUS7-Related Neurodevelopmental Disorder
creation_date: "2026-08-01T00:00:00Z"
category: Mendelian
description: >-
  PUS7-related neurodevelopmental disorder (intellectual developmental disorder
  with abnormal behavior, microcephaly, and short stature; IDDABS, MIM 618342) is
  an ultra-rare autosomal recessive disorder caused by biallelic variants in PUS7,
  which encodes the RNA-independent pseudouridine synthase 7. The core clinical
  picture is moderate to severe intellectual disability with delayed or absent
  speech, postnatal and often progressive microcephaly, poor somatic growth with
  short stature, and behavioural disturbance dominated by aggression that begins
  unusually early. Less common but more distinctive findings include sensorineural
  hearing loss, autistic traits, self-injurious behaviour, motor stereotypies and
  sleep disturbance. Mechanistically, disease alleles abolish PUS7 catalytic
  activity, removing pseudouridine from position 13 of at least ten cytosolic
  tRNAs and from PUS7-dependent mRNA and tRNA-derived-fragment substrates.
  Because PUS7-modified tRNA-derived fragments normally restrain translation
  initiation, loss of the enzyme deregulates global protein synthesis, and the
  developing brain appears to be the tissue least able to tolerate that
  perturbation.
notes: >-
  Named-entity-confusion guardrail. This entry is anchored strictly on
  MONDO:0032687 / OMIM:618342 / PUS7 (HGNC:26033); the anchor was confirmed by
  running `runoak -i sqlite:obo:mondo info MONDO:0032687 -O obo` and reading the
  `relationship: RO:0004003 HGNC:26033 ! PUS7` line before any curation began.
  The pseudouridine synthase family is a high-risk named-entity-confusion class
  because several of its members cause independent Mendelian diseases and the
  literature routinely uses the shared phrase "impaired pseudouridylation" for
  all of them. Three sibling entities are deliberately kept separate here and are
  recorded in `differential_diagnoses`: PUS1 (hgnc:15508) causes myopathy, lactic
  acidosis and sideroblastic anaemia 1 (MONDO:0024553), a mitochondrial
  muscle/marrow disease with no intellectual disability; PUS3 (hgnc:25461) causes
  MONDO:0014886, a distinct autosomal recessive intellectual disability and
  microcephaly syndrome acting at tRNA positions 38 and 39 rather than position
  13; and PUS7L (hgnc:25276) is a separate paralogous gene. Every citation used
  in this entry was checked to name PUS7 specifically, and the several dozen
  PUS7 PubMed hits that are cancer-biology or epitranscriptomic-methodology
  papers were excluded from all clinical claims.

  Blended-phenotype and attribution discipline. Two of the reported cohorts carry
  a confounding second locus or a second diagnosis. (1) In PMID:33100873 the two
  affected Saudi brothers carry, in addition to the homozygous PUS7 frameshift, a
  splice-acceptor variant in AASS, the hyperlysinaemia type I gene; that paper
  itself states that hyperlysinaemia type I patients have "nonspecific seizure,
  hypotonia, mildly delayed psychomotor development". The seizure and hypotonia
  observed in those brothers are therefore curated with `supports: PARTIAL` and
  are explicitly flagged as unattributable to PUS7 alone, and hyperlysinaemia is
  listed as a differential. (2) In PMID:35144859 the two NIH Undiagnosed Diseases
  Program siblings have Lesch-Nyhan-like hyperuricaemia and self-injurious
  behaviour but no HPRT1 variant; the authors propose a secondary,
  translation-mediated reduction in HPRT1 protein as the explanation, which is
  curated as a mechanism node and as a Lesch-Nyhan differential.

  Frequency discipline. Bands are derived only from published individual-level
  denominators and the arithmetic is recorded in each phenotype's `notes:`. The
  usable cohorts are PMID:30526862 (6 individuals), PMID:30778726 (3
  individuals), PMID:31583274 (2 siblings), PMID:33100873 (2 brothers),
  PMID:35144859 (2 siblings) and PMID:37067188 (1 individual). Where only a
  qualitative statement exists (for example the PMID:42226002 review's list of
  "the most frequent features" across 17 cases, with no per-feature counts) the
  band is omitted rather than guessed; the sole exception is the group of
  features that review explicitly calls "less common", which is mapped to
  OCCASIONAL and is stated as such in the relevant notes. The 13-patient cohort
  in PMID:42249560 reports no per-feature counts in its abstract, so it
  contributes to the case-count prevalence estimate but not to any frequency
  band.

  GeneReviews. No GeneReviews chapter exists for this disorder. Two PubMed
  E-utilities searches were run and both returned zero results: `PUS7
  GeneReviews[All Fields]` and `pseudouridine synthase GeneReviews[TI]`. A
  `grep -rl "PUS7" references_cache/` at curation time returned only the primary
  papers cited below plus PMID:39091849 (a tRNA-acetylation paper that cites
  PMID:30526862 in its bibliography), confirming no cached GeneReviews text was
  overlooked.

  Structured-source citations unavailable, and in this case largely unavailable
  upstream too. Two things were checked rather than assumed. (1) Orphanet: an
  EBI OLS4 search of ORDO for `PUS7` returns 0 hits, and the deep-research run
  independently reported that no PUS7-specific ORPHA entity exists. There is
  therefore no ORPHA code to cite, not merely an uncachable one. (2) ClinGen:
  the deep-research run reports zero gene-disease validity, dosage, and
  actionability assertions for PUS7, so there is no `CGGV:` or `CGDS:` assertion
  to cite either. Independently of that, `data/orphadata/`, `data/clingen/` and
  `data/clingen-dosage/` in this working tree contain only MANIFEST.yaml stubs
  with no bulk data, and those pins are stale and un-refreshable pending #7622,
  so no structured-source record could have been generated regardless. The
  gene-disease relationship is supported here entirely by primary literature.
  Gene2Phenotype does carry PUS7 on the DD panel (G2P02633, biallelic,
  loss of function, confidence Strong) but dismech has no G2P reference prefix.

  Deep research provenance. `just research-disorder claude_code
  PUS7-Related_Neurodevelopmental_Disorder` was run on 2026-08-01 (17.5 minutes,
  12 web searches, 95 turns, 47 citations, models claude-haiku-4-5 and
  claude-opus-5[1m]); the report is at
  research/PUS7-Related_Neurodevelopmental_Disorder-deep-research-claude_code.md.
  Its NEC preflight independently reached the same conclusion recorded above.
  Every PMID it suggested that is cited here was fetched with
  `just fetch-reference` and every snippet was taken from the resulting cache
  file, not from the report.

  Oncology-literature guardrail. Roughly half of the PUS7 PubMed record set is
  cancer biology in which PUS7 is OVEREXPRESSED and its INHIBITION is the
  proposed therapy - the mechanistic opposite of this recessive
  loss-of-function disorder. The PUS7 inhibitors developed for glioblastoma (C4
  and C17/NSC107512, PMID:35121864) are therefore conceptually contraindicated
  here and are deliberately not curated as treatments. PMID:35121864 and
  PMID:35292784 are cited in this entry only for the substrate-level mechanisms
  they establish (codon-specific translational control via tRNA pseudouridine,
  and the mTOG-PABPC1 translational brake), never for their prognostic or
  therapeutic claims.

  Full-text versus abstract snippets. PMID:30778726 and PMID:27055666 are cached
  as PubMed Central full text, so several snippets in this entry are taken from
  their bodies rather than their abstracts (the individual patient descriptions,
  the PUS1/PUS3/PUS7L paragraph, and the treatment sentences). All other snippets
  are from abstracts.
disease_term:
  preferred_term: PUS7-related neurodevelopmental disorder
  term:
    id: MONDO:0032687
    label: intellectual developmental disorder with abnormal behavior, microcephaly, and short stature
parents:
- Neurodevelopmental Disorder
- Intellectual Disability
synonyms:
- intellectual developmental disorder with abnormal behavior, microcephaly, and short stature
- IDDABS
- PUS7 deficiency
- PUS7-related syndrome
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      The clinical burden is overwhelmingly neurodevelopmental and behavioural:
      intellectual disability, speech delay, microcephaly, aggression, autistic
      traits and stereotypies.
    evidence:
    - reference: PMID:42226002
      reference_title: "PUS7 Deficiency: Phenotypical Expansion of PUS7-Related Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Pathogenic variants in PUS7, encoding pseudouridine synthase 7, cause a
        rare neurodevelopmental disorder marked by intellectual disability,
        microcephaly, short stature, and behavioral disturbances.
      explanation: >-
        The 2026 review states in one sentence that the disorder is defined by
        neurological and behavioural features, supporting a neurologic chapter
        assignment.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A monogenic autosomal recessive Mendelian disorder identified and diagnosed
      by exome or genome sequencing.
    evidence:
    - reference: PMID:33100873
      reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Intellectual developmental disorder with abnormal behavior, microcephaly
        and short stature (IDDABS), (OMIM# 618342) is an autosomal recessive
        condition
      explanation: >-
        Names the OMIM entity that MONDO:0032687 cross-references and states its
        autosomal recessive Mendelian basis.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Disease requires biallelic PUS7 variants. Every family reported to date has
    been homozygous, and most have been consanguineous; heterozygous carrier
    parents are unaffected. Recurrence risk for siblings of an affected proband is
    25 percent, and carrier testing plus genetic counselling are indicated for
    at-risk relatives.
  evidence:
  - reference: PMID:33100873
    reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intellectual developmental disorder with abnormal behavior, microcephaly and
      short stature (IDDABS) is an autosomal recessive disorder is caused by
      homozygous mutation in the PUS7 gene (616261) that is located on chromosome
      7q22.
    explanation: >-
      States the autosomal recessive mode and the biallelic (homozygous)
      requirement at the PUS7 locus.
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe two families in which two different homozygous PUS7 mutations
      (missense and frameshift deletion) segregate with a phenotype comprising
      intellectual disability and progressive microcephaly.
    explanation: >-
      Documents segregation of homozygous alleles with the phenotype in two
      independent consanguineous families.
prevalence:
- population: Worldwide reported literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based prevalence study exists. The published case count is the
    only defensible measure. PMID:42226002 (2026) states that only 16 patients had
    been described since the first report in 2018 and reviews 17 cases including
    its own; PMID:42249560 (2026) adds 13 further patients carrying 15 new
    variants. The cumulative published total is therefore about 30 individuals
    worldwide, which places the disorder in the ultra-rare band. No Orphanet
    prevalence class is adopted, because no Orphanet entity for this disorder
    exists to adopt one from. An earlier revision of this note asserted
    "Orphanet codes the disorder as ORPHA:544510"; that identifier was unsourced
    and is retracted here. It appears nowhere in the deep-research report or its
    citations sidecar, and MONDO:0032687 carries no ORPHA xref at all - its
    cross-references are DOID:0081265, GARD:0018516, MEDGEN:1675423, OMIM:618342
    and UMLS:C5193039. This matches the entry-level notes, which record that an
    OLS4 search of ORDO for PUS7 returns zero hits. Because the claim sat in
    prose rather than in a snippet, the reference validator could not have
    caught it.
  evidence:
  - reference: PMID:42226002
    reference_title: "PUS7 Deficiency: Phenotypical Expansion of PUS7-Related Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since the first report in 2018, only 16 patients have been described.
    explanation: >-
      Gives the published worldwide case count as of the 2026 review, supporting
      an ultra-rare classification based on cases in the literature.
  - reference: PMID:42249560
    reference_title: "Novel Variants in PUS7 Associated With Intellectual Disability and Growth Retardation: Expanding the Clinical Spectrum in 13 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, we report 13 new cases carrying 15 new variants.
    explanation: >-
      Supplies the second component of the cumulative published case count.
pathophysiology:
- name: Biallelic PUS7 Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    The disorder is initiated by inheritance of two damaging PUS7 alleles. The
    reported allelic spectrum includes frameshift alleles, nonsense alleles, a
    deletion of the penultimate exon that escapes nonsense-mediated decay but
    removes the C-terminal catalytic region, and missense alleles. Missense
    alleles appear to behave as hypomorphs, producing a milder phenotype without
    microcephaly or short stature.
  genes:
  - preferred_term: PUS7
    term:
      id: hgnc:26033
      label: PUS7
  evidence:
  - reference: PMID:30526862
    reference_title: "Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe six persons from three families with three homozygous protein
      truncating variants in PUS7
    explanation: >-
      Establishes biallelic protein-truncating PUS7 alleles as the initiating
      lesion in the founding cohort.
  - reference: PMID:31583274
    reference_title: "A novel PUS7 mutation causes intellectual disability with autistic and aggressive behaviors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The absence of highly extreme phenotypes such as short stature or
      microcephaly in this family might reflect genotype–phenotype correlation,
      since this family presented with a PUS7 missense mutation that may be
      hypomorphic, while previously reported families carried nonsense or
      frameshift mutations that may cause loss of function.
    explanation: >-
      Documents the allelic spectrum and the proposed hypomorph-versus-null
      genotype-phenotype gradient.
  downstream:
  - target: Loss of Pseudouridine Synthase 7 Catalytic Activity
    description: >-
      Damaging biallelic alleles remove or inactivate the TruD-family
      pseudouridine synthase encoded by PUS7.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30526862
      reference_title: "Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We show that the disease-related variants lead to abolishment of PUS7
        activity on both tRNA and mRNA substrates.
      explanation: >-
        Directly links the patient alleles to abolished enzymatic activity.
- name: Loss of Pseudouridine Synthase 7 Catalytic Activity
  biological_scale: MOLECULAR
  description: >-
    PUS7 is an RNA-independent (stand-alone) pseudouridine synthase of the TruD
    family that isomerises uridine to 5-ribosyluracil without a guide snoRNA. Loss
    of its activity removes pseudouridine from every class of PUS7 substrate at
    once: cytosolic tRNAs, a defined set of mRNAs, and tRNA-derived small
    fragments.
  molecular_functions:
  - preferred_term: pseudouridine synthase activity
    term:
      id: GO:0009982
      label: pseudouridine synthase activity
    modifier: DECREASED
  - preferred_term: tRNA pseudouridine synthase activity
    term:
      id: GO:0106029
      label: tRNA pseudouridine synthase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: pseudouridine synthesis
    term:
      id: GO:0001522
      label: pseudouridine synthesis
    modifier: DECREASED
  evidence:
  - reference: PMID:30526862
    reference_title: "Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PUS7 encodes the RNA-independent pseudouridylate synthase 7.
    explanation: >-
      Identifies the gene product whose activity is lost, and its RNA-independent
      (guide-RNA-free) mode of substrate recognition.
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Furthermore, the missense variant of the S. cerevisiae ortholog failed to
      complement the growth defect of S. cerevisiae pus7Δ trm8Δ mutants.
    explanation: >-
      Yeast complementation shows that a patient missense allele is a complete
      loss-of-function at the level of enzyme activity, not merely a
      destabilising substitution.
  downstream:
  - target: Depletion of tRNA Pseudouridine at Position 13
    description: >-
      Loss of the enzyme removes the position-13 pseudouridine it normally
      installs in cytosolic tRNAs.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30778726
      reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Functional characterization of the two mutations confirmed that both
        result in decreased levels of Ψ13 in tRNAs.
      explanation: >-
        Patient-derived lymphoblastoid cells show the specific loss of the
        PUS7-dependent tRNA modification.
  - target: Loss of PUS7-Dependent mRNA Pseudouridylation
    description: >-
      The same catalytic loss removes pseudouridine from PUS7-dependent mRNA
      substrates.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33100873
      reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Pseudouridylation of mRNA was also decreased, but the functional
        significance of this observation was unclear.
      explanation: >-
        Documents the mRNA arm of the substrate loss and, honestly, its uncertain
        functional weight.
  - target: Loss of Pseudouridylation and Activation of tRNA-Derived Fragments
    description: >-
      PUS7 also pseudouridylates and thereby activates a network of tRNA-derived
      small fragments; loss of the enzyme leaves these fragments unmodified and
      inactive.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29628141
      reference_title: "Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Mechanistically, the Ψ "writer" PUS7 modifies and activates a novel
        network of tRNA-derived small fragments (tRFs) targeting the translation
        initiation complex.
      explanation: >-
        Establishes tRNA-derived fragments as a distinct PUS7 substrate class
        whose activation depends on the modification.
  - target: Loss of 7SK snRNA Pseudouridylation and Enhanced Pol II Elongation
    description: >-
      PUS7 also pseudouridylates the 7SK small nuclear RNA, which restrains RNA
      polymerase II promoter-proximal pausing. Whether this arm contributes to
      the human disorder is untested, so the edge belongs to an emerging rather
      than the canonical mechanism model.
    causal_link_type: DIRECT
    hypothesis_groups:
    - pus7_non_translational_arms
    evidence:
    - reference: PMID:41168165
      reference_title: "Pseudouridylation of 7SK by PUS7 regulates Pol II transcription elongation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, we report that pseudouridine synthase 7 (PUS7) can mediate
        pseudouridylation of 7SK small nuclear RNA (snRNA), a regulator of RNA
        polymerase II (Pol II) promoter-proximal pausing.
      explanation: >-
        Establishes 7SK snRNA as a fourth PUS7 substrate class, distinct from
        tRNA, mRNA and tRNA-derived fragments.
- name: Loss of 7SK snRNA Pseudouridylation and Enhanced Pol II Elongation
  biological_scale: MOLECULAR
  description: >-
    Loss of PUS7 leaves 7SK snRNA hypo-pseudouridylated, which releases the
    positive transcription elongation factor b complex from 7SK, raises serine-2
    phosphorylation of the RNA polymerase II C-terminal domain, and enhances
    transcription elongation. This is a transcription-level rather than a
    translation-level consequence of the same enzymatic deficit. It is included
    because it is mechanistically established for PUS7 loss, but its relevance
    to the neurodevelopmental phenotype is entirely untested: the work was done
    in colorectal cancer cells, and no patient tissue has been examined.
  biological_processes:
  - preferred_term: regulation of transcription elongation by RNA polymerase II
    term:
      id: GO:0034243
      label: regulation of transcription elongation by RNA polymerase II
    modifier: INCREASED
  evidence:
  - reference: PMID:41168165
    reference_title: "Pseudouridylation of 7SK by PUS7 regulates Pol II transcription elongation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      PUS7 loss leads to hypo-pseudouridylation of 7SK, which promotes
      dissociation of the positive transcription elongation factor b (P-TEFb)
      complex from 7SK. The release of P-TEFb from 7SK increases serine 2
      phosphorylation (Ser2P) in the RNA Pol II C-terminal domain and enhances
      transcription elongation.
    explanation: >-
      The full molecular chain from PUS7 loss to enhanced Pol II elongation,
      demonstrated in cell lines.
- name: Depletion of tRNA Pseudouridine at Position 13
  biological_scale: MOLECULAR
  description: >-
    Patient cells lose pseudouridine specifically at position 13 of at least ten
    different cytosolic tRNAs, with other pseudouridine positions in the same
    tRNAs preserved. The defect is therefore a clean, position-specific ablation
    of one modification rather than a general collapse of tRNA maturation.
  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:33100873
    reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient-derived cells showed decreased pseudouridylation signals
      specifically for PUS7 substrates at position 13 of at least 10 different
      cytosolic tRNAs, but not at other positions.
    explanation: >-
      States both the breadth (at least ten tRNAs) and the specificity (position
      13 only) of the modification loss in patient cells.
  - reference: PMID:31583274
    reference_title: "A novel PUS7 mutation causes intellectual disability with autistic and aggressive behaviors."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All identified PUS7 variants resulted in aberrant pseudouridylation of at
      least 10 cytosolic tRNAs at position 13.
    explanation: >-
      Independent confirmation that the position-13 defect is common to the whole
      reported allelic series.
  downstream:
  - target: Deregulated Global Protein Synthesis
    description: >-
      Loss of a conserved tRNA body modification perturbs the translational
      apparatus. The authors of the founding cohorts attribute the disease to a
      deleterious effect on protein synthesis, but the quantitative step from
      missing Psi-13 to altered translation output has not been measured
      directly in neurons.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30778726
      reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We and others have previously emphasized the predilection of Mendelian
        diseases caused by tRNA modification genes to CNS involvement and how this
        suggests the vulnerability of the brain to any perturbation of tRNA
        modification, presumably through its deleterious effect on protein
        synthesis
      explanation: >-
        The authors state this link as an inference ("presumably"), so the edge is
        curated as INDIRECT with PARTIAL support rather than as a demonstrated
        mechanism.
  - target: Loss of Codon-Specific Translational Control
    description: >-
      PUS7-dependent tRNA pseudouridine is required for codon-biased regulation
      of translation, so losing it releases codon-specific control over which
      transcripts are efficiently translated.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35121864
      reference_title: "Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Mechanistically, we identify PUS7 targets in GSCs through small RNA
        pseudouridine sequencing and show that pseudouridylation of
        PUS7-regulated transfer RNA is critical for codon-specific translational
        control of key regulators of GSCs.
      explanation: >-
        Establishes that the tRNA pseudouridine PUS7 installs governs
        codon-specific translation. The experimental system is glioblastoma stem
        cells rather than neurons, so the substrate-level claim is imported but
        no oncologic claim is.
- name: Loss of Codon-Specific Translational Control
  biological_scale: MOLECULAR
  description: >-
    PUS7-dependent tRNA pseudouridylation biases translation toward or away from
    particular codons, so its loss changes which transcripts are efficiently
    decoded. This is the most satisfying available answer to the central puzzle
    of the disorder: how the loss of a broadly expressed housekeeping RNA writer
    produces a selective, largely neurological phenotype rather than uniform
    cellular failure. The mapping was performed in glioblastoma stem cells, and
    the equivalent codon-level analysis has never been done in neurons or neural
    progenitors.
  biological_processes:
  - preferred_term: regulation of translation
    term:
      id: GO:0006417
      label: regulation of translation
    modifier: DECREASED
  evidence:
  - reference: PMID:35121864
    reference_title: "Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mechanistically, we identify PUS7 targets in GSCs through small RNA
      pseudouridine sequencing and show that pseudouridylation of PUS7-regulated
      transfer RNA is critical for codon-specific translational control of key
      regulators of GSCs.
    explanation: >-
      The direct demonstration that PUS7-dependent tRNA pseudouridine controls
      translation in a codon-specific rather than a global manner.
  downstream:
  - target: Deregulated Global Protein Synthesis
    description: >-
      Loss of codon-level control contributes to the overall derangement of
      translational output.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35121864
      reference_title: "Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: >-
        PUS7 expression and catalytic activity are required for glioblastoma stem
        cell (GSC) tumorigenesis.
      explanation: >-
        Support is PARTIAL: the cited work establishes that PUS7 catalytic
        activity has a translational output with cellular consequences, but it
        does so in a cancer stem cell system, and the quantitative contribution of
        the codon-specific arm to the translational phenotype of PUS7-deficient
        patient cells has not been measured.
- name: Loss of PUS7-Dependent mRNA Pseudouridylation
  biological_scale: MOLECULAR
  description: >-
    PUS7 recognises a UNPsiAR-type sequence motif and pseudouridylates a defined
    set of mRNAs. Patient cells show reduced mRNA pseudouridylation, although the
    functional consequence of this arm has not been established as
    disease-relevant.
  biological_processes:
  - preferred_term: mRNA modification
    term:
      id: GO:0016556
      label: mRNA modification
    modifier: DECREASED
  evidence:
  - reference: PMID:30526862
    reference_title: "Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that the disease-related variants lead to abolishment of PUS7
      activity on both tRNA and mRNA substrates.
    explanation: >-
      Establishes mRNA as a genuine second substrate class lost in patients, not
      only tRNA.
  downstream:
  - target: Deregulated Global Protein Synthesis
    description: >-
      Loss of mRNA pseudouridylation is a candidate contributor to the
      translational phenotype, but its functional weight is explicitly
      undetermined in the source literature.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33100873
      reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: >-
        Pseudouridylation of mRNA was also decreased, but the functional
        significance of this observation was unclear.
      explanation: >-
        The cited text supports the existence of the mRNA defect while explicitly
        declining to attribute function to it, so the edge is PARTIAL.
- name: Loss of Pseudouridylation and Activation of tRNA-Derived Fragments
  biological_scale: MOLECULAR
  description: >-
    PUS7 pseudouridylates a network of tRNA-derived small fragments (tRFs). The
    modification is what activates them; unmodified tRFs cannot engage the
    translation initiation complex.
  evidence:
  - reference: PMID:29628141
    reference_title: "Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mechanistically, the Ψ "writer" PUS7 modifies and activates a novel network
      of tRNA-derived small fragments (tRFs) targeting the translation initiation
      complex.
    explanation: >-
      Identifies the tRF arm and its molecular target, the translation initiation
      complex.
  downstream:
  - target: Failure of tRF-Mediated Restraint of Translation Initiation
    description: >-
      Without the activating pseudouridine, the tRF network can no longer repress
      translation initiation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29628141
      reference_title: "Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        PUS7 inactivation in embryonic stem cells impairs tRF-mediated translation
        regulation, leading to increased protein biosynthesis and defective germ
        layer specification.
      explanation: >-
        Loss-of-function experiment in stem cells demonstrating the failure of the
        tRF regulatory arm.
- name: Failure of tRF-Mediated Restraint of Translation Initiation
  biological_scale: CELLULAR
  description: >-
    PUS7-modified tRFs act as brakes on the translation initiation complex. The
    best-resolved arm is the mini-tRF carrying a 5-prime terminal oligoguanine
    (mTOG): its pseudouridine engages the RNA-recognition-motif domains of
    PABPC1, which blocks recruitment of the translational co-activator PAIP1 and
    represses translation of transcripts carrying pyrimidine-enriched and
    5-prime terminal oligopyrimidine sequences, many of which encode components
    of the protein-synthesis machinery itself. Removing the brake therefore
    releases initiation from its normal ceiling, and does so in a feed-forward
    way because the derepressed transcripts build more translational machinery.
  biological_processes:
  - preferred_term: regulation of translational initiation
    term:
      id: GO:0006446
      label: regulation of translational initiation
    modifier: DECREASED
  - preferred_term: negative regulation of translation
    term:
      id: GO:0017148
      label: negative regulation of translation
    modifier: DECREASED
  evidence:
  - reference: PMID:29628141
    reference_title: "Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      PUS7 inactivation in embryonic stem cells impairs tRF-mediated translation
      regulation, leading to increased protein biosynthesis and defective germ
      layer specification.
    explanation: >-
      Directly names the loss of tRF-mediated translation regulation as the
      consequence of PUS7 inactivation.
  - reference: PMID:35292784
    reference_title: "Pseudouridine-modified tRNA fragments repress aberrant protein synthesis and predict leukaemic progression in myelodysplastic syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Building on evidence that mTOG-Ψ targets polyadenylate-binding protein
      cytoplasmic 1 (PABPC1), we employed isotope exchange proteomics to reveal
      critical interactions between mTOG and functional RNA-recognition motif
      (RRM) domains of PABPC1.
    explanation: >-
      Identifies PABPC1 as the direct molecular target of the pseudouridylated
      tRF, which is what makes this the mechanistically best-resolved arm.
  - reference: PMID:35292784
    reference_title: "Pseudouridine-modified tRNA fragments repress aberrant protein synthesis and predict leukaemic progression in myelodysplastic syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mechanistically, this hinders the recruitment of translational co-activator
      PABPC1-interacting protein 1 (PAIP1)3 and strongly represses the
      translation of transcripts sharing pyrimidine-enriched sequences (PES) at
      the 5' untranslated region (UTR), including 5' terminal oligopyrimidine
      tracts (TOP) that encode protein machinery components
    explanation: >-
      Spells out the repressive step that is lost in PUS7 deficiency and names
      the class of transcripts derepressed, including those encoding the
      translational machinery itself.
  downstream:
  - target: Deregulated Global Protein Synthesis
    description: >-
      Release of the initiation brake increases global protein biosynthesis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35144859
      reference_title: "PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Patient fibroblasts demonstrated upregulation of protein synthesis,
        including elevated MYC protein, but did not exhibit increased rates of
        cell proliferation.
      explanation: >-
        Confirms in cells from PUS7-deficient patients, not only in engineered
        stem cells, that global protein synthesis is upregulated.
- name: Deregulated Global Protein Synthesis
  biological_scale: CELLULAR
  description: >-
    The convergent cellular consequence of losing PUS7 across all three substrate
    classes is loss of translational homeostasis. Fibroblasts from PUS7-deficient
    patients show upregulated protein synthesis with elevated MYC protein, and
    notably this occurs without a corresponding increase in proliferation rate,
    which distinguishes the neurodevelopmental consequence from the proliferative
    consequence of upregulated translation in cancer.
  biological_processes:
  - preferred_term: cytoplasmic translation
    term:
      id: GO:0002181
      label: cytoplasmic translation
    modifier: INCREASED
  - preferred_term: positive regulation of translation
    term:
      id: GO:0045727
      label: positive regulation of translation
    modifier: INCREASED
  cell_types:
  - preferred_term: patient dermal fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:35144859
    reference_title: "PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient fibroblasts demonstrated upregulation of protein synthesis,
      including elevated MYC protein, but did not exhibit increased rates of cell
      proliferation.
    explanation: >-
      The primary human-cell evidence for the translational phenotype, including
      the dissociation from proliferation.
  - reference: PMID:35144859
    reference_title: "PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings strengthen the correlation between neurodevelopmental
      disease, particularly autism spectrum disorders, and the rate of protein
      translation.
    explanation: >-
      Links the translational phenotype to the neurodevelopmental outcome in the
      authors' own framing.
  downstream:
  - target: Impaired Neuronal Development and Function
    description: >-
      Neurons appear to be the cell type least tolerant of deregulated
      translation, which is the proposed reason the phenotype is dominated by
      brain involvement.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30526862
      reference_title: "Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our findings demonstrate that RNA pseudouridylation by PUS7 is essential
        for proper neuronal development and function.
      explanation: >-
        States the neuronal endpoint of the pathway as the founding study's main
        conclusion.
  - target: Secondary Reduction of HPRT1 Protein
    description: >-
      In the two NIH Undiagnosed Diseases Program siblings, deregulated
      translation was accompanied by a mild reduction in HPRT1 protein despite
      normal HPRT1 sequence.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35144859
      reference_title: "PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: >-
        Interestingly, the dysregulation of protein translation also resulted in
        mildly decreased levels of HPRT1 protein suggesting an association between
        dysregulated protein translation and the LNS-like phenotypic findings.
      explanation: >-
        The authors themselves describe this as a suggested association, so the
        edge is INDIRECT with PARTIAL support.
  - target: Impaired Somatic Growth
    description: >-
      Poor pre- and postnatal growth with short stature is a consistent feature of
      the loss-of-function cohorts, plausibly reflecting the same translational
      defect in non-neural tissue, though this has not been demonstrated
      experimentally.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42249560
      reference_title: "Novel Variants in PUS7 Associated With Intellectual Disability and Growth Retardation: Expanding the Clinical Spectrum in 13 Patients."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Recently, papers reported that variants in PUS7 in 16 patients were
        involved in marked growth retardation with microcephaly, associated with
        intellectual disability and behavioral issues such as self-injurious and
        aggressive behavior.
      explanation: >-
        Establishes growth retardation as a core clinical consequence of PUS7
        variants; the mechanistic link to translation is inferred, not measured,
        so the edge is PARTIAL.
- name: Secondary Reduction of HPRT1 Protein
  biological_scale: MOLECULAR
  description: >-
    A translation-level, sequence-independent reduction in hypoxanthine-guanine
    phosphoribosyltransferase protein. This is a proposed explanation for the
    Lesch-Nyhan-like hyperuricaemia and self-injurious behaviour observed in one
    sibling pair, and it has not been replicated in other PUS7 cohorts.
  evidence:
  - reference: PMID:35144859
    reference_title: "PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Interestingly, the dysregulation of protein translation also resulted in
      mildly decreased levels of HPRT1 protein suggesting an association between
      dysregulated protein translation and the LNS-like phenotypic findings.
    explanation: >-
      Reports the reduced HPRT1 protein level and the authors' proposed link to
      the Lesch-Nyhan-like features.
  downstream:
  - target: Purine Metabolic Derangement and Lesch-Nyhan-Like Features
    description: >-
      Reduced HPRT1 protein is proposed to underlie the hyperuricaemia and
      self-injurious behaviour seen without any HPRT1 sequence variant.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35144859
      reference_title: "PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both patients also had features of Lesch-Nyhan syndrome, including
        hyperuricemia and self-injurious behavior, but without pathogenic variants
        in HPRT1.
      explanation: >-
        Documents the clinical endpoint and the crucial negative HPRT1 genotype;
        the causal attribution to reduced HPRT1 protein remains a proposal.
- name: Purine Metabolic Derangement and Lesch-Nyhan-Like Features
  biological_scale: ORGANISM
  description: >-
    Hyperuricaemia with self-injurious behaviour resembling Lesch-Nyhan syndrome,
    observed in PUS7-deficient siblings with a normal HPRT1 gene. This branch of
    the graph is reported in a single family and should not be treated as a core
    feature of the disorder.
  evidence:
  - reference: PMID:35144859
    reference_title: "PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients also had features of Lesch-Nyhan syndrome, including
      hyperuricemia and self-injurious behavior, but without pathogenic variants in
      HPRT1.
    explanation: >-
      The clinical observation defining this node.
- name: Impaired Neuronal Development and Function
  biological_scale: CELLULAR
  description: >-
    The convergent neural consequence. Human evidence is the invariant cognitive
    and behavioural phenotype; experimental support comes from pus7 knockout in
    Drosophila, which reproduces increased activity, disorientation and
    aggressiveness, and from mouse infralimbic prefrontal cortex knockdown, which
    selectively impairs an activity-dependent synaptic plasticity behaviour.
  biological_processes:
  - preferred_term: neuron development
    term:
      id: GO:0048666
      label: neuron development
    modifier: ABNORMAL
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:30526862
    reference_title: "Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Moreover, pus7 knockout in Drosophila melanogaster results in a number of
      behavioral defects, including increased activity, disorientation, and
      aggressiveness supporting that neurological defects are caused by PUS7
      variants.
    explanation: >-
      Animal loss-of-function evidence that the neurological and specifically
      aggressive phenotype follows from loss of the enzyme.
  - reference: PMID:41094471
    reference_title: "PUS7-dependent Ψ reshapes specific synaptic gene exons to facilitate fear extinction memory formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Crucially, PUS7 knockdown in the ILPFC selectively impaired fear extinction
      memory formation without altering baseline fear expression, establishing a
      causal link between Ψ-dependent RNA processing and activity-dependent
      synaptic structural remodeling in this microcircuit.
    explanation: >-
      Region-specific mouse knockdown showing that PUS7 is required for
      activity-dependent synaptic remodelling, a plausible cellular substrate for
      the cognitive phenotype.
  - reference: PMID:33100873
    reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The findings indicated that RNA pseudouridylation, along with tRNA
      modification is important for proper neural development
    explanation: >-
      Independent restatement that the pseudouridylation defect converges on
      neural development.
  downstream:
  - target: Impaired Postnatal Brain Growth
    description: >-
      Defective neuronal development and function translates into failure of
      postnatal head growth.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30778726
      reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In conclusion, we confirm that biallelic PUS7 mutations in humans produce a
        syndrome of intellectual disability, progressive microcephaly and other
        variable features.
      explanation: >-
        Establishes progressive (i.e. postnatal) microcephaly as an outcome of the
        biallelic lesion.
  - target: Cognitive and Behavioural Dysfunction
    description: >-
      The dominant clinical output: intellectual disability, speech delay and
      early-onset aggression.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30526862
      reference_title: "Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All these individuals have intellectual disability with speech delay, short
        stature, microcephaly, and aggressive behavior.
      explanation: >-
        The founding cohort's clinical endpoint, present in all six individuals.
  - target: Impaired Activity-Dependent Synaptic Remodelling
    description: >-
      Beyond the developmental deficit, PUS7 is required in mature mammalian
      cortex for the pseudouridine-dependent RNA processing that supports
      experience-driven synaptic change.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41094471
      reference_title: "PUS7-dependent Ψ reshapes specific synaptic gene exons to facilitate fear extinction memory formation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Fear extinction in the ILPFC drives concomitant exonic Ψ deposition and
        upregulation of synaptogenic transcripts, processes that involve
        pseudouridine synthase PUS7.
      explanation: >-
        Places PUS7 inside the activity-dependent synaptic program in adult
        mammalian prefrontal cortex.
- name: Impaired Activity-Dependent Synaptic Remodelling
  biological_scale: CELLULAR
  description: >-
    A distinct, more disease-proximal neuronal mechanism than the developmental
    one. In mouse infralimbic prefrontal cortex, learning drives pseudouridine
    deposition on exons of synaptic regulatory genes and upregulation of
    synaptogenic transcripts, and PUS7 is required for this. Knocking PUS7 down
    in that region selectively blocks extinction learning while leaving baseline
    behaviour intact, which shows the requirement is for plasticity rather than
    for maintenance. This provides a candidate substrate for the cognitive and
    behavioural phenotype that is separable from the growth phenotype. It is
    mouse knockdown in adult cortex, not a germline model of the human disorder,
    so it is a mechanistic analogy and not a demonstration.
  biological_processes:
  - preferred_term: regulation of synapse structure or activity
    term:
      id: GO:0050803
      label: regulation of synapse structure or activity
    modifier: DECREASED
  - preferred_term: learning
    term:
      id: GO:0007612
      label: learning
    modifier: DECREASED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:41094471
    reference_title: "PUS7-dependent Ψ reshapes specific synaptic gene exons to facilitate fear extinction memory formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Crucially, PUS7 knockdown in the ILPFC selectively impaired fear extinction
      memory formation without altering baseline fear expression, establishing a
      causal link between Ψ-dependent RNA processing and activity-dependent
      synaptic structural remodeling in this microcircuit.
    explanation: >-
      Region-specific mouse knockdown establishing a causal, plasticity-specific
      requirement for PUS7.
  downstream:
  - target: Cognitive and Behavioural Dysfunction
    description: >-
      Failure of activity-dependent synaptic remodelling is a candidate
      contributor to the learning and behavioural phenotype, in addition to the
      developmental deficit.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41094471
      reference_title: "PUS7-dependent Ψ reshapes specific synaptic gene exons to facilitate fear extinction memory formation."
      supports: PARTIAL
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our findings demonstrate that PUS7-mediated Ψ modification
        spatiotemporally regulates activity-dependent RNA dynamics in the ILPFC,
        providing the evidence that epitranscriptomic mechanisms precisely
        coordinate synaptic gene expression within behaviorally defined brain
        sub-region.
      explanation: >-
        Support is PARTIAL because the behavioural readout is rodent fear
        extinction, not the human cognitive or aggressive phenotype, and no
        patient tissue has been examined.
- name: Impaired Postnatal Brain Growth
  biological_scale: ORGANISM
  description: >-
    Head circumference is typically normal or near-normal at birth and falls
    progressively across childhood, which is why the microcephaly is described as
    progressive or acquired rather than congenital. Brain MRI architecture is
    normal in most reported patients.
  biological_processes:
  - preferred_term: brain development
    term:
      id: GO:0007420
      label: brain development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37067188
    reference_title: "A PUS7 gene pathogenic variant causing self-injurious behavior, sleep disturbances, and developmental delay: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PUS7 gene pathogenic variants cause a deficiency in an RNA-independent
      pseudouridine synthase, which results in a neurodevelopmental phenotype
      characterized by various degrees of psychomotor delay, acquired
      microcephaly, aggressive behavior, and intellectual disability.
    explanation: >-
      Explicitly characterises the microcephaly as acquired rather than
      congenital.
- name: Impaired Somatic Growth
  biological_scale: ORGANISM
  description: >-
    Poor overall growth with short stature and low weight, described as marked
    growth retardation in the larger cohorts. Growth failure is a feature of the
    truncating-allele families and was absent in the one reported missense
    (hypomorphic) family.
  evidence:
  - reference: PMID:42249560
    reference_title: "Novel Variants in PUS7 Associated With Intellectual Disability and Growth Retardation: Expanding the Clinical Spectrum in 13 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recently, papers reported that variants in PUS7 in 16 patients were involved
      in marked growth retardation with microcephaly, associated with intellectual
      disability and behavioral issues such as self-injurious and aggressive
      behavior.
    explanation: >-
      Summarises growth retardation as a defining feature of the previously
      published cohort.
- name: Cognitive and Behavioural Dysfunction
  biological_scale: ORGANISM
  description: >-
    Moderate to severe intellectual disability with delayed or absent speech, plus
    a behavioural signature dominated by aggression of unusually early onset, and
    in a minority autistic traits, self-injury, stereotypies and sleep
    disturbance. The 2026 review argues that the core features are non-specific
    but that the very early onset of aggressiveness is the discriminating clue.
  evidence:
  - reference: PMID:42226002
    reference_title: "PUS7 Deficiency: Phenotypical Expansion of PUS7-Related Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These features are common but non-specific, with the exception of
      aggressiveness that manifests at a very early age.
    explanation: >-
      Identifies the discriminating behavioural feature within the otherwise
      non-specific phenotype.
phenotypes:
- name: Intellectual Disability
  category: Neurologic
  description: >-
    Moderate to severe intellectual disability is present in essentially every
    reported individual. Formal IQ measurements in the two Egyptian siblings were
    44 and 48; in one Saudi girl formal testing repeatedly failed because of
    aggression but was judged to be in the severe range.
  frequency: VERY_FREQUENT
  notes: >-
    Derivation: 6/6 in PMID:30526862, 3/3 in PMID:30778726, 2/2 in PMID:31583274,
    2/2 in PMID:33100873 and 1/1 in PMID:37067188, i.e. 14/14 individuals in the
    cohorts that report individual-level data (100 percent, VERY_FREQUENT band
    80-100 percent). The PMID:42226002 review independently lists moderate/severe
    intellectual disability first among the most frequent features across 17
    cases.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:30526862
    reference_title: "Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All these individuals have intellectual disability with speech delay, short
      stature, microcephaly, and aggressive behavior.
    explanation: >-
      Documents intellectual disability in all six individuals of the founding
      cohort.
  - reference: PMID:42226002
    reference_title: "PUS7 Deficiency: Phenotypical Expansion of PUS7-Related Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Across 17 cases, the most frequent features were moderate/severe
      intellectual disability, delayed/absent speech, aggressive behavior,
      microcephaly, mild facial dysmorphisms, motor delay, and short stature.
    explanation: >-
      Confirms moderate to severe intellectual disability as the leading feature
      across the whole published series.
- name: Delayed Speech and Language Development
  category: Neurologic
  description: >-
    Speech delay is a near-universal and frequently disproportionate feature, with
    expressive vocabulary sometimes limited to a few dozen words into adolescence.
  frequency: VERY_FREQUENT
  notes: >-
    Derivation: 6/6 in PMID:30526862 (speech delay named in the title and in the
    all-individuals sentence), plus both siblings in PMID:31583274 and both
    brothers in PMID:33100873, i.e. at least 10/10 of the individuals for whom the
    feature is reported. The PMID:42226002 review lists delayed/absent speech
    second among the most frequent features across 17 cases.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:30526862
    reference_title: "Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All these individuals have intellectual disability with speech delay, short
      stature, microcephaly, and aggressive behavior.
    explanation: >-
      Speech delay in all six individuals of the founding cohort.
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He showed a severe speech delay and his expressive vocabulary was limited to
      about 30 words.
    explanation: >-
      Illustrates the severity of the expressive language deficit at age 16 in one
      proband.
- name: Absent or Near-Absent Speech
  category: Neurologic
  description: >-
    A subset of individuals never acquire useful speech at all, which the reviews
    describe as delayed/absent speech.
  notes: >-
    No frequency band is asserted. The distinction between severely delayed and
    truly absent speech is not separately counted in any cohort abstract; the
    PMID:42226002 review groups the two together as "delayed/absent speech", and
    PMID:33100873 reports two brothers who cannot speak. That is not a usable
    denominator for absent speech alone.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:33100873
    reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      described as developmental delay, poor or absent speech, intellectual
      disability, short stature, mild to progressive microcephaly
    explanation: >-
      Names poor or absent speech as part of the defining IDDABS description.
- name: Progressive Microcephaly
  category: Neurologic
  description: >-
    Head circumference is typically normal at birth and declines progressively,
    reaching values as low as minus 6 standard deviations in adolescence. Brain
    MRI architecture is usually normal, so the microcephaly reflects failure of
    postnatal brain growth rather than a malformation.
  frequency: FREQUENT
  notes: >-
    Derivation: 6/6 in PMID:30526862, 3/3 in PMID:30778726, 0/2 in PMID:31583274
    (the missense family explicitly lacks microcephaly), 1/2 in PMID:33100873
    (microcephaly documented for patient IV-1 only) and 1/1 in PMID:37067188 =
    11/14, i.e. 79 percent, which falls in the FREQUENT band (30-79 percent). The
    band is deliberately not raised to VERY_FREQUENT because the hypomorphic
    missense genotype spares head growth.
  phenotype_term:
    preferred_term: Progressive microcephaly
    term:
      id: HP:0000253
      label: Progressive microcephaly
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe two families in which two different homozygous PUS7 mutations
      (missense and frameshift deletion) segregate with a phenotype comprising
      intellectual disability and progressive microcephaly.
    explanation: >-
      Establishes the progressive character of the microcephaly in three
      individuals from two families.
  - reference: PMID:31583274
    reference_title: "A novel PUS7 mutation causes intellectual disability with autistic and aggressive behaviors."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a novel PUS7 homozygous mutation resulting in p.Gly128Arg
      amino-acid translation in a consanguineous Afghani family presenting with
      similar but milder clinical features without microcephaly and short stature
    explanation: >-
      Recorded as PARTIAL because it documents the exception: a PUS7 family with
      no microcephaly at all. This is the observation that keeps the band at
      FREQUENT rather than VERY_FREQUENT.
- name: Short Stature
  category: Growth
  description: >-
    Poor linear growth with height frequently below minus 4 standard deviations,
    accompanied by low weight. Described as marked growth retardation in the
    larger cohorts.
  frequency: FREQUENT
  notes: >-
    Derivation: 6/6 in PMID:30526862, 2/3 in PMID:30778726 (index 1 had normal
    height at the 33rd centile; the two Egyptian siblings had heights of minus 4
    and minus 6.6 standard deviations) and 0/2 in PMID:31583274 = 8/11, i.e. 73
    percent, in the FREQUENT band (30-79 percent). PMID:33100873, PMID:35144859
    and PMID:37067188 do not give per-individual stature data in their abstracts
    and are excluded from the denominator.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:30526862
    reference_title: "Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All these individuals have intellectual disability with speech delay, short
      stature, microcephaly, and aggressive behavior.
    explanation: >-
      Short stature in all six individuals of the founding cohort.
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Short stature and hearing loss were variable in these patients.
    explanation: >-
      Recorded as PARTIAL because it documents the variability that keeps the band
      below VERY_FREQUENT.
- name: Aggressive Behavior
  category: Behavioral
  description: >-
    Aggression is the behavioural hallmark of the disorder and, unusually, begins
    at a very early age. It can be severe enough to prevent formal cognitive
    testing, and it has been treated pharmacologically with risperidone in at
    least one individual.
  frequency: VERY_FREQUENT
  notes: >-
    Derivation: 6/6 in PMID:30526862, 2/3 in PMID:30778726 (index 3 was described
    as an obedient child and explicitly did not show aggressiveness like his
    brother), 2/2 in PMID:31583274 and 1/1 in PMID:37067188 = 11/12, i.e. 92
    percent, in the VERY_FREQUENT band (80-100 percent).
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:30526862
    reference_title: "Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All these individuals have intellectual disability with speech delay, short
      stature, microcephaly, and aggressive behavior.
    explanation: >-
      Aggressive behaviour in all six individuals of the founding cohort.
  - reference: PMID:42226002
    reference_title: "PUS7 Deficiency: Phenotypical Expansion of PUS7-Related Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These features are common but non-specific, with the exception of
      aggressiveness that manifests at a very early age.
    explanation: >-
      Establishes the early age of onset that makes aggression the discriminating
      feature of this disorder.
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Psychological evaluation indicated attention deficit hyperactivity but he did
      not show aggressiveness like his brother.
    explanation: >-
      Recorded as PARTIAL because it is the one documented affected sibling without
      aggression, and it is the case that keeps the derived band at 11/12 rather
      than 12/12.
- name: Global Developmental Delay
  category: Neurologic
  description: >-
    Global developmental delay with variable psychomotor involvement precedes the
    diagnosis of intellectual disability in most children. Motor milestones are
    frequently delayed, though some individuals walk on time.
  notes: >-
    No frequency band is asserted. The PMID:42226002 review lists motor delay
    among the most frequent features across 17 cases but gives no count, and the
    individual cohorts describe motor development inconsistently (some children
    walked at a normal age, others at 20 to 24 months). Rather than convert a
    qualitative list position into a band, the band is omitted.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:37067188
    reference_title: "A PUS7 gene pathogenic variant causing self-injurious behavior, sleep disturbances, and developmental delay: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      which results in a neurodevelopmental phenotype characterized by various
      degrees of psychomotor delay, acquired microcephaly, aggressive behavior,
      and intellectual disability
    explanation: >-
      Names variable psychomotor delay as a defining component of the phenotype.
- name: Motor Delay
  category: Neurologic
  description: >-
    Delayed acquisition of gross motor milestones, with independent walking
    achieved at up to 24 months in the more severely affected children.
  notes: >-
    No frequency band is asserted, for the same reason as global developmental
    delay: the PMID:42226002 review names motor delay among the most frequent
    features across 17 cases but publishes no per-feature count, and no cohort
    abstract supplies a usable denominator.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:42226002
    reference_title: "PUS7 Deficiency: Phenotypical Expansion of PUS7-Related Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Across 17 cases, the most frequent features were moderate/severe
      intellectual disability, delayed/absent speech, aggressive behavior,
      microcephaly, mild facial dysmorphisms, motor delay, and short stature.
    explanation: >-
      Lists motor delay among the most frequent features of the published series.
  - reference: PMID:33100873
    reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had ID, gross motor delay along with hypotonia.
    explanation: >-
      Individual-level documentation of gross motor delay in one affected brother.
- name: Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Sensorineural hearing loss, sometimes initially misattributed to chronic
    middle ear effusion, and sometimes severe enough to require a hearing aid.
    It is one of the less common but more diagnostically suggestive features.
  frequency: OCCASIONAL
  notes: >-
    Derivation: reported in 2 of the 3 patients in PMID:30778726 and in both
    brothers in PMID:33100873, i.e. 4 individuals in total. Against the roughly 17
    cases enumerated in the PMID:42226002 review that is approximately 24 percent,
    which lies in the OCCASIONAL band (5-29 percent). This agrees with that
    review's own classification of sensorineural hearing loss as one of the "less
    common" findings, which the curation SOP maps to OCCASIONAL. Note that
    PMID:30778726 warns that de Brouwer's cohort did not specifically comment on
    hearing, so the true rate may be higher than the published counts suggest.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, we note the presence of sensorineural hearing loss in two of our
      patients.
    explanation: >-
      Explicit count of affected individuals within a defined three-patient cohort.
  - reference: PMID:42226002
    reference_title: "PUS7 Deficiency: Phenotypical Expansion of PUS7-Related Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Less common but more peculiar findings included sensorineural hearing loss,
      autistic traits, self-injurious behavior, and motor stereotypies.
    explanation: >-
      Places sensorineural hearing loss in the less common but more specific
      category across the whole published series.
- name: Self-Injurious Behavior
  category: Behavioral
  description: >-
    Self-injury has been reported in a minority of individuals and is one of the
    features that, together with hyperuricaemia, prompted a Lesch-Nyhan syndrome
    differential in one sibling pair.
  frequency: OCCASIONAL
  notes: >-
    Derivation: 1/1 in PMID:37067188 and 2/2 in PMID:35144859, i.e. 3 individuals
    against the roughly 17 enumerated in the PMID:42226002 review, approximately
    18 percent, in the OCCASIONAL band (5-29 percent). That review independently
    classifies self-injurious behaviour as one of the "less common" findings.
  phenotype_term:
    preferred_term: Self-injurious behavior
    term:
      id: HP:0100716
      label: Self-injurious behavior
  evidence:
  - reference: PMID:37067188
    reference_title: "A PUS7 gene pathogenic variant causing self-injurious behavior, sleep disturbances, and developmental delay: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe the case of a male infant with a homozygous truncating pathogenic
      variant in the PUS7 gene (c.329_332delCTGA; p.Thr110Argfs*4) who, in addition
      to the previously mentioned features, displays self-injurious behavior, sleep
      disturbances and motor stereotypies.
    explanation: >-
      First dedicated report of self-injurious behaviour in a genetically confirmed
      PUS7 patient.
  - reference: PMID:35144859
    reference_title: "PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients also had features of Lesch-Nyhan syndrome, including
      hyperuricemia and self-injurious behavior, but without pathogenic variants in
      HPRT1.
    explanation: >-
      Independent replication in two further PUS7-deficient siblings, with the
      HPRT1 genotype excluded.
- name: Autistic Behavior
  category: Behavioral
  description: >-
    Autistic traits, and in one proband a formal diagnosis of autism spectrum
    disorder, have been reported in a minority of individuals.
  frequency: OCCASIONAL
  notes: >-
    Derivation: autistic features in both siblings of PMID:31583274 and a formal
    autism spectrum disorder diagnosis in the proband of PMID:35144859, i.e. 3
    individuals against roughly 17 enumerated in the PMID:42226002 review,
    approximately 18 percent, in the OCCASIONAL band (5-29 percent). That review
    independently classifies autistic traits as one of the "less common" findings.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:31583274
    reference_title: "A novel PUS7 mutation causes intellectual disability with autistic and aggressive behaviors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      further confirming the pathogenic role of PUS7 in ID syndromes with autistic
      features, speech delays, and aggressive behaviors
    explanation: >-
      Documents autistic features in a genetically confirmed PUS7 family.
  - reference: PMID:35144859
    reference_title: "PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients exhibited a neurodevelopmental phenotype including autism
      spectrum disorder in the proband.
    explanation: >-
      Formal autism spectrum disorder diagnosis in an independent PUS7-deficient
      proband.
- name: Motor Stereotypy
  category: Behavioral
  description: >-
    Stereotyped movements including head nodding and other repetitive motor
    patterns.
  frequency: OCCASIONAL
  notes: >-
    Derivation: motor stereotypies in 1/1 in PMID:37067188 and inappropriate
    stereotypic movements with head nodding in 1 of the 3 patients in
    PMID:30778726, i.e. 2 individuals against roughly 17 enumerated in the
    PMID:42226002 review, approximately 12 percent, in the OCCASIONAL band (5-29
    percent). That review independently classifies motor stereotypies as one of
    the "less common" findings.
  phenotype_term:
    preferred_term: Motor stereotypy
    term:
      id: HP:0000733
      label: Motor stereotypy
  evidence:
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He also had behavioral problems including inappropriate stereotypic
      movements, head nodding, bruxism and sometimes tantrums.
    explanation: >-
      Individual-level documentation of stereotyped movements in an affected
      proband.
  - reference: PMID:42226002
    reference_title: "PUS7 Deficiency: Phenotypical Expansion of PUS7-Related Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Less common but more peculiar findings included sensorineural hearing loss,
      autistic traits, self-injurious behavior, and motor stereotypies.
    explanation: >-
      Places motor stereotypies among the less common but diagnostically
      suggestive findings.
- name: Sleep Disturbance
  category: Neurologic
  description: >-
    Disturbed sleep reported as part of the behavioural phenotype expansion.
  notes: >-
    No frequency band is asserted. Sleep disturbance is documented in the single
    patient of PMID:37067188 and is not enumerated in any cohort with a
    denominator; a single case is below the 1 percent threshold at which the
    curation SOP directs the band to be omitted entirely.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:37067188
    reference_title: "A PUS7 gene pathogenic variant causing self-injurious behavior, sleep disturbances, and developmental delay: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      displays self-injurious behavior, sleep disturbances and motor stereotypies
    explanation: >-
      The single-case report that introduced sleep disturbance into the phenotype.
- name: Hyperactivity
  category: Behavioral
  description: >-
    Hyperactivity and attention deficit are described both in the defining IDDABS
    description and at the individual level, including a formal impression of
    attention deficit hyperactivity in one sibling.
  notes: >-
    No frequency band is asserted; no cohort reports a count for hyperactivity
    against a stated denominator.
  phenotype_term:
    preferred_term: Hyperactivity
    term:
      id: HP:0000752
      label: Hyperactivity
  evidence:
  - reference: PMID:33100873
    reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      delayed psychomotor development, hyperactivity, seizure, along with mild to
      swear aggressive behavior
    explanation: >-
      Hyperactivity is part of the published clinical description of IDDABS.
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Psychological evaluation indicated attention deficit hyperactivity but he did
      not show aggressiveness like his brother.
    explanation: >-
      Individual-level documentation of attention deficit hyperactivity in an
      affected sibling.
- name: Abnormal Facial Shape
  category: Craniofacial
  description: >-
    Facial dysmorphism is mild and non-diagnostic. Reported features include a
    triangular face, prominent glabella, arched eyebrows, deep-set eyes,
    infraorbital creases, anteverted nostrils, prominent ears with a simple helix,
    smooth philtrum, everted lower lip, epicanthal folds, down-slanting palpebral
    fissures and dental anomalies.
  notes: >-
    No frequency band is asserted. The PMID:42226002 review lists mild facial
    dysmorphisms among the most frequent features across 17 cases but gives no
    count, and the individual features vary between families.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
    severity: MILD
  evidence:
  - reference: PMID:33100873
    reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      behavioral abnormalities, including aggression and short temper with variable
      dysmorphic features, including smooth philtrum, epicanthal folds, down
      slanting palpebral fissures, broad nasal root, full lips, everted lower lip,
      hypodontia, and misaligned or conical shaped teeth
    explanation: >-
      Enumerates the reported dysmorphic features and states their variability.
  - reference: PMID:42226002
    reference_title: "PUS7 Deficiency: Phenotypical Expansion of PUS7-Related Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Across 17 cases, the most frequent features were moderate/severe
      intellectual disability, delayed/absent speech, aggressive behavior,
      microcephaly, mild facial dysmorphisms, motor delay, and short stature.
    explanation: >-
      Confirms that facial dysmorphism is common but mild across the published
      series.
- name: Smooth Philtrum
  category: Craniofacial
  description: >-
    A smooth or short philtrum is one of the recurrent minor facial features.
  notes: >-
    No frequency band is asserted; the feature is described qualitatively as one
    of several variable dysmorphic findings without a denominator.
  phenotype_term:
    preferred_term: Smooth philtrum
    term:
      id: HP:0000319
      label: Smooth philtrum
  evidence:
  - reference: PMID:33100873
    reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      variable dysmorphic features, including smooth philtrum, epicanthal folds,
      down slanting palpebral fissures
    explanation: >-
      Names smooth philtrum among the recurrent dysmorphic features.
- name: Everted Lower Lip Vermilion
  category: Craniofacial
  description: >-
    An everted lower lip is reported both in the aggregate description of IDDABS
    and at the individual level.
  notes: >-
    No frequency band is asserted; the feature is described qualitatively without
    a denominator.
  phenotype_term:
    preferred_term: Everted lower lip vermilion
    term:
      id: HP:0000232
      label: Everted lower lip vermilion
  evidence:
  - reference: PMID:33100873
    reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      full lips, everted lower lip, hypodontia, and misaligned or conical shaped
      teeth
    explanation: >-
      Names the everted lower lip among the recurrent oro-facial features.
- name: Hyperuricemia
  category: Metabolic
  description: >-
    Elevated serum urate was found in two siblings from the NIH Undiagnosed
    Diseases Program alongside self-injurious behaviour, mimicking Lesch-Nyhan
    syndrome, but with a normal HPRT1 genotype. The authors attribute it to a
    secondary, translation-mediated reduction in HPRT1 protein.
  notes: >-
    No frequency band is asserted. Hyperuricaemia has been reported in exactly one
    family (two siblings) out of the roughly 30 published patients, and no other
    cohort reports urate measurements at all, so there is no denominator for a
    population estimate and the observation may be family-specific.
  phenotype_term:
    preferred_term: Hyperuricemia
    term:
      id: HP:0002149
      label: Hyperuricemia
  evidence:
  - reference: PMID:35144859
    reference_title: "PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients also had features of Lesch-Nyhan syndrome, including
      hyperuricemia and self-injurious behavior, but without pathogenic variants in
      HPRT1.
    explanation: >-
      The only published observation of hyperuricaemia in PUS7 deficiency, with
      the HPRT1 differential explicitly excluded.
- name: Hypotonia
  category: Neurologic
  description: >-
    Generalised hypotonia was documented in the two Saudi brothers of
    PMID:33100873. Neurological examination showed normal tone in the three
    patients of PMID:30778726, so hypotonia is not a consistent feature.
  notes: >-
    Attribution caveat, not a frequency claim. Both brothers in PMID:33100873 also
    carry a splice-acceptor variant in AASS, and that same paper states that
    hyperlysinaemia type I (the AASS phenotype) itself presents with "nonspecific
    seizure, hypotonia, mildly delayed psychomotor development". The hypotonia in
    those two boys therefore cannot be attributed to PUS7 alone, which is why the
    evidence is curated as PARTIAL and no frequency band is given. See the
    hyperlysinaemia entry in differential_diagnoses.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:33100873
    reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had ID, gross motor delay along with hypotonia.
    explanation: >-
      Documents hypotonia in a PUS7 patient who also carries an AASS variant, so
      the attribution to PUS7 is partial.
- name: Seizure
  category: Neurologic
  description: >-
    Seizures are NOT a typical feature. Epilepsy was explicitly absent in the
    Shaheen cohort, and the one reported seizure occurred in a boy who also
    carries an AASS splice variant, the gene for hyperlysinaemia type I, a
    condition whose own description includes nonspecific seizures.
  notes: >-
    Deliberately curated with a REFUTE item alongside the report. The IDDABS
    description in PMID:33100873 lists seizure, but the only individual-level
    seizure in that paper is in a proband with a second pathogenic locus (AASS),
    and PMID:30778726 states positively that its three patients lacked epilepsy.
    No frequency band is asserted, and clinicians should not expect epilepsy in
    this disorder.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33100873
    reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was also reported difficulties in swallowing with nonspecific seizure,
      hypotonia, mildly delayed psychomotor development.
    explanation: >-
      The only individual-level seizure report in the PUS7 literature, in a proband
      who also carries an AASS splice-acceptor variant, hence PARTIAL.
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While the phenotype we present in the three study patients supports the
      consistent involvement of cognition and postnatal brain growth and lack of
      epilepsy in PUS7 deficiency, it also suggests that other aspects are more
      variable.
    explanation: >-
      Positively asserts the absence of epilepsy as a consistent feature of PUS7
      deficiency, refuting seizures as a core phenotype.
genetic:
- name: PUS7
  gene_term:
    preferred_term: PUS7
    term:
      id: hgnc:26033
      label: PUS7
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    PUS7 (7q22.3, MIM 616261) encodes the RNA-independent pseudouridine synthase
    7, a stand-alone TruD-family enzyme that isomerises uridine to pseudouridine
    without a guide RNA. The protein contains an N-terminal R3H domain and a
    C-terminal TruD (PseudoU_synth_ScPUS7) catalytic domain spanning approximately
    residues 370 to 580. All reported disease alleles are biallelic and either
    truncate the protein before the catalytic domain, delete the C-terminus, or
    substitute conserved residues within or near the TruD domain. Inheritance is
    autosomal recessive; the structured Inheritance record is at disease level.

    Gene identity was verified against the MONDO gene-association relation
    (`RO:0004003 HGNC:26033 ! PUS7`) and against the HGNC record
    (`hgnc:26033`, omim:616261). This is deliberately distinct from the paralogue
    PUS7L (hgnc:25276) and from the family members PUS1 (hgnc:15508) and PUS3
    (hgnc:25461), each of which causes a separate disease; see
    differential_diagnoses. Note that MIM 616261 is the PUS7 GENE entry, whereas
    MIM 618342 is the DISEASE entry (IDDABS) that MONDO:0032687 cross-references;
    PMID:33100873 quotes both numbers.
  evidence:
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results confirm that PUS7 is a bona fide Mendelian disease gene and
      expand the list of human diseases caused by impaired pseudouridylation.
    explanation: >-
      Independent replication establishing PUS7 as a definitive Mendelian disease
      gene.
  - reference: PMID:31583274
    reference_title: "A novel PUS7 mutation causes intellectual disability with autistic and aggressive behaviors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PUS7 encodes for a pseudouridine synthase 7 that catalyzes the isomerization
      of RNA uridine to RNA pseudouridine (Psi), which is the most abundant
      modified nucleotide found in all cellular RNAs and which may function as an
      RNA chaperone.
    explanation: >-
      Describes the gene product and its enzymatic function.
  variants:
  - name: c.89_90del (p.Thr30Lysfs*20)
    type: FRAMESHIFT
    clinical_significance: PATHOGENIC
    description: >-
      Homozygous frameshift in one of the three founding families; triggers
      nonsense-mediated decay.
    evidence:
    - reference: PMID:31583274
      reference_title: "A novel PUS7 mutation causes intellectual disability with autistic and aggressive behaviors."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Two homozygous mutations c.89_90del (p.Thr30Lysfs20*) and c.1348C>T
        (p.Arg450*) resulted in nonsense-mediated mRNA decay
      explanation: >-
        Names the allele and its nonsense-mediated-decay consequence.
  - name: c.1348C>T (p.Arg450*)
    type: NONSENSE
    clinical_significance: PATHOGENIC
    description: >-
      Homozygous nonsense allele in a founding family; triggers nonsense-mediated
      decay.
    evidence:
    - reference: PMID:31583274
      reference_title: "A novel PUS7 mutation causes intellectual disability with autistic and aggressive behaviors."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Two homozygous mutations c.89_90del (p.Thr30Lysfs20*) and c.1348C>T
        (p.Arg450*) resulted in nonsense-mediated mRNA decay
      explanation: >-
        Names the allele and its nonsense-mediated-decay consequence.
  - name: Deletion of the penultimate exon 15
    type: DELETION
    clinical_significance: PATHOGENIC
    description: >-
      A homozygous deletion of the penultimate exon that escapes nonsense-mediated
      decay and produces a protein lacking the C-terminal TruD catalytic domain.
    evidence:
    - reference: PMID:31583274
      reference_title: "A novel PUS7 mutation causes intellectual disability with autistic and aggressive behaviors."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        while the third mutation, consisting of a homozygous deletion encompassing
        the penultimate exon 15, escaped the nonsense-mediated mRNA decay to encode
        a mutant protein missing the C terminus including the TruD catalytic domain
      explanation: >-
        Describes the allele's escape from decay and the resulting catalytically
        dead protein.
  - name: c.1507G>T (p.Asp503Tyr)
    type: MISSENSE
    clinical_significance: PATHOGENIC
    description: >-
      A homozygous missense allele within the TRUD catalytic domain. Its yeast
      equivalent (pus7-D478Y) fails to complement a pus7 growth defect, showing it
      is a complete loss of function rather than a partial one.
    evidence:
    - reference: PMID:30778726
      reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the missense variant p. (Asp503Tyr) is located within the TRUD domain (the
        pseudouridine catalytic domain of PUS7), predicted to be probably damaging
        (1) by Polyphen-2, deleterious by SIFT (0), "disease causing" by
        MutationTaster and has a CADD_phred of 29.4
      explanation: >-
        Localises the allele to the catalytic domain and summarises the in silico
        pathogenicity evidence.
  - name: c.329_332delCTGA (p.Thr110Argfs*4)
    type: FRAMESHIFT
    clinical_significance: PATHOGENIC
    description: >-
      A recurrent homozygous frameshift reported independently in a Saudi girl and
      in an Italian male infant with self-injurious behaviour, sleep disturbance
      and motor stereotypies.
    evidence:
    - reference: PMID:37067188
      reference_title: "A PUS7 gene pathogenic variant causing self-injurious behavior, sleep disturbances, and developmental delay: A case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We describe the case of a male infant with a homozygous truncating
        pathogenic variant in the PUS7 gene (c.329_332delCTGA; p.Thr110Argfs*4)
      explanation: >-
        Names the allele in the Italian proband.
  - name: c.606_607delGA (p.Ser282CysfsTer9)
    type: FRAMESHIFT
    clinical_significance: PATHOGENIC
    description: >-
      A homozygous frameshift identified in two Saudi brothers who also carry an
      AASS splice-acceptor variant.
    evidence:
    - reference: PMID:33100873
      reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We detected two mutations one homozygous frameshift mutation
        c.606_607delGA, p.Ser282CysfsTer9 in the PUS7 gene and other splice
        acceptor variants c.1767-1 G > A in the AASS gene in the analysis.
      explanation: >-
        Names the PUS7 allele and, in the same sentence, the confounding AASS
        allele that requires the attribution caveats recorded elsewhere in this
        entry.
  - name: c.382G>A (p.Gly128Arg)
    type: MISSENSE
    clinical_significance: PATHOGENIC
    description: >-
      A homozygous missense allele in a consanguineous Afghani family with a milder
      presentation lacking microcephaly and short stature; proposed to be
      hypomorphic.
    evidence:
    - reference: PMID:31583274
      reference_title: "A novel PUS7 mutation causes intellectual disability with autistic and aggressive behaviors."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a novel PUS7 homozygous mutation resulting in p.Gly128Arg
        amino-acid translation in a consanguineous Afghani family presenting with
        similar but milder clinical features without microcephaly and short stature
      explanation: >-
        Names the allele and documents its milder genotype-phenotype correlation.
diagnosis:
- name: Molecular diagnosis by exome or genome sequencing
  description: >-
    Biallelic PUS7 variants are identified by exome or genome sequencing. There
    is no clinically distinctive gestalt, so molecular testing establishes the
    diagnosis rather than confirming a clinical suspicion.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:30778726
    reference_title: "Biallelic PUS7 mutations cause intellectual disability, microcephaly, delayed development, and speech impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "exome/genome sequencing of children with intellectual disability will incorporate it in their annotation"
    explanation: >-
      The authors state that PUS7 variants will be encountered through exome or
      genome sequencing of children with intellectual disability, which is the
      diagnostic route this entry describes.
  - reference: PMID:30778726
    reference_title: "Biallelic PUS7 mutations cause intellectual disability, microcephaly, delayed development, and speech impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome capture was performed using the TruSeq Exome Enrichment kit"
    explanation: >-
      Documents that exome sequencing was the method actually applied to the
      affected individuals in the founding series.
- name: tRNA pseudouridine-13 assay for variant interpretation
  description: >-
    Loss of pseudouridine at position 13 in patient-derived tRNA is the direct
    functional readout of PUS7 deficiency, and is the assay that distinguishes a
    pathogenic PUS7 variant from a variant of uncertain significance.
  diagnosis_term:
    preferred_term: molecular analysis
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:30778726
    reference_title: "Biallelic PUS7 mutations cause intellectual disability, microcephaly, delayed development, and speech impairment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "this may also serve as a very helpful assay for the proper classification of variants of unknown significance"
    explanation: >-
      The authors state directly that the pseudouridylation assay can be used to
      classify variants of unknown significance in PUS7.
  - reference: PMID:30778726
    reference_title: "Biallelic PUS7 mutations cause intellectual disability, microcephaly, delayed development, and speech impairment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both variants were associated with a specific reduction of Ψ13 in their tRNAs."
    explanation: >-
      Establishes reduced tRNA pseudouridine-13 in patient-derived cells as the
      functional readout the assay measures.
- name: Neuroimaging and EEG as exclusionary investigations
  description: >-
    Brain MRI and EEG are typically normal in this disorder. Their value is
    exclusionary - normal structural imaging and a normal EEG argue against the
    structural brain malformations and epileptic encephalopathies that otherwise
    sit in the differential.
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:30778726
    reference_title: "Biallelic PUS7 mutations cause intellectual disability, microcephaly, delayed development, and speech impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EEG recording was normal. Brain MRI showed normal brain architecture."
    explanation: >-
      Documents normal EEG and normal brain architecture in an affected
      individual, supporting both investigations as exclusionary rather than
      confirmatory.
- name: Audiometric assessment for sensorineural hearing loss
  description: >-
    Formal audiometry is warranted because the sensorineural hearing loss in this
    disorder can be misattributed to a coincidental conductive cause. In the
    founding series the hearing loss was first ascribed to chronic middle ear
    effusion and was only recognised as sensorineural after ventilation tubes
    failed to help, so a poor response to conductive management should prompt
    re-evaluation rather than reassurance.
  diagnosis_term:
    preferred_term: audiometry
    term:
      id: NCIT:C38036
      label: Audiometric Test
  evidence:
  - reference: PMID:30778726
    reference_title: "Biallelic PUS7 mutations cause intellectual disability, microcephaly, delayed development, and speech impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss was suspected due to chronic middle ear effusion but her poor response to ventilation tubes prompted re-evaluation and sensorineural hearing loss was confirmed."
    explanation: >-
      Documents the initial misattribution to middle ear effusion and the
      re-evaluation that confirmed sensorineural hearing loss.
treatments:
- name: Special Education and Developmental Support
  description: >-
    There is no disease-modifying therapy. Management is entirely supportive and
    is built around structured special education, which affected children in the
    published cohorts have received.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: special education
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  notes: >-
    NCIT:C159269 (Special Education) exists but is not reachable from
    NCIT:C25218, the clinical-intervention root that the TreatmentTerm dynamic
    enum is constrained to, so the more general Supportive Care term is bound
    here and the specific action is carried in preferred_term.
  evidence:
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was admitted in a school for special education.
    explanation: >-
      Documents special-education placement as the management actually applied to
      an affected proband.
- name: Speech and Language Therapy
  description: >-
    Speech delay is near-universal and is often the presenting complaint, so
    speech and language therapy is a core component of supportive management.
    Expressive vocabulary can remain very limited into adolescence, and
    augmentative communication should be considered where speech is absent.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Speech Language Therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  notes: >-
    This is a standard-of-care inference from the documented severity of the
    speech deficit rather than a therapy whose efficacy has been tested in PUS7
    deficiency; no trial or outcome data exist for this disorder. The cited
    snippet establishes the indication, not the outcome.
  evidence:
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He showed a severe speech delay and his expressive vocabulary was limited to
      about 30 words.
    explanation: >-
      Establishes the indication for speech and language therapy; no efficacy data
      exist, so support is PARTIAL.
- name: Risperidone for Aggressive Behavior
  description: >-
    Aggression is the most burdensome behavioural feature and has been managed
    pharmacologically. Risperidone was introduced in a 16-year-old proband who
    presented with aggressive behaviour.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: risperidone
      term:
        id: CHEBI:8871
        label: risperidone
  target_phenotypes:
  - preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  notes: >-
    This is a single-patient observation of treatment initiation, with no reported
    outcome. It is recorded because it is the only pharmacological intervention
    documented anywhere in the PUS7 literature, and evidence is set to PARTIAL to
    reflect that the source reports the prescription but not its effect.
  evidence:
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We re-evaluated him at age 16 yrs, he presented with aggressive behavior and
      Risperidone treatment was introduced.
    explanation: >-
      Documents that risperidone was used for the aggression, without reporting
      response.
- name: Hearing Amplification
  description: >-
    Sensorineural hearing loss can be progressive and severe, and can be masked
    early on by coexisting middle-ear effusion. Formal audiological assessment is
    warranted in every affected child, and hearing aids have been fitted in at
    least one reported patient.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing aid provision
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  notes: >-
    NCIT:C183182 (Hearing Aid) is a device concept and is not reachable from
    NCIT:C25218, so it cannot be used in the TreatmentTerm slot; the generic
    Supportive Care action term is bound and the specific action is carried in
    preferred_term with therapeutic_modality DEVICE.
  evidence:
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further, he developed severe sensorineural hearing loss and hearing aid was
      used.
    explanation: >-
      Documents hearing-aid use in an affected proband with progressive
      sensorineural hearing loss.
- name: Allopurinol for Hyperuricemia
  description: >-
    Where hyperuricaemia is present it is treatable and its complications (urate
    nephropathy, nephrolithiasis, gout) are preventable, which makes measuring
    serum urate one of the few actionable investigations in this disorder. The
    two siblings in whom hyperuricaemia was documented were treated with
    allopurinol.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: allopurinol
      term:
        id: CHEBI:40279
        label: allopurinol
  target_phenotypes:
  - preferred_term: Hyperuricemia
    term:
      id: HP:0002149
      label: Hyperuricemia
  notes: >-
    Evidence limitation, stated precisely. The statement that these patients
    required allopurinol is in the PMC full text of PMID:35144859, not in its
    abstract. The cached record references_cache/PMID_35144859.md is
    abstract-only (content_type abstract_only), and `grep -c
    "allopurinol\|Allopurinol" references_cache/PMID_35144859.md` returns 0, so
    no verbatim snippet for the allopurinol statement itself can be taken from
    the cache in this working tree. The snippet cited below therefore supports
    the indication (hyperuricaemia in PUS7 deficiency), not the prescription.
    Retrieving the PMC full text and quoting the treatment sentence directly is
    the right way to close this gap in a follow-up pass. Applies only to the
    minority of patients with documented hyperuricaemia; urate has not been
    measured in most published cases. Standard allopurinol hypersensitivity
    risk applies, including the HLA-B*58:01-associated severe cutaneous adverse
    reaction covered by the dismech Allopurinol_Induced_SJS_TEN entry.
  evidence:
  - reference: PMID:35144859
    reference_title: "PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients also had features of Lesch-Nyhan syndrome, including
      hyperuricemia and self-injurious behavior, but without pathogenic variants in
      HPRT1.
    explanation: >-
      Establishes the treatable indication. Support is PARTIAL because the cached
      abstract documents the hyperuricaemia but not the allopurinol prescription
      or its outcome.
- name: Genetic Counselling and Carrier Testing
  description: >-
    Because inheritance is autosomal recessive and most reported families are
    consanguineous, carrier testing and counselling with a 25 percent sibling
    recurrence risk follow directly from a molecular diagnosis. The diagnostic
    testing itself is modelled in the diagnosis: section rather than here.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:42226002
    reference_title: "PUS7 Deficiency: Phenotypical Expansion of PUS7-Related Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We recommend looking for PUS7 pathological variants when performing whole
      exome sequencing in children with this constellation of neurodevelopmental
      and behavioral signs.
    explanation: >-
      An explicit diagnostic recommendation from the most recent review of the
      disorder.
differential_diagnoses:
- name: PUS3-related intellectual disability and microcephaly syndrome
  disease_term:
    preferred_term: PUS3-related intellectual disability syndrome (MRT55)
    term:
      id: MONDO:0014886
      label: severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome
  description: >-
    The single most confusable entity. PUS3 (hgnc:25461) is another stand-alone
    pseudouridine synthase whose loss causes an autosomal recessive intellectual
    disability and microcephaly syndrome (MONDO:0014886, OMIM:617051, also known
    as MRT55). Both disorders are described in the literature as caused by
    "impaired pseudouridylation" and both were characterised by overlapping author
    groups, so 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 positions 38 and 39,
    whereas PUS7 acts at position 13 (and at position 35 of pre-tRNA-Tyr). A
    tRNA modification assay therefore distinguishes them biochemically, and this
    is the cleanest functional discriminator.
  - >-
    Clinical: the PUS3 MONDO entity carries severe growth deficiency, strabismus
    and extensive dermal melanocytosis as label-level features. Dermal
    melanocytosis has never been reported in PUS7 deficiency, and the PUS7
    behavioural signature of very-early-onset aggression is not part of the PUS3
    label.
  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: >-
      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:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 2016, we described a novel intellectual disability and microcephaly
      syndrome in three affected siblings who all shared a homozygous truncating
      variant in PUS3 (Shaheen et al. 2016).
    explanation: >-
      The PUS7 paper itself distinguishes the PUS3 syndrome as a separate entity,
      in the same authors' words.
- name: PUS1-related myopathy, lactic acidosis and sideroblastic anaemia (MLASA1)
  disease_term:
    preferred_term: MLASA1 (PUS1-related)
    term:
      id: MONDO:0024553
      label: myopathy, lactic acidosis, and sideroblastic anemia 1
  description: >-
    The first pseudouridine synthase disease described in humans, caused by
    biallelic PUS1 variants (hgnc:15508). Despite sharing the "deficient
    pseudouridylation" mechanism language with PUS7 disease, the phenotype is
    almost disjoint: a mitochondrial oxidative-phosphorylation disorder restricted
    to skeletal muscle and bone marrow.
  distinguishing_features:
  - >-
    Molecular: PUS1 (hgnc:15508) versus PUS7 (hgnc:26033); MONDO:0024553 versus
    MONDO:0032687.
  - >-
    Compartment: PUS1 deficiency is proposed to act through deficient
    pseudouridylation of MITOCHONDRIAL tRNAs, whereas PUS7 acts on cytosolic tRNAs,
    mRNAs and tRNA-derived fragments. This is the mechanistic reason the two
    phenotypes barely overlap.
  - >-
    Clinical: MLASA1 presents with exercise intolerance, myopathy, lactic acidosis
    and sideroblastic anaemia. Intellectual disability, microcephaly and aggression
    are not part of it, and conversely myopathy, lactic acidosis and sideroblastic
    anaemia have never been reported in PUS7 deficiency. A patient with anaemia and
    a raised lactate is not a PUS7 candidate.
  evidence:
  - reference: PMID:15108122
    reference_title: "Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mitochondrial myopathy and sideroblastic anemia (MLASA) is a rare, autosomal
      recessive oxidative phosphorylation disorder specific to skeletal muscle and
      bone marrow.
    explanation: >-
      Defines the MLASA phenotype as tissue-restricted to muscle and marrow, which
      is the clinical discriminator from the CNS-dominated PUS7 disorder.
  - reference: PMID:15108122
    reference_title: "Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We propose deficient pseudouridylation of mitochondrial tRNAs as an etiology
      of MLASA.
    explanation: >-
      States the mitochondrial-tRNA compartment that separates the PUS1 mechanism
      from the cytosolic PUS7 mechanism, while showing exactly why the shared
      "deficient pseudouridylation" phrasing is a confusion hazard.
- name: PUS7L-related neurodevelopmental disorder
  description: >-
    PUS7L (hgnc:25276) is the paralogue of PUS7 and is a separate gene. A patient
    with severe global developmental delay and epilepsy carrying a homozygous
    truncating PUS7L variant was noted in passing by the same group that
    characterised PUS7 disease. Because the gene symbols differ by a single
    trailing character, this is a high-risk symbol-level confusion, distinct from
    the mechanism-level confusion posed by PUS1 and PUS3.
  distinguishing_features:
  - >-
    Molecular: PUS7L is hgnc:25276, PUS7 is hgnc:26033. They are distinct
    paralogous genes at distinct loci, and PUS7L has its own tRNA targets, mapped
    in PMID:41136621.
  - >-
    Clinical: the reported PUS7L phenotype prominently included epilepsy, whereas
    PMID:30778726 positively asserts the LACK of epilepsy as a consistent feature
    of PUS7 deficiency. Seizures should therefore push a differential toward
    PUS7L, not PUS7.
  notes: >-
    Deliberately left UNBOUND. `runoak -i sqlite:obo:mondo relationships
    --direction down HGNC:25276` returns no rows, and a MONDO label search for
    PUS7L returns nothing, so there is no MONDO disease term for a PUS7L-related
    disorder to bind to. Binding a generic neurodevelopmental-disorder term here
    would assert an entity that does not exist in the ontology. The gene identity
    is instead carried in the description and distinguishing features. When MONDO
    mints a PUS7L disease class this record should be bound.
  evidence:
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, we recently encountered a patient with severe global
      developmental delay and epilepsy with a homozygous truncating variant in
      PUS7L (manuscript under review).
    explanation: >-
      The only clinical description of a PUS7L patient in the cited literature,
      written by the PUS7 authors themselves, and the source of the
      epilepsy-versus-no-epilepsy discriminator.
  - reference: PMID:41136621
    reference_title: "A comprehensive tRNA pseudouridine map uncovers targets dependent on human stand-alone pseudouridine synthases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Through this approach, we uncovered previously unknown targets of several PUS
      enzymes, including RPUSD1, RPUSD2, PUS3, PUSL1 and PUS7L.
    explanation: >-
      Confirms PUS7L as an enzymatically distinct family member with its own
      substrate set, not a synonym or isoform of PUS7.
- name: Lesch-Nyhan syndrome
  disease_term:
    preferred_term: Lesch-Nyhan syndrome
    term:
      id: MONDO:0010298
      label: Lesch-Nyhan syndrome
  description: >-
    An X-linked disorder of purine metabolism caused by HPRT deficiency, presenting
    with hyperuricaemia, intellectual disability and severe self-injurious
    behaviour. Two PUS7-deficient siblings were investigated for Lesch-Nyhan
    syndrome because they had exactly this combination, and no HPRT1 variant was
    found. This is therefore a real, documented diagnostic trap, not a theoretical
    one.
  distinguishing_features:
  - >-
    Molecular: Lesch-Nyhan is X-linked and caused by HPRT1 variants; PUS7 disease
    is autosomal recessive with biallelic PUS7 variants and a NORMAL HPRT1
    sequence. Sequencing resolves it.
  - >-
    Biochemical nuance: HPRT1 protein was mildly REDUCED in the PUS7 siblings
    despite a normal HPRT1 gene, attributed to deregulated translation. A
    protein-level or enzyme-activity assay may therefore be mildly abnormal in PUS7
    disease and should not be read as confirming Lesch-Nyhan.
  - >-
    Clinical: microcephaly, short stature and early-onset aggression point to PUS7;
    the dystonia, choreoathetosis and gouty arthropathy of classic Lesch-Nyhan have
    not been reported in PUS7 deficiency.
  evidence:
  - reference: PMID:35144859
    reference_title: "PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients also had features of Lesch-Nyhan syndrome, including
      hyperuricemia and self-injurious behavior, but without pathogenic variants in
      HPRT1.
    explanation: >-
      Documents the actual clinical confusion and its genetic resolution.
  - reference: PMID:35144859
    reference_title: "PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Interestingly, the dysregulation of protein translation also resulted in
      mildly decreased levels of HPRT1 protein suggesting an association between
      dysregulated protein translation and the LNS-like phenotypic findings.
    explanation: >-
      Explains why an HPRT1 protein assay can be misleading in PUS7 deficiency.
- name: Hyperlysinaemia type I (AASS-related)
  disease_term:
    preferred_term: hyperlysinemia
    term:
      id: MONDO:0009388
      label: hyperlysinemia
  description: >-
    Not a phenotypic mimic so much as a documented co-occurring second diagnosis.
    The two Saudi brothers reported in PMID:33100873 carry both a homozygous PUS7
    frameshift and a splice-acceptor variant in AASS, the hyperlysinaemia type I
    gene (OMIM:238700, the OMIM xref of MONDO:0009388). Any curator importing that
    paper's phenotype list must decide which findings belong to which locus.
  distinguishing_features:
  - >-
    Attribution, not exclusion: the two diagnoses coexist in the same children, so
    finding one does not exclude the other. That paper itself states that
    hyperlysinaemia type I presents with nonspecific seizure, hypotonia and mildly
    delayed psychomotor development, all of which are also recorded for those
    brothers.
  - >-
    Biochemical: hyperlysinaemia is confirmed by elevated plasma lysine and
    saccharopinuria, which are not features of PUS7 deficiency and have never been
    measured in any other PUS7 cohort.
  notes: >-
    Cross-reference: the Seizure and Hypotonia phenotypes in this entry both derive
    from these two brothers, both carry supports PARTIAL, and both name this record
    in their attribution notes. PMID:30778726 separately and positively asserts the
    absence of epilepsy in PUS7 deficiency, which is curated as a REFUTE evidence
    item on the Seizure phenotype.
  evidence:
  - reference: PMID:33100873
    reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient with hyperlysinemia Type 1 (OMIM# 238700) having nonspecific seizure,
      hypotonia, mildly delayed psychomotor development, while patients with
      Saccharopinuria (OMIM# 268700) show mild developmental delay, hyperactivity
      and speech delay.
    explanation: >-
      The dual-locus paper's own statement that the AASS phenotype includes
      seizure, hypotonia and psychomotor delay, which is exactly why those findings
      in its probands cannot be attributed to PUS7 alone.
- name: Smith-Magenis syndrome
  disease_term:
    preferred_term: Smith-Magenis syndrome
    term:
      id: MONDO:0008434
      label: Smith-Magenis syndrome
  description: >-
    The closest non-genetic-family phenocopy on behavioural grounds. Smith-Magenis
    syndrome, caused by the recurrent 17p11.2 deletion or by intragenic RAI1
    variants, combines intellectual disability, sleep disturbance, aggression,
    self-injurious behaviour, motor stereotypies and short stature. That is a
    near-complete overlap with the "less common but more peculiar" cluster that
    PMID:42226002 proposes as the discriminating signature of PUS7 deficiency,
    which means the very features that are supposed to raise suspicion of PUS7
    disease also describe Smith-Magenis. This differential exists because the
    behavioural gestalt collides, not because the genes or mechanisms are related.
  distinguishing_features:
  - >-
    Molecular: a 17p11.2 microdeletion or heterozygous RAI1 variant, autosomal
    dominant and usually de novo, versus biallelic recessive PUS7. Chromosomal
    microarray detects the common deletion and will be normal in PUS7 disease.
  - >-
    Sleep: Smith-Magenis has a characteristic inverted circadian melatonin rhythm
    with the classic phenotype of daytime sleepiness and night waking. The sleep
    disturbance reported in PUS7 deficiency is a single-case observation with no
    described circadian signature.
  - >-
    Head size: progressive postnatal microcephaly is a core PUS7 feature and is
    not characteristic of Smith-Magenis, so serial head-circumference plotting is
    a cheap discriminator.
  - >-
    Visceral involvement: Smith-Magenis includes craniofacial, skeletal and
    visceral anomalies. PUS7 deficiency has mild non-specific facial dysmorphism
    and no visceral anomalies.
  evidence:
  - reference: PMID:20932317
    reference_title: "Frameshift mutation hotspot identified in Smith-Magenis syndrome: case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Smith-Magenis syndrome (SMS) is a complex syndrome involving intellectual
      disabilities, sleep disturbance, behavioural problems, and a variety of
      craniofacial, skeletal, and visceral anomalies.
    explanation: >-
      States the overlapping triad of intellectual disability, sleep disturbance
      and behavioural problems that makes this a genuine clinical differential,
      and the visceral involvement that separates it.
  - reference: PMID:20932317
    reference_title: "Frameshift mutation hotspot identified in Smith-Magenis syndrome: case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While the majority of SMS cases harbor an ~3.5 Mb common deletion on 17p11.2
      that encompasses the retinoic acid induced-1 (RAI1) gene, some patients carry
      small intragenic deletions or point mutations in RAI1.
    explanation: >-
      Gives the molecular discriminator and, importantly, the reason a normal
      microarray does not exclude Smith-Magenis; RAI1 sequencing is still needed.
- name: Other tRNA-modification intellectual disability syndromes
  disease_term:
    preferred_term: ADAT3-related intellectual disability-strabismus syndrome
    term:
      id: MONDO:0014119
      label: intellectual disability-strabismus syndrome
  description: >-
    PUS7 disease sits inside a growing class of autosomal recessive intellectual
    disability syndromes caused by loss of a single tRNA modification, all of which
    share intellectual disability with variable microcephaly and short stature and
    are therefore clinically indistinguishable without sequencing. The record is
    bound to the ADAT3 entity (MONDO:0014119, adenosine-to-inosine editing at
    wobble position 34), which is the most common cause of autosomal recessive
    intellectual disability in Arabia and is therefore the highest-prior
    alternative in the very populations where PUS7 families have been ascertained.
  distinguishing_features:
  - >-
    Molecular: ADAT3 (hgnc:25151) wobble-position inosine editing, NSUN2
    (hgnc:25994, MONDO:0012613) 5-methylcytosine, TRMT10A 1-methylguanosine at
    position 9, WDR4 7-methylguanosine at position 46, THUMPD1 tRNA acetylation.
    None of these is a pseudouridine synthase, and none produces a position-13
    pseudouridine defect.
  - >-
    Assay: the discriminating test is which modification is missing. PUS7 disease
    shows loss of pseudouridine at tRNA position 13 with other pseudouridine
    positions in the same tRNAs intact.
  - >-
    Clinical: strabismus is a label-level feature of the ADAT3 entity and is not
    reported in PUS7 deficiency; conversely very-early-onset aggression is the PUS7
    signature.
  notes: >-
    One record is used for the class rather than one per gene, because the shared
    diagnostic logic (sequence the child; identify which tRNA modification is
    absent) is identical for all of them and duplicating it per gene would add
    length without adding discrimination. The bound term is the ADAT3 entity;
    NSUN2 disease is MONDO:0012613, and dismech already carries a separate entry
    for the THUMPD1-related disorder. The class-level point is supported by the
    quoted sentences, which name the class explicitly.
  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: >-
      For example, the most common form of autosomal recessive ID in Arabia was
      found to be due to mutation of ADAT3, which edits adenosine to inosine at the
      wobble position 34 of mature tRNA
    explanation: >-
      Establishes ADAT3 disease as the highest-prior alternative diagnosis in the
      populations where PUS7 families have been ascertained, and names its distinct
      modification chemistry.
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional Mendelian disorders include TRM10A- and NSUN2-related syndromes of
      intellectual disability, microcephaly and short stature
    explanation: >-
      Names two further tRNA-modification syndromes whose stated triad
      (intellectual disability, microcephaly, short stature) is the same as this
      disorder's, which is precisely why sequencing rather than phenotyping is the
      discriminator.
mechanistic_hypotheses:
- hypothesis_group_id: pus7_translational_control
  hypothesis_label: Loss of PUS7-dependent translational restraint as the disease mechanism
  status: CANONICAL
  description: >-
    The default explanatory model. Loss of PUS7 removes pseudouridine from
    cytosolic tRNAs, from PUS7-dependent mRNAs, and from the tRNA-derived
    fragments that hold the translation initiation complex in check. The
    convergent consequence is loss of translational homeostasis, demonstrated
    directly in PUS7-deficient patient fibroblasts, and the developing brain is
    the tissue least able to tolerate it. Every edge in this entry that is not
    explicitly assigned to another hypothesis group belongs to this model.
  evidence:
  - reference: PMID:35144859
    reference_title: "PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient fibroblasts demonstrated upregulation of protein synthesis,
      including elevated MYC protein, but did not exhibit increased rates of cell
      proliferation.
    explanation: >-
      The human-cell demonstration on which the canonical translational model
      rests.
- hypothesis_group_id: pus7_non_translational_arms
  hypothesis_label: Contribution of the transcription-elongation and splicing arms of PUS7
  status: EMERGING
  description: >-
    PUS7 also pseudouridylates 7SK snRNA, controlling RNA polymerase II
    promoter-proximal pausing, and has reported effects on pre-mRNA splicing via
    U2 snRNA. Both are established for PUS7 loss in cell lines. Neither has been
    connected to the human neurodevelopmental phenotype in any way: no patient
    tissue has been assayed for 7SK pseudouridine, Pol II serine-2
    phosphorylation, or splicing abnormalities. Edges opting into this group are
    curated because the enzymology is real, not because the disease relevance is
    established.
  evidence:
  - reference: PMID:41168165
    reference_title: "Pseudouridylation of 7SK by PUS7 regulates Pol II transcription elongation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Whether and how Ψ may regulate transcription have not been adequately
      studied.
    explanation: >-
      The authors' own framing of the transcription arm as newly opened rather
      than settled, which is why the hypothesis group status is EMERGING.
discussions:
- discussion_id: pus7_no_mouse_model
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does germline Pus7 loss in the mouse reproduce the human neurodevelopmental
    phenotype at all, and if not, why?
  attaches_to:
  - pathophysiology#Impaired Neuronal Development and Function
  rationale: >-
    The only in vivo evidence that PUS7 loss produces the behavioural phenotype
    comes from Drosophila, and the only mammalian in vivo evidence is a
    region-specific adult knockdown in mouse infralimbic prefrontal cortex, which
    models plasticity rather than development. No published Pus7-null mouse has
    been characterised for brain size, growth, or behaviour, even though mouse
    alleles exist. The mismatch matters because the two headline human features,
    progressive microcephaly and growth retardation, have no described animal
    counterpart at all: Drosophila cannot model them, and the mouse has not been
    asked. Without a mammalian germline model the causal step from deregulated
    translation to failed postnatal brain growth remains an inference.
  proposed_experiments:
  - experiment_id: exp_pus7_germline_mouse_phenotyping
    name: Deep phenotyping of a germline Pus7-null mouse
    description: >-
      Characterise a germline Pus7-null mouse for serial head and brain volume,
      body growth, cortical progenitor dynamics, and home-cage aggression, rather
      than relying on the existing high-throughput phenotyping-pipeline summary,
      which reports systems that do not obviously map onto the human phenotype.
  - experiment_id: exp_pus7_conditional_neural_deletion
    name: Conditional Pus7 deletion to test neuron autonomy of brain growth failure
    description: >-
      Delete Pus7 conditionally in neural progenitors versus post-mitotic neurons
      and compare brain-growth outcomes, to determine whether any mammalian
      brain-size phenotype is neuron-autonomous or secondary to systemic growth
      failure.
  evidence:
  - reference: PMID:41094471
    reference_title: "PUS7-dependent Ψ reshapes specific synaptic gene exons to facilitate fear extinction memory formation."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Crucially, PUS7 knockdown in the ILPFC selectively impaired fear extinction
      memory formation without altering baseline fear expression, establishing a
      causal link between Ψ-dependent RNA processing and activity-dependent
      synaptic structural remodeling in this microcircuit.
    explanation: >-
      The best available mammalian in vivo evidence, and simultaneously the
      demonstration of the gap: it is an adult, region-restricted knockdown, not a
      germline developmental model.
- discussion_id: pus7_haematopoietic_discrepancy
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why do PUS7-depleted human haematopoietic stem and progenitor cells show a
    severe commitment defect while PUS7-deficient patients have no reported
    haematological disease?
  attaches_to:
  - pathophysiology#Failure of tRF-Mediated Restraint of Translation Initiation
  rationale: >-
    The tRF arm of PUS7 biology was discovered in haematopoiesis, and PUS7
    depletion impairs stem cell commitment and is implicated in aggressive
    myelodysplastic syndrome. Yet no PUS7-deficient patient has been reported with
    cytopenia, marrow failure, or a myeloid neoplasm. Either the human requirement
    is dosage- or context-dependent in a way the depletion experiments do not
    capture, or the haematological phenotype exists and has never been looked for
    because the patients present to neurology and clinical genetics. Resolving
    this affects how much weight the tRF arm should carry in the disease model.
  proposed_experiments:
  - experiment_id: exp_pus7_haematology_ascertainment
    name: Systematic haematological assessment of published PUS7 cohorts
    description: >-
      Report full blood counts and, where justified, marrow morphology across the
      existing PUS7 patient cohorts. This distinguishes a genuine absence of
      haematological phenotype from an absence of ascertainment, which is the
      first thing that must be settled before the discrepancy can be interpreted.
  - experiment_id: exp_pus7_tissue_specific_trf_compensation
    name: Tissue-specific comparison of tRF pseudouridylation and TOP mRNA translation
    description: >-
      Compare tRNA-derived-fragment pseudouridine levels and translation of
      5-prime terminal oligopyrimidine mRNAs between patient-derived
      haematopoietic cells and patient fibroblasts, to test whether the
      haematopoietic compartment compensates for PUS7 loss in a way that
      fibroblasts do not.
  evidence:
  - reference: PMID:29628141
    reference_title: "Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Remarkably, dysregulation of this posttranscriptional regulatory circuitry
      impairs hematopoietic stem cell commitment and is common to aggressive
      subtypes of human myelodysplastic syndromes.
    explanation: >-
      States the haematopoietic requirement that patients do not appear to
      manifest.
- discussion_id: pus7_microcephaly_causal_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what cellular route does deregulated translation reduce postnatal brain
    growth in PUS7 deficiency?
  attaches_to:
  - pathophysiology#Impaired Postnatal Brain Growth
  rationale: >-
    The molecular defect and the clinical endpoint are both well established, but
    the step between them is entirely inferred. There is no evidence in any human
    or model system for neural progenitor pool depletion, altered cell cycle exit,
    increased apoptosis, or reduced neuronal arborisation in PUS7 deficiency. The
    published framing of the link is explicitly hedged, using the word
    "presumably". Because brain MRI architecture is normal in most patients, the
    deficit is one of growth rather than malformation, which narrows the candidate
    mechanisms but does not identify them. No iPSC-derived neural or organoid
    model of PUS7 deficiency exists.
  proposed_experiments:
  - experiment_id: exp_pus7_ipsc_neural_organoid
    name: PUS7-null iPSC-derived neural progenitors and cortical organoids
    description: >-
      Generate PUS7-null induced pluripotent stem cell lines and differentiate
      them to neural progenitors and cortical organoids, measuring progenitor
      proliferation, cell-cycle exit, apoptosis, and organoid size against
      isogenic controls. No such model currently exists, and it is the most direct
      test of whether the microcephaly reflects progenitor pool depletion.
  - experiment_id: exp_pus7_neural_ribosome_profiling
    name: Ribosome profiling in PUS7-null neural progenitors
    description: >-
      Perform ribosome profiling in PUS7-null neural progenitors to identify which
      transcripts change translational efficiency, and test specifically whether
      any are established microcephaly genes. This would convert the inferred
      translation-to-brain-growth link into a named set of effectors.
  evidence:
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We and others have previously emphasized the predilection of Mendelian
      diseases caused by tRNA modification genes to CNS involvement and how this
      suggests the vulnerability of the brain to any perturbation of tRNA
      modification, presumably through its deleterious effect on protein synthesis
    explanation: >-
      The hedged wording is itself the evidence for the gap: the field states the
      link as a presumption, not a finding.
- discussion_id: pus7_no_adult_natural_history
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the adult course, life expectancy, and adult morbidity profile of
    PUS7-related neurodevelopmental disorder?
  attaches_to:
  - pathophysiology#Cognitive and Behavioural Dysfunction
  rationale: >-
    Roughly 30 patients have been published and the oldest are adolescents; one
    cohort states its patients ranged from 2 to 18 years. No adult patient has
    been described, no natural-history study or registry exists, and no deaths
    have been reported. Two features are documented as progressive into
    adolescence, head circumference and hearing, and behaviour worsens over the
    same period, so extrapolating a stable adult course from paediatric
    cross-sections is not safe. Families cannot currently be given prognostic
    information beyond childhood.
  proposed_experiments:
  - experiment_id: exp_pus7_natural_history_registry
    name: International PUS7 natural-history registry
    description: >-
      Establish a prospective international registry collecting longitudinal head
      circumference, growth, audiometry, behavioural, and adaptive-function
      measures on genotype-confirmed individuals, with the explicit aim of
      extending observation past adolescence.
  - experiment_id: exp_pus7_family_recontact
    name: Recontact of previously published PUS7 families
    description: >-
      Recontact the published families, several of which were reported five or
      more years ago, to obtain adolescent and adult follow-up. This is the
      fastest available route to any adult data at all and requires no new
      ascertainment.
  evidence:
  - reference: PMID:33100873
    reference_title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      nine patients ranged in age from 2 to 18 years old
    explanation: >-
      Documents the paediatric ceiling of the published age range.
- discussion_id: pus7_genotype_phenotype_unresolved
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Do PUS7 missense alleles behave as hypomorphs that spare growth and head
    circumference, or as complete loss of function indistinguishable from
    truncating alleles?
  attaches_to:
  - pathophysiology#Biallelic PUS7 Loss-of-Function Variants
  rationale: >-
    Two published positions conflict. Darvish and colleagues propose that their
    missense family's milder phenotype, without microcephaly or short stature,
    reflects a hypomorphic allele in contrast to the null truncating alleles.
    Against that, the missense allele in the Shaheen cohort produced severe
    microcephaly and behaved as a complete loss of function in yeast
    complementation. A truncating-versus-missense severity rule therefore cannot
    currently be given to families. The 13-patient, 15-variant cohort of
    PMID:42249560 is framed by its own authors as improving genotype-phenotype
    correlation and is the priority source for resolving this, but its full text
    was not accessible during this curation pass.
  proposed_experiments:
  - experiment_id: exp_pus7_uniform_missense_functional_assay
    name: Uniform functional assay of all reported PUS7 missense alleles
    description: >-
      Assay every reported PUS7 missense allele in the same yeast complementation
      and tRNA pseudouridine-13 systems, so that residual catalytic activity is
      measured on one scale rather than being inferred backwards from clinical
      severity. This is the only way to test the hypomorph hypothesis
      independently of the phenotype it is meant to explain.
  - experiment_id: exp_pus7_pooled_genotype_phenotype_analysis
    name: Pooled genotype-phenotype analysis including the 2026 cohort
    description: >-
      Extract per-variant phenotype data from the 13-patient, 15-variant cohort of
      PMID:42249560 once full text is accessible, pool it with the earlier
      cohorts, and test the missense-versus-truncating severity hypothesis across
      the combined series.
  evidence:
  - reference: PMID:31583274
    reference_title: "A novel PUS7 mutation causes intellectual disability with autistic and aggressive behaviors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The absence of highly extreme phenotypes such as short stature or
      microcephaly in this family might reflect genotype–phenotype correlation,
      since this family presented with a PUS7 missense mutation that may be
      hypomorphic, while previously reported families carried nonsense or
      frameshift mutations that may cause loss of function.
    explanation: >-
      One side of the controversy: the hypomorphic-missense proposal.
  - reference: PMID:30778726
    reference_title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Furthermore, the missense variant of the S. cerevisiae ortholog failed to
      complement the growth defect of S. cerevisiae pus7Δ trm8Δ mutants.
    explanation: >-
      The other side: a patient missense allele that is a complete loss of
      function in a functional assay, in patients who did have severe
      microcephaly.
references:
- reference: PMID:30526862
  title: "Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior."
- reference: PMID:30778726
  title: "PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly."
- reference: PMID:31583274
  title: "A novel PUS7 mutation causes intellectual disability with autistic and aggressive behaviors."
- reference: PMID:33100873
  title: "Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability, developmental delay, dysmorphic feature and microcephaly."
- reference: PMID:35144859
  title: "PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation."
- reference: PMID:37067188
  title: "A PUS7 gene pathogenic variant causing self-injurious behavior, sleep disturbances, and developmental delay: A case report."
- reference: PMID:42226002
  title: "PUS7 Deficiency: Phenotypical Expansion of PUS7-Related Neurodevelopmental Disorders."
- reference: PMID:42249560
  title: "Novel Variants in PUS7 Associated With Intellectual Disability and Growth Retardation: Expanding the Clinical Spectrum in 13 Patients."
- reference: PMID:29628141
  title: "Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells."
- reference: PMID:41094471
  title: "PUS7-dependent Ψ reshapes specific synaptic gene exons to facilitate fear extinction memory formation."
- reference: PMID:41136621
  title: "A comprehensive tRNA pseudouridine map uncovers targets dependent on human stand-alone pseudouridine synthases."
- reference: PMID:27055666
  title: "A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition."
- reference: PMID:15108122
  title: "Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA)."
- reference: PMID:35292784
  title: "Pseudouridine-modified tRNA fragments repress aberrant protein synthesis and predict leukaemic progression in myelodysplastic syndrome."
- reference: PMID:35121864
  title: "Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis."
- reference: PMID:41168165
  title: "Pseudouridylation of 7SK by PUS7 regulates Pol II transcription elongation."
- reference: PMID:20932317
  title: "Frameshift mutation hotspot identified in Smith-Magenis syndrome: case report and review of literature."

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References & Deep Research

References

PMID:30526862

Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior.