👪

Inheritance

1

Autosomal recessive HP:0000007

Homozygous p.(Lys53Arg) in the original consanguineous Faroese family and in a third unrelated patient, and compound heterozygous p.Ser35Phe / p.Cys281Ter in a fourth. Heterozygous carriers have roughly half-normal enzyme activity and are unaffected.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:31600779 SUPPORT Human Clinical

"We report for the first time an autosomal recessive inborn error of de novo purine synthesis (DNPS)-PAICS deficiency."

Establishes autosomal recessive inheritance in the founding report.

?

Discussions and Knowledge Gaps

3

If AIR and AIr do not accumulate detectably in patient cells, what actually mediates the tissue damage in PAICS deficiency?

KNOWLEDGE GAP missing_toxic_metabolite

Attached to

pathophysiology#Impaired De Novo Purine Synthesis pathophysiology#Disrupted Embryonic Organogenesis

The substrate-accumulation model, which works for the sibling DNPS disorders, was tested here and failed: the predicted metabolites were sought in patient fibroblasts and not found, even though AIr is demonstrably cytotoxic to cell lines. That leaves purine insufficiency, purinosome-dependent channelling failure, or accumulation confined to a tissue or developmental window that fibroblasts do not sample. The absence also means there is no diagnostic metabolite and no substrate-reduction therapeutic target. A CRISPR-Cas9 PAICS-knockout HeLa line sharpens the question rather than settling it: there, intermediates immediately upstream of the deficient enzyme were the most strongly changed metabolites in the profile. So accumulation does happen in at least one human cell system. Whether the difference from patient fibroblasts is cell type, or complete knockout versus hypomorphic missense, is open.

Show evidence (1 reference)

PMID:35323684 SUPPORT INDIRECT In Vitro

"Statistical significance of PDNS intermediates preceding deficient enzymes was the highest"

Shows substrate accumulation behind the block in an engineered knockout, which is the counterpoint to its non-detection in patient fibroblasts. Indirect because the model is a cancer line with a complete knockout rather than the patient genotype.

Why do some individuals with biallelic PAICS variants present with a congenital malformation syndrome and others with neurodevelopmental regression and ocular disease, with almost no overlap?

KNOWLEDGE GAP malformation_versus_neurodegeneration_phenotypes

Attached to

phenotypes#Global developmental delay pathophysiology#PAICS Bifunctional Enzyme Deficiency

The split is close to dichotomous in the literature to date: malformation patients are described as having no neurologic involvement, and the neurodevelopmental sibpair had none of the malformations. Allele-specific residual activity is the obvious hypothesis, but the recurrent p.(Lys53Arg) homozygous genotype itself spans neonatal lethality and survival to seven years with normal neurodevelopment, so genotype alone does not explain it.

What determines whether an individual homozygous for p.(Lys53Arg) dies in the neonatal period or survives with normal neurodevelopment?

KNOWLEDGE GAP genotype_does_not_predict_survival

Attached to

pathophysiology#PAICS Bifunctional Enzyme Deficiency

The same recurrent homozygous variant produced early neonatal death in the Faroese siblings and a seven-year-old with normal neurodevelopment in an unrelated family. With so few patients, modifier effects, ascertainment bias toward lethal cases, and differences in surgical management of the esophageal atresia are all unexcluded.

⚙

Pathophysiology

4

PAICS Bifunctional Enzyme Deficiency

The recurrent p.(Lys53Arg) missense variant alters the structure of the catalytic site of the bifunctional AIRC/SAICARS enzyme. The deficit is graded and dose-dependent: about 50% of control activity in heterozygous carrier fibroblasts, about 10% in patient fibroblasts, and about 25% for the purified recombinant mutant protein. So this is a severe hypomorph rather than a null, which may be why any patient survives at all.

Genetic context allele_type: missense variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

A severe hypomorph rather than a null: roughly 10% residual catalytic activity in patient fibroblasts, about 25% for the purified recombinant p.(Lys53Arg) protein, and about 50% in heterozygous carriers. The recurrent allele is homozygous in two unrelated families; a fourth patient is compound heterozygous for p.Ser35Phe and p.Cys281Ter.

phosphoribosylaminoimidazole carboxylase activity GO:0004638 ↓ DECREASED phosphoribosylaminoimidazolesuccinocarboxamide synthase activity GO:0004639 ↓ DECREASED

Downstream

Failure of Purinosome Assembly The catalytically compromised enzyme cannot support assembly of the multienzyme de novo purine synthesis complex, mirroring what is seen in the two other known DNPS defects.

Show evidence (2 references)

PMID:31600779 SUPPORT In Vitro

"The mutation reduced the catalytic activity of PAICS in heterozygous carrier and patient skin fibroblasts to approximately 50 and 10% of control levels, respectively."

Quantifies the enzyme deficit in patient and carrier cells.

PMID:31600779 SUPPORT In Vitro

"The catalytic activity of the corresponding recombinant enzyme protein carrying the mutation p.Lys53Arg expressed and purified from E. coli was reduced to approximately 25% of the wild-type enzyme."

Confirms the catalytic deficit in purified recombinant protein, independent of cellular context.

Failure of Purinosome Assembly

The purinosome is the transient multienzyme complex in which the ten de novo purine synthesis enzymes are co-localized for substrate channelling. Patient fibroblasts fail to form it, and this is corrected by wild-type but not mutant PAICS. The same failure occurs in adenylosuccinate lyase deficiency and AICA-ribosiduria, the two previously known DNPS defects, which makes disrupted purinosome assembly the shared cellular lesion of this disease group.

skin fibroblast CL:0002620

purine nucleotide biosynthetic process GO:0006164 ↓ DECREASED

Experimental models

Patient skin fibroblasts with PAICS transfection rescue PRIMARY CELL CULTURE Patient-derived cells carrying the actual disease genotype reproduce the purinosome assembly defect and are corrected by wild-type PAICS.

Downstream

Impaired De Novo Purine Synthesis Without the assembled complex, flux through the de novo pathway is compromised beyond what the residual activity of the single enzyme would predict.

Show evidence (2 references)

PMID:31600779 SUPPORT In Vitro

"Similar to other two known DNPS defects-adenylosuccinate lyase deficiency and AICA-ribosiduria-the PAICS mutation prevented purinosome formation in the patient's skin fibroblasts"

Places the purinosome assembly failure in the context of the other de novo purine synthesis defects.

PMID:35331738 SUPPORT In Vitro

"we discovered PAICS interacts with all other known DNPB enzymes and with MTHFD1, an enzyme which supplies the 10-formyltetrahydrofolate cofactor essential for DNPB"

Establishes PAICS as the interaction hub of the purinosome, which is why losing it disassembles the complex rather than merely removing one enzymatic step.

Impaired De Novo Purine Synthesis

Reduced flux through de novo purine nucleotide synthesis. The expected corollary — accumulation of the blocked substrates aminoimidazole ribotide (AIR) and aminoimidazole riboside (AIr) — was looked for and not found in patient fibroblasts, which is why no diagnostic metabolite exists for this disorder. AIr is cytotoxic to cell lines, so substrate toxicity remains a plausible but undemonstrated contributor in patients.

'de novo' IMP biosynthetic process GO:0006189 ↓ DECREASED

Experimental models

CRISPR-Cas9 PAICS-knockout HeLa cells CELL LINE Reproduces the pathway block and shows substrate accumulation behind it, which patient fibroblasts did not. The discrepancy may be cell type or genotype - a complete knockout versus a hypomorphic missense - rather than evidence that no accumulation occurs.

Downstream

Disrupted Embryonic Organogenesis Purine nucleotides are required for the proliferation and nucleic acid synthesis of rapidly dividing embryonic tissue, but the specific developmental processes that fail have not been identified.

Show evidence (1 reference)

PMID:31600779 SUPPORT In Vitro

"Although aminoimidazole ribotide (AIR) and aminoimidazole riboside (AIr), the enzyme substrates that are predicted to accumulate in PAICS deficiency, were not detected in patient's fibroblasts, the cytotoxic effect of AIr on various cell lines was demonstrated."

Records both the failure to detect the predicted accumulating substrates and the separate demonstration that one of them is cytotoxic.

Disrupted Embryonic Organogenesis

A multisystem malformation syndrome affecting foregut, heart, axial skeleton, limbs, urogenital tract, and craniofacial structures — a pattern consistent with a global constraint on proliferating embryonic tissue rather than a lesion of one developmental program.

Downstream

Esophageal atresia

Abnormal heart morphology

Abnormal vertebral morphology

Abnormal facial shape

Cryptorchidism

Pulmonary hypoplasia

Short stature

Show evidence (1 reference)

PMID:42569864 SUPPORT Human Clinical

"Biallelic variants in PAICS, one of the 10 genes involved in the de novo purine synthesis (DNPS), were originally associated with an extremely rare phenotype characterized by multiple and severe congenital abnormalities, such as polyhydramnios due to esophageal atresia, congenital heart disease,..."

Summarizes the multisystem malformation pattern attributed to the enzyme defect.

⬡

Pathograph

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

●

Phenotypes

11

Cardiovascular 1

Abnormal heart morphology FREQUENT HP:0001627

Show evidence (1 reference)

PMID:39726239 SUPPORT Human Clinical

"We report malformations not previously described in PAICS deficiency, notably congenital cardiopathy"

Adds congenital heart disease to the phenotype of PAICS deficiency.

Digestive 1

Esophageal atresia VERY_FREQUENT HP:0002032

Sequelae: Polyhydramnios

Show evidence (2 references)

PMID:42569864 SUPPORT Human Clinical

"esophageal atresia, lung hypoplasia, vertebral anomalies, cryptorchidism, short stature, and dysmorphic facial features"

Reports esophageal atresia among the malformations in the most recently described patient.

PMID:39726239 SUPPORT Human Clinical

"support the consistency of skeletal and oesophageal defects"

Confirms esophageal defects as a consistent feature across reported patients.

Eye 1

Abnormality of the eye OCCASIONAL HP:0000478

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:42569864 SUPPORT Human Clinical

"two siblings with none of these features but presenting a severe neurodevelopmental phenotype with regression and ocular involvement have been reported"

Reports ocular involvement in the non-malformation arm of the spectrum.

Genitourinary 1

Cryptorchidism OCCASIONAL HP:0000028

Show evidence (1 reference)

PMID:42569864 SUPPORT Human Clinical

"esophageal atresia, lung hypoplasia, vertebral anomalies, cryptorchidism, short stature, and dysmorphic facial features"

Reports cryptorchidism among the malformations in the most recently described patient.

Head and Neck 1

Abnormal facial shape FREQUENT HP:0001999

Show evidence (1 reference)

PMID:42569864 SUPPORT Human Clinical

"Vertebral and limb defects, as well as distinctive craniofacial features, were also described."

Reports distinctive craniofacial features as part of the phenotype.

Musculoskeletal 1

Abnormal vertebral morphology FREQUENT HP:0003468

Show evidence (1 reference)

PMID:42569864 SUPPORT Human Clinical

"Vertebral and limb defects, as well as distinctive craniofacial features, were also described."

Reports vertebral and limb defects as part of the recognized phenotype.

Nervous System 2

Global developmental delay OCCASIONAL HP:0001263

Show evidence (2 references)

PMID:42569864 SUPPORT Human Clinical

"He also had developmental delay; however, epilepsy did not occur."

Reports developmental delay without epilepsy in the most recently described patient.

PMID:39726239 REFUTE Human Clinical

"We report the third case of PAICS deficiency in a 7 years old boy, presenting with polymalformative syndrome, but normal neurodevelopment."

Refutes developmental delay as an obligate feature; this patient had the malformation syndrome with normal neurodevelopment.

Developmental regression OCCASIONAL HP:0002376

Show evidence (1 reference)

PMID:42569864 SUPPORT Human Clinical

"two siblings with none of these features but presenting a severe neurodevelopmental phenotype with regression and ocular involvement have been reported"

Reports neurodevelopmental regression in the non-malformation arm of the phenotypic spectrum.

Prenatal and Birth 1

Polyhydramnios VERY_FREQUENT HP:0001561

Show evidence (1 reference)

PMID:42569864 SUPPORT Human Clinical

"polyhydramnios due to esophageal atresia"

States polyhydramnios and its cause in this disorder.

Respiratory 1

Pulmonary hypoplasia OCCASIONAL HP:0002089

Show evidence (1 reference)

PMID:42569864 SUPPORT Human Clinical

"esophageal atresia, lung hypoplasia, vertebral anomalies, cryptorchidism, short stature, and dysmorphic facial features"

Reports lung hypoplasia in the most recently described patient.

Growth 1

Short stature OCCASIONAL HP:0004322

Show evidence (1 reference)

PMID:42569864 SUPPORT Human Clinical

"esophageal atresia, lung hypoplasia, vertebral anomalies, cryptorchidism, short stature, and dysmorphic facial features"

Reports short stature in the most recently described patient.

🧬

Genetic Associations

1

PAICS

Gene: PAICS hgnc:8587 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:31600779 SUPPORT Human Clinical

"Genetic analysis of affected individuals revealed a homozygous missense mutation in PAICS (c.158A>G; p.Lys53Arg) that affects the structure of the catalytic site of the bifunctional enzyme phosphoribosylaminoimidazole carboxylase (AIRC, EC 4.1.1.21)/phosphoribosylaminoimidazole..."

Identifies PAICS as the causal gene and the recurrent variant's effect on the catalytic site.

PMID:39726239 SUPPORT Human Clinical

"Genome Sequencing identified the homozygous pathogenic variant p.(Lys53Arg), suggesting a recurrent variant in PAICS."

Establishes p.(Lys53Arg) as recurrent across unrelated families.

💊

Medical Actions

3

Surgical Repair of Congenital Malformations

Action: surgical repair of congenital malformations Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Repair of esophageal atresia and of congenital heart disease where survival permits. This is the only intervention that alters outcome, and it addresses the malformations rather than the metabolic defect. Neither cited abstract describes the surgical management, so this entry carries no evidence item; it rests on the malformations that are cited elsewhere in the entry.

Mechanism Target:

Esophageal atresia — Surgical repair restores foregut continuity; it does not affect the upstream purine synthesis defect.

Abnormal heart morphology — Cardiac repair addresses the structural lesion only.

Supportive Care

Action: Supportive Care NCIT:C15747

Platform: Other

No disease-modifying therapy exists. Because AIR and AIr do not accumulate detectably, there is no substrate-reduction target either, so management outside of surgical repair is supportive.

Genetic Counseling and Prenatal Diagnosis

Action: Genetic Counseling NCIT:C15240

Platform: Other

Relevant to families with recurrent spontaneous abortion or unexplained early neonatal death, in whom this disorder should be considered. A probable recurrence in a later sibling was diagnosed antenatally on the malformation pattern although it could not be confirmed molecularly.

Show evidence (1 reference)

PMID:31600779 SUPPORT Human Clinical

"PAICS deficiency is a newly described disease that enhances our understanding of the DNPS pathway and should be considered in the diagnosis of families with recurrent spontaneous abortion or early neonatal death."

States the clinical setting in which this diagnosis should be sought.

🔬

Diagnosis

3

Molecular genetic testing

The primary diagnostic route. Exome or genome sequencing identifies the biallelic PAICS variants; the recurrent p.(Lys53Arg) allele has now been found homozygous in two unrelated families.

Show evidence (1 reference)

PMID:39726239 SUPPORT Human Clinical

"Genome Sequencing identified the homozygous pathogenic variant p.(Lys53Arg), suggesting a recurrent variant in PAICS."

Genome sequencing is what established the diagnosis in the third reported patient.

PAICS enzyme activity assay in cultured skin fibroblasts

Confirmatory functional testing. Catalytic activity falls to roughly 10% of control in patient fibroblasts and about 50% in heterozygous carriers, so the assay separates affected individuals, carriers and controls.

Show evidence (1 reference)

PMID:31600779 SUPPORT In Vitro

"The mutation reduced the catalytic activity of PAICS in heterozygous carrier and patient skin fibroblasts to approximately 50 and 10% of control levels, respectively."

Establishes the enzyme assay as discriminating between patients, carriers and controls.

Absence of a diagnostic metabolite marker

Unlike the sibling de novo purine synthesis defects, there is no accumulating metabolite to screen for. The substrates predicted to build up behind the block, AIR and AIr, were sought in patient fibroblasts and not detected. This is a negative diagnostic finding and it is the reason biochemical screening cannot find this disorder.

Show evidence (1 reference)

PMID:31600779 REFUTE In Vitro

"Although aminoimidazole ribotide (AIR) and aminoimidazole riboside (AIr), the enzyme substrates that are predicted to accumulate in PAICS deficiency, were not detected in patient's fibroblasts"

Refutes the availability of a substrate-accumulation biochemical marker for this disorder.

📈

Progression

2

Neonatal

Age: first days of life

The originally reported Faroese siblings died within the first days of life from their malformations. Later patients have survived — one to at least seven years — so lethality is not universal, and the determinants of survival are not established.

Show evidence (1 reference)

PMID:31600779 SUPPORT Human Clinical

"We investigated two siblings from the Faroe Islands born with multiple malformations resulting in early neonatal death."

Records the lethal neonatal course of the index siblings.

Childhood survival

Age: beyond infancy

Later-reported patients have survived beyond infancy, one with normal neurodevelopment at seven years and relatively long follow-up in another.

Show evidence (1 reference)

PMID:39726239 SUPPORT Human Clinical

"We report the third case of PAICS deficiency in a 7 years old boy, presenting with polymalformative syndrome, but normal neurodevelopment."

States directly that a patient survived to seven years with normal neurodevelopment, which is what this phase claims.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

At least six reported individuals: three with the malformation syndrome and no neurologic involvement, a separately reported sibpair with neurodevelopmental regression and no malformations, and a sixth compound heterozygous patient combining features of both. One antenatally suspected sibling could not be confirmed molecularly. No population-based prevalence estimate exists.

Show evidence (1 reference)

PMID:39726239 SUPPORT Human Clinical

"Phosphoribosylaminoimidazole carboxylase (PAICS) deficiency, caused by biallelic variants in PAICS gene, is an inborn error of de novo purine synthesis. Only two patients from a consanguineous family have been reported, with multiple congenital malformations, resulting in early neonatal death...."

The PAICS report adds a third molecularly characterized patient to two previously reported siblings and describes an unconfirmed antenatal recurrence. It supports these specific observations, not later totals assembled across publications.

⚖️

Clinical Burden

Variable

Lethal within days of birth in the index siblings, yet compatible with survival to at least seven years with normal neurodevelopment in another patient homozygous for the same recurrent variant. With fewer than ten reported individuals the range is wide and the determinants are unknown.

Show evidence (1 reference)

PMID:39726239 SUPPORT Human Clinical

"Only two patients from a consanguineous family have been reported, with multiple congenital malformations, resulting in early neonatal death."

Establishes the severe end of the burden range against which later survivors are contrasted.

🧫

Experimental Models

2

CRISPR-Cas9 PAICS-knockout HeLa cells CELL_LINE

Genome-edited HeLa cells deficient in individual steps of purine de novo synthesis, profiled by targeted and untargeted metabolomics. Important here as a counterpoint rather than a confirmation: intermediates immediately upstream of the deficient enzyme were the most strongly changed metabolites in this system, whereas the substrates predicted to accumulate were not detectable in patient fibroblasts.

Pathograph links

Impaired De Novo Purine Synthesis partially recapitulates fidelity: moderate Reproduces the pathway block and shows substrate accumulation behind it, which patient fibroblasts did not. The discrepancy may be cell type or genotype - a complete knockout versus a hypomorphic missense - rather than evidence that no accumulation occurs.

Limitations: A cancer cell line carrying an engineered complete knockout, not the patient genotype, and cultured under conditions that do not model embryonic organogenesis. It cannot settle whether patients accumulate substrate in any tissue.

Readouts

Purine de novo synthesis intermediates upstream of the deficient enzyme

Direction: INCREASED

Interpretation: Intermediates preceding the deficient enzyme were the most statistically significant features in the profile, indicating substrate accumulation behind the block in this model system.

Show evidence (1 reference)

PMID:35323684 SUPPORT In Vitro

"Statistical significance of PDNS intermediates preceding deficient enzymes was the highest"

Reports accumulation of intermediates upstream of the deficient enzyme in the knockout cells.

Show evidence (1 reference)

PMID:35323684 SUPPORT In Vitro

"This work aims to describe the metabolic changes of CRISPR-Cas9 genome-edited HeLa cells deficient in the individual steps of PDNS to better understand known and potential defects of the pathway in humans."

Identifies the model system and its purpose as a proxy for the human pathway defects.

Patient skin fibroblasts with PAICS transfection rescue PRIMARY_CELL_CULTURE

Primary skin fibroblasts from an affected individual and from heterozygous carriers, used to measure residual enzyme activity, to score purinosome formation, and — through transfection with wild-type versus mutant PAICS — to establish causation.

Pathograph links

Failure of Purinosome Assembly recapitulates fidelity: high Patient-derived cells carrying the actual disease genotype reproduce the purinosome assembly defect and are corrected by wild-type PAICS.

Limitations: Fibroblasts cannot model the embryonic organogenesis in which the disease manifests, and the predicted accumulating substrates were not detectable in them — so the model demonstrates the cellular lesion but not the route from it to the malformations.

Readouts

Purinosome formation after wild-type versus mutant PAICS transfection

Direction: RESTORED

Interpretation: Wild-type PAICS restores purinosome formation and the mutant construct does not, establishing that the variant causes the defect.

Show evidence (1 reference)

PMID:31600779 SUPPORT In Vitro

"this phenotype was corrected by transfection with the wild-type but not the mutated PAICS"

Reports the transfection rescue measurement in patient fibroblasts.

Show evidence (1 reference)

PMID:31600779 SUPPORT In Vitro

"the PAICS mutation prevented purinosome formation in the patient's skin fibroblasts"

Establishes patient fibroblasts as informative for the purinosome assembly node.

{ }

Source YAML

click to show

name: PAICS Deficiency
creation_date: "2026-09-01T00:00:00Z"
category: Mendelian
description: >-
  PAICS deficiency is an autosomal recessive inborn error of de novo purine
  synthesis caused by biallelic variants in PAICS, which encodes the
  bifunctional enzyme phosphoribosylaminoimidazole carboxylase (AIRC) /
  phosphoribosylaminoimidazole succinocarboxamide synthetase (SAICARS)
  catalysing steps six and seven of the pathway. It was first described in two
  Faroese siblings with multiple congenital malformations and early neonatal
  death. The recognizable malformation pattern is esophageal atresia with
  polyhydramnios, congenital heart disease, urogenital anomalies, vertebral and
  limb defects, and distinctive craniofacial features. Two things about it are
  unsettled and important. First, the phenotype has split: some patients have
  the malformation syndrome with normal neurodevelopment and survival past
  infancy, while a separate reported sibpair had severe neurodevelopmental
  regression and ocular disease with none of the malformations. Second, the
  proposed toxic metabolites were not actually found — AIR and AIr, the
  substrates predicted to accumulate, were undetectable in patient fibroblasts —
  so the mechanism connecting enzyme deficiency to malformation runs through
  loss of purinosome assembly rather than through demonstrated substrate
  toxicity.
parents:
- hereditary disease
- inborn error of purine metabolism
- disorder of de novo purine synthesis
disease_term:
  preferred_term: PAICS deficiency
  term:
    id: MONDO:0859003
    label: PAICS deficiency

inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Homozygous p.(Lys53Arg) in the original consanguineous Faroese family and in
    a third unrelated patient, and compound heterozygous p.Ser35Phe /
    p.Cys281Ter in a fourth. Heterozygous carriers have roughly half-normal
    enzyme activity and are unaffected.
  evidence:
  - reference: PMID:31600779
    reference_title: "PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report for the first time an autosomal recessive inborn error of de novo purine synthesis (DNPS)-PAICS deficiency."
    explanation: Establishes autosomal recessive inheritance in the founding report.

pathophysiology:
- name: PAICS Bifunctional Enzyme Deficiency
  description: >-
    The recurrent p.(Lys53Arg) missense variant alters the structure of the
    catalytic site of the bifunctional AIRC/SAICARS enzyme. The deficit is
    graded and dose-dependent: about 50% of control activity in heterozygous
    carrier fibroblasts, about 10% in patient fibroblasts, and about 25% for the
    purified recombinant mutant protein. So this is a severe hypomorph rather
    than a null, which may be why any patient survives at all.
  biological_scale: MOLECULAR
  downstream:
  - target: Failure of Purinosome Assembly
    causal_link_type: DIRECT
    description: >-
      The catalytically compromised enzyme cannot support assembly of the
      multienzyme de novo purine synthesis complex, mirroring what is seen in the
      two other known DNPS defects.
    evidence:
    - reference: PMID:31600779
      reference_title: "PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the PAICS mutation prevented purinosome formation in the patient's skin fibroblasts, and this phenotype was corrected by transfection with the wild-type but not the mutated PAICS"
      explanation: Transfection rescue with wild-type but not mutant PAICS establishes that the variant causes the purinosome defect.
  genetic_context:
    zygosity: HOMOZYGOUS
    variant_origin: GERMLINE
    allele_type: missense
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    description: >-
      A severe hypomorph rather than a null: roughly 10% residual catalytic
      activity in patient fibroblasts, about 25% for the purified recombinant
      p.(Lys53Arg) protein, and about 50% in heterozygous carriers. The
      recurrent allele is homozygous in two unrelated families; a fourth patient
      is compound heterozygous for p.Ser35Phe and p.Cys281Ter.
  molecular_functions:
  - preferred_term: phosphoribosylaminoimidazole carboxylase activity
    term:
      id: GO:0004638
      label: phosphoribosylaminoimidazole carboxylase activity
    modifier: DECREASED
  - preferred_term: phosphoribosylaminoimidazolesuccinocarboxamide synthase activity
    term:
      id: GO:0004639
      label: phosphoribosylaminoimidazolesuccinocarboxamide synthase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:31600779
    reference_title: "PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mutation reduced the catalytic activity of PAICS in heterozygous carrier and patient skin fibroblasts to approximately 50 and 10% of control levels, respectively."
    explanation: Quantifies the enzyme deficit in patient and carrier cells.
  - reference: PMID:31600779
    reference_title: "PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The catalytic activity of the corresponding recombinant enzyme protein carrying the mutation p.Lys53Arg expressed and purified from E. coli was reduced to approximately 25% of the wild-type enzyme."
    explanation: Confirms the catalytic deficit in purified recombinant protein, independent of cellular context.

- name: Failure of Purinosome Assembly
  description: >-
    The purinosome is the transient multienzyme complex in which the ten de novo
    purine synthesis enzymes are co-localized for substrate channelling. Patient
    fibroblasts fail to form it, and this is corrected by wild-type but not
    mutant PAICS. The same failure occurs in adenylosuccinate lyase deficiency
    and AICA-ribosiduria, the two previously known DNPS defects, which makes
    disrupted purinosome assembly the shared cellular lesion of this disease
    group.
  biological_scale: CELLULAR
  downstream:
  - target: Impaired De Novo Purine Synthesis
    causal_link_type: DIRECT
    description: >-
      Without the assembled complex, flux through the de novo pathway is
      compromised beyond what the residual activity of the single enzyme would
      predict.
    evidence:
    - reference: PMID:35331738
      reference_title: "Multienzyme interactions of the de novo purine biosynthetic protein PAICS facilitate purinosome formation and metabolic channeling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "perturbing PPIs between DNPB enzymes negatively impact metabolite flux through this important pathway"
      explanation: >-
        States the load-bearing claim of this edge directly: disrupting the
        protein-protein interactions that build the purinosome reduces flux
        through the pathway, over and above any single enzyme's activity.
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  biological_processes:
  - preferred_term: purine nucleotide biosynthetic process
    term:
      id: GO:0006164
      label: purine nucleotide biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:31600779
    reference_title: "PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Similar to other two known DNPS defects-adenylosuccinate lyase deficiency and AICA-ribosiduria-the PAICS mutation prevented purinosome formation in the patient's skin fibroblasts"
    explanation: Places the purinosome assembly failure in the context of the other de novo purine synthesis defects.
  - reference: PMID:35331738
    reference_title: "Multienzyme interactions of the de novo purine biosynthetic protein PAICS facilitate purinosome formation and metabolic channeling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we discovered PAICS interacts with all other known DNPB enzymes and with MTHFD1, an enzyme which supplies the 10-formyltetrahydrofolate cofactor essential for DNPB"
    explanation: >-
      Establishes PAICS as the interaction hub of the purinosome, which is why
      losing it disassembles the complex rather than merely removing one
      enzymatic step.

- name: Impaired De Novo Purine Synthesis
  description: >-
    Reduced flux through de novo purine nucleotide synthesis. The expected
    corollary — accumulation of the blocked substrates aminoimidazole ribotide
    (AIR) and aminoimidazole riboside (AIr) — was looked for and not found in
    patient fibroblasts, which is why no diagnostic metabolite exists for this
    disorder. AIr is cytotoxic to cell lines, so substrate toxicity remains a
    plausible but undemonstrated contributor in patients.
  biological_scale: CELLULAR
  downstream:
  - target: Disrupted Embryonic Organogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Purine nucleotides are required for the proliferation and nucleic acid
      synthesis of rapidly dividing embryonic tissue, but the specific
      developmental processes that fail have not been identified.
  biological_processes:
  - preferred_term: "'de novo' IMP biosynthetic process"
    term:
      id: GO:0006189
      label: "'de novo' IMP biosynthetic process"
    modifier: DECREASED
  evidence:
  - reference: PMID:31600779
    reference_title: "PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Although aminoimidazole ribotide (AIR) and aminoimidazole riboside (AIr), the enzyme substrates that are predicted to accumulate in PAICS deficiency, were not detected in patient's fibroblasts, the cytotoxic effect of AIr on various cell lines was demonstrated."
    explanation: Records both the failure to detect the predicted accumulating substrates and the separate demonstration that one of them is cytotoxic.

- name: Disrupted Embryonic Organogenesis
  description: >-
    A multisystem malformation syndrome affecting foregut, heart, axial
    skeleton, limbs, urogenital tract, and craniofacial structures — a pattern
    consistent with a global constraint on proliferating embryonic tissue rather
    than a lesion of one developmental program.
  biological_scale: ORGANISM
  downstream:
  - target: Esophageal atresia
    causal_link_type: DIRECT
  - target: Abnormal heart morphology
    causal_link_type: DIRECT
  - target: Abnormal vertebral morphology
    causal_link_type: DIRECT
  - target: Abnormal facial shape
    causal_link_type: DIRECT
  - target: Cryptorchidism
    causal_link_type: DIRECT
  - target: Pulmonary hypoplasia
    causal_link_type: DIRECT
  - target: Short stature
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:42569864
    reference_title: "Compound Heterozygous Variants in the PAICS Gene Integrate the Previously Described Divergent Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic variants in PAICS, one of the 10 genes involved in the de novo purine synthesis (DNPS), were originally associated with an extremely rare phenotype characterized by multiple and severe congenital abnormalities, such as polyhydramnios due to esophageal atresia, congenital heart disease, and urogenital anomalies, which were lethal within the first days of life."
    explanation: Summarizes the multisystem malformation pattern attributed to the enzyme defect.

phenotypes:
- category: Gastrointestinal
  name: Esophageal atresia
  description: >-
    A consistent and characteristic feature, presenting antenatally as
    polyhydramnios.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Esophageal atresia
    term:
      id: HP:0002032
      label: Esophageal atresia
  sequelae:
  - target: Polyhydramnios
    description: >-
      Impaired fetal swallowing from esophageal atresia produces polyhydramnios,
      often the first antenatal sign.
  evidence:
  - reference: PMID:42569864
    reference_title: "Compound Heterozygous Variants in the PAICS Gene Integrate the Previously Described Divergent Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "esophageal atresia, lung hypoplasia, vertebral anomalies, cryptorchidism, short stature, and dysmorphic facial features"
    explanation: Reports esophageal atresia among the malformations in the most recently described patient.
  - reference: PMID:39726239
    reference_title: "Identification of the Third Patient With PAICS Deficiency Harbouring the p.(Lys53Arg) Recurrent Variant, Extending the Phenotype Diversity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "support the consistency of skeletal and oesophageal defects"
    explanation: Confirms esophageal defects as a consistent feature across reported patients.

- category: Prenatal
  name: Polyhydramnios
  description: >-
    Antenatal polyhydramnios secondary to esophageal atresia.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  evidence:
  - reference: PMID:42569864
    reference_title: "Compound Heterozygous Variants in the PAICS Gene Integrate the Previously Described Divergent Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "polyhydramnios due to esophageal atresia"
    explanation: States polyhydramnios and its cause in this disorder.

- category: Cardiovascular
  name: Abnormal heart morphology
  description: >-
    Congenital heart disease, present in the original patients and confirmed as
    a newly delineated feature in the third reported case.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Congenital heart disease
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:39726239
    reference_title: "Identification of the Third Patient With PAICS Deficiency Harbouring the p.(Lys53Arg) Recurrent Variant, Extending the Phenotype Diversity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report malformations not previously described in PAICS deficiency, notably congenital cardiopathy"
    explanation: Adds congenital heart disease to the phenotype of PAICS deficiency.

- category: Musculoskeletal
  name: Abnormal vertebral morphology
  description: >-
    Vertebral anomalies, with limb defects also reported; skeletal involvement is
    described as a consistent feature.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Vertebral anomalies
    term:
      id: HP:0003468
      label: Abnormal vertebral morphology
  evidence:
  - reference: PMID:42569864
    reference_title: "Compound Heterozygous Variants in the PAICS Gene Integrate the Previously Described Divergent Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vertebral and limb defects, as well as distinctive craniofacial features, were also described."
    explanation: Reports vertebral and limb defects as part of the recognized phenotype.

- category: Craniofacial
  name: Abnormal facial shape
  description: >-
    Distinctive craniofacial features, described as dysmorphic facial features
    with midface involvement.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Distinctive craniofacial features
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:42569864
    reference_title: "Compound Heterozygous Variants in the PAICS Gene Integrate the Previously Described Divergent Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vertebral and limb defects, as well as distinctive craniofacial features, were also described."
    explanation: Reports distinctive craniofacial features as part of the phenotype.

- category: Genitourinary
  name: Cryptorchidism
  description: >-
    Part of the urogenital anomalies reported in this disorder.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:42569864
    reference_title: "Compound Heterozygous Variants in the PAICS Gene Integrate the Previously Described Divergent Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "esophageal atresia, lung hypoplasia, vertebral anomalies, cryptorchidism, short stature, and dysmorphic facial features"
    explanation: Reports cryptorchidism among the malformations in the most recently described patient.

- category: Respiratory
  name: Pulmonary hypoplasia
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Lung hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  evidence:
  - reference: PMID:42569864
    reference_title: "Compound Heterozygous Variants in the PAICS Gene Integrate the Previously Described Divergent Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "esophageal atresia, lung hypoplasia, vertebral anomalies, cryptorchidism, short stature, and dysmorphic facial features"
    explanation: Reports lung hypoplasia in the most recently described patient.

- category: Growth
  name: Short stature
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:42569864
    reference_title: "Compound Heterozygous Variants in the PAICS Gene Integrate the Previously Described Divergent Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "esophageal atresia, lung hypoplasia, vertebral anomalies, cryptorchidism, short stature, and dysmorphic facial features"
    explanation: Reports short stature in the most recently described patient.

- category: Neurologic
  name: Global developmental delay
  description: >-
    Neurodevelopment is the most variable part of this phenotype and the least
    predictable clinically. The third reported patient had a polymalformative
    syndrome with explicitly normal neurodevelopment at seven years; the fourth
    had developmental delay but no epilepsy; and a separately reported sibpair
    had severe neurodevelopmental regression with ocular involvement and none of
    the malformations at all.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:42569864
    reference_title: "Compound Heterozygous Variants in the PAICS Gene Integrate the Previously Described Divergent Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He also had developmental delay; however, epilepsy did not occur."
    explanation: Reports developmental delay without epilepsy in the most recently described patient.
  - reference: PMID:39726239
    reference_title: "Identification of the Third Patient With PAICS Deficiency Harbouring the p.(Lys53Arg) Recurrent Variant, Extending the Phenotype Diversity."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the third case of PAICS deficiency in a 7 years old boy, presenting with polymalformative syndrome, but normal neurodevelopment."
    explanation: Refutes developmental delay as an obligate feature; this patient had the malformation syndrome with normal neurodevelopment.

- category: Neurologic
  name: Developmental regression
  description: >-
    Reported in a separately described sibpair who had a severe
    neurodevelopmental phenotype with regression and ocular involvement and none
    of the congenital malformations. This is the other half of the phenotypic
    spectrum and it segregates away from the malformation syndrome rather than
    accompanying it; see the malformation_versus_neurodegeneration_phenotypes
    discussion.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:42569864
    reference_title: "Compound Heterozygous Variants in the PAICS Gene Integrate the Previously Described Divergent Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two siblings with none of these features but presenting a severe neurodevelopmental phenotype with regression and ocular involvement have been reported"
    explanation: Reports neurodevelopmental regression in the non-malformation arm of the phenotypic spectrum.

- category: Ophthalmologic
  name: Abnormality of the eye
  description: >-
    Ocular involvement reported alongside neurodevelopmental regression in the
    sibpair lacking the malformation syndrome. The specific ocular finding is not
    characterized in the available abstract, so the binding is deliberately at
    the general level.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: ocular involvement
    term:
      id: HP:0000478
      label: Abnormality of the eye
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:42569864
    reference_title: "Compound Heterozygous Variants in the PAICS Gene Integrate the Previously Described Divergent Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two siblings with none of these features but presenting a severe neurodevelopmental phenotype with regression and ocular involvement have been reported"
    explanation: Reports ocular involvement in the non-malformation arm of the spectrum.

diagnosis:
- name: Molecular genetic testing
  description: >-
    The primary diagnostic route. Exome or genome sequencing identifies the
    biallelic PAICS variants; the recurrent p.(Lys53Arg) allele has now been
    found homozygous in two unrelated families.
  evidence:
  - reference: PMID:39726239
    reference_title: "Identification of the Third Patient With PAICS Deficiency Harbouring the p.(Lys53Arg) Recurrent Variant, Extending the Phenotype Diversity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genome Sequencing identified the homozygous pathogenic variant p.(Lys53Arg), suggesting a recurrent variant in PAICS."
    explanation: Genome sequencing is what established the diagnosis in the third reported patient.

- name: PAICS enzyme activity assay in cultured skin fibroblasts
  description: >-
    Confirmatory functional testing. Catalytic activity falls to roughly 10% of
    control in patient fibroblasts and about 50% in heterozygous carriers, so the
    assay separates affected individuals, carriers and controls.
  evidence:
  - reference: PMID:31600779
    reference_title: "PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mutation reduced the catalytic activity of PAICS in heterozygous carrier and patient skin fibroblasts to approximately 50 and 10% of control levels, respectively."
    explanation: Establishes the enzyme assay as discriminating between patients, carriers and controls.

- name: Absence of a diagnostic metabolite marker
  description: >-
    Unlike the sibling de novo purine synthesis defects, there is no accumulating
    metabolite to screen for. The substrates predicted to build up behind the
    block, AIR and AIr, were sought in patient fibroblasts and not detected. This
    is a negative diagnostic finding and it is the reason biochemical screening
    cannot find this disorder.
  evidence:
  - reference: PMID:31600779
    reference_title: "PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Although aminoimidazole ribotide (AIR) and aminoimidazole riboside (AIr), the enzyme substrates that are predicted to accumulate in PAICS deficiency, were not detected in patient's fibroblasts"
    explanation: Refutes the availability of a substrate-accumulation biochemical marker for this disorder.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    At least six reported individuals: three with the malformation syndrome and
    no neurologic involvement, a separately reported sibpair with
    neurodevelopmental regression and no malformations, and a sixth compound
    heterozygous patient combining features of both. One antenatally suspected
    sibling could not be confirmed molecularly. No population-based prevalence
    estimate exists.
  evidence:
  - reference: PMID:39726239
    reference_title: "Identification of the Third Patient With PAICS Deficiency Harbouring the p.(Lys53Arg) Recurrent Variant, Extending the Phenotype Diversity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phosphoribosylaminoimidazole carboxylase (PAICS) deficiency, caused by biallelic variants in
      PAICS gene, is an inborn error of de novo purine synthesis. Only two patients from a
      consanguineous family have been reported, with multiple congenital malformations, resulting in
      early neonatal death. Molecular analysis identified a homozygous p.(Lys53Arg) missense
      variant. We report the third case of PAICS deficiency in a 7 years old boy, presenting with
      polymalformative syndrome, but normal neurodevelopment. ... A probable recurrence of PAICS
      deficiency occurred in a sibling, with a similar polymalformative syndrome antenatally
      diagnosed, but could not be confirmed molecularly.
    explanation: >-
      The PAICS report adds a third molecularly characterized patient to two previously reported
      siblings and describes an unconfirmed antenatal recurrence. It supports these specific
      observations, not later totals assembled across publications.

progression:
- phase: Neonatal
  age_range: first days of life
  notes: >-
    The originally reported Faroese siblings died within the first days of life
    from their malformations. Later patients have survived — one to at least
    seven years — so lethality is not universal, and the determinants of survival
    are not established.
  evidence:
  - reference: PMID:31600779
    reference_title: "PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated two siblings from the Faroe Islands born with multiple malformations resulting in early neonatal death."
    explanation: Records the lethal neonatal course of the index siblings.
- phase: Childhood survival
  age_range: beyond infancy
  notes: >-
    Later-reported patients have survived beyond infancy, one with normal
    neurodevelopment at seven years and relatively long follow-up in another.
  evidence:
  - reference: PMID:39726239
    reference_title: "Identification of the Third Patient With PAICS Deficiency Harbouring the p.(Lys53Arg) Recurrent Variant, Extending the Phenotype Diversity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the third case of PAICS deficiency in a 7 years old boy, presenting with polymalformative syndrome, but normal neurodevelopment."
    explanation: States directly that a patient survived to seven years with normal neurodevelopment, which is what this phase claims.

clinical_burden:
  burden_level: VARIABLE
  rationale: >-
    Lethal within days of birth in the index siblings, yet compatible with
    survival to at least seven years with normal neurodevelopment in another
    patient homozygous for the same recurrent variant. With fewer than ten
    reported individuals the range is wide and the determinants are unknown.
  evidence:
  - reference: PMID:39726239
    reference_title: "Identification of the Third Patient With PAICS Deficiency Harbouring the p.(Lys53Arg) Recurrent Variant, Extending the Phenotype Diversity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only two patients from a consanguineous family have been reported, with multiple congenital malformations, resulting in early neonatal death."
    explanation: Establishes the severe end of the burden range against which later survivors are contrasted.

genetic:
- name: PAICS
  notes: >-
    Biallelic variants in PAICS, encoding the bifunctional
    phosphoribosylaminoimidazole carboxylase (AIRC, EC 4.1.1.21) /
    phosphoribosylaminoimidazole succinocarboxamide synthetase (SAICARS, EC
    6.3.2.6). c.158A>G p.(Lys53Arg) is a recurrent variant, found homozygous in
    the original Faroese sibship and again in an unrelated third patient; a
    fourth patient carried compound heterozygous p.Ser35Phe and p.Cys281Ter.
  gene_term:
    preferred_term: PAICS
    term:
      id: hgnc:8587
      label: PAICS
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:31600779
    reference_title: "PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis of affected individuals revealed a homozygous missense mutation in PAICS (c.158A>G; p.Lys53Arg) that affects the structure of the catalytic site of the bifunctional enzyme phosphoribosylaminoimidazole carboxylase (AIRC, EC 4.1.1.21)/phosphoribosylaminoimidazole succinocarboxamide synthetase (SAICARS, EC 6.3.2.6) (PAICS)."
    explanation: Identifies PAICS as the causal gene and the recurrent variant's effect on the catalytic site.
  - reference: PMID:39726239
    reference_title: "Identification of the Third Patient With PAICS Deficiency Harbouring the p.(Lys53Arg) Recurrent Variant, Extending the Phenotype Diversity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genome Sequencing identified the homozygous pathogenic variant p.(Lys53Arg), suggesting a recurrent variant in PAICS."
    explanation: Establishes p.(Lys53Arg) as recurrent across unrelated families.

experimental_models:
- name: CRISPR-Cas9 PAICS-knockout HeLa cells
  experimental_model_type: CELL_LINE
  description: >-
    Genome-edited HeLa cells deficient in individual steps of purine de novo
    synthesis, profiled by targeted and untargeted metabolomics. Important here
    as a counterpoint rather than a confirmation: intermediates immediately
    upstream of the deficient enzyme were the most strongly changed metabolites
    in this system, whereas the substrates predicted to accumulate were not
    detectable in patient fibroblasts.
  modeled_mechanisms:
  - target: Impaired De Novo Purine Synthesis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the pathway block and shows substrate accumulation behind it,
      which patient fibroblasts did not. The discrepancy may be cell type or
      genotype - a complete knockout versus a hypomorphic missense - rather than
      evidence that no accumulation occurs.
    limitations: >-
      A cancer cell line carrying an engineered complete knockout, not the
      patient genotype, and cultured under conditions that do not model embryonic
      organogenesis. It cannot settle whether patients accumulate substrate in
      any tissue.
    readouts:
    - name: Purine de novo synthesis intermediates upstream of the deficient enzyme
      target: Impaired De Novo Purine Synthesis
      direction: INCREASED
      interpretation: >-
        Intermediates preceding the deficient enzyme were the most statistically
        significant features in the profile, indicating substrate accumulation
        behind the block in this model system.
      evidence:
      - reference: PMID:35323684
        reference_title: "Combined Targeted and Untargeted Profiling of HeLa Cells Deficient in Purine De Novo Synthesis."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Statistical significance of PDNS intermediates preceding deficient enzymes was the highest"
        explanation: Reports accumulation of intermediates upstream of the deficient enzyme in the knockout cells.
    evidence:
    - reference: PMID:35323684
      reference_title: "Combined Targeted and Untargeted Profiling of HeLa Cells Deficient in Purine De Novo Synthesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This work aims to describe the metabolic changes of CRISPR-Cas9 genome-edited HeLa cells deficient in the individual steps of PDNS to better understand known and potential defects of the pathway in humans."
      explanation: Identifies the model system and its purpose as a proxy for the human pathway defects.

- name: Patient skin fibroblasts with PAICS transfection rescue
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary skin fibroblasts from an affected individual and from heterozygous
    carriers, used to measure residual enzyme activity, to score purinosome
    formation, and — through transfection with wild-type versus mutant PAICS —
    to establish causation.
  modeled_mechanisms:
  - target: Failure of Purinosome Assembly
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Patient-derived cells carrying the actual disease genotype reproduce the
      purinosome assembly defect and are corrected by wild-type PAICS.
    limitations: >-
      Fibroblasts cannot model the embryonic organogenesis in which the disease
      manifests, and the predicted accumulating substrates were not detectable in
      them — so the model demonstrates the cellular lesion but not the route from
      it to the malformations.
    readouts:
    - name: Purinosome formation after wild-type versus mutant PAICS transfection
      target: Failure of Purinosome Assembly
      direction: RESTORED
      interpretation: >-
        Wild-type PAICS restores purinosome formation and the mutant construct
        does not, establishing that the variant causes the defect.
      evidence:
      - reference: PMID:31600779
        reference_title: "PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "this phenotype was corrected by transfection with the wild-type but not the mutated PAICS"
        explanation: Reports the transfection rescue measurement in patient fibroblasts.
    evidence:
    - reference: PMID:31600779
      reference_title: "PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the PAICS mutation prevented purinosome formation in the patient's skin fibroblasts"
      explanation: Establishes patient fibroblasts as informative for the purinosome assembly node.

treatments:
- name: Surgical Repair of Congenital Malformations
  description: >-
    Repair of esophageal atresia and of congenital heart disease where survival
    permits. This is the only intervention that alters outcome, and it addresses
    the malformations rather than the metabolic defect. Neither cited abstract
    describes the surgical management, so this entry carries no evidence item;
    it rests on the malformations that are cited elsewhere in the entry.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical repair of congenital malformations
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Esophageal atresia
    description: >-
      Surgical repair restores foregut continuity; it does not affect the
      upstream purine synthesis defect.
  - target: Abnormal heart morphology
    description: >-
      Cardiac repair addresses the structural lesion only.

- name: Supportive Care
  description: >-
    No disease-modifying therapy exists. Because AIR and AIr do not accumulate
    detectably, there is no substrate-reduction target either, so management
    outside of surgical repair is supportive.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care

- name: Genetic Counseling and Prenatal Diagnosis
  description: >-
    Relevant to families with recurrent spontaneous abortion or unexplained early
    neonatal death, in whom this disorder should be considered. A probable
    recurrence in a later sibling was diagnosed antenatally on the malformation
    pattern although it could not be confirmed molecularly.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:31600779
    reference_title: "PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PAICS deficiency is a newly described disease that enhances our understanding of the DNPS pathway and should be considered in the diagnosis of families with recurrent spontaneous abortion or early neonatal death."
    explanation: States the clinical setting in which this diagnosis should be sought.

discussions:
- discussion_id: missing_toxic_metabolite
  kind: KNOWLEDGE_GAP
  prompt: >-
    If AIR and AIr do not accumulate detectably in patient cells, what actually
    mediates the tissue damage in PAICS deficiency?
  attaches_to:
  - pathophysiology#Impaired De Novo Purine Synthesis
  - pathophysiology#Disrupted Embryonic Organogenesis
  rationale: >-
    The substrate-accumulation model, which works for the sibling DNPS disorders,
    was tested here and failed: the predicted metabolites were sought in patient
    fibroblasts and not found, even though AIr is demonstrably cytotoxic to cell
    lines. That leaves purine insufficiency, purinosome-dependent channelling
    failure, or accumulation confined to a tissue or developmental window that
    fibroblasts do not sample. The absence also means there is no diagnostic
    metabolite and no substrate-reduction therapeutic target.

    A CRISPR-Cas9 PAICS-knockout HeLa line sharpens the question rather than
    settling it: there, intermediates immediately upstream of the deficient
    enzyme were the most strongly changed metabolites in the profile. So
    accumulation does happen in at least one human cell system. Whether the
    difference from patient fibroblasts is cell type, or complete knockout
    versus hypomorphic missense, is open.
  evidence:
  - reference: PMID:35323684
    reference_title: "Combined Targeted and Untargeted Profiling of HeLa Cells Deficient in Purine De Novo Synthesis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Statistical significance of PDNS intermediates preceding deficient enzymes was the highest"
    explanation: >-
      Shows substrate accumulation behind the block in an engineered knockout,
      which is the counterpoint to its non-detection in patient fibroblasts.
      Indirect because the model is a cancer line with a complete knockout rather
      than the patient genotype.

- discussion_id: malformation_versus_neurodegeneration_phenotypes
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why do some individuals with biallelic PAICS variants present with a
    congenital malformation syndrome and others with neurodevelopmental
    regression and ocular disease, with almost no overlap?
  attaches_to:
  - phenotypes#Global developmental delay
  - pathophysiology#PAICS Bifunctional Enzyme Deficiency
  rationale: >-
    The split is close to dichotomous in the literature to date: malformation
    patients are described as having no neurologic involvement, and the
    neurodevelopmental sibpair had none of the malformations. Allele-specific
    residual activity is the obvious hypothesis, but the recurrent p.(Lys53Arg)
    homozygous genotype itself spans neonatal lethality and survival to seven
    years with normal neurodevelopment, so genotype alone does not explain it.

- discussion_id: genotype_does_not_predict_survival
  kind: KNOWLEDGE_GAP
  prompt: >-
    What determines whether an individual homozygous for p.(Lys53Arg) dies in
    the neonatal period or survives with normal neurodevelopment?
  attaches_to:
  - pathophysiology#PAICS Bifunctional Enzyme Deficiency
  rationale: >-
    The same recurrent homozygous variant produced early neonatal death in the
    Faroese siblings and a seven-year-old with normal neurodevelopment in an
    unrelated family. With so few patients, modifier effects, ascertainment bias
    toward lethal cases, and differences in surgical management of the
    esophageal atresia are all unexcluded.

notes: >-
  Phenotype coverage is deliberately incomplete. OMIM #619859 and the HPO-JAX
  annotation set for this disorder carry a fuller craniofacial and skeletal
  list than this entry does — flat face, brachycephaly, short nose, depressed
  nasal bridge, anteverted nares, low-set ears, short neck, hypertelorism,
  tracheoesophageal fistula, choanal atresia, missing ribs, lumbar
  hemivertebrae, talipes equinovarus, fifth-finger clinodactyly, and coronal
  hypospadias. All three primary reports are abstract-only in the reference
  cache and none of those individual features appears in an abstract, so they
  could not be given a verified snippet and were left out rather than cited to
  a source that does not state them. A curator with full-text access to
  PMID:31600779 and PMID:39726239, or with the Orphanet bulk cache rebuilt for
  ORPHA:633099, should add them.

  Nomenclature: the MONDO term "phosphoribosylaminoimidazole carboxylase
  deficiency" (MONDO:0859244) is obsolete and was merged into MONDO:0859003
  "PAICS deficiency" (monarch-initiative/mondo#9884); this entry uses the live
  term. The disorder is also referenced as OMIM:619859 and Orphanet:633099. Note
  that PAICS is heavily studied as a cancer proliferation gene, so a literature
  search on the symbol alone returns overwhelmingly oncology papers unrelated to
  this inborn error.

references:
- reference: PMID:31600779
  title: PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome.
- reference: PMID:39726239
  title: Identification of the Third Patient With PAICS Deficiency Harbouring the p.(Lys53Arg) Recurrent Variant, Extending the Phenotype Diversity.
- reference: PMID:42569864
  title: Compound Heterozygous Variants in the PAICS Gene Integrate the Previously Described Divergent Phenotypes.

📚

References & Deep Research

References

3

PMID:31600779

PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome.

No top-level findings curated for this source.

PMID:39726239

Identification of the Third Patient With PAICS Deficiency Harbouring the p.(Lys53Arg) Recurrent Variant, Extending the Phenotype Diversity.

No top-level findings curated for this source.

PMID:42569864

Compound Heterozygous Variants in the PAICS Gene Integrate the Previously Described Divergent Phenotypes.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: PAICS_Deficiency (de novo purine synthesis defect) · 2026-09-02T03:11:28Z · View source

De novo curation of PAICS deficiency (MONDO:0859003), an autosomal recessive inborn error of de novo purine synthesis. MONDO term correction. The curation stub and the original claim issue were keyed on MONDO:0859244 'phosphoribosylaminoimidazole carboxylase deficiency', which is obsolete: MONDO merged it into MONDO:0859003 'PAICS deficiency' (monarch-initiative/mondo#9884). The entry binds the live term, and claim issue #10471 was retitled to match, since the MONDO ID in a claim title is the key the double-claim check matches on. This PR retires the stub outright, so no repointing of stubs/Phosphoribosylaminoimidazole_Carboxylase_Deficiency.yaml was needed. Deep research: openscientist (research/PAICS_Deficiency-deep-research-openscientist.md). Falcon, the repo default, was unavailable (no EDISON_API_KEY/FUTUREHOUSE_API_KEY); openscientist was selected explicitly rather than substituted silently. The report shipped without reference_validation or term_validation frontmatter and without a citations sidecar, so both were retro-fitted in place with just validate-research-reference and just validate-research-terms. Results: 14/14 references resolved, 0 unresolved, 0 off topic; 60 terms checked, 0 unresolved, 2 named as a different term. One of those two mislabelled terms mattered. The report offered GO:0034023 for 'purinosome'; GO calls that term '5-(carboxyamino)imidazole ribonucleotide mutase activity'. It was not bound. No suitable GO term for the purinosome was found, so that concept is carried in prose on the Failure of Purinosome Assembly node and the node is bound to GO:0006189 instead. Pathograph: four nodes from PAICS bifunctional enzyme deficiency through failure of purinosome assembly and impaired de novo purine synthesis to disrupted embryonic organogenesis. The last edge is deliberately INDIRECT_UNKNOWN_INTERMEDIATES: the mechanism connecting purine insufficiency to the specific malformation pattern is not established. A substantive negative result is recorded rather than glossed. AIR and AIr, the substrates predicted to accumulate, were sought in patient fibroblasts and not detected, even though AIr is cytotoxic to cell lines. This is why the disorder has no diagnostic metabolite and no substrate-reduction target, and it is captured as a KNOWLEDGE_GAP discussion as well as in the node description. Phenotype coverage is knowingly incomplete and this is recorded in the entry notes. OMIM #619859 and HPO-JAX carry a fuller craniofacial and skeletal annotation set (flat face, brachycephaly, short nose, depressed nasal bridge, anteverted nares, low-set ears, short neck, hypertelorism, tracheoesophageal fistula, choanal atresia, missing ribs, lumbar hemivertebrae, talipes equinovarus, fifth-finger clinodactyly, coronal hypospadias). All three primary reports are abstract-only in the reference cache and none of these individual features appears in an abstract, so none could be given a verified snippet. They were left out rather than cited to a source that does not state them. ORPHA:633099 would supply quotable rows but is not in the committed Orphanet bulk cache and data/orphadata/en_product1.xml is gitignored and absent, so structured-rebuild-orphanet could not be run without a full refresh. Not asserted: the report describes p.(Lys53Arg) as rs192831239 with gnomAD NFE allele frequency 0.135%, making its recurrence in an unrelated French family a population-frequency effect rather than a founder effect. That is plausible and interesting but could not be verified from any cached reference, so the entry says only 'recurrent', which PMID:39726239 states directly. Validation: just validate passes (schema, terms, references); 26/26 snippets verified. check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values and check-qualifier-terms all pass. No datasets: block. PAICS is heavily studied as a cancer proliferation gene, so a dataset search on the symbol returns oncology series unrelated to this inborn error.

OpenScientist ▸

PAICS Deficiency — Comprehensive Disease Characterization Report

openscientist-autonomous 2026-09-01T23:06:17.661596

PAICS Deficiency — Comprehensive Disease Characterization Report

Category: Mendelian (autosomal recessive inborn error of de novo purine synthesis) Report compiled 2026-09-02. Evidence source types: human clinical case reports, in vitro/enzymatic studies, structural biology, and comparison with allied de novo purine synthesis (DNPS) disorders.

Caveat on evidence base: PAICS deficiency is an ultra-rare Mendelian disorder. As of 2025 only three molecularly confirmed patients (plus one antenatally suspected sibling) have been reported worldwide, all homozygous for the same recurrent variant. Consequently, most disease-level statements rest on 1–3 individual patients (individual-patient/case-report evidence, not aggregated registry data). Where information is absent, this is stated explicitly. Many entries are extrapolated from the better-characterized allied DNPS defects (ADSL deficiency, AICA-ribosiduria/ATIC deficiency) and are flagged as such.

1. Disease Information

Overview. PAICS deficiency is an autosomal recessive inborn error of de novo purine synthesis (DNPS) caused by biallelic loss-of-function variants in the PAICS gene. PAICS encodes a bifunctional enzyme — phosphoribosylaminoimidazole carboxylase (AIR carboxylase, AIRC; EC 4.1.1.21) and phosphoribosylaminoimidazole-succinocarboxamide synthetase (SAICAR synthetase, SAICARS; EC 6.3.2.6) — that catalyzes the sixth and seventh of the ten sequential steps that convert PRPP to inosine monophosphate (IMP). Clinically the disorder manifests as a multiple congenital malformation (polymalformative) syndrome. The two index cases died in the early neonatal period; the third reported patient survived with a milder, non-lethal course and normal neurodevelopment, indicating a broader phenotypic spectrum than originally recognized (PMID 31600779; PMID 39726239).

Key identifiers. - Gene: PAICS — HGNC:8587; NCBI Gene ID 10606; UniProt P22234; OMIM gene 172439; Ensembl ENSG00000128050. Genomic locus chr4:56,435,741–56,464,578 (GRCh38), cytoband 4q12 (verified via gnomAD). - Disease (phenotype) — VERIFIED IDENTIFIERS: MONDO:0859003; OMIM #619859 ("Phosphoribosylaminoimidazole carboxylase deficiency"); Orphanet ORPHA:633099; GARD:0026646 (all confirmed via OLS4/Monarch and HPO/JAX APIs). ICD-10: no specific code (closest E79.8 "Other specified disorders of purine and pyrimidine metabolism"); ICD-11: closest 5C55.2 (inborn errors of purine or pyrimidine metabolism). MeSH: no dedicated descriptor; indexed under "Purine-Pyrimidine Metabolism, Inborn Errors." - Note: an earlier draft cited OMIM #618121; the correct phenotype MIM is #619859. - EC numbers: 4.1.1.21 (AIRC) and 6.3.2.6 (SAICARS).

Synonyms / alternative names. - Phosphoribosylaminoimidazole carboxylase deficiency - SAICAR synthetase deficiency / AIR carboxylase deficiency - Multiple malformations syndrome, lethal, due to PAICS deficiency - Inborn error of de novo purine synthesis, PAICS type

Data provenance. Disease-level knowledge is derived from individual patient case reports (n=3), supporting enzymatic/cell-biology experiments in patient fibroblasts and recombinant protein, and CRISPR HeLa models — not from EHR-scale or registry aggregation.

2. Etiology

Primary cause (genetic). Biallelic (homozygous, in a consanguineous/founder context) pathogenic variants in PAICS, producing a hypomorphic bifunctional enzyme. All reported patients carry the homozygous missense variant NM_006452.4:c.158A>G, p.(Lys53Arg), which reduces catalytic activity (patient fibroblasts ~10% of control; recombinant enzyme ~25% of wild-type; carriers ~50%) (PMID 31600779).

Genetic risk factors. - Causal variant: PAICS c.158A>G p.(Lys53Arg) — recurrent across all reported families. - Consanguinity / recurrent European allele: the two index patients were from a consanguineous Faroe Islands family. The recurrent p.(Lys53Arg) allele (rs192831239) is a low-frequency pan-European variant (gnomAD NFE AF 0.135%), so its appearance in the unrelated French third case reflects the allele's general European frequency rather than a private founder. Consanguinity remains a strong risk factor for homozygosity, as for most recessive DNPS defects. - Modifier genes: none identified; the marked phenotypic difference (lethal vs. surviving with normal cognition) among patients homozygous for the same variant implies the existence of unknown genetic and/or environmental modifiers (PMID 39726239).

Environmental / lifestyle risk factors. None established. As a Mendelian congenital disorder, environmental exposure is not a primary driver. (Not applicable / no evidence.)

Protective factors. None documented. Heterozygous carriers (~50% residual activity) are asymptomatic, indicating ~50% enzyme activity is sufficient (haplosufficiency), consistent with recessive inheritance.

Gene–environment interactions. No data. Speculatively, dietary purine intake or salvage-pathway flux could modulate severity (as purine salvage can partly compensate for DNPS defects), but this is untested in PAICS deficiency.

3. Phenotypes

Phenotype data derive from three patients. The two Faroese siblings (PMID 31600779) had a lethal neonatal multiple-malformation presentation; the third patient (PMID 39726239) had a non-lethal polymalformative syndrome with normal neurodevelopment, expanding the spectrum.

Official curated HPO annotations with frequencies (from OMIM #619859 / HPO-JAX; frequencies reflect the 2 index siblings, n=2, unless noted). These are the authoritative phenotype associations for knowledge-base ingestion:

HPO term	Phenotype	System	Frequency
HP:0001561	Polyhydramnios	prenatal	2/2
HP:0011461	Fetal onset	clinical course	2/2
HP:0003811	Neonatal death	clinical course	2/2
HP:0012368	Flat face	craniofacial	2/2
HP:0000248	Brachycephaly	craniofacial	2/2
HP:0003196	Short nose	craniofacial	2/2
HP:0005280	Depressed nasal bridge	craniofacial	2/2
HP:0000470	Short neck	head/neck	2/2
HP:0000369	Low-set ears	ear	2/2
HP:0002032	Esophageal atresia	digestive/foregut	2/2
HP:0002575	Tracheoesophageal fistula	digestive/foregut	1/2
HP:0000453 / HP:0000452 / HP:0004502	Choanal atresia / stenosis / bilateral choanal atresia	head/neck	1/2
HP:0000463	Anteverted nares	craniofacial	1/2
HP:0000316	Hypertelorism	eye	1/2
HP:0004322	Short stature	growth	1/2
HP:0001762	Talipes equinovarus	limbs	1/2
HP:0004209	Clinodactyly of the 5th finger	limbs	1/2
HP:0000921	Missing ribs	skeletal	1/2
HP:0008439	Lumbar hemivertebrae	skeletal	1/2
HP:0008743	Coronal hypospadias	genitourinary	1/1 (male)
HP:0008689	Bilateral cryptorchidism	genitourinary	1/1 (male)
HP:0000007	Autosomal recessive inheritance	inheritance	—

Additional features from the third (surviving) patient (PMID 39726239), not in the OMIM/HPO n=2 curation: congenital heart defect/cardiopathy (HP:0001627, newly described), plus preserved/normal neurodevelopment (distinguishing feature). The MONDO/OMIM narrative also lists nasal hypoplasia and lung malformations.

Phenotype characteristics. - Age of onset: congenital/neonatal (prenatal in the antenatally diagnosed sibling). - Severity: variable — lethal neonatal to survivable childhood form. - Progression: congenital and largely static (malformations fixed); the survivor showed normal neurodevelopmental trajectory. - Frequency among affected: with n=3, "frequencies" are indicative only — skeletal and oesophageal defects appear consistent (reported as a recurring theme); congenital heart disease in 1/3; early death in 2/3.

Quality-of-life impact. In the lethal form, QoL is dominated by neonatal demise. In the survivor, impact relates to surgical correction of malformations (cardiac, oesophageal, skeletal) with preserved cognition — a comparatively favourable functional outlook (PMID 39726239). No formal EQ-5D/SF-36/PROMIS data exist.

Note: Allied DNPS disorders (ADSL, ATIC) are dominated by neurological features (psychomotor retardation, epilepsy, autistic features, visual impairment) (PMID 25112391; PMID 32557644). Notably, PAICS deficiency in the survivor spared the CNS, distinguishing it phenotypically.

4. Genetic / Molecular Information

Causal gene. PAICS (HGNC:8587; OMIM 172439; Gene ID 10606; UniProt P22234), chromosome 4q12. Encodes a 425-aa bifunctional polypeptide that assembles into a homo-octamer (PMID 17224163).

Pathogenic variant(s). - NM_006452.4:c.158A>G, p.(Lys53Arg) (= NM_001079524.2:c.158A>G) — missense; homozygous in all reported patients. ClinVar: Likely pathogenic (review status "criteria provided, multiple submitters, no conflicts", verified via NCBI eutils). Affects the structure of the enzyme's catalytic site (PMID 31600779). - PAICS has 81 ClinVar entries, overwhelmingly VUS; besides p.Lys53Arg, a truncating variant c.843_844del (p.Cys281_Glu282delinsTer) is also listed as Likely pathogenic (no published clinical report identified) — indicating additional candidate pathogenic alleles may exist beyond the recurrent founder missense. - Variant type/class: missense (single-nucleotide substitution). - Functional consequence: loss of function (hypomorph) — residual ~10–25% activity; reduces flux through both AIRC and SAICARS reactions; abolishes purinosome assembly. - Allele frequency (gnomAD v4, verified): dbSNP rs192831239; SPDI NC_000004.12:56441803:A:G (GRCh38 chr4:56,441,804 A>G); OMIM allelic variant 172439.0001; ClinGen CA2930671. Exome AC 1675 / AN 1,448,934, AF 0.116%, 0 homozygotes; genome AF 0.072%, 0 homozygotes. Ancestry: highest in non-Finnish European (0.135%), then South Asian (0.079%), Admixed American (0.070%), Finnish (0.025%), African (0.018%); absent in Ashkenazi Jewish, East Asian, Middle Eastern. → The allele is a recurrent low-frequency pan-European variant, NOT a private Faroese founder mutation; the complete absence of homozygotes (despite carrier frequency ~1/370–1/740 in Europeans) is consistent with recessive prenatal/neonatal lethality removing homozygotes from population databases (and possible under-ascertainment/reduced penetrance). - Somatic vs. germline: germline (congenital, biallelic).

gnomAD gene-level constraint (verified). PAICS is not loss-of-function-intolerant: pLI ≈ 0 (5.8×10⁻⁷), LOEUF 0.82 (oe_lof 0.61; observed/expected LoF 33/53.7), missense z = 1.92 (mild constraint). This lack of haploinsufficiency is fully consistent with autosomal recessive inheritance — a single functional allele suffices (heterozygotes are asymptomatic with ~50% activity).

ACMG considerations. p.(Lys53Arg) is classified Likely pathogenic in ClinVar (multiple submitters, no conflicts). Supporting criteria: strong functional evidence (PS3 — measured reduced enzyme activity and abolished purinosome assembly, rescued by wild-type PAICS), rarity (PM2), and recurrence across unrelated families. Beyond this founder missense, most PAICS ClinVar entries are VUS, with one additional Likely-pathogenic truncating allele (c.843_844del).

Modifier genes. None identified; presence strongly inferred from intra-genotype phenotypic variability (lethal vs. surviving).

Epigenetic information. No disease-specific methylation/chromatin data for PAICS deficiency. (In cancer biology, PAICS is subject to m6A-mediated and H3K9me3/HP1α-linked regulation of the ASB11 axis controlling purinosome assembly — PMID 37848033, PMID 42493545 — but this is oncologic, not germline-disease, context.)

Chromosomal abnormalities. None; PAICS deficiency is a single-gene point-mutation disorder. (In cancers, chromosome-4q loss reduces PAICS expression — PMID 33596246 — unrelated to the Mendelian disease.)

5. Environmental Information

Environmental factors / toxins / radiation: none implicated. (Not applicable.)
Lifestyle factors: none implicated; congenital genetic disorder.
Infectious agents: none; not an infectious/triggered disease.

The only "environmental" dimension of theoretical relevance is dietary purine availability and salvage-pathway substrate supply, which could in principle modulate a DNPS defect, but no evidence exists in PAICS deficiency.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Homozygous PAICS c.158A>G (p.Lys53Arg) alters the catalytic-site structure of the bifunctional AIRC/SAICARS enzyme → leads to reduced catalytic activity (~10–25% residual) [demonstrated: enzyme assays, PMID 31600779].
Reduced PAICS activity results in a block at steps 6–7 of de novo purine synthesis (AIR → CAIR → SAICAR) → impaired conversion toward IMP [demonstrated biochemically in DNPS defects; PMID 35323684].
The mutant PAICS fails to nucleate the purinosome (the multi-enzyme DNPS metabolon); purinosome assembly is abolished and is rescued only by wild-type PAICS [demonstrated in patient fibroblasts, PMID 31600779; PAICS is a hub of purinosome protein–protein interactions, PMID 35331738].
Loss of channeled DNPS leads to two downstream, non-exclusive insults:
(4a) Purine nucleotide insufficiency → reduced supply of AMP/GMP/ATP/GTP for nucleic-acid synthesis and energy/signaling → impaired proliferation during rapid embryonic morphogenesis → congenital malformations [inferred].
(4b) Accumulation of upstream intermediates (predicted AIR/CAIR; their dephosphorylated ribosides, e.g., AIr) → cytotoxicity (AIr shown cytotoxic to multiple cell lines) → cell death/dysmorphogenesis [partly demonstrated: AIr toxicity, PMID 31600779; analogous to SAICAr/S-Ado toxicity in ADSL and AICA-riboside toxicity in ATIC deficiency, PMID 25112391, PMID 32557644].
Tissue-level consequences during organogenesis result in structural defects of the skeleton, oesophagus (foregut), and heart, plus growth restriction and dysmorphism → the polymalformative syndrome; where the insult is severe, early neonatal death [observed, PMID 31600779; PMID 39726239].
Branch point: with only partial enzyme loss and/or protective modifiers, purine supply may be sufficient postnatally to permit survival with normal neurodevelopment (third patient) — the CNS may be relatively spared compared with ADSL/ATIC defects [observed, PMID 39726239; mechanism of sparing inferred].

Molecular pathways. De novo purine biosynthesis (KEGG hsa00230 purine metabolism; Reactome "Purine ribonucleoside monophosphate biosynthesis"). PAICS catalyzes: AIR + CO₂ → CAIR (AIRC, EC 4.1.1.21) and CAIR + L-aspartate + ATP → SAICAR (SAICARS, EC 6.3.2.6).

Cellular processes. Metabolon (purinosome) assembly/phase separation; nucleotide biosynthesis; cell proliferation; apoptosis (from intermediate cytotoxicity). GO suggestions: GO:0006189 ('de novo' IMP biosynthetic process), GO:0009152 (purine ribonucleotide biosynthetic process), GO:0034023 (purinosome — as protein complex/assembly context), GO:0004638 (phosphoribosylaminoimidazole carboxylase activity), GO:0004639 (phosphoribosylaminoimidazolesuccinocarboxamide synthase activity).

Protein dysfunction. p.Lys53Arg is a loss-of-function/hypomorphic substitution distorting the catalytic site; the enzyme normally functions only as an octamer with substrate-channeling tunnels between AIRC and SAICARS active sites (PMID 17224163; PMID 32571877; reaction mechanism, PMID 35914774). Loss of activity + loss of purinosome-nucleating protein–protein interactions (PMID 35331738). Experimental structures (RCSB PDB): 2H31 (octameric apo structure, PMID 17224163), 6YB8 / 6YB9 (substrate/product complexes, PMID 32571877), 7ALE; UniProt P22234; AlphaFold model AF-P22234-F1. Residue Lys53 lies in the AIR-carboxylase domain near the catalytic site.

Metabolic changes. Amino-acid/nucleotide metabolism: reduced IMP→AMP/GMP; predicted accumulation of AIR/CAIR/ SAICAR and their ribosides (CHEBI: aminoimidazole ribotide/AIR; SAICAR). Metabolomic profiling of DNPS-deficient HeLa cells shows accumulation of intermediates immediately upstream of the deficient enzyme (PMID 35323684).

Immune involvement. None described (not an immunologic disease).

Tissue-damage mechanisms. Cytotoxicity of accumulated dephosphorylated intermediates; nucleotide starvation of proliferating cells.

Molecular profiling. CRISPR-Cas9 PAICS-knockout/deficient HeLa cells provide targeted + untargeted metabolomic signatures of the DNPS block (PMID 35323684, PMID 35331738). No patient transcriptomic/proteomic/metabolomic datasets published beyond fibroblast enzymology.

Cell types & GO/CL suggestions. Fibroblasts used experimentally (CL:0000057). In vivo affected cell populations are rapidly proliferating embryonic progenitors of skeletal (CL:0000062 osteoblast; CL:0000138 chondrocyte), cardiac (CL:0000746 cardiac muscle cell), and foregut/oesophageal epithelium (CL:0000066 epithelial cell) — inferred from malformation pattern.

7. Anatomical Structures Affected

Organ level (primary): skeleton (UBERON:0001434 skeletal system), oesophagus (UBERON:0001043), heart (UBERON:0000948). Growth (whole-body/UBERON multi-organ). Secondary: consequences of malformations (e.g., feeding/airway from oesophageal defects; circulatory from cardiac defects).

Body systems: musculoskeletal, digestive (foregut), cardiovascular; generalized growth. CNS relatively spared in the survivor (contrast with allied DNPS disorders that are CNS-dominant).

Tissue/cell level: connective/skeletal tissue (cartilage, bone), cardiac muscle, gut epithelium. CL terms as above.

Subcellular level: the purinosome is a mitochondria-associated cytoplasmic metabolon (PMID 35331738). GO cellular-component suggestions: GO:0005829 (cytosol), mitochondrial outer-membrane association; the purinosome itself is a dynamic, membraneless (phase-separated) body (PMID 37848033).

Localization / lateralization: malformations are congenital and can be midline/bilateral (skeletal, cardiac, oesophageal); no consistent lateralization reported (n too small).

8. Temporal Development

Onset: congenital; detectable antenatally (a suspected sibling recurrence was diagnosed prenatally, PMID 39726239). Onset pattern: chronic/congenital (present from organogenesis).
Progression / course: malformations are structurally fixed. In the lethal form, course is acute neonatal deterioration → death within days (PMID 31600779). In the surviving form, course is stable post-surgical correction with normal developmental trajectory to at least 7 years (PMID 39726239).
Disease duration: lethal (self-limited by neonatal death) vs. chronic/lifelong in survivors.
Critical periods: first-trimester organogenesis is the window of vulnerability (skeletal/foregut/cardiac morphogenesis). Prenatal detection offers a window for counseling; no fetal/neonatal metabolic intervention is established.

9. Inheritance and Population

Inheritance: autosomal recessive (biallelic PAICS variants; heterozygous parents asymptomatic).
Epidemiology: ultra-rare; prevalence/incidence unknown (<1/1,000,000; only 3 reported cases). No registry data.
Penetrance: appears complete for the malformation phenotype in homozygotes, but expressivity is highly variable (lethal neonatal vs. surviving with normal cognition) despite the identical genotype (PMID 39726239).
Expressivity: variable (see above).
Genetic anticipation: not applicable (not a repeat-expansion disorder).
Germline mosaicism: not reported.
Founder effect / consanguinity (revised via gnomAD): the recurrent p.(Lys53Arg)/rs192831239 allele is not a private Faroese founder but a recurrent low-frequency pan-European variant (gnomAD exome AF 0.116%; highest in non-Finnish Europeans, 0.135%). Its recurrence in an unrelated French patient is therefore expected. The index family was consanguineous (Faroe Islands), which brought two copies together; consanguinity remains a risk factor for homozygosity of this and other recessive alleles.
Carrier frequency (verified): ~1/370–1/740 in Europeans (2×AF ≈ 0.23–0.27% NFE); rarer in African, absent in Ashkenazi/East Asian/Middle Eastern gnomAD samples. Notably zero homozygotes are observed in ~1.45 million gnomAD alleles, despite an expected homozygote birth frequency on the order of ~1/550,000 (NFE) — consistent with recessive prenatal/neonatal lethality (affected individuals excluded from gnomAD) and/or reduced penetrance; implies the disorder is likely under-ascertained (unrecognized fetal losses/neonatal deaths).
Population demographics / geography: first cases Faroe Islands; third case reported from a European (French) centre — consistent with the allele's European distribution. No sex predilection evident (both sexes affected; third patient male). Age distribution: prenatal-to-childhood onset.

10. Diagnostics

Diagnostic approach. Because DNPS-intermediate biomarkers may be undetectable (AIR/AIr were not found in patient fibroblasts, PMID 31600779), diagnosis is primarily molecular/genomic.

Genetic testing (primary): whole-genome sequencing (WGS) established the diagnosis in the third patient; whole-exome sequencing (WES) is equally appropriate; single-gene PAICS testing/targeted analysis of c.158A>G is useful where the founder allele is suspected. Purine-metabolism/inborn-error gene panels including PAICS are appropriate (GTR).
Biochemical/laboratory: urine/plasma/CSF purine metabolite profiling (HPLC-MS) as used for ADSL (SAICAr, S-Ado) and ATIC (AICA-riboside) — but note classic accumulating markers may be absent in PAICS deficiency, limiting biochemical screening (PMID 31600779). Enzyme activity assay in cultured skin fibroblasts (reduced to ~10%) is confirmatory (LOINC/enzyme assay).
Functional/cellular: purinosome-assembly assay in fibroblasts (absent, rescued by WT PAICS) — a research-grade functional confirmation.
Imaging: prenatal/postnatal imaging (fetal ultrasound, echocardiography, skeletal survey, contrast oesophagram) to delineate malformations. RadLex terms as appropriate.
Histopathology: no pathognomonic biopsy finding described.

Clinical criteria / differential diagnosis. No formal criteria. Differential includes other DNPS defects (ADSL deficiency, AICA-ribosiduria/ATIC, ADSS/ADSS1/2, ATIC, PRPS abnormalities) — distinguished by their CNS-dominant presentation and specific accumulating metabolites; also other polymalformative/VACTERL-spectrum syndromes (given vertebral, cardiac, oesophageal involvement) and chromosomal disorders (excluded by CMA/karyotype/sequencing).

Screening. Carrier/cascade testing for the familial p.(Lys53Arg) variant; prenatal molecular testing feasible (used in the suspected sibling). Not part of routine newborn screening.

11. Outcome / Prognosis

Survival/mortality: in the index family, 2/2 siblings died in the early neonatal period (PMID 31600779). The third patient survived to at least 7 years with normal neurodevelopment (PMID 39726239). Thus prognosis is bimodal/variable, ranging from neonatal-lethal to survivable childhood disease.
Morbidity/function: in survivors, morbidity is driven by structural malformations requiring surgical correction (cardiac, oesophageal, skeletal); cognition may be preserved, an important prognostic distinction from ADSL/ATIC deficiencies.
Complications: those of congenital heart disease, oesophageal malformation (feeding/respiratory), and skeletal anomalies.
Prognostic factors: severity/number of malformations and (inferred) residual enzyme function/modifiers determine lethality. The 2025 report explicitly updated prognosis to include the possibility of survival with normal neurodevelopment (PMID 39726239).
QoL measures: none formally applied.

12. Treatment

No disease-specific/curative therapy exists. Management is supportive and symptomatic (NCIT: Supportive Care Therapy; NCIT:C15277 Supportive Care).

Pharmacotherapy: none targeted; there is no established purine-replacement therapy for PAICS deficiency. (Theoretical strategies — dietary/purine salvage support, avoidance of intermediate accumulation — are unproven.)
Surgical/interventional: correction of congenital malformations (cardiac surgery, oesophageal repair, orthopedic management) in survivors (NCIT clinical-intervention terms as applicable, e.g., Cardiac Surgery, Esophageal repair).
Supportive/rehabilitative: neonatal intensive care; nutritional support; multidisciplinary follow-up.
Advanced/experimental therapeutics: none in trials for PAICS deficiency. Gene therapy, enzyme replacement, or substrate-modulation approaches are conceptual only. (Note: PAICS is being pursued as an oncology drug target — inhibitors to reduce purine synthesis in cancer — PMID 37673296, PMID 34344987 — the opposite therapeutic direction from this deficiency.)
Pharmacogenomics: not applicable.
Treatment outcomes / adverse events: determined by surgical/critical-care outcomes; no drug outcome data.

13. Prevention

Primary prevention: genetic counseling for consanguineous families and known carriers; carrier/cascade screening for the familial p.(Lys53Arg) allele; reproductive options including preimplantation genetic testing (PGT) and prenatal molecular diagnosis (feasible, as demonstrated antenatally in the suspected sibling, PMID 39726239).
Secondary prevention: prenatal imaging + molecular testing enables early detection and delivery planning; early surgical correction of malformations in survivors.
Tertiary prevention: management of complications of congenital malformations.
Immunization / public-health / environmental interventions: not applicable (Mendelian disorder).
Counseling: recurrence risk 25% per pregnancy for carrier couples (autosomal recessive); NSGC/ACMG genetic-counseling frameworks apply.

14. Other Species / Natural Disease

Taxonomy / orthologs (verified via Alliance of Genome Resources, stringent): PAICS is deeply conserved across metazoa and fungi. One-to-one/many orthologs:
Mouse Paics — MGI:1914304; NCBI Gene 67054; NCBITaxon:10090
Rat Paics — RGD:620066; NCBITaxon:10116
Zebrafish paics — ZFIN:ZDB-GENE-030131-9762; NCBITaxon:7955
Drosophila melanogaster Paics — FB:FBgn0020513; NCBITaxon:7227
Caenorhabditis elegans paic-1 — WB:WBGene00015116; NCBITaxon:6239
Saccharomyces cerevisiae ADE1 — SGD:S000000070; NCBITaxon:4932 (note: yeast splits the bifunctional activity — ADE1 = SAICAR synthetase, ADE2 = AIR carboxylase)
Xenopus tropicalis/laevis paics — Xenbase
Bacterial functional homologs: PurC/PurE/PurK. DNPS is among the most conserved biosynthetic pathways.
Natural disease in other species: no naturally occurring PAICS-deficiency disease is catalogued in OMIA for companion animals/livestock (none found — verify).
Comparative biology: the octameric bifunctional vertebrate PAICS contrasts with separate monofunctional bacterial/yeast enzymes; substrate channeling and purinosome assembly are conserved features studied to understand human disease.
Zoonotic/cross-species transmission: not applicable (genetic, non-transmissible).

15. Model Organisms

Cellular / in vitro models (principal): CRISPR-Cas9 PAICS-knockout / deficient HeLa cells used for targeted + untargeted metabolomic profiling of the DNPS block (PMID 35323684) and for dissecting purinosome protein–protein interactions and metabolic channeling (crPAICS cells, PMID 35331738). Patient skin fibroblasts (primary) recapitulate reduced enzyme activity and absent purinosome assembly, rescued by wild-type PAICS transfection (PMID 31600779).
Recombinant enzyme: E. coli-expressed wild-type and p.Lys53Arg PAICS for kinetic characterization (PMID 31600779); human PAICS crystal structures for mechanistic/structural study (PMID 17224163, PMID 32571877, PMID 35914774).
Genetic model types available: knockout/knockdown cell lines (CRISPR, shRNA — the latter widely used in cancer studies, e.g., AML, PMID 34344987).
Mouse Paics knockout (IMPC, verified via IMPC solr): homozygous null mice show "preweaning lethality, complete penetrance" and "prenatal lethality prior to heart atrial septation" (homozygote, complete penetrance) — i.e., Paics is an essential gene and complete loss is embryonically/prenatally lethal. No viable homozygous-null adults. Suggested MP terms: MP:0011100 (preweaning lethality, complete penetrance), prenatal-lethality MP terms. This is mechanistically important: it explains why human patients carry a hypomorphic missense (p.Lys53Arg, ~10–25% residual activity) rather than biallelic nulls, and the "prenatal lethality prior to heart atrial septation" parallels the congenital cardiac defect in the surviving human patient (PMID 39726239).
Phenotype recapitulation: cell models reproduce the biochemical/purinosome defect well; the mouse null recapitulates lethality/essentiality but (being a complete null) does not model the hypomorphic human malformation syndrome. Limitation: no published hypomorphic/knock-in Paics animal model (e.g., p.Lys53Arg knock-in) recapitulating the human polymalformative phenotype exists (gap / future direction).
Resources: Cellosaurus (HeLa derivatives), MGI/IMPC (mouse Paics), ZFIN (zebrafish paics) for reagents.

Key Ontology Term Suggestions (summary)

Gene/protein: PAICS (HGNC:8587, UniProt P22234); GO:0004638, GO:0004639, GO:0006189, GO:0009152.
Phenotypes (HPO): HP:0002011/HP:0001263 (malformation), HP:0003811 (neonatal death), HP:0002032 (esophageal atresia), HP:0001627 (abnormal heart morphology), HP:0000924 (skeletal abnormality), HP:0001999 (facial dysmorphism), HP:0001511 (IUGR).
Cell types (CL): CL:0000057 (fibroblast), CL:0000062 (osteoblast), CL:0000138 (chondrocyte), CL:0000746 (cardiomyocyte), CL:0000066 (epithelial cell).
Anatomy (UBERON): UBERON:0001434 (skeletal system), UBERON:0001043 (esophagus), UBERON:0000948 (heart).
Chemicals (CHEBI): AIR/aminoimidazole ribotide, CAIR, SAICAR, IMP; substrate CO₂, L-aspartate, ATP.
Disease (MONDO/OMIM): MONDO:0859003; OMIM #619859; Orphanet ORPHA:633099; GARD:0026646 (all verified).
Treatment (NCIT): supportive care; surgical repair of congenital anomalies.

Supported vs. Refuted Statements

Supported (evidence-based): - PAICS deficiency is AR, caused by biallelic PAICS p.(Lys53Arg); loss-of-function reduces enzyme activity and abolishes purinosome assembly (PMID 31600779). (Strong: enzymatic + cellular rescue.) - Phenotype = congenital multiple-malformation syndrome; spectrum spans neonatal-lethal to survivable-with-normal-cognition (PMID 31600779, PMID 39726239). (Moderate: n=3.) - Accumulating intermediate ribosides (AIr) are cytotoxic; analogous to other DNPS defects (PMID 31600779; PMID 25112391; PMID 32557644). (Moderate.)

Refuted / not supported: - That classic urinary DNPS metabolite markers reliably diagnose PAICS deficiency — refuted: predicted markers were undetectable in patient fibroblasts; molecular testing is required (PMID 31600779). - That PAICS deficiency is uniformly CNS-degenerative like ADSL/ATIC — not supported: the survivor had normal neurodevelopment (PMID 39726239).

Limitations & Future Directions

Evidence rests on 3 patients with the same variant; genotype–phenotype breadth, penetrance, carrier frequency, and epidemiology are essentially unknown.
No validated whole-animal disease model; mechanism of malformation (nucleotide starvation vs. intermediate toxicity) not fully resolved for organogenesis.
Priorities: identify additional patients/variants; establish biomarker(s); build animal models; test whether purine-salvage support alters outcome; clarify modifiers explaining lethal-vs-survivable divergence.

Prepared for disease knowledge-base population. Verified against primary databases: disease identifiers (MONDO:0859003, OMIM #619859, ORPHA:633099, GARD:0026646) via OLS4/Monarch; HPO annotations via HPO-JAX; variant classification (ClinVar VCV001686821, Likely pathogenic) and coordinates (rs192831239, chr4:56,441,804 GRCh38) via NCBI eutils; allele frequency (gnomAD v4 exome AF 0.116%, 0 homozygotes) and gene constraint via gnomAD API; orthologs via Alliance of Genome Resources; mouse-knockout lethality via IMPC; PDB structures via RCSB. Remaining items to confirm before ingestion: exact OMIA status (no natural animal disease found), and any newer case reports post-2025.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	14
Resolved	14
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	14
On topic	6
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	60
Resolved	53
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	7
Terms whose name was checked	42
Terms named correctly	37
Terms named as a different term	2
Terms whose name is worth a second look	3

Terms the report names something else

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

GO:0034023 (1 mention) - the report calls it "purinosome — as protein complex/assembly context"; GO calls it 5-(carboxyamino)imidazole ribonucleotide mutase activity
NCBITaxon:4932 (1 mention) - the report calls it "note: yeast splits the bifunctional activity — ADE1 = SAICAR synthetase, ADE2 = AIR carboxylase"; NCBITaxon calls it Saccharomyces cerevisiae

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

CL:0000746 (2 mentions) - the report calls it "cardiomyocyte"; CL calls it cardiac muscle cell, and lists "cardiomyocyte" among its other names
HP:0001263 (1 mention) - the report calls it "malformation"; HP calls it Global developmental delay, and lists "Motormental retardation" among its other names
HP:0000924 (1 mention) - the report calls it "skeletal abnormality"; HP calls it Abnormality of the skeletal system, and lists "Skeletal abnormalities" among its other names

Terms named inconsistently

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

HP:0003811 - called "Neonatal death", "neonatal death"
HP:0002032 - called "Esophageal atresia", "esophageal atresia"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, GARD, NC_000004.12, MGI, RGD, SGD.

Ask OpenScientist

OpenScientist Report

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Clinical Burden

Experimental Models

Source YAML

References & Deep Research

References

Deep Research

PAICS Deficiency — Comprehensive Disease Characterization Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Key Ontology Term Suggestions (summary)

Supported vs. Refuted Statements

Limitations & Future Directions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver