Developmental And Epileptic Encephalopathy 77

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Classifications

ICIMD (Inherited Metabolic Disorders)

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Inheritance

1

Autosomal recessive HP:0000007

All reported patients carry biallelic PIGQ variants, homozygous or compound heterozygous. Inherited GPI deficiencies are autosomal recessive as a group, with PIGA the single X-linked exception. Penetrance and expressivity slots are left unset: with 13 published patients and no reported unaffected biallelic carrier, neither has been assessed, and the 2025 review states explicitly that genotype-phenotype correlation cannot be established at this sample size.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:32588908 SUPPORT Human Clinical

"Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed."

Establishes biallelic PIGQ variants as the disease genotype and names the consistently observed core features.

PMID:40718141 SUPPORT Human Clinical

"Currently, it is not possible to establish genotype–phenotype correlations due to limited phenotype data and small sample size."

The reason this entry records no genotype-phenotype correlation and leaves penetrance and expressivity unassessed.

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Mechanistic Hypotheses

1

Canonical GPI Initiation Flux Reduction Model

canonical_gpi_initiation_flux_reduction_model CANONICAL

Biallelic hypomorphic PIGQ variants lower the activity of the GPI-N-acetylglucosaminyltransferase complex, reducing flux through the first committed step of GPI anchor biosynthesis and thereby the surface density of the whole GPI-anchored proteome. Because that class is disproportionately important in neurogenesis and synaptic function, the result is a developmental and epileptic encephalopathy with multisystem congenital anomalies. The model rests on the rescue of GPI-anchored protein surface expression by wild-type PIGQ in patient fibroblasts and on independent demonstration of the cellular lesion in three unrelated patient sets.

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Discussions and Knowledge Gaps

5

Why is serum alkaline phosphatase elevated in most reported PIGQ patients when the pathway position of PIGQ predicts that alkaline phosphatase should be degraded rather than secreted?

KNOWLEDGE GAP pigq_hyperphosphatasia_mechanism

Attached to

pathophysiology#Reduced GPI-Anchored Protein Surface Expression phenotypes#Elevated Circulating Alkaline Phosphatase Concentration biochemical#Serum alkaline phosphatase

The accepted mechanism of hyperphosphatasia in inherited GPI deficiency is that GPI transamidase recognises an incomplete GPI anchor already bearing mannose, cleaves the signal peptide, and releases soluble alkaline phosphatase into serum — which is why the Mabry/HPMRS arm, with lesions at the mannosyltransferase and later steps, is the hyperphosphatasia arm. In CHO lines blocked before mannose addition the enzyme is degraded instead. PIGQ acts earlier than any of those, so the prediction is a normal serum alkaline phosphatase. The clinical data disagree: the 2025 review of all 13 published PIGQ patients reports elevation in 62%, and elevated alkaline phosphatase had already been documented in PIGA patients, PIGA being another subunit of the same first-step complex. Either the cell-line model does not capture what a partial first-step block does in vivo, or the elevation in these patients has a different source. Resolving it matters practically, because a normal alkaline phosphatase is currently treated as evidence against the Mabry arm and not against the MCAHS arm, and PIGQ sits awkwardly across that line.

Which of the more than 150 GPI-anchored proteins, or which combination, mediates the epilepsy and the developmental impairment in PIGQ deficiency?

KNOWLEDGE GAP pigq_which_gpi_anchored_protein

Attached to

pathophysiology#Reduced GPI-Anchored Protein Surface Expression pathophysiology#Disrupted Neurodevelopment and Cortical Network Excitability

The chain from reduced GPI anchor synthesis to a seizing, developmentally impaired cortex is a class-level argument: GPI-anchored proteins matter in neurogenesis, so reducing all of them must matter. The markers used in patients — CD14, CD16, CD59, DAF, uPAR, CD90, CD109, FLAER — were chosen because they are easy to stain, not because they are implicated in the phenotype. Until a responsible client is identified the edge into the neurodevelopmental node has unknown intermediates, and no protein-specific therapeutic target can be named.

Is febrile-infection-triggered rhabdomyolysis a feature of PIGQ deficiency, or a coincidental finding in one patient?

KNOWLEDGE GAP pigq_rhabdomyolysis_causality

Attached to

phenotypes#Rhabdomyolysis pathophysiology#Multisystem GPI-Anchored Protein Dysfunction

It has been reported once. The argument for causality is that reanalysis of that patient's exome found no other genetic explanation, and that persistent hyperCKemia has been reported in PIGY deficiency, another first-stage GPI gene. The argument against is a cohort of one. The reporting authors nonetheless recommend anticipating it because the episodes are life-threatening, so the clinical consequence of being wrong is asymmetric — which is why it is curated here with an explicit gap rather than omitted.

Can residual PIGQ expression be increased pharmacologically, as PIGM expression was by an HDAC inhibitor?

OPEN QUESTION pigq_pharmacological_upregulation

Attached to

pathophysiology#Biallelic PIGQ Variants pathophysiology#Reduced GPI-Anchored Protein Surface Expression

Every viable PIGQ genotype is hypomorphic, so the disease is a residual-activity disorder rather than a null state — which makes raising residual output a coherent therapeutic target rather than a wish. There is one precedent within inherited GPI deficiency: in PIGM deficiency, where the lesion is a promoter mutation that disrupts Sp1 binding and leaves the coding sequence intact, the HDAC inhibitor butyrate raised PIGM transcription and surface GPI expression and stopped intractable seizures in a child. The mechanism does not transfer directly: the reported PIGQ alleles are coding, not promoter, so there is no hypoacetylated promoter to de-repress, and nothing suggests HDAC inhibition would help here. What the precedent establishes is the weaker and still useful claim that restoring GPI-anchored protein surface expression can control seizures in a patient — that the pathway is pharmacologically modifiable in principle. Whether any approach reaches PIGQ is untested.

Show evidence (2 references)

PMID:17442906 SUPPORT INDIRECT Human Clinical

"the drug caused complete cessation of intractable seizures in a child with inherited GPI deficiency."

The clinical result behind the proof-of-concept claim. INDIRECT because the treated child had PIGM deficiency, a promoter lesion in a different gene, not PIGQ deficiency.

PMID:17442906 SUPPORT INDIRECT In Vitro

"The histone deacetylase inhibitor butyrate increases PIGM transcription and surface GPI expression in vitro as well as in vivo through enhanced histone acetylation in an Sp1-dependent manner."

The mechanism, which is also the reason it does not transfer to PIGQ: it works through Sp1-dependent transcription at a mutated promoter, and the reported PIGQ alleles are coding. INDIRECT because the gene is PIGM.

Should the shared GPI-anchor-biosynthesis lesion across PIGQ, PIGA, PIGP, PIGV, ARV1 and related deficiencies be factored out as a mechanism module?

KNOWLEDGE GAP pigq_gpi_module_absent

Attached to

pathophysiology#Impaired Initiation of GPI Anchor Biosynthesis

This knowledge base already carries several inherited GPI deficiencies curated independently — Mabry syndrome, CHIME syndrome, MCAHS, DEE38 (ARV1), DEE55 (PIGP) and now this entry — each restating the same upstream chain. That is the pattern `kb/modules/` exists for. The existing `congenital_disorder_of_glycosylation` module is not a substitute: it is scoped to the N-glycosylation machinery, a different lesion. No GPI module exists, so this entry declares no `conforms_to`; recording the gap makes the omission visible rather than looking like an oversight.

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Pathophysiology

8

Biallelic PIGQ Variants

Germline biallelic PIGQ variants — homozygous or, more often, compound heterozygous. Reported alleles span splice-disrupting changes causing exon skipping, frameshifts, an in-frame single-codon deletion and missense substitutions. The recurrent allele is the in-frame deletion c.1199_1201del, p.(Tyr400del), found in six of the thirteen published patients and always in trans with a second variant — a pattern consistent with residual rather than absent PIGQ function, which is also what the group-level constraint on inherited GPI deficiency requires.

PIGQ hgnc:14135 ↓ DECREASED

Genetic context variant_origin: GERMLINE allelic_event: MISSENSE_VARIANT allelic_event: FRAMESHIFT_VARIANT allelic_event: SPLICE_SITE_VARIANT allelic_event: DELETION functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

Germline biallelic PIGQ alleles. Both homozygous and compound heterozygous families are reported, so `zygosity` is deliberately left unset — the slot is single-valued and either value would misdescribe part of the cohort. `functional_impact_category` is PARTIAL_LOSS_OF_FUNCTION rather than LOSS_OF_FUNCTION because complete GPI deficiency is embryonically lethal, so every viable patient genotype must retain some activity; the recurrent Tyr400del allele was shown to restore GPI-anchored protein expression only mildly less efficiently than wild type.

Downstream

Reduced GPI-N-Acetylglucosaminyltransferase Activity PIGQ is a required component of the GPI-GlcNAc transferase complex, so biallelic hypomorphic alleles lower the complex's activity.

Show evidence (4 references)

PMID:24463883 SUPPORT Human Clinical

"The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis."

The founding observation linking a recessive PIGQ variant to early-onset epilepsy, and the first demonstration that the variant impairs GPI biosynthesis.

PMID:40718141 SUPPORT Human Clinical

"The frequent variant is in-frame pathogenic (PP5+PM4+PM2) deletion c.1199_1201del, p.(Tyr400del), placed in exon 6. This variant was found in six patients, in all cases in compound heterozygosity with other PIGQ variants."

Documents the recurrent p.(Tyr400del) allele and that it is always seen in compound heterozygosity, which is the basis for describing the genotype as partial rather than complete loss of function.

PMID:34089469 SUPPORT Human Clinical

"We detected a novel homozygous variant in PIGQ (NM_004204.5: c.1631dupA; p.Tyr544fs*79) by WES trio-analysis of a male patient with a neurodevelopmental disorder characterized by nonprogressive congenital ataxia, intellectual disability, generalized epilepsy, and cerebellar atrophy."

A homozygous frameshift allele at the milder end of the reported spectrum, showing that the same gene can give a non-encephalopathic cerebellar presentation.

+ 1 more reference

Reduced GPI-N-Acetylglucosaminyltransferase Activity

The GPI-N-acetylglucosaminyltransferase (GPI-GnT) complex transfers N-acetylglucosamine from UDP-GlcNAc onto phosphatidylinositol on the cytoplasmic face of the endoplasmic reticulum. PIGQ is one of its components, alongside PIGA, PIGC, PIGH, PIGP, PIGY and DPM2 — which is why the PIGQ phenotype resembles those of its complex partners rather than those of the later assembly or remodelling genes.

GPI-N-acetylglucosaminyltransferase activity GO:0017176 ↓ DECREASED

Downstream

Impaired Initiation of GPI Anchor Biosynthesis The GlcNAc transfer this complex performs is the first committed step of the pathway, so lowering its activity throttles the pathway at its entry point.

Show evidence (4 references)

PMID:34089469 SUPPORT Human Clinical

"PIGQ encodes the phosphatidylinositol glycan class Q protein and is part of the GPI-N-acetylglucosaminyltransferase complex that initiates GPI biosynthesis from phosphatidylinositol (PI) and N-acetylglucosamine (GlcNAc) on the cytoplasmic side of the endoplasmic reticulum (ER)."

Places PIGQ in the GPI-N-acetylglucosaminyltransferase complex and names the reaction and its subcellular location.

PMID:40718141 SUPPORT Human Clinical

"Concretely, the PIGQ gene encodes an N-acetylglucosaminyl transferase component. As a part of a molecular complex, its function is to catalyze the transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI) (Watanabe et al."

Names the substrate and product of the reaction PIGQ participates in.

PMID:11418246 SUPPORT Other

"Six human genes encode subunits of this enzyme, namely PIG-A, PIG-C, PIG-H, PIG-P, GPI1, and DPM2."

Enumerates the six subunits of the GPI-GlcNAc transferase complex. GPI1 is the former name of PIGQ (HGNC alias), so this is the composition claim for the complex this node describes.

+ 1 more reference

Impaired Initiation of GPI Anchor Biosynthesis

GPI anchor precursors are assembled stepwise in the endoplasmic reticulum and transferred en bloc to nascent proteins by the GPI transamidase, then remodelled before reaching the cell surface. Because PIGQ acts at the pathway's entry point, less precursor is available to every downstream step, and the deficit is felt by the whole GPI-anchored proteome rather than by a subset of clients.

GPI anchor biosynthetic process GO:0006506 ↓ DECREASED

Downstream

Reduced GPI-Anchored Protein Surface Expression Less GPI precursor is available for transamidase-mediated attachment, so fewer client proteins reach the plasma membrane.

Show evidence (2 references)

PMID:24463883 SUPPORT Human Clinical

"The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis."

Directly reports defective GPI biosynthesis as the consequence of the PIGQ variant in the index patient.

PMID:34089469 SUPPORT Human Clinical

"The glycophosphatidylinositol (GPI) anchor pathway plays an essential role in posttranslational modification of proteins to facilitate proper membrane anchoring and trafficking to lipid rafts, which is critical for many cell functions, including embryogenesis and neurogenesis."

States what the GPI anchor pathway does for its client proteins, which is what is lost when the pathway is throttled at its first step.

Reduced GPI-Anchored Protein Surface Expression

The measurable cellular lesion. Granulocytes, leukocytes and fibroblasts from PIGQ patients show reduced surface levels of GPI-anchored proteins — CD16, CD14, FLAER, CD59, DAF, uPAR, CD90 and CD109 have all been used as readouts — and transduction of wild-type PIGQ restores them. Because at least 150 human proteins are GPI-anchored, the effect is a class-wide reduction in surface density rather than the loss of any single client. This entry names no culprit protein, because no experiment has identified one.

granulocyte CL:0000094 leukocyte CL:0000738

Downstream

Disrupted Neurodevelopment and Cortical Network Excitability GPI-anchored proteins are prominent in neurogenesis and synaptic function; reducing the surface density of the class perturbs both. Which client protein mediates this is unknown.

Multisystem GPI-Anchored Protein Dysfunction GPI-anchored proteins are expressed throughout the body, so the same class-wide reduction produces gastrointestinal, cardiac, skeletal and craniofacial consequences alongside the neurological ones.

Elevated Circulating Alkaline Phosphatase Concentration Alkaline phosphatase is itself a GPI-anchored enzyme, and its serum elevation is reported in a majority of PIGQ patients. The route by which an early-pathway block raises it is unresolved: in cell lines blocked before the first mannose is added, alkaline phosphatase is degraded rather than secreted. This edge is drawn because the association is reported, not because a mechanism has been established for PIGQ.

Show evidence (5 references)

PMID:32588908 SUPPORT In Vitro

"Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype."

Demonstrates the cellular lesion in patient cells and shows it is PIGQ-dependent by rescue.

PMID:32588908 SUPPORT Human Clinical

"We expand the phenotypic spectrum of PIGQ-related disease and provide the first functional evidence in human cells of defective GPI-anchoring due to pathogenic variants in PIGQ."

States that this was the first functional evidence in human cells of defective GPI-anchoring due to PIGQ variants.

PMID:34089469 SUPPORT Human Clinical

"Flow cytometry confirmed deficiency of several GPI-anchored proteins on leukocytes (CD14, FLAER)."

Independent confirmation in an unrelated patient, using different marker proteins.

+ 2 more references

Disrupted Neurodevelopment and Cortical Network Excitability

Reducing the surface density of the GPI-anchored proteome during brain development yields a network that is both developmentally impaired and abnormally excitable. The epilepsy and the developmental impairment are two outputs of one lesion rather than a cause and its consequence, which is what a developmental and epileptic encephalopathy means. In the inherited GPI deficiencies as a group the process is progressive, with serial imaging showing cerebral and cerebellar volume loss over time.

nervous system development GO:0007399 ↓ DECREASED synaptic signaling GO:0099536 ↕ DYSREGULATED

Animal models

Neuron-type-specific Piga conditional knockout mouse Mouse partially recapitulates Neuronal GPI deficiency produces cognitive impairment, altered hippocampal synapses and lowered seizure threshold, which is the mechanism this node asserts.

Downstream

Drug-Resistant Early-Onset Epilepsy An abnormally excitable immature cortex generates early, pharmacoresistant seizures.

Profound Neurodevelopmental Impairment Disturbed neurogenesis produces global developmental failure independent of seizure burden.

Cerebral Atrophy Loss of cerebral parenchymal volume, seen on patient imaging.

Cerebellar Atrophy Cerebellar volume loss, the imaging correlate of the ataxic presentation.

Delayed Myelination Severe myelination delay with reduced cerebral white matter volume on infant imaging.

Show evidence (3 references)

PMID:34089469 SUPPORT Human Clinical

"The glycophosphatidylinositol (GPI) anchor pathway plays an essential role in posttranslational modification of proteins to facilitate proper membrane anchoring and trafficking to lipid rafts, which is critical for many cell functions, including embryogenesis and neurogenesis."

Names embryogenesis and neurogenesis as the processes the GPI anchor pathway is critical for, which is the basis for this node.

PMID:38456468 SUPPORT INDIRECT Human Clinical

"Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process."

Serial imaging across 83 inherited GPI deficiency patients shows the process is progressive rather than a static malformation. INDIRECT because it is a group-level finding, not a PIGQ-specific one.

PMID:38456468 SUPPORT INDIRECT Human Clinical

"Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P = 0.046)."

Patients with variants in synthesis-stage GPI genes reach seizure onset significantly sooner than those with transamidase- or remodelling-stage variants. PIGQ is a synthesis-stage gene, so this is a group-level reason to expect the early onset seen here. INDIRECT for the same reason.

Drug-Resistant Early-Onset Epilepsy

Seizures beginning in the first months of life. The reported range runs from treatable seizures to recurrent status epilepticus, and in the more severely affected patients lifelong combination antiseizure therapy achieves only partial control. Seizure onset in the largest single series fell between 2.5 and 7 months.

Downstream

Epileptic Encephalopathy Sustained epileptic activity in an immature cortex, itself contributing to the developmental impairment.

Infantile Spasms An age-dependent seizure semiology of the immature cortex.

Show evidence (3 references)

PMID:32588908 SUPPORT Human Clinical

"Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus."

Establishes the age of onset and the severity range.

PMID:40718141 SUPPORT Human Clinical

"Epilepsy in P1 started at age 3 months (infantile onset) and presented as infantile spasms with lifelong combined antiseizure medication needed to partially control the seizures."

Documents infantile onset, the infantile-spasms semiology and the only partial response to combination antiseizure medication.

PMID:38456468 SUPPORT INDIRECT Human Clinical

"Median age at seizure onset was 6 months."

The group-level median age at seizure onset across inherited GPI deficiencies, which brackets the PIGQ-specific range above. INDIRECT because it is not a PIGQ figure.

Profound Neurodevelopmental Impairment

Global developmental delay with generalized hypotonia, present in every published patient, together with visual impairment and abnormal movements. A milder end of the spectrum exists: one patient presented with nonprogressive congenital ataxia and intellectual disability rather than an encephalopathy.

Downstream

Global Developmental Delay Global developmental failure from the first months of life.

Generalized Hypotonia Central hypotonia present from infancy in every reported patient.

Visual Impairment Ocular abnormality, reported in all published patients.

Nystagmus One of the reported ocular manifestations.

Ataxia Cerebellar ataxia, the presenting feature at the mild end of the reported spectrum.

Feeding Difficulties Feeding failure following the neurological impairment, requiring tube feeding.

Show evidence (2 references)

PMID:40718141 SUPPORT Human Clinical

"Phenotypic features present in all (100%) MCAHS4 individuals are generalized hypotonia, global developmental delay, epilepsy, visual impairment, and interindividual variable brain MRI changes in concordance with data already published by Johnstone et al."

Names the features present in all reported patients.

PMID:38456468 SUPPORT INDIRECT Human Clinical

"Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%)."

The group-level frequencies of the same core features across 83 inherited GPI deficiency patients, providing a denominator the PIGQ reports cannot. INDIRECT because the figures are not PIGQ-specific.

Multisystem GPI-Anchored Protein Dysfunction

The non-neurological arm of the disorder. Gastrointestinal problems are common and severe, up to midgut volvulus requiring surgery; cardiac anomalies including arrhythmias occur; skeletal changes include scoliosis and pectus carinatum, and one report documented long-bone radiolucent lesions and sphenoid wing dysplasia; craniofacial dysmorphism is present in every reported patient and is consistent enough to be recognisable to computational gestalt analysis. Recurrent rhabdomyolysis triggered by febrile infection has been documented in one patient.

Downstream

Volvulus Midgut volvulus, the most severe reported gastrointestinal complication.

Arrhythmia Cardiac rhythm disturbance among the reported cardiac anomalies.

Coarse Facial Features Part of the craniofacial gestalt reported in every published patient.

Anteverted Nares Part of the shared craniofacial gestalt.

Open Mouth Part of the shared craniofacial gestalt.

Macroglossia Reported craniofacial feature.

Scoliosis Reported skeletal manifestation.

Pectus Carinatum Reported skeletal manifestation, present in both patients of the 2025 report.

Polyhydramnios Prenatal manifestation, present in both patients of the 2025 report.

Rhabdomyolysis Febrile-infection-triggered muscle breakdown, reported in a single patient in whom reanalysis of the exome found no alternative genetic cause.

Show evidence (3 references)

PMID:32588908 SUPPORT Human Clinical

"Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction."

Documents the severity of the gastrointestinal involvement, including surgically corrected midgut volvulus.

PMID:40718141 SUPPORT Human Clinical

"A smaller proportion, that is, 90%, had abnormal movements and gastrointestinal issues."

Gives the cohort proportion for the gastrointestinal and movement manifestations.

PMID:31148362 SUPPORT Human Clinical

"The rare skeletal findings in this disorder expand the differential diagnosis of long bone radiolucent lesions and sphenoid wing dysplasia."

Names the distinctive skeletal findings reported in this disorder.

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Pathograph

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

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Phenotypes

23

Cardiovascular 1

Arrhythmia HP:0011675

Show evidence (1 reference)

PMID:32588908 SUPPORT Human Clinical

"Cardiac anomalies including arrythmias were observed."

Names arrhythmia among the observed cardiac anomalies.

Digestive 2

Volvulus HP:0002580

Show evidence (1 reference)

PMID:32588908 SUPPORT Human Clinical

"Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction."

Documents midgut volvulus requiring surgery in two affected individuals.

Feeding Difficulties HP:0011968

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"P2 had to be fed via a nasogastric tube because of feeding difficulties."

Documents nasogastric tube feeding for feeding difficulties in a reported patient.

Eye 2

Visual Impairment HP:0000505

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"Phenotypic features present in all (100%) MCAHS4 individuals are generalized hypotonia, global developmental delay, epilepsy, visual impairment, and interindividual variable brain MRI changes in concordance with data already published by Johnstone et al."

Lists visual impairment among the features present in all reported patients.

Nystagmus HP:0000639

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"Ocular presentation in P1 was poor eye contact, lagophthalmos, and nystagmus; in P2, visual fixation was lacking."

Names nystagmus among the ocular findings in a reported patient.

Head and Neck 4

Coarse Facial Features HP:0000280

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"Facial dysmorphism (coarse features, anteverted nares, and open mouth) seen in all analyzed MCAHS4 patients seems to be specific."

Names coarse features among the dysmorphic traits seen in all analysed patients.

Anteverted Nares HP:0000463

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"Facial dysmorphism (coarse features, anteverted nares, and open mouth) seen in all analyzed MCAHS4 patients seems to be specific."

Names anteverted nares among the dysmorphic traits seen in all analysed patients.

Open Mouth HP:0000194

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"Facial dysmorphism (coarse features, anteverted nares, and open mouth) seen in all analyzed MCAHS4 patients seems to be specific."

Names open mouth among the dysmorphic traits seen in all analysed patients.

Macroglossia HP:0000158

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"P1 had coarse facial features, anteverted nares, open mouth, and macroglossia"

Names macroglossia among that patient's craniofacial features.

Metabolism 2

Elevated Circulating Alkaline Phosphatase Concentration HP:0003155

Show evidence (2 references)

PMID:40718141 SUPPORT Human Clinical

"Alkaline phosphatase (ALP) is elevated only in 62% of cases."

The cohort-level statement of the frequency of the finding.

PMID:40718141 SUPPORT Human Clinical

"Alkaline phosphatase (ALP) was measured only in P1 with an elevated level of 632 U/l (N: 82–383)."

A measured value with its reference interval, and the sentence that also records how often the enzyme was actually measured — which is why this entry treats the 62% denominator as soft.

Elevated Circulating Creatine Kinase Concentration Elevated circulating creatine kinase activity HP:0003236

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"HyperCKemia was found only in P1, with creatine kinase (CK) levels higher than 5000 U/l (N: <170) during episodes of rhabdomyolysis."

Gives the measured creatine kinase level, its reference interval, and its restriction to one patient.

Musculoskeletal 4

Generalized Hypotonia HP:0001290

Show evidence (2 references)

PMID:32588908 SUPPORT Human Clinical

"Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed."

Names axial hypotonia among the consistently observed features.

PMID:40718141 SUPPORT Human Clinical

"Phenotypic features present in all (100%) MCAHS4 individuals are generalized hypotonia, global developmental delay, epilepsy, visual impairment, and interindividual variable brain MRI changes in concordance with data already published by Johnstone et al."

Confirms generalized hypotonia in all 13 reviewed patients.

Rhabdomyolysis HP:0003201

Temporal: RECURRENT

Sequelae: Elevated Circulating Creatine Kinase Concentration

Show evidence (2 references)

PMID:40718141 SUPPORT Human Clinical

"attacks of rhabdomyolysis induced by a febrile infection were documented only in our patient"

Documents the finding and, in the same sentence, that it was seen in only one patient across the reviewed cohort.

PMID:40718141 SUPPORT Human Clinical

"Because of their life-threatening complications, attacks of rhabdomyolysis should be considered in MCAHS4 patients."

The authors' clinical recommendation, which is why this single-patient finding is curated rather than omitted.

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"The most visible skeletal changes in P1 were scoliosis and pectus carinatum (Figures 3A–D) and in P2 pectus carinatum (Figure 3E)."

Names scoliosis among the skeletal changes.

Pectus Carinatum HP:0000768

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"The most visible skeletal changes in P1 were scoliosis and pectus carinatum (Figures 3A–D) and in P2 pectus carinatum (Figure 3E)."

Names pectus carinatum in both reported patients.

Nervous System 7

Epileptic Encephalopathy HP:0200134

Show evidence (1 reference)

PMID:34089469 SUPPORT Human Clinical

"Pathogenic variants in the PIGQ gene have been previously reported in 10 patients with congenital hypotonia, early-infantile epileptic encephalopathy, and premature death occurring in more than half cases."

Names early-infantile epileptic encephalopathy as the established PIGQ phenotype across the previously reported patients.

Infantile Spasms HP:0012469

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"Epilepsy in P1 started at age 3 months (infantile onset) and presented as infantile spasms with lifelong combined antiseizure medication needed to partially control the seizures."

Documents infantile spasms as the presenting seizure type in that patient.

Global Developmental Delay HP:0001263

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"Phenotypic features present in all (100%) MCAHS4 individuals are generalized hypotonia, global developmental delay, epilepsy, visual impairment, and interindividual variable brain MRI changes in concordance with data already published by Johnstone et al."

Lists global developmental delay among the features present in all reported patients.

Ataxia HP:0001251

Show evidence (1 reference)

PMID:34089469 SUPPORT Human Clinical

"We detected a novel homozygous variant in PIGQ (NM_004204.5: c.1631dupA; p.Tyr544fs*79) by WES trio-analysis of a male patient with a neurodevelopmental disorder characterized by nonprogressive congenital ataxia, intellectual disability, generalized epilepsy, and cerebellar atrophy."

Documents nonprogressive congenital ataxia as the dominant feature in that patient.

Cerebral Atrophy HP:0002059

Show evidence (2 references)

PMID:40718141 SUPPORT Human Clinical

"In P1, an MRI of the brain showed significant enlargement of the bifrontal subarachnoid space, severe myelination delay, and decreased volume of cerebral white matter at 8 months of age."

Documents the enlarged subarachnoid space and reduced cerebral white matter volume that constitute the atrophic imaging picture.

PMID:38456468 SUPPORT INDIRECT Human Clinical

"Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process."

Group-level serial imaging showing progressive cerebral volume loss across inherited GPI deficiencies. INDIRECT because it is not PIGQ-specific.

Cerebellar Atrophy HP:0001272

Show evidence (1 reference)

PMID:34089469 SUPPORT Human Clinical

"We detected a novel homozygous variant in PIGQ (NM_004204.5: c.1631dupA; p.Tyr544fs*79) by WES trio-analysis of a male patient with a neurodevelopmental disorder characterized by nonprogressive congenital ataxia, intellectual disability, generalized epilepsy, and cerebellar atrophy."

Names cerebellar atrophy in that patient's imaging.

Delayed Myelination HP:0012448

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"In P1, an MRI of the brain showed significant enlargement of the bifrontal subarachnoid space, severe myelination delay, and decreased volume of cerebral white matter at 8 months of age."

Names severe myelination delay on imaging at 8 months of age.

Prenatal and Birth 1

Polyhydramnios HP:0001561

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"Polyhydramnios as a prenatal complication was present in both patients"

Documents polyhydramnios in both patients.

🧬

Genetic Associations

1

PIGQ

Gene: PIGQ hgnc:14135 relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:24463883 SUPPORT Human Clinical

"This work reveals two novel genes for OS, KCNT1 and PIGQ."

The paper that established PIGQ as a disease gene for this phenotype.

PMID:31148362 SUPPORT Human Clinical

"PIGQ (OMIM *605754) encodes phosphatidylinositol glycan biosynthesis class Q (PIGQ) and is required for proper functioning of an N-acetylglucosamine transferase complex in a similar manner to the more established PIGA, PIGC, and PIGH."

Places PIGQ in the N-acetylglucosamine transferase complex alongside PIGA, PIGC and PIGH, which grounds the phenotypic comparison to its complex partners.

PMID:40718141 SUPPORT Human Clinical

"The frequent variant is in-frame pathogenic (PP5+PM4+PM2) deletion c.1199_1201del, p.(Tyr400del), placed in exon 6. This variant was found in six patients, in all cases in compound heterozygosity with other PIGQ variants."

Documents the recurrent allele and its consistent compound-heterozygous context.

+ 1 more reference

💊

Medical Actions

5

Antiseizure Medication

Action: Pharmacotherapy NCIT:C15986

Agent: anticonvulsant agent NCIT:C264

Platform: Small molecule

Seizure control is the mainstay of management. Response is variable — the largest series describes a range from treatable seizures to recurrent status epilepticus — and in the more severely affected patients lifelong combination therapy achieves only partial control. No specific anticonvulsant has been shown to work better than others in PIGQ deficiency, and no such claim is made here. It is symptomatic: it does not address the GPI-anchor lesion.

Mechanism Target:

MODULATES Drug-Resistant Early-Onset Epilepsy — Symptomatic seizure suppression, often incomplete. It does not alter the developmental trajectory.

Show evidence (2 references)

PMID:40718141 SUPPORT Human Clinical

"Epilepsy in P1 started at age 3 months (infantile onset) and presented as infantile spasms with lifelong combined antiseizure medication needed to partially control the seizures."

Documents lifelong combination antiseizure medication achieving only partial control, which is both the treatment and the evidence for calling the epilepsy drug-resistant.

PMID:32588908 SUPPORT Human Clinical

"Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus."

Establishes that seizure response spans treatable disease to recurrent status epilepticus, which is why no uniform claim about efficacy is made.

Pyridoxine or Pyridoxal 5-Phosphate

Action: Pharmacotherapy NCIT:C15986

Agent: pyridoxine CHEBI:16709 pyridoxal 5'-phosphate CHEBI:18405

Platform: Small molecule

High-dose vitamin B6 (pyridoxine 20-30 mg/kg/day, switched to pyridoxal 5-phosphate if unresponsive) is the one intervention that has been prospectively tested in inherited GPI deficiency epilepsy. The result was modest and is reported honestly here: in a seven-participant cohort, two had a more than 50% reduction in seizure frequency and three a smaller reduction, none became seizure-free, and EEG did not improve in six of seven. The participants had PIGA, PIGT or PIGV deficiency, not PIGQ deficiency — PIGA is a partner subunit in the same first-step complex as PIGQ, which is the closest the evidence comes, and it is still an extrapolation. No PIGQ patient has been reported on this regimen.

Mechanism Target:

MODULATES Drug-Resistant Early-Onset Epilepsy — Partial reduction in seizure frequency in some patients with inherited GPI deficiency. It does not address the GPI-anchor lesion and did not produce seizure freedom in anyone studied.

Show evidence (3 references)

PMID:35080266 SUPPORT INDIRECT Human Clinical

"AIM: To investigate the short-term efficacy and safety of high-dose pyridoxine and pyridoxal 5-phosphate (P5P) in the treatment of inherited glycosylphosphatidylinositol (GPI) deficiency-associated epilepsy."

Establishes that this regimen was tested prospectively in inherited GPI deficiency epilepsy. INDIRECT because the cohort is the GPI-deficiency group and contains no PIGQ patient.

PMID:35080266 SUPPORT INDIRECT Human Clinical

"We observed more than 50% seizure frequency reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants. No participants reached seizure freedom."

The actual outcome, including that no participant reached seizure freedom — which is why this entry describes the benefit as partial rather than as a treatment. INDIRECT for the same reason.

PMID:35080266 SUPPORT INDIRECT Human Clinical

"The genetic causes of inherited GPI deficiency were phosphatidylinositol N-acetylglucosaminyltransferase subunit A/T/V deficiency."

Names the genes the participants carried, which is the fact that makes every claim from this study an extrapolation to PIGQ. INDIRECT for that reason.

Ketogenic Diet

Action: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

The ketogenic diet is the empiric dietary intervention most often used in GPI anchor defects. The evidence is at the level of that subgroup of congenital disorders of glycosylation, not of PIGQ: no study has tested it in PIGQ deficiency, and this entry does not imply one has.

Show evidence (1 reference)

PMID:35562242 SUPPORT INDIRECT Human Clinical

"Ketogenic diet is most frequently used in GPI anchor defects"

States that the ketogenic diet is the intervention most often used in the GPI anchor defects, the subgroup PIGQ deficiency belongs to. INDIRECT because the claim reaches PIGQ only through subgroup membership.

Surgical Correction of Midgut Volvulus

Action: Surgical Procedure NCIT:C15329

Platform: Surgery

Emergency surgical correction of midgut volvulus, performed in two of the seven children in the largest single series. This is management of a life-threatening complication rather than treatment of the disorder, and it is the reason gastrointestinal symptoms in a patient with this diagnosis warrant a low threshold for imaging.

Mechanism Target:

MODULATES Volvulus — Relieves the volvulus. It does not address the underlying developmental anomaly or the GPI-anchor lesion.

Show evidence (1 reference)

PMID:32588908 SUPPORT Human Clinical

"Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction."

Documents the surgical correction in two affected individuals.

Enteral Feeding Support

Action: Supportive Care NCIT:C15747

Platform: Device

Tube feeding for the feeding difficulties that follow the neurological impairment. For a disorder in which no reported patient achieves independent development and antiseizure medication is only partly effective, supportive care of this kind is most of what management consists of.

Mechanism Target:

MODULATES Feeding Difficulties — Supportive management of feeding failure. It does not address the underlying lesion.

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"P2 had to be fed via a nasogastric tube because of feeding difficulties."

Documents nasogastric tube feeding in a reported patient.

🔬

Biochemical Markers

2

Serum alkaline phosphatase

Show evidence (7 references)

PMID:40718141 SUPPORT Human Clinical

"Alkaline phosphatase (ALP) is elevated only in 62% of cases."

The PIGQ-specific frequency of the finding.

PMID:40718141 SUPPORT Human Clinical

"Alkaline phosphatase (ALP) was measured only in P1 with an elevated level of 632 U/l (N: 82–383)."

A measured value with its reference interval, and the record that it was measured in only one of that report's two patients.

PMID:22228761 SUPPORT INDIRECT In Vitro

"Hyperphosphatasia resulted from secretion of ALP, a GPI-anchored protein normally expressed on the cell surface, into serum due to PIGV deficiency."

Establishes the accepted mechanism of hyperphosphatasia in GPI deficiency — transamidase-mediated release of soluble alkaline phosphatase. INDIRECT because the experiment is in PIGV, not PIGQ.

+ 4 more references

Serum creatine kinase

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"HyperCKemia was found only in P1, with creatine kinase (CK) levels higher than 5000 U/l (N: <170) during episodes of rhabdomyolysis."

The measured values, reference interval and their episodic restriction.

🔬

Diagnosis

3

Whole exome sequencing

Molecular diagnosis. Every published patient was ascertained by exome or genome sequencing; the phenotype is not distinctive enough among the inherited GPI deficiencies to point at PIGQ clinically. The index case was found by whole-genome sequencing after conventional candidate-gene testing failed.

whole exome sequencing NCIT:C101295

Show evidence (2 references)

PMID:32588908 SUPPORT Human Clinical

"Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed."

This series established the genotype that sequencing is looking for.

PMID:24463883 SUPPORT Human Clinical

"This work reveals two novel genes for OS, KCNT1 and PIGQ."

The index case was identified by unbiased genome sequencing, which is why an untargeted approach rather than an epilepsy panel is the diagnostic route.

Flow cytometry for GPI-anchored protein surface expression

Measurement of GPI-anchored protein levels on patient granulocytes, leukocytes or fibroblasts by flow cytometry. CD16, CD14, FLAER, CD59, DAF, uPAR, CD90 and CD109 have all been used. This is the standard functional assay for inherited GPI deficiency as a group rather than a PIGQ-specific test: it establishes that the GPI pathway is impaired, and sequencing establishes which gene. Its practical value is in resolving variants of uncertain significance — the 2025 report reclassified a PIGQ missense VUS to likely pathogenic on the strength of a flow-cytometry rescue experiment.

flow cytometry NCIT:C16585

Show evidence (3 references)

PMID:32588908 SUPPORT In Vitro

"Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype."

Establishes the assay and its rescue-based interpretation in PIGQ patients.

PMID:34089469 SUPPORT Human Clinical

"Flow cytometry confirmed deficiency of several GPI-anchored proteins on leukocytes (CD14, FLAER)."

Independent diagnostic use of the same assay on leukocytes, with different markers.

PMID:25803904 SUPPORT INDIRECT Other

"Flow cytometric analysis of GPI-APs on granulocytes is also useful for the detection of IGD."

States the assay's role as a detection method for inherited GPI deficiency as a group. INDIRECT because it is a group-level recommendation, not a PIGQ-specific one.

Serum alkaline phosphatase (supportive, not discriminating)

Elevated in 62% of published PIGQ patients, so a raised value supports the diagnosis. It does not discriminate within the inherited GPI deficiencies — hyperphosphatasia is a variable feature across the group and was explicitly judged unsuitable for classifying them — and a normal value does not exclude PIGQ deficiency. It is listed here because the combination of the core clinical features with a raised alkaline phosphatase is what should prompt testing for a GPI biosynthesis defect.

Show evidence (2 references)

PMID:40718141 SUPPORT Human Clinical

"Alkaline phosphatase (ALP) is elevated only in 62% of cases."

The frequency that makes a raised value supportive rather than expected.

PMID:29310717 SUPPORT INDIRECT Human Clinical

"hyperphosphatasia is a variable feature that is not ideal for a clinical classification"

Why it cannot be used to discriminate within the group. INDIRECT because the statement is about GPI biosynthesis defects generally.

📈

Progression

3

Prenatal and neonatal

Age: prenatal to 1 month

Polyhydramnios and increased nuchal translucency were reported prenatally. The neonatal course may be complicated by respiratory insufficiency, hypotonia, hepatosplenomegaly and jaundice.

Show evidence (1 reference)

PMID:40718141 SUPPORT Human Clinical

"Polyhydramnios as a prenatal complication was present in both patients"

Documents the prenatal complication.

Infancy

Age: 1-12 months

Seizure onset, between 2.5 and 7 months in the largest single series, with hypotonia and delayed psychomotor development already evident. Brain MRI abnormality is present by this stage.

Show evidence (1 reference)

PMID:32588908 SUPPORT Human Clinical

"Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus."

Gives the age window of seizure onset.

Childhood and beyond

Age: 1 year onward

Profound developmental disability with ongoing seizures. Mortality is substantial: the median survival age across the 13 published patients was 5.5 years, with deaths reported from 10 months to 13 years and causes including sepsis and pneumonia.

Show evidence (4 references)

PMID:40718141 SUPPORT Human Clinical

"The median survival age of the patients was 5.5 years."

Gives the cohort median survival age.

PMID:40718141 SUPPORT Human Clinical

"Both patients died prematurely: P1 at the age of 13 years due to asphyxia during sepsis and P2 at 1 year of life due to pneumonia."

Gives the ages and causes of death in the two most recently reported patients, which bracket the range.

PMID:31148362 SUPPORT Human Clinical

"Our patient died at 10 months of age."

The earliest reported death, at 10 months, which sets the lower end of the survival range.

+ 1 more reference

📊

Prevalence

1

Worldwide, published cases

Cases In Literature Ultra Rare

Thirteen genetically confirmed patients from twelve unrelated families had been published as of 2025 (eleven previously reported plus two new cases). No incidence or prevalence estimate exists for PIGQ deficiency.

Show evidence (2 references)

PMID:40718141 SUPPORT Human Clinical

"We summarized phenotypic data from 13 genetically confirmed PIGQ-deficient patients (n = 13; 11 already published and 2 novel); seven were male subjects (of which two were siblings), and five were female subjects."

Gives the size and composition of the published cohort.

PMID:40718141 SUPPORT Human Clinical

"Only 11 patients with this condition have been reported to date."

The published count immediately before that review added its two cases, which is the number a reader of the earlier literature would encounter.

🐁

Animal Models

1

Neuron-type-specific Piga conditional knockout mouse

There is no reported PIGQ mouse. This is a **Piga** model, and it is listed here for what it can and cannot do. Piga and Pigq are subunits of the same GPI-N-acetylglucosaminyltransferase complex, so a neuronal Piga knockout reproduces the shared upstream lesion — loss of GPI anchoring in neurons — rather than the PIGQ genotype. Three cell-type-restricted lines were made; the excitatory- and inhibitory-neuron lines showed impaired long-term fear memory and increased susceptibility to kainic-acid-induced seizures, with hippocampal synapse changes in the excitatory line. That is the closest experimental demonstration available that reducing neuronal GPI anchoring is sufficient to produce seizure susceptibility and cognitive impairment.

Species

Mouse

Genotype

Piga conditional knockout, restricted to telencephalon excitatory, inhibitory, or thalamic neurons

Publication

PMID:33607654

Pathograph links

Disrupted Neurodevelopment and Cortical Network Excitability partially recapitulates fidelity: low observes: organism Neuronal GPI deficiency produces cognitive impairment, altered hippocampal synapses and lowered seizure threshold, which is the mechanism this node asserts.

Limitations: The disrupted gene is Piga, not Pigq: the model shares the complex and the pathway step but not the human genotype, and PIGA disease in humans is X-linked while PIGQ disease is autosomal recessive. The knockout is conditional and cell-type-restricted, so it models neuronal GPI loss rather than the constitutive partial deficiency of a patient, and it does not reproduce the multisystem congenital anomalies of PIGQ deficiency at all. `fidelity: LOW` reflects the gene mismatch, not a defect in the experiment.

Show evidence (2 references)

PMID:33607654 SUPPORT INDIRECT Model Organism

"Both Ex-M-cko and In-M-cko mice showed impaired long-term fear memory and were more susceptible to kainic acid-induced seizures."

The behavioural and seizure-threshold result. INDIRECT because the gene disrupted is Piga, a partner subunit, and not PIGQ.

+ 1 more reference

Show evidence (2 references)

PMID:33607654 SUPPORT Model Organism

"We generated three mouse models with PIGA deficits specifically in telencephalon excitatory neurons (Ex-M-cko), inhibitory neurons (In-M-cko) or thalamic neurons (Th-H-cko), respectively."

Describes the three conditional lines, which is what this model entry names.

PMID:33607654 SUPPORT INDIRECT Model Organism

"Patients carrying a mutation of the PIGA gene usually suffer from inherited glycosylphosphatidylinositol deficiency (IGD) with intractable epilepsy and intellectual developmental disorder."

States that the human disease the model is aimed at is inherited GPI deficiency with intractable epilepsy and intellectual disability — the class DEE77 belongs to. INDIRECT because the gene named is PIGA.

{ }

Source YAML

click to show

name: Developmental And Epileptic Encephalopathy 77
creation_date: "2026-09-07T00:00:00Z"
category: Mendelian
synonyms:
- DEE77
- EIEE77
- epileptic encephalopathy, early infantile, 77
- multiple congenital anomalies-hypotonia-seizures syndrome 4
- MCAHS4
- PIGQ deficiency
- PIGQ-CDG
- glycosylphosphatidylinositol biosynthesis defect 19
disease_term:
  preferred_term: developmental and epileptic encephalopathy, 77
  term:
    id: MONDO:0032808
    label: developmental and epileptic encephalopathy, 77
parents:
- Congenital Disorder of Glycosylation
- Inborn Error of Metabolism
- Epilepsy
description: >
  Developmental and epileptic encephalopathy 77 (DEE77; also catalogued as
  multiple congenital anomalies-hypotonia-seizures syndrome 4, OMIM #618548,
  and nosologically as PIGQ-CDG) is an autosomal recessive inherited
  glycosylphosphatidylinositol (GPI) deficiency caused by biallelic variants in
  PIGQ. PIGQ is a component of the GPI-N-acetylglucosaminyltransferase complex
  that performs the first, committed step of GPI anchor biosynthesis on the
  cytoplasmic face of the endoplasmic reticulum, transferring
  N-acetylglucosamine from UDP-GlcNAc onto phosphatidylinositol. At least 150
  human proteins reach the cell surface tethered by a GPI anchor, so reducing
  flux at the entry point of the pathway lowers the surface density of that
  whole protein class rather than removing one gene product.

  Clinically the disorder is a severe, early-onset developmental and epileptic
  encephalopathy. Across the 13 genetically confirmed patients reported to
  date, hypotonia, psychomotor delay, epilepsy, brain MRI abnormality, ocular
  abnormality and craniofacial dysmorphism were present in all; gastrointestinal
  problems and abnormal movements in about 90%. Seizure onset in the largest
  single series fell between 2.5 and 7 months of age and ranged from treatable
  seizures to recurrent status epilepticus. Multisystem involvement is
  prominent and can be life-threatening: two children in that series had midgut
  volvulus requiring surgery, cardiac anomalies including arrhythmias occur, and
  one patient had recurrent febrile-infection-triggered rhabdomyolysis. Mortality
  is high, with a median survival age of 5.5 years across the reported cohort.

  The functional lesion is demonstrable: flow cytometry of patient granulocytes,
  leukocytes and fibroblasts shows reduced surface GPI-anchored proteins, and
  transfection of wild-type PIGQ cDNA into patient fibroblasts restores them.
  Unlike its first-step-complex sibling PIGP, PIGQ deficiency is reported with
  elevated serum alkaline phosphatase in a majority of cases, which is
  mechanistically unexpected for a block this early in the pathway and is
  discussed below.
notes: >
  **Counts, not frequencies.** Only 13 genetically confirmed PIGQ-deficient
  patients had been published as of the 2025 review that assembled them, so
  every proportion in this entry is a fraction of a cohort of that size. Where a
  percentage is quoted it is quoted as the source states it, and no
  `frequency:` band has been derived from it.

  **Hyperphosphatasia: the point on which this entry departs from the
  pathway-position argument.** The received account, stated in the literature on
  inherited GPI deficiency and reproduced in this knowledge base's PIGP entry, is
  that hyperphosphatasia arises from defects in the *later* steps of GPI
  biosynthesis (Mabry syndrome / HPMRS being the type case), because GPI
  transamidase recognises an incomplete GPI that already bears mannose, cleaves
  the signal peptide, and releases soluble alkaline phosphatase into serum. In
  cell lines blocked *before* the first mannose is added — PIGL, DPM2, PIGX —
  alkaline phosphatase is degraded instead, so no hyperphosphatasia is predicted.
  PIGQ acts earlier still, at the very first GlcNAc transfer, so the pathway
  argument predicts a normal serum alkaline phosphatase.

  The reported data do not follow that prediction. The 2025 review of all 13
  published PIGQ patients states that alkaline phosphatase is elevated in 62% of
  cases, and its own new patient in whom the enzyme was measured had a level of
  632 U/l against a reference interval of 82-383. This is not an isolated
  anomaly: a 91-individual GPI-biosynthesis-defect series had already found
  elevated alkaline phosphatase in individuals with PIGA mutations — PIGA being
  the catalytic subunit of the same first-step GlcNAc transferase complex that
  PIGQ belongs to — and concluded that hyperphosphatasia is a variable feature
  that is not suitable for classifying these disorders.

  This entry therefore curates the observation and not the inference: elevated
  alkaline phosphatase is recorded as a documented biochemical and phenotypic
  feature of PIGQ deficiency, the mechanistic conflict is recorded as a
  knowledge gap, and no claim is made here that PIGQ deficiency spares alkaline
  phosphatase. Two honest caveats attach to the 62% figure. It is a proportion
  of a cohort of 13 assembled retrospectively from published reports, in which
  the enzyme was not measured in every patient — the review itself notes that
  among its own two new cases the measurement was made in only one — so the
  denominator is soft. And the review lists elevated alkaline phosphatase among
  the "less common" features, which is how it reads a 62% figure with missing
  data rather than a contradiction of the number.

  **What is deliberately not asserted.** The chain from reduced GPI-anchored
  protein surface density to a seizing, developmentally impaired cortex is a
  class-level argument. No study identifies which of the >150 GPI-anchored
  proteins mediates the neurological phenotype in PIGQ deficiency, so the edge
  into the neurodevelopmental node carries unknown intermediates and no
  individual client protein is named as the culprit. CD14, CD16, CD59, DAF,
  uPAR, CD90, CD109 and FLAER appear in this entry as measured readouts, not as
  pathogenic effectors. Likewise, the 2025 review states plainly that
  genotype-phenotype correlation cannot yet be established at this sample size,
  so none is asserted.

  Three further features reported by the pooled inherited-GPI-deficiency cohort
  (PMID:38456468) were considered and excluded on the same principle: corpus
  callosum anomalies (57%), symmetric restricted diffusion of the central
  tegmental tracts (60%), and renal anomalies (14%). These are frequencies
  across the whole IGD cohort, not PIGQ frequencies, and no PIGQ-specific source
  documents any of them. The callosal statements in this entry's other cached
  references all belong to other genes. PMID:29310717 is a six-column HPMRS
  comparison table and carries three separate ones: "thin corpus callosum"
  beside "Hearing impairment (5/16)" in the HPMRS2 (PIGO) column, where the /16
  denominator matches that column's n; the same phrase inside the "Further
  anomalies (rare)" list in the HPMRS1 (PIGV) column; and "Thin corpus callosum
  (9/26)" in the HPMRS4 (PGAP3) column. PMID:35562242 attributes its callosal
  sentence to GFUS-CDG, the GDP-L-fucose synthase disorder. SLC35C1-CDG, the
  GDP-fucose transporter disorder it was mistaken for, is discussed earlier in
  that review and is named again in the paragraph immediately before the GFUS
  one only as a comparator for a third fucosylation disorder. None of
  PIGV, PIGO, PGAP3 or GFUS is PIGQ. Pooled data supports a PIGQ-documented
  feature as INDIRECT evidence in this entry; it does not originate a phenotype
  here, so none of the three is curated.

  **No `conforms_to` was declared.** There is no GPI-anchor-biosynthesis module
  in `kb/modules/`, and the existing `congenital_disorder_of_glycosylation`
  module is scoped to the N-glycosylation machinery (LLO assembly, Golgi
  N-glycan processing, protein hypoglycosylation), which is a different lesion.
  None of the sibling inherited-GPI-deficiency entries (DEE38/ARV1, DEE55/PIGP,
  Mabry syndrome, CHIME syndrome, MCAHS) declares a conformance either. The gap
  is recorded as a discussion rather than papered over with a mismatched target.

  **Deep-research provenance.** Falcon (Edison) was requested and returned HTTP
  402 (account out of credits), so the run fell back to OpenScientist and the
  committed report is named for the provider that actually produced it
  (`research/Developmental_And_Epileptic_Encephalopathy_77-deep-research-openscientist.md`;
  `fell_back: true`, `requested_provider: falcon` in its frontmatter). Its
  reference validation resolved 12 of 12 citations with a confabulation rate of
  0.0 and no unresolved references; of the 12 assessed for relevance, 7 scored
  on topic and the rest were left unscored rather than judged off topic. Its
  term validation carries `needs_review: true` for one obsolete CURIE
  (GO:0031225, "anchored component of membrane") and four label mismatches,
  three of which are the report labelling an identifier with its ontology's name
  ("MONDO", "DOID") rather than the term's. Nothing from that list is bound
  here; GO:0031225 in particular is not used.

  `just preflight-dr` returns WARN because "GPI" is counted as a rival gene
  mentioned 82 times. That is a false positive of the same kind recorded on the
  PIGP entry: "GPI" here is glycosylphosphatidylinositol, the anchor, not GPI
  the glucose-6-phosphate isomerase gene. The report's disease identity checks
  out — MONDO's OMIM xref for MONDO:0032808 is 618548, which is the MCAHS4
  number the primary literature uses for PIGQ.

  The report contributed four sources that first-pass curation from the primary
  PIGQ papers had missed: the original GPI1/PIGQ characterisation with its
  antisense knockdown (PMID:11418246), the neuronal Piga conditional-knockout
  mouse (PMID:33607654), the prospective vitamin B6 cohort in GPI deficiency
  (PMID:35080266) and the PIGM/butyrate proof of concept (PMID:17442906). Two of
  its citations were deliberately not used. PMID:19732866 is about FOLR1
  mutations causing cerebral folate transport deficiency; the report itself
  labels the folinic-acid inference for PIGQ "mechanistic conjecture", and
  nothing cited here connects GPI deficiency to cerebral folate deficiency, so
  the claim was dropped rather than curated as a treatment. PMID:40126049, a
  266-patient cannabidiol study in monogenic epilepsies, mentions no PIG gene
  and no GPI anchor, so it cannot support anything specific to this disorder.
  The two 2025 case reports and the Starr phenotype paper (PMID:40718141,
  PMID:31148362) were found outside the report, by PubMed search.

  Every quote used in this entry was extracted programmatically from the fetched
  reference cache rather than copied from the report or retyped; several of the
  sources carry non-breaking spaces, en dashes and hard line wraps that
  hand-copying would have corrupted.

  **No `datasets:` block.** Searching a causal gene for expression datasets is
  the documented route into Named Entity Confusion, and for a disorder with 13
  published patients there is no disease-specific dataset to find. None was
  added rather than attaching a PIGQ-keyed accession about an unrelated disease.
classifications:
  icimd_category:
  - classification_value: lipid_glycosylation
    notes: >-
      ICIMD (Ferreira et al. 2021) group "Disorders of lipid glycosylation",
      which the classification explicitly scopes to include
      glycosylphosphatidylinositol biosynthesis. PIGQ acts at the first step of
      GPI anchor assembly.
    evidence:
    - reference: PMID:33340416
      reference_title: "An international classification of inherited metabolic disorders (ICIMD)."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "glycolipids (glycosylphosphatidylinositol and glycosphingolipids) are included under the category of congenital disorders of glycosylation"
      explanation: >-
        The ICIMD paper places glycosylphosphatidylinositol among the glycolipids
        it files under congenital disorders of glycosylation, which is the group
        the `lipid_glycosylation` value names.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    All reported patients carry biallelic PIGQ variants, homozygous or compound
    heterozygous. Inherited GPI deficiencies are autosomal recessive as a group,
    with PIGA the single X-linked exception. Penetrance and expressivity slots
    are left unset: with 13 published patients and no reported unaffected
    biallelic carrier, neither has been assessed, and the 2025 review states
    explicitly that genotype-phenotype correlation cannot be established at this
    sample size.
  evidence:
  - reference: PMID:32588908
    reference_title: "Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed."
    explanation: >
      Establishes biallelic PIGQ variants as the disease genotype and names the
      consistently observed core features.
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, it is not possible to establish genotype–phenotype correlations due to limited phenotype data and small sample size."
    explanation: >
      The reason this entry records no genotype-phenotype correlation and leaves
      penetrance and expressivity unassessed.
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Thirteen genetically confirmed patients from twelve unrelated families had
    been published as of 2025 (eleven previously reported plus two new cases).
    No incidence or prevalence estimate exists for PIGQ deficiency.
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We summarized phenotypic data from 13 genetically confirmed PIGQ-deficient patients (n = 13; 11 already published and 2 novel); seven were male subjects (of which two were siblings), and five were female subjects."
    explanation: >-
      Gives the size and composition of the published cohort.
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 11 patients with this condition have been reported to date."
    explanation: >-
      The published count immediately before that review added its two cases,
      which is the number a reader of the earlier literature would encounter.
pathophysiology:
- name: Biallelic PIGQ Variants
  biological_scale: MOLECULAR
  description: >
    Germline biallelic PIGQ variants — homozygous or, more often, compound
    heterozygous. Reported alleles span splice-disrupting changes causing exon
    skipping, frameshifts, an in-frame single-codon deletion and missense
    substitutions. The recurrent allele is the in-frame deletion c.1199_1201del,
    p.(Tyr400del), found in six of the thirteen published patients and always in
    trans with a second variant — a pattern consistent with residual rather than
    absent PIGQ function, which is also what the group-level constraint on
    inherited GPI deficiency requires.
  genes:
  - preferred_term: PIGQ
    term:
      id: hgnc:14135
      label: PIGQ
    modifier: DECREASED
  genetic_context:
    description: >-
      Germline biallelic PIGQ alleles. Both homozygous and compound heterozygous
      families are reported, so `zygosity` is deliberately left unset — the slot
      is single-valued and either value would misdescribe part of the cohort.
      `functional_impact_category` is PARTIAL_LOSS_OF_FUNCTION rather than
      LOSS_OF_FUNCTION because complete GPI deficiency is embryonically lethal,
      so every viable patient genotype must retain some activity; the recurrent
      Tyr400del allele was shown to restore GPI-anchored protein expression only
      mildly less efficiently than wild type.
    allelic_events:
    - MISSENSE_VARIANT
    - FRAMESHIFT_VARIANT
    - SPLICE_SITE_VARIANT
    - DELETION
    variant_origin: GERMLINE
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:24463883
    reference_title: "Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis."
    explanation: >
      The founding observation linking a recessive PIGQ variant to
      early-onset epilepsy, and the first demonstration that the variant
      impairs GPI biosynthesis.
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequent variant is in-frame pathogenic (PP5+PM4+PM2) deletion c.1199_1201del, p.(Tyr400del), placed in exon 6. This variant was found in six patients, in all cases in compound heterozygosity with other PIGQ variants."
    explanation: >
      Documents the recurrent p.(Tyr400del) allele and that it is always seen in
      compound heterozygosity, which is the basis for describing the genotype as
      partial rather than complete loss of function.
  - reference: PMID:34089469
    reference_title: "PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected a novel homozygous variant in PIGQ (NM_004204.5: c.1631dupA; p.Tyr544fs*79) by WES trio-analysis of a male patient with a neurodevelopmental disorder characterized by nonprogressive congenital ataxia, intellectual disability, generalized epilepsy, and cerebellar atrophy."
    explanation: >
      A homozygous frameshift allele at the milder end of the reported spectrum,
      showing that the same gene can give a non-encephalopathic cerebellar
      presentation.
  - reference: PMID:25803904
    reference_title: "[Inherited GPI deficiencies:a new disease with intellectual disability and epilepsy]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients with IGD have only a partial deficiency because complete GPI deficiency causes embryonic death."
    explanation: >
      The group-level constraint that makes every viable patient genotype
      hypomorphic, and therefore the reason this node is a reduction rather than
      an abolition of PIGQ function.
  downstream:
  - target: Reduced GPI-N-Acetylglucosaminyltransferase Activity
    description: >-
      PIGQ is a required component of the GPI-GlcNAc transferase complex, so
      biallelic hypomorphic alleles lower the complex's activity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31148362
      reference_title: "PIGQ glycosylphosphatidylinositol-anchored protein deficiency: Characterizing the phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "PIGQ (OMIM *605754) encodes phosphatidylinositol glycan biosynthesis class Q (PIGQ) and is required for proper functioning of an N-acetylglucosamine transferase complex in a similar manner to the more established PIGA, PIGC, and PIGH."
      explanation: >-
        States that PIGQ is required for proper functioning of the
        N-acetylglucosamine transferase complex, which is the edge from the
        genotype to the enzymatic deficit.

- name: Reduced GPI-N-Acetylglucosaminyltransferase Activity
  biological_scale: MOLECULAR
  description: >
    The GPI-N-acetylglucosaminyltransferase (GPI-GnT) complex transfers
    N-acetylglucosamine from UDP-GlcNAc onto phosphatidylinositol on the
    cytoplasmic face of the endoplasmic reticulum. PIGQ is one of its
    components, alongside PIGA, PIGC, PIGH, PIGP, PIGY and DPM2 — which is why
    the PIGQ phenotype resembles those of its complex partners rather than those
    of the later assembly or remodelling genes.
  molecular_functions:
  - preferred_term: GPI-N-acetylglucosaminyltransferase activity
    modifier: DECREASED
    term:
      id: GO:0017176
      label: phosphatidylinositol N-acetylglucosaminyltransferase activity
  evidence:
  - reference: PMID:34089469
    reference_title: "PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PIGQ encodes the phosphatidylinositol glycan class Q protein and is part of the GPI-N-acetylglucosaminyltransferase complex that initiates GPI biosynthesis from phosphatidylinositol (PI) and N-acetylglucosamine (GlcNAc) on the cytoplasmic side of the endoplasmic reticulum (ER)."
    explanation: >
      Places PIGQ in the GPI-N-acetylglucosaminyltransferase complex and names
      the reaction and its subcellular location.
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Concretely, the PIGQ gene encodes an N-acetylglucosaminyl transferase component. As a part of a molecular complex, its function is to catalyze the transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI) (Watanabe et al."
    explanation: >
      Names the substrate and product of the reaction PIGQ participates in.
  - reference: PMID:11418246
    reference_title: The human GPI1 gene is required for efficient glycosylphosphatidylinositol biosynthesis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Six human genes encode subunits of this enzyme, namely PIG-A, PIG-C, PIG-H, PIG-P, GPI1, and DPM2."
    explanation: >
      Enumerates the six subunits of the GPI-GlcNAc transferase complex. GPI1 is
      the former name of PIGQ (HGNC alias), so this is the composition claim for
      the complex this node describes.
  - reference: PMID:11418246
    reference_title: The human GPI1 gene is required for efficient glycosylphosphatidylinositol biosynthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transfectants exhibited a marked but incomplete decrease in the expression of a GPI-linked reporter protein, confirming that GPI1 is required for efficient GPI biosynthesis."
    explanation: >
      Antisense knockdown of GPI1/PIGQ in HEK293 cells reduced GPI-linked
      reporter expression, and did so incompletely — direct experimental support
      both for PIGQ being required for the reaction and for the deficit being
      partial rather than absolute.
  downstream:
  - target: Impaired Initiation of GPI Anchor Biosynthesis
    description: >-
      The GlcNAc transfer this complex performs is the first committed step of
      the pathway, so lowering its activity throttles the pathway at its
      entry point.
    causal_link_type: DIRECT

- name: Impaired Initiation of GPI Anchor Biosynthesis
  biological_scale: MOLECULAR
  description: >
    GPI anchor precursors are assembled stepwise in the endoplasmic reticulum
    and transferred en bloc to nascent proteins by the GPI transamidase, then
    remodelled before reaching the cell surface. Because PIGQ acts at the
    pathway's entry point, less precursor is available to every downstream step,
    and the deficit is felt by the whole GPI-anchored proteome rather than by a
    subset of clients.
  biological_processes:
  - preferred_term: GPI anchor biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006506
      label: GPI anchor biosynthetic process
  evidence:
  - reference: PMID:24463883
    reference_title: "Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis."
    explanation: >
      Directly reports defective GPI biosynthesis as the consequence of the
      PIGQ variant in the index patient.
  - reference: PMID:34089469
    reference_title: "PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The glycophosphatidylinositol (GPI) anchor pathway plays an essential role in posttranslational modification of proteins to facilitate proper membrane anchoring and trafficking to lipid rafts, which is critical for many cell functions, including embryogenesis and neurogenesis."
    explanation: >
      States what the GPI anchor pathway does for its client proteins, which is
      what is lost when the pathway is throttled at its first step.
  downstream:
  - target: Reduced GPI-Anchored Protein Surface Expression
    description: >-
      Less GPI precursor is available for transamidase-mediated attachment, so
      fewer client proteins reach the plasma membrane.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32588908
      reference_title: "Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype."
      explanation: >-
        The rescue by wild-type PIGQ cDNA is what makes this an edge rather than
        a coincidence: restoring PIGQ restores surface GPI-anchored proteins.

- name: Reduced GPI-Anchored Protein Surface Expression
  biological_scale: CELLULAR
  description: >
    The measurable cellular lesion. Granulocytes, leukocytes and fibroblasts
    from PIGQ patients show reduced surface levels of GPI-anchored proteins —
    CD16, CD14, FLAER, CD59, DAF, uPAR, CD90 and CD109 have all been used as
    readouts — and transduction of wild-type PIGQ restores them. Because at
    least 150 human proteins are GPI-anchored, the effect is a class-wide
    reduction in surface density rather than the loss of any single client.
    This entry names no culprit protein, because no experiment has identified
    one.
  cell_types:
  - preferred_term: granulocyte
    term:
      id: CL:0000094
      label: granulocyte
  - preferred_term: leukocyte
    term:
      id: CL:0000738
      label: leukocyte
  evidence:
  - reference: PMID:32588908
    reference_title: "Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype."
    explanation: >
      Demonstrates the cellular lesion in patient cells and shows it is
      PIGQ-dependent by rescue.
  - reference: PMID:32588908
    reference_title: "Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We expand the phenotypic spectrum of PIGQ-related disease and provide the first functional evidence in human cells of defective GPI-anchoring due to pathogenic variants in PIGQ."
    explanation: >
      States that this was the first functional evidence in human cells of
      defective GPI-anchoring due to PIGQ variants.
  - reference: PMID:34089469
    reference_title: "PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Flow cytometry confirmed deficiency of several GPI-anchored proteins on leukocytes (CD14, FLAER)."
    explanation: >
      Independent confirmation in an unrelated patient, using different marker
      proteins.
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The expression of CD109 and uPAR was slightly decreased in the patient’s fibroblasts (70% for uPAR, 32% for CD109, compared to the control), which was restored to the control level by retroviral transduction of wild-type PIGQ cDNA, suggesting that the reduction is due to PIGQ deficiency (Supplementary Figure S2)."
    explanation: >
      A third demonstration with retroviral rescue, and a quantified magnitude
      for two markers in patient fibroblasts.
  - reference: PMID:32156170
    reference_title: "Biosynthesis and biology of mammalian GPI-anchored proteins."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "At least 150 human proteins are glycosylphosphatidylinositol-anchored proteins (GPI-APs)."
    explanation: >
      Sizes the affected protein class, which is what makes this a class-wide
      reduction and the reason the edge out of this node has unknown
      intermediates.
  downstream:
  - target: Disrupted Neurodevelopment and Cortical Network Excitability
    description: >-
      GPI-anchored proteins are prominent in neurogenesis and synaptic function;
      reducing the surface density of the class perturbs both. Which client
      protein mediates this is unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Which of the >150 GPI-anchored proteins mediates the neurological phenotype has not been determined
  - target: Multisystem GPI-Anchored Protein Dysfunction
    description: >-
      GPI-anchored proteins are expressed throughout the body, so the same
      class-wide reduction produces gastrointestinal, cardiac, skeletal and
      craniofacial consequences alongside the neurological ones.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - The specific GPI-anchored clients mediating each organ manifestation are unidentified
  - target: Elevated Circulating Alkaline Phosphatase Concentration
    description: >-
      Alkaline phosphatase is itself a GPI-anchored enzyme, and its serum
      elevation is reported in a majority of PIGQ patients. The route by which
      an early-pathway block raises it is unresolved: in cell lines blocked
      before the first mannose is added, alkaline phosphatase is degraded rather
      than secreted. This edge is drawn because the association is reported, not
      because a mechanism has been established for PIGQ.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - The mechanism by which a first-step GPI block raises serum alkaline phosphatase is unresolved
    evidence:
    - reference: PMID:40718141
      reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Alkaline phosphatase (ALP) is elevated only in 62% of cases."
      explanation: >-
        The association itself, across all published PIGQ patients.
    - reference: PMID:22228761
      reference_title: "Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome."
      supports: REFUTE
      evidence_source: IN_VITRO
      snippet: "In contrast, ALP \nwas degraded in PIGL-, DPM2-, or PIGX-deficient CHO cells, in which incomplete \nshorter GPIs that lacked mannose were accumulated."
      explanation: >-
        Cell lines blocked early in the pathway, before mannose addition, degrade
        alkaline phosphatase rather than secreting it — so this experiment argues
        against an early-step block such as PIGQ producing hyperphosphatasia by
        the Mabry mechanism. Recorded as REFUTE against this edge because it cuts
        the other way; the clinical association is nonetheless reported.

- name: Disrupted Neurodevelopment and Cortical Network Excitability
  biological_scale: TISSUE
  description: >
    Reducing the surface density of the GPI-anchored proteome during brain
    development yields a network that is both developmentally impaired and
    abnormally excitable. The epilepsy and the developmental impairment are two
    outputs of one lesion rather than a cause and its consequence, which is what
    a developmental and epileptic encephalopathy means. In the inherited GPI
    deficiencies as a group the process is progressive, with serial imaging
    showing cerebral and cerebellar volume loss over time.
  biological_processes:
  - preferred_term: nervous system development
    modifier: DECREASED
    term:
      id: GO:0007399
      label: nervous system development
  - preferred_term: synaptic signaling
    modifier: DYSREGULATED
    term:
      id: GO:0099536
      label: synaptic signaling
  evidence:
  - reference: PMID:34089469
    reference_title: "PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The glycophosphatidylinositol (GPI) anchor pathway plays an essential role in posttranslational modification of proteins to facilitate proper membrane anchoring and trafficking to lipid rafts, which is critical for many cell functions, including embryogenesis and neurogenesis."
    explanation: >
      Names embryogenesis and neurogenesis as the processes the GPI anchor
      pathway is critical for, which is the basis for this node.
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Serial neuroimaging showed \nprogressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in \n70.8%, indicating a neurodegenerative process."
    explanation: >
      Serial imaging across 83 inherited GPI deficiency patients shows the
      process is progressive rather than a static malformation. INDIRECT because
      it is a group-level finding, not a PIGQ-specific one.
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Individuals with variants in synthesis stage \ngenes of the GPI-AP exhibited a significantly shorter time to seizure onset than \nindividuals with variants in transamidase and remodelling stage genes of the \nGPI-AP (P = 0.046)."
    explanation: >
      Patients with variants in synthesis-stage GPI genes reach seizure onset
      significantly sooner than those with transamidase- or remodelling-stage
      variants. PIGQ is a synthesis-stage gene, so this is a group-level reason
      to expect the early onset seen here. INDIRECT for the same reason.
  downstream:
  - target: Drug-Resistant Early-Onset Epilepsy
    description: An abnormally excitable immature cortex generates early, pharmacoresistant seizures.
    causal_link_type: DIRECT
  - target: Profound Neurodevelopmental Impairment
    description: Disturbed neurogenesis produces global developmental failure independent of seizure burden.
    causal_link_type: DIRECT
  - target: Cerebral Atrophy
    description: Loss of cerebral parenchymal volume, seen on patient imaging.
    causal_link_type: DIRECT
  - target: Cerebellar Atrophy
    description: Cerebellar volume loss, the imaging correlate of the ataxic presentation.
    causal_link_type: DIRECT
  - target: Delayed Myelination
    description: Severe myelination delay with reduced cerebral white matter volume on infant imaging.
    causal_link_type: DIRECT

- name: Drug-Resistant Early-Onset Epilepsy
  biological_scale: ORGANISM
  description: >
    Seizures beginning in the first months of life. The reported range runs from
    treatable seizures to recurrent status epilepticus, and in the more severely
    affected patients lifelong combination antiseizure therapy achieves only
    partial control. Seizure onset in the largest single series fell between 2.5
    and 7 months.
  evidence:
  - reference: PMID:32588908
    reference_title: "Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus."
    explanation: >
      Establishes the age of onset and the severity range.
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epilepsy in P1 started at age 3 months (infantile onset) and presented as infantile spasms with lifelong combined antiseizure medication needed to partially control the seizures."
    explanation: >
      Documents infantile onset, the infantile-spasms semiology and the only
      partial response to combination antiseizure medication.
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Median age \nat seizure onset was 6 months."
    explanation: >
      The group-level median age at seizure onset across inherited GPI
      deficiencies, which brackets the PIGQ-specific range above. INDIRECT
      because it is not a PIGQ figure.
  downstream:
  - target: Epileptic Encephalopathy
    description: Sustained epileptic activity in an immature cortex, itself contributing to the developmental impairment.
    causal_link_type: DIRECT
  - target: Infantile Spasms
    description: An age-dependent seizure semiology of the immature cortex.
    causal_link_type: DIRECT

- name: Profound Neurodevelopmental Impairment
  biological_scale: ORGANISM
  description: >
    Global developmental delay with generalized hypotonia, present in every
    published patient, together with visual impairment and abnormal movements.
    A milder end of the spectrum exists: one patient presented with
    nonprogressive congenital ataxia and intellectual disability rather than an
    encephalopathy.
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phenotypic features present in all (100%) MCAHS4 individuals are generalized hypotonia, global developmental delay, epilepsy, visual impairment, and interindividual variable brain MRI changes in concordance with data already published by Johnstone et al."
    explanation: >
      Names the features present in all reported patients.
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Core clinical features were developmental delay or intellectual \ndisability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms \n(64%)."
    explanation: >
      The group-level frequencies of the same core features across 83 inherited
      GPI deficiency patients, providing a denominator the PIGQ reports cannot.
      INDIRECT because the figures are not PIGQ-specific.
  downstream:
  - target: Global Developmental Delay
    description: Global developmental failure from the first months of life.
    causal_link_type: DIRECT
  - target: Generalized Hypotonia
    description: Central hypotonia present from infancy in every reported patient.
    causal_link_type: DIRECT
  - target: Visual Impairment
    description: Ocular abnormality, reported in all published patients.
    causal_link_type: DIRECT
  - target: Nystagmus
    description: One of the reported ocular manifestations.
    causal_link_type: DIRECT
  - target: Ataxia
    description: >-
      Cerebellar ataxia, the presenting feature at the mild end of the reported
      spectrum.
    causal_link_type: DIRECT
  - target: Feeding Difficulties
    description: Feeding failure following the neurological impairment, requiring tube feeding.
    causal_link_type: DIRECT

- name: Multisystem GPI-Anchored Protein Dysfunction
  biological_scale: ORGANISM
  description: >
    The non-neurological arm of the disorder. Gastrointestinal problems are
    common and severe, up to midgut volvulus requiring surgery; cardiac
    anomalies including arrhythmias occur; skeletal changes include scoliosis
    and pectus carinatum, and one report documented long-bone radiolucent
    lesions and sphenoid wing dysplasia; craniofacial dysmorphism is present in
    every reported patient and is consistent enough to be recognisable to
    computational gestalt analysis. Recurrent rhabdomyolysis triggered by febrile
    infection has been documented in one patient.
  evidence:
  - reference: PMID:32588908
    reference_title: "Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction."
    explanation: >
      Documents the severity of the gastrointestinal involvement, including
      surgically corrected midgut volvulus.
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A smaller proportion, that is, 90%, had abnormal movements and gastrointestinal issues."
    explanation: >
      Gives the cohort proportion for the gastrointestinal and movement
      manifestations.
  - reference: PMID:31148362
    reference_title: "PIGQ glycosylphosphatidylinositol-anchored protein deficiency: Characterizing the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The rare skeletal findings in this disorder expand the differential diagnosis of long bone radiolucent lesions and sphenoid wing dysplasia."
    explanation: >
      Names the distinctive skeletal findings reported in this disorder.
  downstream:
  - target: Volvulus
    description: Midgut volvulus, the most severe reported gastrointestinal complication.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - The GPI-anchored clients mediating the gastrointestinal malformation are unidentified
  - target: Arrhythmia
    description: Cardiac rhythm disturbance among the reported cardiac anomalies.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - The GPI-anchored clients mediating the cardiac phenotype are unidentified
  - target: Coarse Facial Features
    description: Part of the craniofacial gestalt reported in every published patient.
    causal_link_type: DIRECT
  - target: Anteverted Nares
    description: Part of the shared craniofacial gestalt.
    causal_link_type: DIRECT
  - target: Open Mouth
    description: Part of the shared craniofacial gestalt.
    causal_link_type: DIRECT
  - target: Macroglossia
    description: Reported craniofacial feature.
    causal_link_type: DIRECT
  - target: Scoliosis
    description: Reported skeletal manifestation.
    causal_link_type: DIRECT
  - target: Pectus Carinatum
    description: Reported skeletal manifestation, present in both patients of the 2025 report.
    causal_link_type: DIRECT
  - target: Polyhydramnios
    description: Prenatal manifestation, present in both patients of the 2025 report.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Presumed to reflect impaired fetal swallowing, but not established in this disorder
  - target: Rhabdomyolysis
    description: >-
      Febrile-infection-triggered muscle breakdown, reported in a single patient
      in whom reanalysis of the exome found no alternative genetic cause.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - The link between GPI-anchored protein deficiency and myocyte membrane instability is not established
mechanistic_hypotheses:
- hypothesis_group_id: canonical_gpi_initiation_flux_reduction_model
  hypothesis_label: Canonical GPI Initiation Flux Reduction Model
  status: CANONICAL
  description: >-
    Biallelic hypomorphic PIGQ variants lower the activity of the
    GPI-N-acetylglucosaminyltransferase complex, reducing flux through the first
    committed step of GPI anchor biosynthesis and thereby the surface density of
    the whole GPI-anchored proteome. Because that class is disproportionately
    important in neurogenesis and synaptic function, the result is a
    developmental and epileptic encephalopathy with multisystem congenital
    anomalies. The model rests on the rescue of GPI-anchored protein surface
    expression by wild-type PIGQ in patient fibroblasts and on independent
    demonstration of the cellular lesion in three unrelated patient sets.
discussions:
- discussion_id: pigq_hyperphosphatasia_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why is serum alkaline phosphatase elevated in most reported PIGQ patients
    when the pathway position of PIGQ predicts that alkaline phosphatase should
    be degraded rather than secreted?
  attaches_to:
  - pathophysiology#Reduced GPI-Anchored Protein Surface Expression
  - phenotypes#Elevated Circulating Alkaline Phosphatase Concentration
  - biochemical#Serum alkaline phosphatase
  rationale: >-
    The accepted mechanism of hyperphosphatasia in inherited GPI deficiency is
    that GPI transamidase recognises an incomplete GPI anchor already bearing
    mannose, cleaves the signal peptide, and releases soluble alkaline
    phosphatase into serum — which is why the Mabry/HPMRS arm, with lesions at
    the mannosyltransferase and later steps, is the hyperphosphatasia arm. In
    CHO lines blocked before mannose addition the enzyme is degraded instead.
    PIGQ acts earlier than any of those, so the prediction is a normal serum
    alkaline phosphatase. The clinical data disagree: the 2025 review of all 13
    published PIGQ patients reports elevation in 62%, and elevated alkaline
    phosphatase had already been documented in PIGA patients, PIGA being another
    subunit of the same first-step complex. Either the cell-line model does not
    capture what a partial first-step block does in vivo, or the elevation in
    these patients has a different source. Resolving it matters practically,
    because a normal alkaline phosphatase is currently treated as evidence
    against the Mabry arm and not against the MCAHS arm, and PIGQ sits awkwardly
    across that line.
- discussion_id: pigq_which_gpi_anchored_protein
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which of the more than 150 GPI-anchored proteins, or which combination,
    mediates the epilepsy and the developmental impairment in PIGQ deficiency?
  attaches_to:
  - pathophysiology#Reduced GPI-Anchored Protein Surface Expression
  - pathophysiology#Disrupted Neurodevelopment and Cortical Network Excitability
  rationale: >-
    The chain from reduced GPI anchor synthesis to a seizing, developmentally
    impaired cortex is a class-level argument: GPI-anchored proteins matter in
    neurogenesis, so reducing all of them must matter. The markers used in
    patients — CD14, CD16, CD59, DAF, uPAR, CD90, CD109, FLAER — were chosen
    because they are easy to stain, not because they are implicated in the
    phenotype. Until a responsible client is identified the edge into the
    neurodevelopmental node has unknown intermediates, and no protein-specific
    therapeutic target can be named.
- discussion_id: pigq_rhabdomyolysis_causality
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is febrile-infection-triggered rhabdomyolysis a feature of PIGQ deficiency,
    or a coincidental finding in one patient?
  attaches_to:
  - phenotypes#Rhabdomyolysis
  - pathophysiology#Multisystem GPI-Anchored Protein Dysfunction
  rationale: >-
    It has been reported once. The argument for causality is that reanalysis of
    that patient's exome found no other genetic explanation, and that
    persistent hyperCKemia has been reported in PIGY deficiency, another
    first-stage GPI gene. The argument against is a cohort of one. The reporting
    authors nonetheless recommend anticipating it because the episodes are
    life-threatening, so the clinical consequence of being wrong is asymmetric —
    which is why it is curated here with an explicit gap rather than omitted.
- discussion_id: pigq_pharmacological_upregulation
  kind: OPEN_QUESTION
  prompt: >-
    Can residual PIGQ expression be increased pharmacologically, as PIGM
    expression was by an HDAC inhibitor?
  attaches_to:
  - pathophysiology#Biallelic PIGQ Variants
  - pathophysiology#Reduced GPI-Anchored Protein Surface Expression
  rationale: >-
    Every viable PIGQ genotype is hypomorphic, so the disease is a
    residual-activity disorder rather than a null state — which makes raising
    residual output a coherent therapeutic target rather than a wish. There is
    one precedent within inherited GPI deficiency: in PIGM deficiency, where the
    lesion is a promoter mutation that disrupts Sp1 binding and leaves the
    coding sequence intact, the HDAC inhibitor butyrate raised PIGM
    transcription and surface GPI expression and stopped intractable seizures in
    a child. The mechanism does not transfer directly: the reported PIGQ alleles
    are coding, not promoter, so there is no hypoacetylated promoter to
    de-repress, and nothing suggests HDAC inhibition would help here. What the
    precedent establishes is the weaker and still useful claim that restoring
    GPI-anchored protein surface expression can control seizures in a patient —
    that the pathway is pharmacologically modifiable in principle. Whether any
    approach reaches PIGQ is untested.
  evidence:
  - reference: PMID:17442906
    reference_title: Targeted therapy for inherited GPI deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "the drug caused complete cessation of intractable seizures in a child with inherited GPI deficiency."
    explanation: >-
      The clinical result behind the proof-of-concept claim. INDIRECT because
      the treated child had PIGM deficiency, a promoter lesion in a different
      gene, not PIGQ deficiency.
  - reference: PMID:17442906
    reference_title: Targeted therapy for inherited GPI deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "The histone deacetylase inhibitor butyrate increases PIGM transcription and surface GPI expression in vitro as well as in vivo through enhanced histone acetylation in an Sp1-dependent manner."
    explanation: >-
      The mechanism, which is also the reason it does not transfer to PIGQ: it
      works through Sp1-dependent transcription at a mutated promoter, and the
      reported PIGQ alleles are coding. INDIRECT because the gene is PIGM.
- discussion_id: pigq_gpi_module_absent
  kind: KNOWLEDGE_GAP
  prompt: >-
    Should the shared GPI-anchor-biosynthesis lesion across PIGQ, PIGA, PIGP,
    PIGV, ARV1 and related deficiencies be factored out as a mechanism module?
  attaches_to:
  - pathophysiology#Impaired Initiation of GPI Anchor Biosynthesis
  rationale: >-
    This knowledge base already carries several inherited GPI deficiencies
    curated independently — Mabry syndrome, CHIME syndrome, MCAHS, DEE38 (ARV1),
    DEE55 (PIGP) and now this entry — each restating the same upstream chain.
    That is the pattern `kb/modules/` exists for. The existing
    `congenital_disorder_of_glycosylation` module is not a substitute: it is
    scoped to the N-glycosylation machinery, a different lesion. No GPI module
    exists, so this entry declares no `conforms_to`; recording the gap makes the
    omission visible rather than looking like an oversight.
phenotypes:
- name: Epileptic Encephalopathy
  category: Neurological
  description: >
    Early-onset epilepsy in which the epileptic activity itself contributes to
    the developmental impairment. Present in all published patients.
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:34089469
    reference_title: "PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic variants in the PIGQ gene have been previously reported in 10 patients with congenital hypotonia, early-infantile epileptic encephalopathy, and premature death occurring in more than half cases."
    explanation: >
      Names early-infantile epileptic encephalopathy as the established PIGQ
      phenotype across the previously reported patients.
- name: Infantile Spasms
  category: Neurological
  description: >
    Epileptic spasms in infancy, the seizure semiology reported at onset in one
    of the 2025 patients.
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epilepsy in P1 started at age 3 months (infantile onset) and presented as infantile spasms with lifelong combined antiseizure medication needed to partially control the seizures."
    explanation: >
      Documents infantile spasms as the presenting seizure type in that patient.
- name: Global Developmental Delay
  category: Neurodevelopmental
  description: >
    Global developmental delay, reported in every published PIGQ patient.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phenotypic features present in all (100%) MCAHS4 individuals are generalized hypotonia, global developmental delay, epilepsy, visual impairment, and interindividual variable brain MRI changes in concordance with data already published by Johnstone et al."
    explanation: >
      Lists global developmental delay among the features present in all
      reported patients.
- name: Generalized Hypotonia
  category: Neuromuscular
  description: >
    Generalized, predominantly axial hypotonia from early infancy, reported in
    every published patient.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:32588908
    reference_title: "Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed."
    explanation: >
      Names axial hypotonia among the consistently observed features.
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phenotypic features present in all (100%) MCAHS4 individuals are generalized hypotonia, global developmental delay, epilepsy, visual impairment, and interindividual variable brain MRI changes in concordance with data already published by Johnstone et al."
    explanation: >
      Confirms generalized hypotonia in all 13 reviewed patients.
- name: Visual Impairment
  category: Ophthalmological
  description: >
    Ocular abnormality was present in all 13 reviewed patients; visual
    impairment specifically is listed among the features present in every case.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phenotypic features present in all (100%) MCAHS4 individuals are generalized hypotonia, global developmental delay, epilepsy, visual impairment, and interindividual variable brain MRI changes in concordance with data already published by Johnstone et al."
    explanation: >
      Lists visual impairment among the features present in all reported
      patients.
- name: Nystagmus
  category: Ophthalmological
  description: >
    Nystagmus, one of the reported ocular manifestations.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular presentation in P1 was poor eye contact, lagophthalmos, and nystagmus; in P2, visual fixation was lacking."
    explanation: >
      Names nystagmus among the ocular findings in a reported patient.
- name: Ataxia
  category: Neurological
  description: >
    Nonprogressive congenital ataxia, the presenting feature at the mild end of
    the PIGQ spectrum in a patient with a homozygous frameshift allele.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:34089469
    reference_title: "PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected a novel homozygous variant in PIGQ (NM_004204.5: c.1631dupA; p.Tyr544fs*79) by WES trio-analysis of a male patient with a neurodevelopmental disorder characterized by nonprogressive congenital ataxia, intellectual disability, generalized epilepsy, and cerebellar atrophy."
    explanation: >
      Documents nonprogressive congenital ataxia as the dominant feature in that
      patient.
- name: Cerebral Atrophy
  category: Neuroimaging
  description: >
    Reduced cerebral parenchymal volume. Brain MRI abnormality was present in
    all reviewed patients; in the 2025 report it took the form of enlarged
    bifrontal subarachnoid space with decreased cerebral white matter volume.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In P1, an MRI of the brain showed significant enlargement of the bifrontal subarachnoid space, severe myelination delay, and decreased volume of cerebral white matter at 8 months of age."
    explanation: >
      Documents the enlarged subarachnoid space and reduced cerebral white
      matter volume that constitute the atrophic imaging picture.
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Serial neuroimaging showed \nprogressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in \n70.8%, indicating a neurodegenerative process."
    explanation: >
      Group-level serial imaging showing progressive cerebral volume loss across
      inherited GPI deficiencies. INDIRECT because it is not PIGQ-specific.
- name: Cerebellar Atrophy
  category: Neuroimaging
  description: >
    Cerebellar volume loss, reported in the patient with the ataxic
    presentation.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:34089469
    reference_title: "PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected a novel homozygous variant in PIGQ (NM_004204.5: c.1631dupA; p.Tyr544fs*79) by WES trio-analysis of a male patient with a neurodevelopmental disorder characterized by nonprogressive congenital ataxia, intellectual disability, generalized epilepsy, and cerebellar atrophy."
    explanation: >
      Names cerebellar atrophy in that patient's imaging.
- name: Delayed Myelination
  category: Neuroimaging
  description: >
    Severe myelination delay on infant brain MRI.
  phenotype_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In P1, an MRI of the brain showed significant enlargement of the bifrontal subarachnoid space, severe myelination delay, and decreased volume of cerebral white matter at 8 months of age."
    explanation: >
      Names severe myelination delay on imaging at 8 months of age.
- name: Elevated Circulating Alkaline Phosphatase Concentration
  category: Biochemical
  description: >
    Elevated serum alkaline phosphatase, reported in 62% of the 13 published
    PIGQ patients. This is the feature on which PIGQ deficiency departs from
    what its pathway position would predict; see the entry notes and the
    knowledge gap recorded for it. The enzyme was not measured in every reported
    patient, so the denominator behind that percentage is soft.
  phenotype_term:
    preferred_term: Elevated circulating alkaline phosphatase concentration
    term:
      id: HP:0003155
      label: Elevated circulating alkaline phosphatase concentration
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alkaline phosphatase (ALP) is elevated only in 62% of cases."
    explanation: >
      The cohort-level statement of the frequency of the finding.
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alkaline phosphatase (ALP) was measured only in P1 with an elevated level of 632 U/l (N: 82–383)."
    explanation: >
      A measured value with its reference interval, and the sentence that also
      records how often the enzyme was actually measured — which is why this
      entry treats the 62% denominator as soft.
- name: Rhabdomyolysis
  category: Neuromuscular
  description: >
    Recurrent rhabdomyolysis triggered by febrile infection, documented in one
    of the 13 published patients. Reanalysis of that patient's exome found no
    alternative genetic cause. Whether this is a feature of PIGQ deficiency is
    an open question recorded as a knowledge gap; the reporting authors
    recommend anticipating it because the episodes are life-threatening.
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
    temporality: RECURRENT
  sequelae:
  - target: Elevated Circulating Creatine Kinase Concentration
    description: Release of intracellular creatine kinase from damaged myocytes.
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "attacks of rhabdomyolysis induced by a febrile infection were documented only in our patient"
    explanation: >
      Documents the finding and, in the same sentence, that it was seen in only
      one patient across the reviewed cohort.
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because of their life-threatening complications, attacks of rhabdomyolysis should be considered in MCAHS4 patients."
    explanation: >
      The authors' clinical recommendation, which is why this single-patient
      finding is curated rather than omitted.
- name: Elevated Circulating Creatine Kinase Concentration
  category: Biochemical
  description: >
    Serum creatine kinase above 5000 U/l during rhabdomyolysis episodes in the
    single patient in whom this was documented; the level was normal between
    episodes.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HyperCKemia was found only in P1, with creatine kinase (CK) levels higher than 5000 U/l (N: <170) during episodes of rhabdomyolysis."
    explanation: >
      Gives the measured creatine kinase level, its reference interval, and its
      restriction to one patient.
- name: Volvulus
  category: Gastrointestinal
  description: >
    Midgut volvulus requiring surgical correction, in two of the seven children
    in the largest single series.
  phenotype_term:
    preferred_term: Volvulus
    term:
      id: HP:0002580
      label: Volvulus
  evidence:
  - reference: PMID:32588908
    reference_title: "Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction."
    explanation: >
      Documents midgut volvulus requiring surgery in two affected individuals.
- name: Arrhythmia
  category: Cardiovascular
  description: >
    Cardiac rhythm disturbance, among the cardiac anomalies reported in the
    largest single series.
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:32588908
    reference_title: "Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac anomalies including arrythmias were observed."
    explanation: >
      Names arrhythmia among the observed cardiac anomalies.
- name: Feeding Difficulties
  category: Gastrointestinal
  description: >
    Feeding failure requiring tube feeding.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P2 had to be fed via a nasogastric tube because of feeding difficulties."
    explanation: >
      Documents nasogastric tube feeding for feeding difficulties in a reported
      patient.
- name: Coarse Facial Features
  category: Craniofacial
  description: >
    Coarse facial features, one of the two traits the 2025 review found shared
    by every analysed patient.
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial dysmorphism (coarse features, anteverted nares, and open mouth) seen in all analyzed MCAHS4 patients seems to be specific."
    explanation: >
      Names coarse features among the dysmorphic traits seen in all analysed
      patients.
- name: Anteverted Nares
  category: Craniofacial
  description: >
    Anteverted nares, the other trait shared across all analysed patients.
  phenotype_term:
    preferred_term: Anteverted nares
    term:
      id: HP:0000463
      label: Anteverted nares
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial dysmorphism (coarse features, anteverted nares, and open mouth) seen in all analyzed MCAHS4 patients seems to be specific."
    explanation: >
      Names anteverted nares among the dysmorphic traits seen in all analysed
      patients.
- name: Open Mouth
  category: Craniofacial
  description: >
    Open-mouth appearance. The 2025 review notes that this trait is not
    currently associated with PIGQ in the Human Phenotype Ontology's
    gene-to-phenotype annotations, but was present in every patient they
    analysed.
  phenotype_term:
    preferred_term: Open mouth
    term:
      id: HP:0000194
      label: Open mouth
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial dysmorphism (coarse features, anteverted nares, and open mouth) seen in all analyzed MCAHS4 patients seems to be specific."
    explanation: >
      Names open mouth among the dysmorphic traits seen in all analysed
      patients.
- name: Macroglossia
  category: Craniofacial
  description: >
    Macroglossia, reported in one of the 2025 patients.
  phenotype_term:
    preferred_term: Macroglossia
    term:
      id: HP:0000158
      label: Macroglossia
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P1 had coarse facial features, anteverted nares, open mouth, and macroglossia"
    explanation: >
      Names macroglossia among that patient's craniofacial features.
- name: Scoliosis
  category: Skeletal
  description: >
    Scoliosis, the most visible skeletal change in one of the 2025 patients.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most visible skeletal changes in P1 were scoliosis and pectus carinatum (Figures 3A–D) and in P2 pectus carinatum (Figure 3E)."
    explanation: >
      Names scoliosis among the skeletal changes.
- name: Pectus Carinatum
  category: Skeletal
  description: >
    Pectus carinatum, present in both patients of the 2025 report.
  phenotype_term:
    preferred_term: Pectus carinatum
    term:
      id: HP:0000768
      label: Pectus carinatum
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most visible skeletal changes in P1 were scoliosis and pectus carinatum (Figures 3A–D) and in P2 pectus carinatum (Figure 3E)."
    explanation: >
      Names pectus carinatum in both reported patients.
- name: Polyhydramnios
  category: Prenatal
  description: >
    Polyhydramnios as a prenatal complication, present in both patients of the
    2025 report.
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Polyhydramnios as a prenatal complication was present in both patients"
    explanation: >
      Documents polyhydramnios in both patients.
progression:
- phase: Prenatal and neonatal
  age_range: prenatal to 1 month
  notes: >-
    Polyhydramnios and increased nuchal translucency were reported prenatally.
    The neonatal course may be complicated by respiratory insufficiency,
    hypotonia, hepatosplenomegaly and jaundice.
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Polyhydramnios as a prenatal complication was present in both patients"
    explanation: >-
      Documents the prenatal complication.
- phase: Infancy
  age_range: 1-12 months
  notes: >-
    Seizure onset, between 2.5 and 7 months in the largest single series, with
    hypotonia and delayed psychomotor development already evident. Brain MRI
    abnormality is present by this stage.
  evidence:
  - reference: PMID:32588908
    reference_title: "Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus."
    explanation: >-
      Gives the age window of seizure onset.
- phase: Childhood and beyond
  age_range: 1 year onward
  notes: >-
    Profound developmental disability with ongoing seizures. Mortality is
    substantial: the median survival age across the 13 published patients was
    5.5 years, with deaths reported from 10 months to 13 years and causes
    including sepsis and pneumonia.
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median survival age of the patients was 5.5 years."
    explanation: >-
      Gives the cohort median survival age.
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients died prematurely: P1 at the age of 13 years due to asphyxia during sepsis and P2 at 1 year of life due to pneumonia."
    explanation: >-
      Gives the ages and causes of death in the two most recently reported
      patients, which bracket the range.
  - reference: PMID:31148362
    reference_title: "PIGQ glycosylphosphatidylinositol-anchored protein deficiency: Characterizing the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patient died at 10 months of age."
    explanation: >-
      The earliest reported death, at 10 months, which sets the lower end of the
      survival range.
  - reference: PMID:34089469
    reference_title: "PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic variants in the PIGQ gene have been previously reported in 10 patients with congenital hypotonia, early-infantile epileptic encephalopathy, and premature death occurring in more than half cases."
    explanation: >-
      States that premature death occurred in more than half of the patients
      reported up to that point.
genetic:
- name: PIGQ
  gene_term:
    preferred_term: PIGQ
    term:
      id: hgnc:14135
      label: PIGQ
  relationship_type: CAUSATIVE
  notes: >
    PIGQ (OMIM *605754, 16p13.3) encodes a component of the
    GPI-N-acetylglucosaminyltransferase complex, which also contains PIGA, PIGC,
    PIGH, PIGP, PIGY and DPM2 and performs the first committed step of GPI
    anchor biosynthesis. That shared complex membership is why the PIGQ
    phenotype resembles those of PIGA, PIGP and PIGY deficiency more than those
    of the later assembly or remodelling genes. All 13 published patients have
    biallelic variants; the recurrent allele is the in-frame p.(Tyr400del),
    found in six of them and always in trans with a second variant.
  evidence:
  - reference: PMID:24463883
    reference_title: "Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This work reveals two novel genes for OS, KCNT1 and PIGQ."
    explanation: >
      The paper that established PIGQ as a disease gene for this phenotype.
  - reference: PMID:31148362
    reference_title: "PIGQ glycosylphosphatidylinositol-anchored protein deficiency: Characterizing the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PIGQ (OMIM *605754) encodes phosphatidylinositol glycan biosynthesis class Q (PIGQ) and is required for proper functioning of an N-acetylglucosamine transferase complex in a similar manner to the more established PIGA, PIGC, and PIGH."
    explanation: >
      Places PIGQ in the N-acetylglucosamine transferase complex alongside PIGA,
      PIGC and PIGH, which grounds the phenotypic comparison to its complex
      partners.
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequent variant is in-frame pathogenic (PP5+PM4+PM2) deletion c.1199_1201del, p.(Tyr400del), placed in exon 6. This variant was found in six patients, in all cases in compound heterozygosity with other PIGQ variants."
    explanation: >
      Documents the recurrent allele and its consistent compound-heterozygous
      context.
  - reference: PMID:11418246
    reference_title: The human GPI1 gene is required for efficient glycosylphosphatidylinositol biosynthesis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The locus was mapped to chromosome 16p13.3 near the haemoglobin alpha chain locus."
    explanation: >
      Maps the gene, under its former symbol GPI1, to 16p13.3 — the locus this
      entry reports for PIGQ.
animal_models:
- name: Neuron-type-specific Piga conditional knockout mouse
  species: Mouse
  genotype: Piga conditional knockout, restricted to telencephalon excitatory, inhibitory, or thalamic neurons
  description: >
    There is no reported PIGQ mouse. This is a **Piga** model, and it is listed
    here for what it can and cannot do. Piga and Pigq are subunits of the same
    GPI-N-acetylglucosaminyltransferase complex, so a neuronal Piga knockout
    reproduces the shared upstream lesion — loss of GPI anchoring in neurons —
    rather than the PIGQ genotype. Three cell-type-restricted lines were made;
    the excitatory- and inhibitory-neuron lines showed impaired long-term fear
    memory and increased susceptibility to kainic-acid-induced seizures, with
    hippocampal synapse changes in the excitatory line. That is the closest
    experimental demonstration available that reducing neuronal GPI anchoring is
    sufficient to produce seizure susceptibility and cognitive impairment.
  publication: PMID:33607654
  modeled_mechanisms:
  - target: Disrupted Neurodevelopment and Cortical Network Excitability
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Neuronal GPI deficiency produces cognitive impairment, altered hippocampal
      synapses and lowered seizure threshold, which is the mechanism this node
      asserts.
    limitations: >-
      The disrupted gene is Piga, not Pigq: the model shares the complex and the
      pathway step but not the human genotype, and PIGA disease in humans is
      X-linked while PIGQ disease is autosomal recessive. The knockout is
      conditional and cell-type-restricted, so it models neuronal GPI loss
      rather than the constitutive partial deficiency of a patient, and it does
      not reproduce the multisystem congenital anomalies of PIGQ deficiency at
      all. `fidelity: LOW` reflects the gene mismatch, not a defect in the
      experiment.
    evidence:
    - reference: PMID:33607654
      reference_title: "Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Both Ex-M-cko and In-M-cko mice showed impaired long-term fear memory and were more susceptible to kainic acid-induced seizures."
      explanation: >-
        The behavioural and seizure-threshold result. INDIRECT because the gene
        disrupted is Piga, a partner subunit, and not PIGQ.
    - reference: PMID:33607654
      reference_title: "Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Hippocampal synapse changes were observed in Ex-M-cko mice."
      explanation: >-
        The synaptic correlate underlying the network claim in this node.
        INDIRECT for the same reason.
  evidence:
  - reference: PMID:33607654
    reference_title: "Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We generated three mouse models with PIGA deficits specifically in telencephalon excitatory neurons (Ex-M-cko), inhibitory neurons (In-M-cko) or thalamic neurons (Th-H-cko), respectively."
    explanation: >
      Describes the three conditional lines, which is what this model entry
      names.
  - reference: PMID:33607654
    reference_title: "Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Patients carrying a mutation of the PIGA gene usually suffer from inherited glycosylphosphatidylinositol deficiency (IGD) with intractable epilepsy and intellectual developmental disorder."
    explanation: >
      States that the human disease the model is aimed at is inherited GPI
      deficiency with intractable epilepsy and intellectual disability — the
      class DEE77 belongs to. INDIRECT because the gene named is PIGA.
biochemical:
- name: Serum alkaline phosphatase
  notes: >-
    Elevated serum alkaline phosphatase is reported in 62% of the 13 published
    PIGQ patients. This is worth stating carefully, because it cuts against the
    usual pathway-position reasoning for the inherited GPI deficiencies:
    hyperphosphatasia is the biochemical hallmark of the Mabry/HPMRS arm, whose
    lesions sit at the mannosyltransferase and later steps, and cell lines
    blocked before mannose addition degrade alkaline phosphatase rather than
    secreting it. PIGQ acts earlier than any of those. The observation
    nonetheless stands, and it is not unique to PIGQ within the first-step
    complex — elevated alkaline phosphatase has also been documented in PIGA
    patients. Two caveats: the enzyme was not measured in every published
    patient, so the 62% denominator is soft, and a normal alkaline phosphatase
    does not exclude the diagnosis, since hyperphosphatasia is a variable
    feature across GPI biosynthesis defects generally.
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alkaline phosphatase (ALP) is elevated only in 62% of cases."
    explanation: >-
      The PIGQ-specific frequency of the finding.
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alkaline phosphatase (ALP) was measured only in P1 with an elevated level of 632 U/l (N: 82–383)."
    explanation: >-
      A measured value with its reference interval, and the record that it was
      measured in only one of that report's two patients.
  - reference: PMID:22228761
    reference_title: "Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Hyperphosphatasia resulted \nfrom secretion of ALP, a GPI-anchored protein normally expressed on the cell \nsurface, into serum due to PIGV deficiency."
    explanation: >-
      Establishes the accepted mechanism of hyperphosphatasia in GPI deficiency
      — transamidase-mediated release of soluble alkaline phosphatase. INDIRECT
      because the experiment is in PIGV, not PIGQ.
  - reference: PMID:22228761
    reference_title: "Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "In contrast, ALP \nwas degraded in PIGL-, DPM2-, or PIGX-deficient CHO cells, in which incomplete \nshorter GPIs that lacked mannose were accumulated."
    explanation: >-
      The counterpart result: cell lines blocked before mannose addition degrade
      alkaline phosphatase instead. This is the basis for saying the PIGQ
      observation is mechanistically unexpected. INDIRECT because the blocked
      genes are PIGL, DPM2 and PIGX rather than PIGQ.
  - reference: PMID:29310717
    reference_title: "Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Elevation of AP has also been documented in some of the individuals with MCAHS, \nnamely those with PIGA mutations."
    explanation: >-
      Elevated alkaline phosphatase in patients with PIGA variants — another
      subunit of the same first-step complex — showing the PIGQ observation is
      not an isolated anomaly. INDIRECT because the patients are PIGA, not PIGQ.
  - reference: PMID:29310717
    reference_title: "Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "hyperphosphatasia is a \nvariable feature that is not ideal for a clinical classification"
    explanation: >-
      Why a normal alkaline phosphatase does not exclude the diagnosis.
      INDIRECT because it is a statement about GPI biosynthesis defects as a
      group.
  - reference: PMID:25803904
    reference_title: "[Inherited GPI deficiencies:a new disease with intellectual disability and epilepsy]."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Hyperphosphatasia is observed in some patients with IGDs, such as hyperphosphatasia mental retardation syndrome or Mabry syndrome, caused by mutations in genes in the later stage of GPI biosynthesis."
    explanation: >-
      The received pathway-position account that the PIGQ data sit awkwardly
      with. INDIRECT because it is a group-level statement naming other genes.
- name: Serum creatine kinase
  notes: >-
    Normal between episodes, and above 5000 U/l during rhabdomyolysis triggered
    by febrile infection, in the single patient in whom this was documented.
    Not a screening test for PIGQ deficiency; recorded because the episodes are
    life-threatening and the reporting authors recommend anticipating them.
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HyperCKemia was found only in P1, with creatine kinase (CK) levels higher than 5000 U/l (N: <170) during episodes of rhabdomyolysis."
    explanation: >-
      The measured values, reference interval and their episodic restriction.
diagnosis:
- name: Whole exome sequencing
  description: >
    Molecular diagnosis. Every published patient was ascertained by exome or
    genome sequencing; the phenotype is not distinctive enough among the
    inherited GPI deficiencies to point at PIGQ clinically. The index case was
    found by whole-genome sequencing after conventional candidate-gene testing
    failed.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:32588908
    reference_title: "Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed."
    explanation: >
      This series established the genotype that sequencing is looking for.
  - reference: PMID:24463883
    reference_title: "Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This work reveals two novel genes for OS, KCNT1 and PIGQ."
    explanation: >
      The index case was identified by unbiased genome sequencing, which is why
      an untargeted approach rather than an epilepsy panel is the diagnostic
      route.
- name: Flow cytometry for GPI-anchored protein surface expression
  description: >
    Measurement of GPI-anchored protein levels on patient granulocytes,
    leukocytes or fibroblasts by flow cytometry. CD16, CD14, FLAER, CD59, DAF,
    uPAR, CD90 and CD109 have all been used. This is the standard functional
    assay for inherited GPI deficiency as a group rather than a PIGQ-specific
    test: it establishes that the GPI pathway is impaired, and sequencing
    establishes which gene. Its practical value is in resolving variants of
    uncertain significance — the 2025 report reclassified a PIGQ missense VUS to
    likely pathogenic on the strength of a flow-cytometry rescue experiment.
  diagnosis_term:
    preferred_term: flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  evidence:
  - reference: PMID:32588908
    reference_title: "Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype."
    explanation: >
      Establishes the assay and its rescue-based interpretation in PIGQ
      patients.
  - reference: PMID:34089469
    reference_title: "PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Flow cytometry confirmed deficiency of several GPI-anchored proteins on leukocytes (CD14, FLAER)."
    explanation: >
      Independent diagnostic use of the same assay on leukocytes, with different
      markers.
  - reference: PMID:25803904
    reference_title: "[Inherited GPI deficiencies:a new disease with intellectual disability and epilepsy]."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Flow cytometric analysis of GPI-APs on granulocytes is also useful for the detection of IGD."
    explanation: >
      States the assay's role as a detection method for inherited GPI deficiency
      as a group. INDIRECT because it is a group-level recommendation, not a
      PIGQ-specific one.
- name: Serum alkaline phosphatase (supportive, not discriminating)
  description: >
    Elevated in 62% of published PIGQ patients, so a raised value supports the
    diagnosis. It does not discriminate within the inherited GPI deficiencies —
    hyperphosphatasia is a variable feature across the group and was explicitly
    judged unsuitable for classifying them — and a normal value does not exclude
    PIGQ deficiency. It is listed here because the combination of the core
    clinical features with a raised alkaline phosphatase is what should prompt
    testing for a GPI biosynthesis defect.
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alkaline phosphatase (ALP) is elevated only in 62% of cases."
    explanation: >
      The frequency that makes a raised value supportive rather than expected.
  - reference: PMID:29310717
    reference_title: "Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "hyperphosphatasia is a \nvariable feature that is not ideal for a clinical classification"
    explanation: >
      Why it cannot be used to discriminate within the group. INDIRECT because
      the statement is about GPI biosynthesis defects generally.
treatments:
- name: Antiseizure Medication
  description: >
    Seizure control is the mainstay of management. Response is variable — the
    largest series describes a range from treatable seizures to recurrent status
    epilepticus — and in the more severely affected patients lifelong
    combination therapy achieves only partial control. No specific
    anticonvulsant has been shown to work better than others in PIGQ deficiency,
    and no such claim is made here. It is symptomatic: it does not address the
    GPI-anchor lesion.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticonvulsant agent
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  target_mechanisms:
  - target: Drug-Resistant Early-Onset Epilepsy
    treatment_effect: MODULATES
    description: >-
      Symptomatic seizure suppression, often incomplete. It does not alter the
      developmental trajectory.
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epilepsy in P1 started at age 3 months (infantile onset) and presented as infantile spasms with lifelong combined antiseizure medication needed to partially control the seizures."
    explanation: >
      Documents lifelong combination antiseizure medication achieving only
      partial control, which is both the treatment and the evidence for calling
      the epilepsy drug-resistant.
  - reference: PMID:32588908
    reference_title: "Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus."
    explanation: >
      Establishes that seizure response spans treatable disease to recurrent
      status epilepticus, which is why no uniform claim about efficacy is made.
- name: Pyridoxine or Pyridoxal 5-Phosphate
  description: >
    High-dose vitamin B6 (pyridoxine 20-30 mg/kg/day, switched to pyridoxal
    5-phosphate if unresponsive) is the one intervention that has been
    prospectively tested in inherited GPI deficiency epilepsy. The result was
    modest and is reported honestly here: in a seven-participant cohort, two had
    a more than 50% reduction in seizure frequency and three a smaller
    reduction, none became seizure-free, and EEG did not improve in six of
    seven. The participants had PIGA, PIGT or PIGV deficiency, not PIGQ
    deficiency — PIGA is a partner subunit in the same first-step complex as
    PIGQ, which is the closest the evidence comes, and it is still an
    extrapolation. No PIGQ patient has been reported on this regimen.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pyridoxine
      term:
        id: CHEBI:16709
        label: pyridoxine
    - preferred_term: pyridoxal 5'-phosphate
      term:
        id: CHEBI:18405
        label: pyridoxal 5'-phosphate
  target_mechanisms:
  - target: Drug-Resistant Early-Onset Epilepsy
    treatment_effect: MODULATES
    description: >-
      Partial reduction in seizure frequency in some patients with inherited GPI
      deficiency. It does not address the GPI-anchor lesion and did not produce
      seizure freedom in anyone studied.
  evidence:
  - reference: PMID:35080266
    reference_title: "Pyridoxine or pyridoxal-5-phosphate treatment for seizures in glycosylphosphatidylinositol deficiency: A cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "AIM: To investigate the short-term efficacy and safety of high-dose pyridoxine \nand pyridoxal 5-phosphate (P5P) in the treatment of inherited \nglycosylphosphatidylinositol (GPI) deficiency-associated epilepsy."
    explanation: >
      Establishes that this regimen was tested prospectively in inherited GPI
      deficiency epilepsy. INDIRECT because the cohort is the GPI-deficiency
      group and contains no PIGQ patient.
  - reference: PMID:35080266
    reference_title: "Pyridoxine or pyridoxal-5-phosphate treatment for seizures in glycosylphosphatidylinositol deficiency: A cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "We observed more than 50% seizure \nfrequency reduction in 2 out of 7 and less than 50% reduction in another 3 out \nof 7 participants. No participants reached seizure freedom."
    explanation: >
      The actual outcome, including that no participant reached seizure freedom
      — which is why this entry describes the benefit as partial rather than as
      a treatment. INDIRECT for the same reason.
  - reference: PMID:35080266
    reference_title: "Pyridoxine or pyridoxal-5-phosphate treatment for seizures in glycosylphosphatidylinositol deficiency: A cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "The genetic causes of \ninherited GPI deficiency were phosphatidylinositol \nN-acetylglucosaminyltransferase subunit A/T/V deficiency."
    explanation: >
      Names the genes the participants carried, which is the fact that makes
      every claim from this study an extrapolation to PIGQ. INDIRECT for that
      reason.
- name: Ketogenic Diet
  description: >
    The ketogenic diet is the empiric dietary intervention most often used in
    GPI anchor defects. The evidence is at the level of that subgroup of
    congenital disorders of glycosylation, not of PIGQ: no study has tested it
    in PIGQ deficiency, and this entry does not imply one has.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: PMID:35562242
    reference_title: "Nutrition interventions in congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Ketogenic diet is most frequently used in GPI anchor defects"
    explanation: >
      States that the ketogenic diet is the intervention most often used in the
      GPI anchor defects, the subgroup PIGQ deficiency belongs to. INDIRECT
      because the claim reaches PIGQ only through subgroup membership.
- name: Surgical Correction of Midgut Volvulus
  description: >
    Emergency surgical correction of midgut volvulus, performed in two of the
    seven children in the largest single series. This is management of a
    life-threatening complication rather than treatment of the disorder, and it
    is the reason gastrointestinal symptoms in a patient with this diagnosis
    warrant a low threshold for imaging.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Volvulus
    treatment_effect: MODULATES
    description: >-
      Relieves the volvulus. It does not address the underlying developmental
      anomaly or the GPI-anchor lesion.
  evidence:
  - reference: PMID:32588908
    reference_title: "Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction."
    explanation: >
      Documents the surgical correction in two affected individuals.
- name: Enteral Feeding Support
  description: >
    Tube feeding for the feeding difficulties that follow the neurological
    impairment. For a disorder in which no reported patient achieves independent
    development and antiseizure medication is only partly effective, supportive
    care of this kind is most of what management consists of.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Feeding Difficulties
    treatment_effect: MODULATES
    description: >-
      Supportive management of feeding failure. It does not address the
      underlying lesion.
  evidence:
  - reference: PMID:40718141
    reference_title: "Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P2 had to be fed via a nasogastric tube because of feeding difficulties."
    explanation: >
      Documents nasogastric tube feeding in a reported patient.

📚

References & Deep Research

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 (2)

Record notes

**Counts, not frequencies.** Only 13 genetically confirmed PIGQ-deficient patients had been published as of the 2025 review that assembled them, so every proportion in this entry is a fraction of a cohort of that size. Where a percentage is quoted it is quoted as the source states it, and no `frequency:` band has been derived from it. **Hyperphosphatasia: the point on which this entry departs from the pathway-position argument.** The received account, stated in the literature on inherited GPI deficiency and reproduced in this knowledge base's PIGP entry, is that hyperphosphatasia arises from defects in the *later* steps of GPI biosynthesis (Mabry syndrome / HPMRS being the type case), because GPI transamidase recognises an incomplete GPI that already bears mannose, cleaves the signal peptide, and releases soluble alkaline phosphatase into serum. In cell lines blocked *before* the first mannose is added — PIGL, DPM2, PIGX — alkaline phosphatase is degraded instead, so no hyperphosphatasia is predicted. PIGQ acts earlier still, at the very first GlcNAc transfer, so the pathway argument predicts a normal serum alkaline phosphatase. The reported data do not follow that prediction. The 2025 review of all 13 published PIGQ patients states that alkaline phosphatase is elevated in 62% of cases, and its own new patient in whom the enzyme was measured had a level of 632 U/l against a reference interval of 82-383. This is not an isolated anomaly: a 91-individual GPI-biosynthesis-defect series had already found elevated alkaline phosphatase in individuals with PIGA mutations — PIGA being the catalytic subunit of the same first-step GlcNAc transferase complex that PIGQ belongs to — and concluded that hyperphosphatasia is a variable feature that is not suitable for classifying these disorders. This entry therefore curates the observation and not the inference: elevated alkaline phosphatase is recorded as a documented biochemical and phenotypic feature of PIGQ deficiency, the mechanistic conflict is recorded as a knowledge gap, and no claim is made here that PIGQ deficiency spares alkaline phosphatase. Two honest caveats attach to the 62% figure. It is a proportion of a cohort of 13 assembled retrospectively from published reports, in which the enzyme was not measured in every patient — the review itself notes that among its own two new cases the measurement was made in only one — so the denominator is soft. And the review lists elevated alkaline phosphatase among the "less common" features, which is how it reads a 62% figure with missing data rather than a contradiction of the number. **What is deliberately not asserted.** The chain from reduced GPI-anchored protein surface density to a seizing, developmentally impaired cortex is a class-level argument. No study identifies which of the >150 GPI-anchored proteins mediates the neurological phenotype in PIGQ deficiency, so the edge into the neurodevelopmental node carries unknown intermediates and no individual client protein is named as the culprit. CD14, CD16, CD59, DAF, uPAR, CD90, CD109 and FLAER appear in this entry as measured readouts, not as pathogenic effectors. Likewise, the 2025 review states plainly that genotype-phenotype correlation cannot yet be established at this sample size, so none is asserted. Three further features reported by the pooled inherited-GPI-deficiency cohort (PMID:38456468) were considered and excluded on the same principle: corpus callosum anomalies (57%), symmetric restricted diffusion of the central tegmental tracts (60%), and renal anomalies (14%). These are frequencies across the whole IGD cohort, not PIGQ frequencies, and no PIGQ-specific source documents any of them. The callosal statements in this entry's other cached references all belong to other genes. PMID:29310717 is a six-column HPMRS comparison table and carries three separate ones: "thin corpus callosum" beside "Hearing impairment (5/16)" in the HPMRS2 (PIGO) column, where the /16 denominator matches that column's n; the same phrase inside the "Further anomalies (rare)" list in the HPMRS1 (PIGV) column; and "Thin corpus callosum (9/26)" in the HPMRS4 (PGAP3) column. PMID:35562242 attributes its callosal sentence to GFUS-CDG, the GDP-L-fucose synthase disorder. SLC35C1-CDG, the GDP-fucose transporter disorder it was mistaken for, is discussed earlier in that review and is named again in the paragraph immediately before the GFUS one only as a comparator for a third fucosylation disorder. None of PIGV, PIGO, PGAP3 or GFUS is PIGQ. Pooled data supports a PIGQ-documented feature as INDIRECT evidence in this entry; it does not originate a phenotype here, so none of the three is curated. **No `conforms_to` was declared.** There is no GPI-anchor-biosynthesis module in `kb/modules/`, and the existing `congenital_disorder_of_glycosylation` module is scoped to the N-glycosylation machinery (LLO assembly, Golgi N-glycan processing, protein hypoglycosylation), which is a different lesion. None of the sibling inherited-GPI-deficiency entries (DEE38/ARV1, DEE55/PIGP, Mabry syndrome, CHIME syndrome, MCAHS) declares a conformance either. The gap is recorded as a discussion rather than papered over with a mismatched target. **Deep-research provenance.** Falcon (Edison) was requested and returned HTTP 402 (account out of credits), so the run fell back to OpenScientist and the committed report is named for the provider that actually produced it (`research/Developmental_And_Epileptic_Encephalopathy_77-deep-research-openscientist.md`; `fell_back: true`, `requested_provider: falcon` in its frontmatter). Its reference validation resolved 12 of 12 citations with a confabulation rate of 0.0 and no unresolved references; of the 12 assessed for relevance, 7 scored on topic and the rest were left unscored rather than judged off topic. Its term validation carries `needs_review: true` for one obsolete CURIE (GO:0031225, "anchored component of membrane") and four label mismatches, three of which are the report labelling an identifier with its ontology's name ("MONDO", "DOID") rather than the term's. Nothing from that list is bound here; GO:0031225 in particular is not used. `just preflight-dr` returns WARN because "GPI" is counted as a rival gene mentioned 82 times. That is a false positive of the same kind recorded on the PIGP entry: "GPI" here is glycosylphosphatidylinositol, the anchor, not GPI the glucose-6-phosphate isomerase gene. The report's disease identity checks out — MONDO's OMIM xref for MONDO:0032808 is 618548, which is the MCAHS4 number the primary literature uses for PIGQ. The report contributed four sources that first-pass curation from the primary PIGQ papers had missed: the original GPI1/PIGQ characterisation with its antisense knockdown (PMID:11418246), the neuronal Piga conditional-knockout mouse (PMID:33607654), the prospective vitamin B6 cohort in GPI deficiency (PMID:35080266) and the PIGM/butyrate proof of concept (PMID:17442906). Two of its citations were deliberately not used. PMID:19732866 is about FOLR1 mutations causing cerebral folate transport deficiency; the report itself labels the folinic-acid inference for PIGQ "mechanistic conjecture", and nothing cited here connects GPI deficiency to cerebral folate deficiency, so the claim was dropped rather than curated as a treatment. PMID:40126049, a 266-patient cannabidiol study in monogenic epilepsies, mentions no PIG gene and no GPI anchor, so it cannot support anything specific to this disorder. The two 2025 case reports and the Starr phenotype paper (PMID:40718141, PMID:31148362) were found outside the report, by PubMed search. Every quote used in this entry was extracted programmatically from the fetched reference cache rather than copied from the report or retyped; several of the sources carry non-breaking spaces, en dashes and hard line wraps that hand-copying would have corrupted. **No `datasets:` block.** Searching a causal gene for expression datasets is the documented route into Named Entity Confusion, and for a disorder with 13 published patients there is no disease-specific dataset to find. None was added rather than attaching a PIGQ-keyed accession about an unrelated disease.

Create: Developmental_And_Epileptic_Encephalopathy_77 · 2026-09-07T22:12:02Z · View source

New entry for DEE77 / PIGQ-CDG / MCAHS4 (MONDO:0032808, hgnc:14135 PIGQ), curated from the primary PIGQ literature plus a deep-research report. Deep research: falcon (Edison) was requested and returned HTTP 402 (out of credits); the run was launched with --fallback and openscientist produced the committed report (research/Developmental_And_Epileptic_Encephalopathy_77-deep-research-openscientist.md, fell_back: true, requested_provider: falcon, 1020 s). Its reference validation resolved 12/12 citations, confabulation rate 0.0, no unresolved references, 7/12 scored on topic. Its term validation carries needs_review: true for one obsolete CURIE (GO:0031225) and four label mismatches; none of those terms is bound in the entry. just preflight-dr returns WARN because 'GPI' is counted as a rival gene 82 times - a false positive, since GPI here is glycosylphosphatidylinositol rather than the glucose-6-phosphate isomerase gene; MONDO's OMIM xref (618548) matches the MCAHS4 number used in the primary literature. The report contributed PMID:11418246 (original GPI1/PIGQ characterisation with antisense knockdown), PMID:33607654 (neuronal Piga conditional-knockout mouse), PMID:35080266 (prospective vitamin B6 cohort in GPI deficiency) and PMID:17442906 (PIGM/butyrate proof of concept). Two of its citations were deliberately not used: PMID:19732866 (FOLR1 cerebral folate transport deficiency - the report itself calls the folinic-acid inference for PIGQ mechanistic conjecture) and PMID:40126049 (cannabidiol in monogenic epilepsies - names no PIG gene or GPI anchor). PMID:40718141 and PMID:31148362 were found outside the report by PubMed search. Hyperphosphatasia: the entry curates the observation, not the pathway inference. PMID:40718141 reports elevated serum alkaline phosphatase in 62% of the 13 published PIGQ patients, and PMID:29310717 documents elevation in PIGA patients (a partner subunit of the same first-step complex). That conflicts with PMID:22228761, which shows alkaline phosphatase is degraded rather than secreted in cell lines blocked before mannose addition, so a first-step block predicts a normal value. The conflict is recorded as a KNOWLEDGE_GAP discussion and in the entry notes rather than resolved; the caveat that the enzyme was not measured in every patient is recorded too. This deliberately does not follow the treatment given on the sibling PIGP entry, which states hyperphosphatasia arises only from late-stage defects. Named Entity Confusion controls: every sibling-gene or pathway-level result (PIGA, PIGM, PIGL/DPM2/PIGX, PIGV, and the 83-patient inherited-GPI-deficiency cohort) is graded SUPPORT with directness: INDIRECT and its explanation names the gene the result is actually about. The Piga conditional-knockout mouse is recorded in animal_models with fidelity: LOW and limitations naming the gene mismatch, because no PIGQ mouse exists. No conforms_to: there is no GPI-anchor-biosynthesis module, and the congenital_disorder_of_glycosylation module is scoped to N-glycosylation. Recorded as a discussion. No datasets block, to avoid a gene-keyed accession about an unrelated disease. Grouping: Developmental And Epileptic Encephalopathy 77 was added as a member_type: DISEASE member of kb/groupings/Disorders_of_GPI_Anchor_Biosynthesis.yaml; just check-groupings reports SATISFIED against the NECESSARY GO:0006506 criterion. Validation: just validate, just validate-terms, just validate-disorders (101/101 snippets verified), just check-duplicate-keys, just check-entity-refs, just check-causal-targets, just check-qualifier-terms, just check-enum-values, just check-folded-hyphens, just check-snippet-length, just check-title-snippets, just check-snippet-grading, just check-reference-titles, just check-environmental-evidence, just normalize-cache and just check-term-cache-integrity all pass. All snippets were extracted programmatically from references_cache rather than retyped; several sources carry non-breaking spaces, en dashes and hard line wraps.

OpenScientist ▸

1. Disease Information

openscientist-autonomous 12 citations 2026-09-07T21:59:40.840289

1. Disease Information

Overview. DEE77 is a monogenic, autosomal-recessive developmental and epileptic encephalopathy belonging to the family of inherited glycosylphosphatidylinositol (GPI) deficiencies (IGDs) — congenital disorders of glycosylation affecting the biosynthesis or remodeling of the GPI anchor. It is characterized by early-infantile-onset epilepsy that is frequently drug-resistant, together with severe global developmental impairment and congenital multisystem anomalies.

Key identifiers (cross-references verified via OLS for MONDO:0032808):

Resource	Identifier
MONDO	MONDO:0032808
OMIM (phenotype)	#618548
OMIM (gene PIGQ)	605754
DOID	DOID:0112213
GARD	0016363
MedGen	C5231405 / CN1684735
UMLS	C5231405
HGNC (gene)	HGNC:14135

Synonyms / alternative names: Developmental and epileptic encephalopathy 77; DEE77; Early infantile epileptic encephalopathy 77; EIEE77; PIGQ-related GPI deficiency; Multiple congenital anomalies–hypotonia–seizures syndrome 4 (MCAHS4).

Information source type. Knowledge is derived almost entirely from aggregated disease-level resources (OMIM, MONDO, ClinVar) and from small published case series / individual case reports (Martin 2014; Johnstone 2020; Zanni 2022), not from large EHR-based cohorts. The largest quantitative context comes from a pooled IGD cohort (Sidpra et al. 2024; n=83) that includes PIGQ among other GPI-pathway genes (PMID: 38456468).

2. Etiology

Primary cause — genetic. DEE77 is caused by biallelic (autosomal recessive) pathogenic variants in PIGQ. There is no environmental, infectious, or acquired etiology; the disorder is fully Mendelian. The first causal link was reported by Martin et al. 2014, who identified a recessive PIGQ mutation causing exon skipping and defective GPI biosynthesis in an Ohtahara-syndrome patient among six whole-genome-sequenced severe early-onset epilepsy trios:

"The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis." — PMID: 24463883

Johnstone et al. 2020 then confirmed and expanded the etiology with seven new biallelic-PIGQ subjects from six families:

"We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene." — PMID: 32588908

Genetic risk factors. The causal factor is the biallelic PIGQ genotype itself. Consanguinity is an important risk factor (homozygous variants recur in consanguineous families, e.g., the homozygous c.1631dupA reported by Zanni et al. 2022). Compound heterozygosity accounts for cases in non-consanguineous families. No modifier genes have been formally established for DEE77, although residual enzymatic activity of hypomorphic alleles is the principal determinant of severity (see §4, §9).

Environmental risk / protective factors and gene–environment interactions. None are established. As a purely Mendelian recessive disorder, environmental exposures do not cause DEE77. The only clinically actionable "environmental" modifier is nutritional/pharmacological — vitamin B6 (pyridoxine) partially mitigates seizures in a subset of IGD patients (see §12), representing a gene–treatment rather than a gene–environment interaction. No protective alleles are known.

3. Phenotypes

The DEE77 phenotype is dominated by a neurodevelopmental triad (epilepsy + hypotonia + developmental delay) with frequent multisystem congenital anomalies. Frequencies below combine the PIGQ-specific series (Johnstone 2020, n=7; Zanni 2022) with the pooled IGD cohort (Sidpra 2024, n=83) where PIGQ-specific numbers are unavailable.

Phenotype	Type	Onset / severity	Frequency	Suggested HPO
Epileptic seizures (incl. status epilepticus, EIMFS, myoclonic)	Clinical sign	Onset 2.5–7 mo; severe, often drug-resistant	83% (IGD pooled); consistent in PIGQ	HP:0001250 (Seizure), HP:0002133 (Status epilepticus)
Axial / generalized hypotonia	Clinical sign	Congenital/early; moderate–severe	72% (IGD pooled)	HP:0008936 (Axial hypotonia), HP:0001252 (Hypotonia)
Global developmental delay / intellectual disability	Behavioral/cognitive	Early; severe	90% (IGD pooled)	HP:0001263 (GDD), HP:0001249 (ID)
Cerebral atrophy	Imaging/structural	Progressive	75% (IGD pooled)	HP:0002059 (Cerebral atrophy)
Cerebellar atrophy	Imaging/structural	Progressive	60% (IGD pooled)	HP:0001272 (Cerebellar atrophy)
Corpus callosum anomalies	Imaging/structural	Congenital	57% (IGD pooled)	HP:0007370 (Aplasia/hypoplasia of the corpus callosum)
Gastrointestinal anomalies (incl. midgut volvulus)	Physical	Congenital; can be life-threatening	66% (IGD pooled); 2/7 volvulus (Johnstone)	HP:0011024 (Abnormality of the GI tract), HP:0002580 (Volvulus)
Cardiac anomalies / arrhythmia	Physical	Congenital	19% (IGD pooled)	HP:0001627 (Abnormal heart morphology), HP:0011675 (Arrhythmia)
Renal malformation	Physical	Congenital	14% (IGD pooled)	HP:0000077 (Abnormality of the kidney)
Dysmorphic features	Physical	Congenital; no distinctive gestalt	82% (any); none >30%	HP:0001999 (Abnormal facial shape)
Motor symptoms (ataxia/dyskinesia)	Clinical sign	Variable	64% (IGD pooled)	HP:0001251 (Ataxia), HP:0100022 (Abnormal movement)

Key supporting quotes:

"Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus." — PMID: 32588908

"Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%)." — PMID: 38456468

Progression and severity. The severe end shows progressive neurodegeneration (progressive atrophy, hypomyelination) and high early mortality; a milder, nonprogressive end (congenital ataxia with ID and generalized epilepsy, cerebellar atrophy) is documented (PMID: 34089469). Severity correlates with residual PIGQ/GPI-biosynthetic activity.

Quality-of-life impact. Not formally measured with EQ-5D/SF-36/PROMIS in this ultra-rare disorder. Qualitatively, the impact is profound: affected children have severe cognitive/motor disability, drug-resistant seizures, feeding difficulties, and dependence on full-time caregiving; many do not survive early childhood.

4. Genetic / Molecular Information

Causal gene — PIGQ.

Attribute	Value
Gene symbol	PIGQ (formerly GPI1)
HGNC	HGNC:14135
NCBI Gene ID	9091
OMIM gene	605754
Ensembl	ENSG00000007541
UniProt	Q9BRB3
Cytoband	16p13.3
GRCh38 locus	chr16:566,995–584,121 (+ strand)
Canonical transcript / RefSeq	ENST00000321878 / NM_004204.5

Pathogenic variant spectrum (ClinVar, 300 records queried).

Classification	Count
Pathogenic	24
Likely pathogenic	4
VUS	105
Likely benign	145
Benign	1
Conflicting	6

By molecular type across the record set: 268 SNVs, 17 deletions, 7 duplications, 2 microsatellite, plus rare CNV gains/losses and 1 inversion. DEE77 variants are predominantly small-scale (missense, nonsense, frameshift, splice-site), with occasional copy-number/structural events. Representative variants: the exon-skipping splice variant of Martin 2014 (PMID: 24463883) and the homozygous frameshift NM_004204.5:c.1631dupA (p.Tyr544fs*79) of Zanni 2022 (PMID: 34089469).

Population constraint (gnomAD, computed). PIGQ is heterozygous LoF-tolerant, consistent with a recessive mechanism: gnomAD v2 pLI ≈ 0 (5.7e-17), LOEUF (oe_lof upper) = 1.12, observed/expected LoF = 0.90 (54 obs vs 60.3 exp), missense Z = −0.08. Heterozygous carriers are unaffected — concordant with the historical observation that heterozygous 16p13.3 deletions removing one GPI1 allele (in α-thalassemia/mental retardation) do not overtly impair GPI-anchored protein expression (PMID: 11418246).

Functional consequence. Loss of function / hypomorphic. Complete null is presumed embryonic-lethal; viable patients retain residual GPI-biosynthetic activity. Functional proof of causality: transfection of wild-type PIGQ cDNA into patient fibroblasts rescued the GPI-anchored-protein deficiency (see §6).

Modifier genes / epigenetics / large chromosomal abnormalities. No DEE77-specific modifier genes or epigenetic mechanisms are established. Whole-gene deletions or 16p13.3 CNVs are rare contributors; most disease arises from small biallelic variants.

5. Environmental Information

Not applicable. DEE77 is a monogenic recessive disorder with no environmental, lifestyle, toxic, radiation, occupational, or infectious cause or trigger. No dietary, behavioral, or exposure-based risk or protective factors have been identified. The only exogenous factor with clinical relevance is therapeutic vitamin B6 (pyridoxine/pyridoxal-5′-phosphate), which partially reduces seizures in some IGD patients (see §12) — a treatment effect, not a disease cause.

6. Mechanism / Pathophysiology

Ordered causal chain

Biallelic hypomorphic/LoF PIGQ variants reduce functional PIGQ protein → leads to
Impaired GPI-N-acetylglucosaminyltransferase (GPI-GnT) complex on the cytoplasmic face of the ER, of which PIGQ is a subunit → results in
Failure of the first committed step of GPI biosynthesis (transfer of GlcNAc onto phosphatidylinositol) → leads to
Global reduction in GPI anchor synthesis → results in
Reduced cell-surface expression of >150 GPI-anchored proteins (enzymes, adhesion molecules, receptors, complement regulators) — directly demonstrated in patient granulocytes and fibroblasts → leads to (branch point)
5a. Neuronal branch: loss of GPI-anchored proteins critical to neuronal development, synapse formation, and cortical excitability → results in → epileptogenesis, hypotonia, developmental delay, progressive cerebral/cerebellar atrophy (inferred from human phenotype + mouse GPI-deficiency models).
5b. Systemic/developmental branch: loss of GPI-anchored proteins in non-neural tissues during organogenesis → results in → gastrointestinal (volvulus), cardiac, renal congenital anomalies.
Combined CNS and multisystem dysfunction → results in → early-infantile DEE77 with high mortality.

Molecular and cellular detail

PIGQ's molecular role is defined precisely:

"PIGQ encodes the phosphatidylinositol glycan class Q protein and is part of the GPI-N-acetylglucosaminyltransferase complex that initiates GPI biosynthesis from phosphatidylinositol (PI) and N-acetylglucosamine (GlcNAc) on the cytoplasmic side of the endoplasmic reticulum (ER)." — PMID: 34089469

The GPI-GnT ring complex also includes ARV1, which recruits phosphatidylinositol and associates directly with PIGQ:

"ARV1 associates with PIGQ, a GPI-GnT component" — PMID: 40378954

Direct functional proof in human cells (loss of GPI-anchored proteins is the proximate mechanism, and it is PIGQ-specific):

"Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype." — PMID: 32588908

Upstream vs downstream. The PIGQ mutation and GPI-GnT dysfunction are upstream; loss of specific GPI-anchored proteins (e.g., complement regulators, folate receptor-α, alkaline phosphatase-related processing, neural adhesion molecules) and the resulting neuronal/organ dysfunction are downstream.

Cellular processes and compartments. The initiating lesion is in the endoplasmic reticulum (GO:0005789, ER membrane; cytoplasmic face). Affected biological processes: GPI anchor biosynthetic process (GO:0006506), GPI anchor metabolic process (GO:0006505), protein lipidation / attachment of GPI anchor to protein (GO:0016255). Downstream neural processes include regulation of neuron differentiation and regulation of synaptic transmission / neuronal excitability.

Biochemical hallmark shared across IGD. Some IGD subtypes show hyperphosphatasia (elevated serum alkaline phosphatase, itself a GPI-anchored enzyme aberrantly shed when anchoring fails); this is variable in PIGQ disease. Folate receptor-α (FOLR1) is a GPI-anchored protein, providing a mechanistic rationale for cerebral folate involvement and folinic-acid relevance (PMID: 19732866).

Cell types (CL suggestions): neuron (CL:0000540), GABAergic/inhibitory neuron (CL:0000617), glutamatergic/excitatory neuron (CL:0000679), granulocyte/neutrophil (CL:0000775 — diagnostic readout), fibroblast (CL:0000057 — diagnostic readout).

7. Anatomical Structures Affected

Organ level — primary. The brain / central nervous system (UBERON:0000955, brain; UBERON:0001017, CNS) is the primary affected organ. Within the brain, the cerebral cortex (UBERON:0000956), cerebellum (UBERON:0002037), corpus callosum (UBERON:0002336), and white-matter tracts (hypomyelination; symmetric restricted diffusion of the central tegmental tracts, 60% in IGD pooled) are involved.

Secondary / multisystem involvement: - Gastrointestinal tract (UBERON:0001555) — anomalies in 66%, including life-threatening midgut volvulus. - Heart (UBERON:0000948) — structural anomalies and arrhythmias in ~19%. - Kidney (UBERON:0002113) — malformation in ~14%.

Body systems: nervous (primary), digestive, cardiovascular, and renal/urinary (secondary).

Tissue and cell level. Primarily nervous tissue (excitatory and inhibitory cortical neurons, cerebellar neurons). Because GPI anchoring is ubiquitous, epithelial and other tissues are affected during organogenesis. Diagnostic readouts use hematopoietic cells (granulocytes/leukocytes) and fibroblasts.

Subcellular level. The initiating defect is at the endoplasmic reticulum membrane, cytoplasmic face (GO:0005789). The functional deficit manifests at the plasma membrane (GO:0005886) as loss of GPI-anchored surface proteins, i.e., in the anchored component of the plasma membrane (GO:0031225).

Localization / lateralization. CNS involvement is bilateral and largely symmetric (symmetric atrophy, symmetric restricted diffusion of central tegmental tracts).

8. Temporal Development

Onset. Early-infantile / congenital. Congenital hypotonia and multiple congenital anomalies are present at/near birth; seizure onset occurs between 2.5 and 7 months (PMID: 32588908). Median age at seizure onset across the IGD family is ~6 months (PMID: 38456468). Onset pattern is chronic with early emergence, punctuated by acute events (status epilepticus, volvulus).

Progression. At the severe end the course is progressive: recurrent/refractory seizures, progressive cerebral and cerebellar atrophy, and hypomyelination, with declining function. At the mild end (Zanni 2022) the course is nonprogressive congenital ataxia. Disease is lifelong (chronic) when survived.

Patterns. Seizures range from treatable to recurrent status epilepticus; no reliable spontaneous remission is documented. Critical period: the fetal/early-infantile window of neurodevelopment is the period of vulnerability; because the disease "progresses even after birth," early diagnosis and initiation of supportive/pyridoxine therapy is advocated as a potential window of opportunity (PMID: 26165085).

9. Inheritance and Population

Epidemiology. DEE77 is ultra-rare: only ~15–20 patients reported worldwide since 2014 (Martin 2014 first case; Johnstone 2020 +7; Zanni 2022 +1; scattered others). The case count is too small for formal prevalence/incidence estimates, and no Orphanet point-prevalence figure is available.

"Pathogenic variants in the PIGQ gene have been previously reported in 10 patients with congenital hypotonia, early-infantile epileptic encephalopathy, and premature death occurring in more than half cases." — PMID: 34089469

Inheritance. Autosomal recessive, biallelic PIGQ — homozygous (often consanguineous) or compound heterozygous.

"The fourth OS patient had a recessive mutation in PIGQ" — PMID: 24463883

Carrier / birth-frequency estimate (gnomAD v4, computed). Summed high-confidence pLoF allele frequency q ≈ 1.75e-3 → naïve Hardy–Weinberg carrier frequency ≈ 2q ≈ 1/286, and biallelic-LoF birth frequency q² ≈ 1/327,600. This markedly overestimates true disease incidence because complete PIGQ null is presumed embryonic-lethal, and viable patients require at least one hypomorphic (residual-activity) allele; the true birth prevalence is far lower and unquantified.

Penetrance / expressivity. Penetrance of biallelic pathogenic genotypes appears complete; expressivity is variable — from lethal early-infantile encephalopathy at the severe end to nonprogressive congenital ataxia at the mild end, tracking residual enzyme activity.

Other genetic features. No genetic anticipation (not a repeat-expansion disorder). No established founder variant. Consanguinity increases risk of homozygosity. No sex predilection (autosomal); reported cases include both sexes.

10. Diagnostics

Genetic testing (primary/definitive). DEE77 is diagnosed by exome (WES) or genome (WGS) sequencing, or by targeted GPI-biosynthesis / epileptic-encephalopathy gene panels that include PIGQ. Because PIGQ is intron-heavy, ES/WGS or panel capture is preferred over single-gene Sanger. Chromosomal microarray can detect rare 16p13.3 CNVs but is low-yield for the typical small biallelic variants. Reference transcript for variant reporting: NM_004204.5.

Functional confirmation. Flow cytometry demonstrating reduced surface GPI-anchored proteins on granulocytes/leukocytes and fibroblasts confirms pathogenicity and functional impact:

"Flow cytometry confirmed deficiency of several GPI-anchored proteins on leukocytes (CD14, FLAER)." — PMID: 34089469

FLAER (fluorescent aerolysin, which binds GPI anchors directly), CD16, CD14, and CD59/CD55 are standard markers.

Laboratory / biomarkers. Serum alkaline phosphatase may be elevated (hyperphosphatasia) in some IGD subtypes (variable in PIGQ). No specific circulating biomarker is validated for PIGQ-DEE77.

Neuroimaging (diagnostic/prognostic). Brain MRI is central:

"Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%)." — PMID: 38456468

Electrophysiology. EEG documents the epileptic encephalopathy (slow background; multifocal/continuous epileptiform activity; patterns including epilepsy of infancy with migrating focal seizures and myoclonic status).

Clinical criteria / differential diagnosis. No disease-specific criteria beyond genotype + GPI-flow-cytometry. Differential diagnosis includes other inherited GPI deficiencies (PIGA, PIGT, PIGV, PIGO, PIGS, PIGW, etc.), other early-infantile DEEs, congenital disorders of glycosylation, and pyridoxine-dependent epilepsies (ALDH7A1) — distinguished by gene-specific sequencing and GPI-anchored-protein assays.

Screening. No population newborn screening exists. Cascade carrier testing of relatives and prenatal/preimplantation testing are available once the familial biallelic variants are known.

11. Outcome / Prognosis

Mortality. Prognosis is poor at the severe end: premature death occurs in >50% of reported PIGQ patients (PMID: 34089469), and biallelic PIGQ variants were explicitly associated with increased mortality:

"Pathogenic biallelic PIGQ variants were associated with increased mortality." — PMID: 32588908

In the pooled IGD cohort, 15/83 were deceased (PMID: 38456468). Deaths are typically from neurologic complications, status epilepticus, or surgical/systemic complications (e.g., midgut volvulus).

Morbidity / function. Survivors have severe, lifelong disability: profound developmental delay/intellectual disability, drug-resistant epilepsy, motor impairment (hypotonia, ataxia, dyskinesia), feeding difficulties, and sensory involvement (vision/hearing) in some. No validated QoL instruments have been applied.

Recovery potential. Limited. No disease-modifying therapy exists; the milder (nonprogressive) subgroup has a more stable but still impaired course.

Prognostic factors. Residual GPI-biosynthetic activity / variant severity is the principal prognostic determinant (severe LoF → early lethality; hypomorphic → milder ataxia). Neuroimaging features (cerebral/cerebellar atrophy, callosal anomalies, central-tegmental-tract diffusion restriction) are prognostically significant. Neonatal onset and refractory seizures portend worse outcome.

12. Treatment

Overview. There is no cure and no disease-modifying therapy for DEE77; management is supportive and symptomatic (anti-seizure medications, nutritional/feeding support, surgical correction of anomalies such as volvulus, developmental therapies). Epilepsy is frequently drug-resistant.

Vitamin B6 (pyridoxine / pyridoxal-5′-phosphate; NCIT: Pyridoxine, C939). A rational adjunct across IGD. A prospective compassionate-use cohort (Bayat et al. 2022; n=7 IGD, PIGA/PIGT/PIGV) using pyridoxine 20–30 mg/kg/day then P5P found partial benefit:

"We observed more than 50% seizure frequency reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants. No participants reached seizure freedom." — PMID: 35080266

"Early diagnosis and treatment are desirable because the disease progresses even after birth and vitamin B6(pyridoxine) is very effective for some patients with intractable seizures." — PMID: 26165085

Proof-of-concept targeted therapy (different GPI gene). Restoring GPI-anchored protein expression can control IGD seizures — an HDAC inhibitor (butyrate) increased PIGM transcription and surface GPI expression:

"the drug caused complete cessation of intractable seizures in a child with inherited GPI deficiency." — PMID: 17442906

This is a mechanism-anchored strategy but has not been tested in PIGQ-DEE77.

Folinic acid. Mechanistically relevant because folate receptor-α (FOLR1) is itself a GPI-anchored protein; cerebral folate deficiency is treatable with folinic acid (PMID: 19732866). Empirical benefit in PIGQ-DEE77 is unproven.

Advanced / experimental therapeutics. No gene therapy, cell therapy, RNA-based therapy, or PIGQ-targeted small molecule exists or is in trials. Highly purified cannabidiol has shown benefit in monogenic epilepsies broadly (PMID: 40126049) but is not PIGQ-specific.

Suggested NCIT clinical-intervention terms: Pyridoxine (C939), Pyridoxal Phosphate (C61970), Anticonvulsant Agent (C264), Folinic Acid/Leucovorin (C576), Supportive Care (C15272).

13. Prevention

Primary prevention. There is no way to prevent the biallelic genotype; primary prevention is reproductive — genetic counseling for at-risk families (especially consanguineous couples) with carrier testing, prenatal diagnosis, and preimplantation genetic testing (PGT-M) once familial PIGQ variants are known.

Secondary prevention. Cascade genetic testing of relatives; early molecular diagnosis to enable prompt supportive care and a trial of pyridoxine/P5P (rationale: the disease progresses postnatally, so early intervention is advocated — PMID: 26165085).

Tertiary prevention. Prevent complications: aggressive seizure management, surveillance and surgical correction of GI anomalies (volvulus), cardiac monitoring for arrhythmias, nutritional support, and developmental/rehabilitative therapies.

Immunization / public-health / environmental interventions. Not applicable (non-infectious, non-environmental Mendelian disorder). Standard childhood immunization for general health.

14. Other Species / Natural Disease

Taxonomy. No naturally occurring PIGQ-DEE77 has been described in companion animals or wildlife (no OMIA entry identified). GPI anchoring is universally essential across eukaryotes, so orthologs exist broadly. Human species: Homo sapiens (NCBI Taxon 9606); mouse: Mus musculus (NCBI Taxon 10090).

Orthologous genes. Mouse Pigq (ortholog of human PIGQ) exists; the pathway ortholog most studied for disease modeling is Piga (see §15).

Comparative biology. GPI-anchor biosynthesis is deeply evolutionarily conserved from yeast to humans; the essentiality of the pathway (embryonic lethality of complete knockout) is conserved, which is why disease modeling relies on conditional/tissue-specific approaches (§15).

Zoonotic / transmission. Not applicable — non-transmissible genetic disorder.

15. Model Organisms

No PIGQ-specific animal model has been published. Because complete GPI biosynthesis knockout is embryonic-lethal (GPI anchoring is essential for embryogenesis), disease modeling uses conditional / tissue-specific knockouts of pathway genes.

Key mouse model (Kandasamy et al. 2021). Neuron-type-specific GPI-deficiency mice were generated by conditional knockout of Piga — the gene catalyzing the same first, committed step of GPI biosynthesis in which PIGQ participates as a GPI-GnT subunit — in telencephalon excitatory neurons (Ex-M-cko), inhibitory neurons (In-M-cko), or thalamic neurons (Th-H-cko). These models recapitulate core DEE77 features:

"Both Ex-M-cko and In-M-cko mice showed impaired long-term fear memory and were more susceptible to kainic acid-induced seizures." — PMID: 33607654

"Phosphatidylinositol glycan biosynthesis class A protein (PIGA) catalyzes the very first step of GPI anchor biosynthesis. Patients carrying a mutation of the PIGA gene usually suffer from inherited glycosylphosphatidylinositol deficiency (IGD) with intractable epilepsy and intellectual developmental disorder." — PMID: 33607654

In-M-cko mice additionally showed a severe limb-clasping phenotype and Ex-M-cko mice showed hippocampal synapse changes.

Model characteristics / recapitulation. The neuronal GPI-deficiency mouse reproduces seizure susceptibility and cognitive deficits — the neurodevelopmental core of DEE77. Limitations: these use Piga (not its GPI-GnT partner Pigq), are conditional (not the constitutive biallelic human genotype), and do not capture the full multisystem congenital-anomaly spectrum (GI/cardiac/renal). In-vitro human models (patient fibroblasts and iPSC-derived systems) complement animal work: patient fibroblasts provided the definitive rescue experiment (PMID: 32588908).

Model databases / resources: MGI (Pigq, Piga), IMPC, IMSR.

Mechanistic Model / Interpretation

  Biallelic hypomorphic/LoF PIGQ variants (16p13.3)
│  (autosomal recessive; >=1 residual-activity allele in viable patients)
v
  Reduced PIGQ subunit  ->  Impaired ER GPI-GnT complex (with PIGA, PIGC, PIGH, PIGP, DPM2, ARV1)
│            [cytoplasmic face of ER membrane; GO:0005789]
v
  Failure of 1st committed GPI step: PI + UDP-GlcNAc -> GlcNAc-PI
│            [GPI anchor biosynthetic process; GO:0006506]
v
  Global reduction in GPI anchor synthesis
│
v
  Deficient surface display of >150 GPI-anchored proteins
  (FLAER-binding anchors, CD16, CD14, CD59, FOLR1, ALPL, adhesion/signaling molecules)
│
+-------+--------------------------------+
v (neuronal branch)                       v (systemic/developmental branch)
  Disrupted neuronal development,           Disrupted organogenesis
  synapse formation, excitability           │
│                                    v
v                             GI (volvulus 66%), cardiac (19%),
  Epilepsy (onset 2.5-7 mo, drug-          renal (14%) congenital anomalies
  resistant), hypotonia, GDD/ID,
  progressive cerebral/cerebellar
  atrophy, hypomyelination
│                                    │
+------------------+-----------------+
           v
DEE77 - early-infantile epileptic encephalopathy
with multisystem anomalies; >50% premature mortality
           │
           v  (partial, non-curative)
High-dose vitamin B6 (pyridoxine/P5P) -> partial seizure reduction in a subset

Interpretation. DEE77 is best understood as a dosage/residual-activity disorder of the GPI-anchor pathway. The PIGQ lesion is upstream and pathway-initiating; the phenotype is the aggregate downstream consequence of losing many functionally diverse GPI-anchored surface proteins simultaneously. Severity is a graded function of how much GPI biosynthesis survives — explaining the continuum from lethal early-infantile encephalopathy to nonprogressive ataxia. The neurodevelopmental prominence reflects the dependence of neuronal differentiation, synaptogenesis, and excitability control on GPI-anchored molecules, validated by conditional neuronal Piga knockout mice that reproduce seizure susceptibility and memory deficits. The partial pyridoxine responsiveness — shared across IGD — and the butyrate proof-of-concept in PIGM deficiency indicate the pathway is pharmacologically modifiable in principle, motivating mechanism-anchored therapy development.

Evidence Base

PMID	Title (abbrev.)	Role in this report
24463883	Clinical WGS in severe early-onset epilepsy	First link of recessive PIGQ (exon-skipping) to early-onset epileptic encephalopathy
32588908	EIEE due to biallelic PIGQ: 7 new subjects	Defines core phenotype, onset, mortality; functional rescue proving causality
34089469	PIGQ-related GPI deficiency with nonprogressive ataxia	Milder-end spectrum; molecular role of PIGQ; >50% premature death; flow-cytometry diagnosis; c.1631dupA variant
40378954	ARV1 in GPI-GnT complex	Confirms PIGQ is a GPI-GnT component
38456468	Clinical/genetic spectrum of IGD (n=83)	Pooled frequencies; neuroimaging prognostic features
33607654	Neuronal GPI-deficiency mouse models	Model organism recapitulation of seizures + cognitive deficits
11418246	Human GPI1 required for efficient GPI biosynthesis	Establishes GPI1/PIGQ function; heterozygous deletion tolerance (recessive mechanism)
35080266	Pyridoxine/P5P for GPI-deficiency seizures	Quantifies partial B6 efficacy
26165085	Inherited GPI deficiency overview	Postnatal progression; B6 effectiveness in a subset
17442906	Targeted therapy for inherited GPI deficiency	Proof-of-concept: restoring GPI expression controls seizures
19732866	FOLR1 cerebral folate transport deficiency	FOLR1 is GPI-anchored → folinic-acid rationale

Evidence source types: human clinical (24463883, 32588908, 34089469, 38456468, 35080266, 26165085, 17442906, 19732866), in vitro (32588908 fibroblast rescue; 11418246 HEK293 antisense), model organism (33607654), computational (gnomAD constraint, ClinVar and OLS queries performed during the investigation).

Limitations and Knowledge Gaps

Ultra-rare evidence base. Fewer than ~20 PIGQ patients are reported; most quantitative frequencies (seizures 83%, DD/ID 90%, etc.) come from the broader IGD cohort (Sidpra 2024), not PIGQ-specific data. PIGQ-specific frequencies, penetrance, and natural history are imprecise.
No formal epidemiology. No validated prevalence/incidence; the gnomAD-derived carrier estimate (~1/286) overestimates disease because it ignores embryonic lethality of complete null and the requirement for a hypomorphic allele.
No PIGQ-specific animal model. Modeling relies on Piga conditional knockouts; genotype–phenotype fidelity for PIGQ is inferred, not demonstrated.
Therapeutics extrapolated. Pyridoxine/P5P and butyrate evidence comes from other GPI genes (PIGA/PIGT/PIGV/PIGM); no PIGQ-specific trial exists. Folinic-acid benefit is mechanistic conjecture.
Genotype–phenotype correlation (which variants give the severe vs. mild spectrum) is not systematically established; residual-activity assays per variant are lacking.
QoL and long-term outcome are not measured with standardized instruments.

Proposed Follow-up Experiments / Actions

Assemble a PIGQ-specific patient registry (via GeneMatcher/consortia) to derive gene-specific phenotype frequencies, survival curves, and genotype–phenotype correlations.
Variant-level functional assays. Quantify residual GPI biosynthesis for each reported PIGQ variant (flow cytometry for surface GPI-APs in patient/edited cells) to build a severity-prediction model that would refine prognosis and counseling.
Generate a Pigq mouse (or zebrafish) model — conditional/hypomorphic neuronal knockouts — to directly test PIGQ (vs Piga) mechanism and the multisystem anomalies (GI/cardiac/renal).
Prospective pyridoxine/P5P trial in PIGQ-DEE77, with EEG/seizure-diary endpoints and GPI-AP flow-cytometry biomarkers, to test whether the subset-benefit seen in other IGDs extends to PIGQ.
Test pathway-restoring agents (HDAC inhibitors as in PIGM; substrate/precursor supplementation) in patient iPSC-derived neurons/organoids for PIGQ-specific rescue.
Evaluate folinic acid empirically, given FOLR1's GPI dependence, measuring CSF 5-MTHF where feasible.
Standardize diagnostic workup: recommend GPI-AP flow cytometry (FLAER/CD16/CD14) as reflex confirmation after ES/WGS identifies biallelic PIGQ variants, plus MRI for prognostic atrophy/tract markers.

Report compiled from 9 confirmed findings and 37 reviewed papers across a 5-iteration autonomous investigation. All mechanistic and clinical claims are anchored to primary literature (PMIDs above) with verified abstract quotations.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	12
Resolved	12
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	12
On topic	7
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	39
Resolved	37
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	1
Terms whose name was checked	18
Terms named correctly	11
Terms named as a different term	4
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:

MONDO:0032808 (3 mentions) - the report calls it "MONDO"; MONDO calls it developmental and epileptic encephalopathy, 77
DOID:0112213 (1 mention) - the report calls it "DOID"; DOID calls it multiple congenital anomalies-hypotonia-seizures syndrome 4
CL:0000775 (1 mention) - the report calls it "diagnostic readout"; CL calls it neutrophil
CL:0000057 (1 mention) - the report calls it "diagnostic readout"; CL calls it fibroblast

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0031225 (obsolete anchored component of membrane) (1 mention) - replaced by GO:0016020

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:

GO:0005789 (3 mentions) - the report calls it "endoplasmic reticulum membrane, cytoplasmic face"; GO calls it endoplasmic reticulum membrane
UBERON:0001555 (1 mention) - the report calls it "Gastrointestinal tract"; UBERON calls it digestive tract
GO:0031225 (1 mention) - the report calls it "anchored component of the plasma membrane"; GO calls it obsolete anchored component of membrane

Terms named inconsistently

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

HGNC:14135 - called "HGNC (gene)", "HGNC"

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