CHIME_syndrome

Genetic MONDO:0010221 Neuroectodermal Disorder

A rare autosomal recessive neuroectodermal disorder characterized by colobomas, congenital heart defects, ichthyosiform dermatosis, intellectual disability, and ear anomalies caused by mutations in the PIGL gene affecting glycosylphosphatidylinositol (GPI) anchor biosynthesis.

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2
Pathophys.
10
Phenotypes
1
Genes
6
Treatments
8
References
2
Deep Research
⚙

Pathophysiology

2
PIGL Gene Mutations
Mutations in PIGL gene disrupt glycosylphosphatidylinositol (GPI) anchor biosynthesis. PIGL encodes a de-N-acetylase required for GPI anchor formation, essential for anchoring various cell surface proteins including receptors, enzymes, and adhesion molecules.
glycosylphosphatidylinositol biosynthetic process link
Show evidence (1 reference)
PMID:22444671 SUPPORT
"CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies, including conductive hearing loss. Whole-exome sequencing on five previously reported cases identified PIGL, the de-N-acetylase required for..."
Establishes PIGL mutations as the cause of CHIME syndrome and describes the gene's role in GPI anchor biosynthesis.
GPI Anchor Deficiency
Reduced levels of GPI-anchored proteins on cell surface due to impaired biosynthesis, affecting normal cellular functions and signaling pathways. This leads to the multisystem phenotype characteristic of CHIME syndrome.
cell adhesion link signal transduction link immune response link
Show evidence (1 reference)
PMID:22444671 SUPPORT
"Furthermore, cell lines derived from these cases had significantly reduced levels of the two GPI anchor markers, CD59 and a GPI-binding toxin, aerolysin (FLAER), confirming the pathogenicity of the mutations."
Demonstrates functional consequences of PIGL mutations showing reduced GPI anchor markers in patient cells.
●

Phenotypes

10
Cardiovascular 1
Congenital Heart Defects VERY_FREQUENT Abnormal heart morphology (HP:0001627)
Show evidence (1 reference)
PMID:22444671 SUPPORT
"CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies"
PIGL mutations cause cardiac defects as a cardinal feature of CHIME syndrome, requiring cardiac surveillance in affected individuals.
Digestive 1
Feeding Difficulties FREQUENT Feeding difficulties (HP:0011968)
Feeding difficulties often present in infancy.
Ear 1
Conductive Hearing Loss VERY_FREQUENT Conductive hearing impairment (HP:0000405)
Ear anomalies and conductive hearing loss due to increased desquamation in auditory canal and structural ear abnormalities related to GPI-AP deficiency during development.
Show evidence (1 reference)
PMID:22444671 SUPPORT
"CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies, including conductive hearing loss"
Landmark PIGL mutation study documenting conductive hearing loss and ear anomalies as defining features of CHIME syndrome.
Eye 1
Chorioretinal Coloboma VERY_FREQUENT Chorioretinal coloboma (HP:0000567)
Chorioretinal colobomas are a defining feature of CHIME syndrome, characterized by absence of regions of the retina, retinal pigment epithelium, and choroid. These reflect disrupted morphogen signaling and cell adhesion during optic fissure closure.
Show evidence (1 reference)
PMID:22444671 SUPPORT
"CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies"
Landmark PIGL mutation study identifying coloboma as a cardinal diagnostic feature of CHIME syndrome.
Genitourinary 1
Genitourinary Abnormalities FREQUENT Abnormality of the genitourinary system (HP:0000119)
May include hydronephrosis and bicornuate uterus.
Head and Neck 1
Dysmorphic Facial Features FREQUENT Abnormal facial shape (HP:0001999)
Includes brachycephaly, hypertelorism, broad flat nasal root, short philtrum, and full lips.
Show evidence (1 reference)
PMID:7666399 SUPPORT
"The main features include ocular colobomas, congenital heart disease, early onset migratory ichthyosiform dermatosis, mental retardation, conductive hearing loss, seizures, and typical facial features."
Early case series identifying typical facial features as a consistent manifestation of CHIME syndrome.
Integument 1
Ichthyosiform Dermatosis VERY_FREQUENT Ichthyosis (HP:0008064)
Migratory ichthyosiform dermatosis present at or within weeks of birth, reflecting defects in keratinocyte membrane protein anchoring due to GPI biosynthesis failure.
Show evidence (1 reference)
PMID:22444671 SUPPORT
"CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies"
Landmark study identifying migratory ichthyosiform dermatosis as a defining feature of PIGL-related CHIME syndrome.
Nervous System 2
Intellectual Disability VERY_FREQUENT Intellectual disability (HP:0001249)
Moderate to severe intellectual disability is a core feature. Present in approximately 90% of individuals with inherited glycosylphosphatidylinositol deficiency.
Show evidence (1 reference)
PMID:22444671 SUPPORT
"CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies"
Landmark study establishing intellectual disability as a defining feature of CHIME syndrome caused by PIGL mutations.
Seizure Disorder FREQUENT Seizure (HP:0001250)
Seizures present in approximately 83% of individuals with inherited glycosylphosphatidylinositol deficiency, with median age of onset around 6 months. Often exacerbated by high environmental temperatures and fever. Synthesis-stage gene variants show earlier seizure onset than transamidase/remodeling stage variants.
Show evidence (2 references)
PMID:7666399 SUPPORT
"The main features include ocular colobomas, congenital heart disease, early onset migratory ichthyosiform dermatosis, mental retardation, conductive hearing loss, seizures, and typical facial features."
Early case series documenting seizures as a defining feature of CHIME syndrome alongside cardinal features.
PMID:7666399 SUPPORT
"Long term follow up information on this patient, as well as the previously described cases, provides information regarding the outcome for these patients, which includes general good health, severe mental retardation, seizures that worsen after puberty, conductive hearing loss, and chronic..."
Long-term follow-up data documenting that seizures are a persistent feature that may worsen after puberty in CHIME syndrome.
Growth 1
Large Birth Size FREQUENT Large for gestational age (HP:0001520)
Show evidence (1 reference)
PMID:9295069 SUPPORT
"Her major problems included a migratory ichthyosiform dermatosis, multiple skin infections and infestations, bilateral retinal coloboma, developmental delay, seizures, infantile macrosomia, facial anomalies, a duplicated renal collecting system, and conductive hearing loss."
Schnur et al. 1997 documents infantile macrosomia as a clinical feature in a CHIME syndrome patient, expanding the growth-related phenotype spectrum.
🧬

Genetic Associations

1
PIGL (Causal)
Show evidence (4 references)
PMID:22444671 SUPPORT
"Whole-exome sequencing on five previously reported cases identified PIGL, the de-N-acetylase required for glycosylphosphatidylinositol (GPI) anchor formation, as a strong candidate."
Identifies PIGL as the causal gene for CHIME syndrome through whole-exome sequencing.
PMID:28371479 SUPPORT
"CHIME syndrome is a rare autosomal recessive neuroectodermal disorder associated with biallelic mutations in PIGL. To date, six molecularly confirmed cases of CHIME syndrome have been reported. Here, we report the seventh patient with biallelic PIGL mutations associated with CHIME syndrome and..."
Knight Johnson et al. 2017 documents the first Alu-mediated intragenic deletion in PIGL as a disease-causing mechanism in CHIME syndrome, expanding the mutation spectrum beyond point mutations.
PMID:29473937 SUPPORT
"In CHIME syndrome, a recurrent missense mutation c.500T > C (p.Leu167Pro) is found in the majority of patients, associated with a null mutation in the other allele, including an overrepresentation of large deletions. The latter are not detected by the standard analysis in sequencing techniques,..."
Ceroni et al. 2018 establishes that large deletions are a common mutational mechanism in CHIME syndrome, often missed by standard sequencing, and recommends active screening for deletions in diagnostic workup.
+ 1 more reference
💊

Treatments

6
Supportive Care
Action: supportive care MAXO:0000950
Multidisciplinary care addressing individual symptoms and complications.
Cardiac Surgery
Action: surgical procedure MAXO:0000004
Surgical correction of congenital heart defects when indicated.
Seizure Management
Action: Pharmacotherapy NCIT:C15986
Antiepileptic medications for seizure control.
Dermatologic Care
Action: Pharmacotherapy NCIT:C15986
Topical and systemic treatments for ichthyosiform dermatosis management, including topical therapies and IL-17 antagonists for severe cases.
Show evidence (1 reference)
PMID:38773877 SUPPORT
"Here, we report a case of severe ichthyosiform dermatosis in a child with CHIME syndrome who was recalcitrant to multiple topical medications and dupilumab. This is the first reported case of successful treatment of congenital ichthyosiform dermatosis in a CHIME syndrome patient with ixekizumab,..."
Flowers et al. 2024 documents the first successful treatment of severe ichthyosiform dermatosis in CHIME syndrome using ixekizumab (IL-17A antagonist), providing a therapeutic option for treatment-resistant cases.
Hearing Aids
Action: supportive care MAXO:0000950
Assistive devices for conductive hearing loss.
Educational Support
Action: behavioral counseling MAXO:0000077
Special educational services tailored to intellectual disability.
{ }

Source YAML

click to show 
name: CHIME_syndrome
creation_date: '2025-12-22T19:53:18Z'
updated_date: '2026-02-17T21:53:14Z'
description: A rare autosomal recessive neuroectodermal disorder characterized
  by colobomas, congenital heart defects, ichthyosiform dermatosis, intellectual
  disability, and ear anomalies caused by mutations in the PIGL gene affecting
  glycosylphosphatidylinositol (GPI) anchor biosynthesis.
category: Genetic
parents:
- Neuroectodermal Disorder
synonyms:
- Zunich neuroectodermal syndrome
- Coloboma-heart-ichthyosis-mental retardation-ear syndrome
prevalence:
- population: Global
  percentage: 0.000001
pathophysiology:
- name: PIGL Gene Mutations
  description: Mutations in PIGL gene disrupt glycosylphosphatidylinositol (GPI)
    anchor biosynthesis. PIGL encodes a de-N-acetylase required for GPI anchor
    formation, essential for anchoring various cell surface proteins including
    receptors, enzymes, and adhesion molecules.
  biological_processes:
  - preferred_term: glycosylphosphatidylinositol biosynthetic process
    term:
      id: GO:0006506
      label: GPI anchor biosynthetic process
  evidence:
  - reference: PMID:22444671
    reference_title: "Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome."
    supports: SUPPORT
    snippet: "CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform
      dermatosis, mental retardation (intellectual disability), and ear anomalies,
      including conductive hearing loss. Whole-exome sequencing on five previously
      reported cases identified PIGL, the de-N-acetylase required for glycosylphosphatidylinositol
      (GPI) anchor formation, as a strong candidate."
    explanation: Establishes PIGL mutations as the cause of CHIME syndrome and
      describes the gene's role in GPI anchor biosynthesis.
- name: GPI Anchor Deficiency
  description: Reduced levels of GPI-anchored proteins on cell surface due to
    impaired biosynthesis, affecting normal cellular functions and signaling
    pathways. This leads to the multisystem phenotype characteristic of CHIME
    syndrome.
  biological_processes:
  - preferred_term: cell adhesion
    term:
      id: GO:0007155
      label: cell adhesion
  - preferred_term: signal transduction
    term:
      id: GO:0007165
      label: signal transduction
  - preferred_term: immune response
    term:
      id: GO:0006955
      label: immune response
  evidence:
  - reference: PMID:22444671
    reference_title: "Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome."
    supports: SUPPORT
    snippet: "Furthermore, cell lines derived from these cases had significantly reduced
      levels of the two GPI anchor markers, CD59 and a GPI-binding toxin, aerolysin
      (FLAER), confirming the pathogenicity of the mutations."
    explanation: Demonstrates functional consequences of PIGL mutations showing
      reduced GPI anchor markers in patient cells.
phenotypes:
- category: Ophthalmic
  name: Chorioretinal Coloboma
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Chorioretinal colobomas are a defining feature of CHIME syndrome,
    characterized by absence of regions of the retina, retinal pigment
    epithelium, and choroid. These reflect disrupted morphogen signaling and
    cell adhesion during optic fissure closure.
  phenotype_term:
    preferred_term: Chorioretinal coloboma
    term:
      id: HP:0000567
      label: Chorioretinal coloboma
  evidence:
  - reference: PMID:22444671
    reference_title: "Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome."
    supports: SUPPORT
    snippet: "CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform
      dermatosis, mental retardation (intellectual disability), and ear anomalies"
    explanation: Landmark PIGL mutation study identifying coloboma as a cardinal
      diagnostic feature of CHIME syndrome.
- category: Cardiac
  name: Congenital Heart Defects
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:22444671
    reference_title: "Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome."
    supports: SUPPORT
    snippet: "CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform
      dermatosis, mental retardation (intellectual disability), and ear anomalies"
    explanation: PIGL mutations cause cardiac defects as a cardinal feature of
      CHIME syndrome, requiring cardiac surveillance in affected individuals.
- category: Dermatologic
  name: Ichthyosiform Dermatosis
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Migratory ichthyosiform dermatosis present at or within weeks of birth,
    reflecting defects in keratinocyte membrane protein anchoring due to GPI
    biosynthesis failure.
  phenotype_term:
    preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: PMID:22444671
    reference_title: "Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome."
    supports: SUPPORT
    snippet: "CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform
      dermatosis, mental retardation (intellectual disability), and ear anomalies"
    explanation: Landmark study identifying migratory ichthyosiform dermatosis
      as a defining feature of PIGL-related CHIME syndrome.
- category: Neurologic
  name: Intellectual Disability
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Moderate to severe intellectual disability is a core feature. Present
    in approximately 90% of individuals with inherited
    glycosylphosphatidylinositol deficiency.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:22444671
    reference_title: "Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome."
    supports: SUPPORT
    snippet: "CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform
      dermatosis, mental retardation (intellectual disability), and ear anomalies"
    explanation: Landmark study establishing intellectual disability as a
      defining feature of CHIME syndrome caused by PIGL mutations.
- category: Auditory
  name: Conductive Hearing Loss
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Ear anomalies and conductive hearing loss due to increased desquamation
    in auditory canal and structural ear abnormalities related to GPI-AP
    deficiency during development.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:22444671
    reference_title: "Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome."
    supports: SUPPORT
    snippet: "CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform
      dermatosis, mental retardation (intellectual disability), and ear anomalies,
      including conductive hearing loss"
    explanation: Landmark PIGL mutation study documenting conductive hearing
      loss and ear anomalies as defining features of CHIME syndrome.
- category: Neurologic
  name: Seizure Disorder
  frequency: FREQUENT
  notes: Seizures present in approximately 83% of individuals with inherited
    glycosylphosphatidylinositol deficiency, with median age of onset around 6
    months. Often exacerbated by high environmental temperatures and fever.
    Synthesis-stage gene variants show earlier seizure onset than
    transamidase/remodeling stage variants.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:7666399
    reference_title: "Neuroectodermal (CHIME) syndrome: an additional case with long term follow up of all reported cases."
    supports: SUPPORT
    snippet: "The main features include ocular colobomas, congenital heart disease,
      early onset migratory ichthyosiform dermatosis, mental retardation, conductive
      hearing loss, seizures, and typical facial features."
    explanation: Early case series documenting seizures as a defining feature of
      CHIME syndrome alongside cardinal features.
  - reference: PMID:7666399
    reference_title: "Neuroectodermal (CHIME) syndrome: an additional case with long term follow up of all reported cases."
    supports: SUPPORT
    snippet: "Long term follow up information on this patient, as well as the previously
      described cases, provides information regarding the outcome for these patients,
      which includes general good health, severe mental retardation, seizures that
      worsen after puberty, conductive hearing loss, and chronic migratory ichthyosiform
      skin rash without scarring."
    explanation: Long-term follow-up data documenting that seizures are a
      persistent feature that may worsen after puberty in CHIME syndrome.
- category: Craniofacial
  name: Dysmorphic Facial Features
  frequency: FREQUENT
  notes: Includes brachycephaly, hypertelorism, broad flat nasal root, short
    philtrum, and full lips.
  phenotype_term:
    preferred_term: Dysmorphic facial features
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:7666399
    reference_title: "Neuroectodermal (CHIME) syndrome: an additional case with long term follow up of all reported cases."
    supports: SUPPORT
    snippet: "The main features include ocular colobomas, congenital heart disease,
      early onset migratory ichthyosiform dermatosis, mental retardation, conductive
      hearing loss, seizures, and typical facial features."
    explanation: Early case series identifying typical facial features as a
      consistent manifestation of CHIME syndrome.
- category: Genitourinary
  name: Genitourinary Abnormalities
  frequency: FREQUENT
  notes: May include hydronephrosis and bicornuate uterus.
  phenotype_term:
    preferred_term: Abnormality of the genitourinary system
    term:
      id: HP:0000119
      label: Abnormality of the genitourinary system
- category: Growth
  name: Large Birth Size
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Large for gestational age
    term:
      id: HP:0001520
      label: Large for gestational age
  evidence:
  - reference: PMID:9295069
    reference_title: "Acute lymphoblastic leukemia in a child with the CHIME neuroectodermal dysplasia syndrome."
    supports: SUPPORT
    snippet: "Her major problems included a migratory ichthyosiform dermatosis, multiple
      skin infections and infestations, bilateral retinal coloboma, developmental
      delay, seizures, infantile macrosomia, facial anomalies, a duplicated renal
      collecting system, and conductive hearing loss."
    explanation: Schnur et al. 1997 documents infantile macrosomia as a clinical
      feature in a CHIME syndrome patient, expanding the growth-related
      phenotype spectrum.
- category: Gastrointestinal
  name: Feeding Difficulties
  frequency: FREQUENT
  notes: Feeding difficulties often present in infancy.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
genetic:
- name: PIGL
  association: Causal
  notes: Autosomal recessive mutations in PIGL gene cause CHIME syndrome. Most
    cases show compound heterozygous mutations with c.500T>C (p.Leu167Pro) being
    frequently observed. Mutations include point mutations, insertions,
    deletions, and Alu-mediated intragenic deletions.
  evidence:
  - reference: PMID:22444671
    reference_title: "Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome."
    supports: SUPPORT
    snippet: "Whole-exome sequencing on five previously reported cases identified
      PIGL, the de-N-acetylase required for glycosylphosphatidylinositol (GPI) anchor
      formation, as a strong candidate."
    explanation: Identifies PIGL as the causal gene for CHIME syndrome through
      whole-exome sequencing.
  - reference: PMID:28371479
    reference_title: "Alu-mediated deletion of PIGL in a Patient with CHIME syndrome."
    supports: SUPPORT
    snippet: "CHIME syndrome is a rare autosomal recessive neuroectodermal disorder
      associated with biallelic mutations in PIGL. To date, six molecularly confirmed
      cases of CHIME syndrome have been reported. Here, we report the seventh patient
      with biallelic PIGL mutations associated with CHIME syndrome and describe the
      first characterization of an intragenic deletion in PIGL."
    explanation: Knight Johnson et al. 2017 documents the first Alu-mediated
      intragenic deletion in PIGL as a disease-causing mechanism in CHIME
      syndrome, expanding the mutation spectrum beyond point mutations.
  - reference: PMID:29473937
    reference_title: "Large deletion in PIGL: a common mutational mechanism in CHIME syndrome?"
    supports: SUPPORT
    snippet: "In CHIME syndrome, a recurrent missense mutation c.500T > C (p.Leu167Pro)
      is found in the majority of patients, associated with a null mutation in the
      other allele, including an overrepresentation of large deletions. The latter
      are not detected by the standard analysis in sequencing techniques, including
      next-generation sequencing. Thus, in individuals with a clinical diagnosis of
      CHIME syndrome in which only one mutation is found, an active search for a large
      deletion should be sought."
    explanation: Ceroni et al. 2018 establishes that large deletions are a
      common mutational mechanism in CHIME syndrome, often missed by standard
      sequencing, and recommends active screening for deletions in diagnostic
      workup.
  - reference: PMID:35258128
    reference_title: "Child with a mild CHIME syndrome phenotype and carrying a novel p.(Asp52Asn) PIGL pathogenic variant in association with the previously reported p.(Leu167Pro) variant: A case report."
    supports: SUPPORT
    snippet: "A novel 'likely pathogenic' PIGL missense variant (c.154G>A, p.(Asp52Asn))
      was detected on the maternal allele. This case provides new insights into the
      clinical spectrum of CHIME syndrome and highlights the potential for phenotypic/genotypic
      variations."
    explanation: Rolland et al. 2022 documents a novel p.(Asp52Asn) PIGL variant
      and demonstrates phenotypic heterogeneity in CHIME syndrome, including
      mild phenotypes with atypical features, emphasizing genotype-phenotype
      variation.
treatments:
- name: Supportive Care
  description: Multidisciplinary care addressing individual symptoms and
    complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
- name: Cardiac Surgery
  description: Surgical correction of congenital heart defects when indicated.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Seizure Management
  description: Antiepileptic medications for seizure control.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Dermatologic Care
  description: Topical and systemic treatments for ichthyosiform dermatosis
    management, including topical therapies and IL-17 antagonists for severe
    cases.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:38773877
    reference_title: "Severe congenital ichthyosiform dermatosis in CHIME syndrome successfully treated with ixekizumab."
    supports: SUPPORT
    snippet: "Here, we report a case of severe ichthyosiform dermatosis in a child
      with CHIME syndrome who was recalcitrant to multiple topical medications and
      dupilumab. This is the first reported case of successful treatment of congenital
      ichthyosiform dermatosis in a CHIME syndrome patient with ixekizumab, an IL-17A
      antagonist."
    explanation: Flowers et al. 2024 documents the first successful treatment of
      severe ichthyosiform dermatosis in CHIME syndrome using ixekizumab (IL-17A
      antagonist), providing a therapeutic option for treatment-resistant cases.
- name: Hearing Aids
  description: Assistive devices for conductive hearing loss.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
- name: Educational Support
  description: Special educational services tailored to intellectual disability.
  treatment_term:
    preferred_term: behavioral counseling
    term:
      id: MAXO:0000077
      label: behavioral counseling
review_notes: CHIME syndrome is an extremely rare autosomal recessive
  neuroectodermal disorder with a distinctive phenotype. Early recognition is
  important due to potential cardiac complications and need for
  multidisciplinary care. Notably, a possible association with malignancy (acute
  lymphoblastic leukemia) has been documented in at least one patient,
  warranting long-term hematologic surveillance. More than eight cases have been
  molecularly confirmed, with varying phenotypic presentations beyond the
  classic CHIME acronym features.
disease_term:
  preferred_term: CHIME syndrome
  term:
    id: MONDO:0010221
    label: CHIME syndrome
references:
- reference: DOI:10.1002/humu.23219
  title: Phenotype-genotype correlations of PIGO deficiency with variable
    phenotypes from infantile lethality to mild learning difficulties
  findings: []
- reference: DOI:10.1007/s00018-024-05284-2
  title: The GPI-anchor biosynthesis pathway is critical for syncytiotrophoblast
    differentiation and placental development
  findings: []
- reference: DOI:10.1016/j.ymgmr.2018.01.007
  title: Hyperphosphatasia with mental retardation syndrome, expanded phenotype
    of PIGL related disorders
  findings: []
- reference: DOI:10.1093/brain/awae056
  title: The clinical and genetic spectrum of inherited
    glycosylphosphatidylinositol deficiency disorders
  findings: []
- reference: DOI:10.1186/s13023-020-01401-z
  title: The Glycosylphosphatidylinositol biosynthesis pathway in human diseases
  findings: []
- reference: DOI:10.1590/1678-4685-gmb-2017-0172
  title: 'Large deletion in PIGL: a common mutational mechanism in CHIME syndrome?'
  findings: []
- reference: DOI:10.3390/ijms24108632
  title: 'Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of
    Carbohydrate Metabolism: A Systematic Review'
  findings: []
- reference: DOI:10.5114/polp.2024.146394
  title: 'Inherited glycosylphosphatidylinositol deficiency disorders: a new group
    of inherited metabolic disorders'
  findings: []
📚

References & Deep Research

References

8
DOI:10.1002/humu.23219
Phenotype-genotype correlations of PIGO deficiency with variable phenotypes from infantile lethality to mild learning difficulties
No top-level findings curated for this source.
DOI:10.1007/s00018-024-05284-2
The GPI-anchor biosynthesis pathway is critical for syncytiotrophoblast differentiation and placental development
No top-level findings curated for this source.
DOI:10.1016/j.ymgmr.2018.01.007
Hyperphosphatasia with mental retardation syndrome, expanded phenotype of PIGL related disorders
No top-level findings curated for this source.
DOI:10.1093/brain/awae056
The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders
No top-level findings curated for this source.
DOI:10.1186/s13023-020-01401-z
The Glycosylphosphatidylinositol biosynthesis pathway in human diseases
No top-level findings curated for this source.
DOI:10.1590/1678-4685-gmb-2017-0172
Large deletion in PIGL: a common mutational mechanism in CHIME syndrome?
No top-level findings curated for this source.
DOI:10.3390/ijms24108632
Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review
No top-level findings curated for this source.
DOI:10.5114/polp.2024.146394
Inherited glycosylphosphatidylinositol deficiency disorders: a new group of inherited metabolic disorders
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: CHIME_syndrome
  • Category: Genetic
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 24

Key Pathophysiology Nodes

  • PIGL Gene Mutations
  • GPI Anchor Deficiency
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1002/humu.23219
  • DOI:10.1007/s00018-024-05284-2
  • DOI:10.1016/j.ymgmr.2018.01.007
  • DOI:10.1093/brain/awae056
  • DOI:10.1186/s13023-020-01401-z
  • DOI:10.1590/1678-4685-gmb-2017-0172
  • DOI:10.3390/ijms24108632
  • DOI:10.5114/polp.2024.146394
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 37 citations 2026-01-05T17:34:16.997832

Disease Pathophysiology Research Report

Target Disease - Disease Name: CHIME syndrome (also known as Zunich neuroectodermal syndrome) - MONDO ID: MONDO:0010221 (OpenTargets association of CHIME syndrome with PIGL) (ceroni2018largedeletionin pages 1-2) - Category: Genetic (inherited glycosylphosphatidylinositol deficiency; IGD)

Pathophysiology description CHIME syndrome is an autosomal recessive inherited glycosylphosphatidylinositol (GPI) deficiency caused by biallelic pathogenic variants in PIGL, which encodes the GlcNAc-PI de-N-acetylase catalyzing the second step of GPI-anchor biosynthesis on the cytoplasmic face of the endoplasmic reticulum (ER) (de-N-acetylation of N-acetylglucosaminyl-phosphatidylinositol, GlcNAc-PI, to glucosaminyl-PI, GlcN-PI) (ceroni2018largedeletionin pages 1-2, altassan2018hyperphosphatasiawithmental pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). Defective PIGL activity impairs production of GPI anchors, reducing cell-surface expression of GPI-anchored proteins (GPI-APs) across multiple tissues. This leads to multisystem disease featuring neurodevelopmental impairment, ocular coloboma, migratory ichthyosiform dermatosis, ear anomalies/hearing loss, and variable cardiac and renal/urogenital malformations (ceroni2018largedeletionin pages 1-2, conte2023metaboliccardiomyopathiesand pages 17-19, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7).

At the cellular level, IGDs—including those caused by PIGL—show reduced GPI-APs detectable by flow cytometry (e.g., decreased CD59 and FLAER on fibroblasts; reduced CD24/CD16 on granulocytes, CD14 on monocytes), reflecting diminished GPI anchoring (wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). A frequent biochemical signature in IGDs is elevated serum alkaline phosphatase (ALP), as TNAP is a GPI-AP that can be shed or misprocessed when GPI biosynthesis is perturbed; marked hyperphosphatasia has been reported in PIGL-related presentations (altassan2018hyperphosphatasiawithmental pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7, patalan2024inheritedglycosylphosphatidylinositoldeficiency pages 1-3). Cohort-level natural history from 83 IGD individuals shows median seizure onset at 6 months, frequent cerebral and cerebellar atrophy and corpus callosum anomalies, and multisystem involvement (gastrointestinal, cardiac, renal) (sidpra2024theclinicaland pages 1-1).

Recent mechanistic data add tissue-specific insight. CRISPR knockout of Pigl in mouse trophoblast stem cells demonstrates that loss of early GPI biosynthesis induces an excessive unfolded protein response (UPR)/ER stress signature and impairs WNT/β-catenin signaling required for syncytiotrophoblast-II (SynT-II) differentiation; β-catenin and early SynT-II markers are rescued by pharmacologic WNT activation (CHIR99021). Pigl/Pigf-deficient trophoblasts also show increased mitochondrial respiration and ROS. These changes correlate with a severely underdeveloped labyrinthine SynT in vivo and a Pigl/Pigf-deficient transcriptomic signature that segregates human preeclampsia placental samples, suggesting a link between GPI pathway integrity and placental pathophysiology (alvarezsanchez2024thegpianchorbiosynthesis pages 8-9, alvarezsanchez2024thegpianchorbiosynthesis pages 1-2, alvarezsanchez2024thegpianchorbiosynthesis pages 9-11, alvarezsanchez2024thegpianchorbiosynthesis pages 2-3, alvarezsanchez2024thegpianchorbiosynthesis pages 4-5, alvarezsanchez2024thegpianchorbiosynthesis pages 3-4).

Core Pathophysiology - Primary mechanisms: Loss of PIGL de-N-acetylase activity in early GPI-anchor biosynthesis reduces/abolishes GPI-AP attachment, leading to impaired cell-surface functions of enzymes, adhesion molecules, and co-receptors and secondary cellular stress responses (ceroni2018largedeletionin pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7, altassan2018hyperphosphatasiawithmental pages 1-2). - Dysregulated pathways: GPI-anchor biogenesis pathway (ER); downstream ER stress/UPR signaling; WNT/β-catenin signaling in trophoblast differentiation; mitochondrial respiratory adaptation/ROS (in trophoblast context) (alvarezsanchez2024thegpianchorbiosynthesis pages 8-9, alvarezsanchez2024thegpianchorbiosynthesis pages 1-2, alvarezsanchez2024thegpianchorbiosynthesis pages 9-11, alvarezsanchez2024thegpianchorbiosynthesis pages 4-5, alvarezsanchez2024thegpianchorbiosynthesis pages 3-4). - Affected cellular processes: Protein maturation/attachment to membranes via GPI-APs; cell-surface signaling and adhesion; ER protein quality control (UPR); trophoblast lineage specification and SynT-II differentiation via WNT signaling (wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7, alvarezsanchez2024thegpianchorbiosynthesis pages 8-9, alvarezsanchez2024thegpianchorbiosynthesis pages 1-2).

Key Molecular Players - Genes/Proteins (HGNC): - PIGL (HGNC:8962): ER GlcNAc-PI de-N-acetylase (step 2 of GPI synthesis) (ceroni2018largedeletionin pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - Representative GPI-anchored proteins affected: tissue-nonspecific alkaline phosphatase (TNAP/ALPL), CD55/DAF, CD59, CD24, CD16, CD14 (as cellular readouts and examples) (wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). Note: specific GPI-AP dependencies may vary by tissue. - Trophoblast signaling components impacted by PIGL loss: WNT ligands (e.g., Wnt3, Wnt4, Wnt5a, Wnt7a, Wnt9a), receptors/co-receptors (Fzd5, Fzd10, ROR2), antagonists (DKK1, NOTUM), β-catenin (CTNNB1) (alvarezsanchez2024thegpianchorbiosynthesis pages 8-9, alvarezsanchez2024thegpianchorbiosynthesis pages 7-8, alvarezsanchez2024thegpianchorbiosynthesis pages 4-5). - Chemical entities (CHEBI): - GPI anchor intermediates: N-acetylglucosaminyl-phosphatidylinositol (GlcNAc-PI) and glucosaminyl-PI (GlcN-PI) (altassan2018hyperphosphatasiawithmental pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - CHIR99021 (GSK3 inhibitor; WNT/β-catenin pathway activator) used to rescue β-catenin/SynT-II markers in Pigl/Pigf-null trophoblasts (alvarezsanchez2024thegpianchorbiosynthesis pages 8-9, alvarezsanchez2024thegpianchorbiosynthesis pages 9-11). - Cell types (CL): - Neurons and glia (neurodevelopmental impairment; IGD cohort) (sidpra2024theclinicaland pages 1-1). - Keratinocytes/epidermal cells (migratory ichthyosiform dermatosis) (ceroni2018largedeletionin pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - Trophoblast stem cells and syncytiotrophoblast (placental SynT-II lineage) (alvarezsanchez2024thegpianchorbiosynthesis pages 8-9, alvarezsanchez2024thegpianchorbiosynthesis pages 2-3). - Hematopoietic cells (granulocytes/monocytes; diagnostic flow cytometry readouts) (wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - Anatomical locations (UBERON): - Brain (cerebral/cerebellar atrophy; corpus callosum anomalies) (sidpra2024theclinicaland pages 1-1). - Eye (optic fissure/coloboma) (ceroni2018largedeletionin pages 1-2). - Skin (epidermis; ichthyosiform dermatosis) (ceroni2018largedeletionin pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - Ear (external/middle ear anomalies; conductive hearing loss) (ceroni2018largedeletionin pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - Heart (congenital heart disease reported in IGDs including PIGL-CDG) (conte2023metaboliccardiomyopathiesand pages 17-19, ceroni2018largedeletionin pages 1-2). - Kidney/urogenital tract (hydronephrosis, urogenital anomalies variably reported) (ceroni2018largedeletionin pages 1-2). - Placenta (labyrinth/SynT-II development in Pigl/Pigf deficiency models) (alvarezsanchez2024thegpianchorbiosynthesis pages 2-3, alvarezsanchez2024thegpianchorbiosynthesis pages 4-5).

Biological Processes (GO annotations; disrupted) - GPI anchor biosynthetic process; ER membrane protein complex assembly; protein–lipid modification and attachment (wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7, ceroni2018largedeletionin pages 1-2). - Response to endoplasmic reticulum stress; regulation of unfolded protein response (UPR) (ATF4/ATF6/IRE1/XBP1 pathways) (alvarezsanchez2024thegpianchorbiosynthesis pages 1-2, alvarezsanchez2024thegpianchorbiosynthesis pages 4-5, alvarezsanchez2024thegpianchorbiosynthesis pages 3-4). - WNT signaling pathway; β-catenin stabilization and target gene expression during trophoblast/SynT-II differentiation (alvarezsanchez2024thegpianchorbiosynthesis pages 8-9, alvarezsanchez2024thegpianchorbiosynthesis pages 9-11, alvarezsanchez2024thegpianchorbiosynthesis pages 7-8). - Cell adhesion and receptor-mediated signaling at the plasma membrane mediated by GPI-APs (wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7).

Cellular Components (where key processes occur) - Endoplasmic reticulum membrane and lumen (early GPI biosynthesis; PIGL localization and UPR activation) (altassan2018hyperphosphatasiawithmental pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7, alvarezsanchez2024thegpianchorbiosynthesis pages 4-5). - Plasma membrane outer leaflet/lipid rafts (localization and function of GPI-APs) (wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - Mitochondrion (respiratory changes and ROS in Pigl/Pigf-deficient trophoblasts) (alvarezsanchez2024thegpianchorbiosynthesis pages 9-11, alvarezsanchez2024thegpianchorbiosynthesis pages 4-5).

Disease Progression (sequence of events) 1) Genotype: Biallelic PIGL variants—commonly a recurrent missense c.500T>C (p.Leu167Pro) in trans with a null allele (often large deletions affecting 5′UTR/exon 1)—reduce/abolish PIGL enzyme function (ceroni2018largedeletionin pages 1-2). 2) Molecular defect: Failure to de-N-acetylate GlcNAc-PI to GlcN-PI blocks early GPI assembly in the ER, limiting the availability of mature GPI anchors (altassan2018hyperphosphatasiawithmental pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). 3) Cellular dysfunction: Reduced cell-surface GPI-APs; possible shedding/release of GPI-APs like TNAP; ER stress/UPR activation in sensitive cell types; tissue-specific pathway disruption (e.g., WNT/β-catenin in trophoblast) (wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7, alvarezsanchez2024thegpianchorbiosynthesis pages 1-2, alvarezsanchez2024thegpianchorbiosynthesis pages 8-9). 4) Organ phenotypes: Neurodevelopmental impairment with early-onset seizures, structural brain changes, ocular coloboma, ichthyosiform dermatosis, ear anomalies/hearing loss; variable cardiac and renal involvement; potential placental insufficiency signatures in model systems (sidpra2024theclinicaland pages 1-1, ceroni2018largedeletionin pages 1-2, conte2023metaboliccardiomyopathiesand pages 17-19, alvarezsanchez2024thegpianchorbiosynthesis pages 8-9, alvarezsanchez2024thegpianchorbiosynthesis pages 2-3).

Phenotypic Manifestations and relation to mechanisms - Neurodevelopmental: DD/ID (90%), seizures (83%), hypotonia (72%), motor symptoms (64%); neuroimaging reveals cerebral and cerebellar atrophy and corpus callosum anomalies. These features are consistent with broad neuronal dependence on GPI-APs for synaptic signaling, adhesion, and complement regulation; cohort median seizure onset is 6 months (sidpra2024theclinicaland pages 1-1). - Dermatologic: Migratory ichthyosiform dermatosis is highly penetrant in reported CHIME cases; keratinocyte membrane protein anchoring defects plausibly contribute (ceroni2018largedeletionin pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - Ocular: Coloboma likely reflects disrupted morphogen signaling and adhesion during optic fissure closure; GPI-AP deficits in ocular development are consistent with reported CHIME cases (ceroni2018largedeletionin pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - Auditory: Ear anomalies and conductive hearing loss reflect structural anomalies and potential GPI-AP deficits in the auditory system (ceroni2018largedeletionin pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - Cardiac: IGD systematic review catalogs cardiac involvement in GPI/CDG disorders including PIGL-CDG, supporting surveillance for congenital heart disease (conte2023metaboliccardiomyopathiesand pages 17-19). - Renal/urogenital: Hydronephrosis/urogenital anomalies variably reported (ceroni2018largedeletionin pages 1-2). - Placenta (mechanistic models): Pigl/Pigf deficiency impairs SynT-II differentiation via ER stress and WNT/β-catenin suppression; pharmacologic WNT activation rescues SynT-II markers in vitro, and gene signatures overlap with human preeclampsia datasets (alvarezsanchez2024thegpianchorbiosynthesis pages 8-9, alvarezsanchez2024thegpianchorbiosynthesis pages 1-2, alvarezsanchez2024thegpianchorbiosynthesis pages 2-3).

Genotype–Phenotype Highlights - Recurrent architecture: PIGL c.500T>C (p.Leu167Pro) frequently occurs in trans with a null allele; large deletions of PIGL (including 5′ UTR/part of exon 1) are overrepresented and often missed by routine sequencing; targeted CNV/large-deletion analysis is recommended when only one variant is found (ceroni2018largedeletionin pages 1-2). - Phenotypic breadth: PIGL variants can present as classic CHIME or with hyperphosphatasia and mental retardation syndrome–like features (HPMRS), including markedly elevated ALP (altassan2018hyperphosphatasiawithmental pages 1-2). IGD cohort data show synthesis-stage gene variants associate with shorter time to seizure onset than transamidase/remodeling genes (sidpra2024theclinicaland pages 1-1).

Diagnostics and Biomarkers - Cellular assays: Flow cytometry for GPI-APs (e.g., FLAER binding and CD55/CD59, CD24/CD16, CD14) can support IGD diagnosis by demonstrating reduced surface GPI-APs (wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). However, cell-surface GPI-AP levels on granulocytes do not consistently correlate with clinical severity across IGDs (tanigawa2017phenotype–genotypecorrelationsof pages 12-15). - Biochemical: Serum ALP often elevated in IGDs and is documented in PIGL-related disease; marked hyperphosphatasia reported (e.g., 968 U/L) (altassan2018hyperphosphatasiawithmental pages 1-2, patalan2024inheritedglycosylphosphatidylinositoldeficiency pages 1-3, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - Genomic: Sequence PIGL and assess for copy-number/structural variants due to frequent large deletions in CHIME (ceroni2018largedeletionin pages 1-2).

Current applications and real-world implementations - Clinical care: Multidisciplinary surveillance for seizures (early-onset), developmental therapies, audiology, ophthalmology for coloboma, dermatology for ichthyosis, and cardiology/renal evaluations given multisystem involvement (sidpra2024theclinicaland pages 1-1, ceroni2018largedeletionin pages 1-2, conte2023metaboliccardiomyopathiesand pages 17-19). Molecular diagnostics guide management and counseling (patalan2024inheritedglycosylphosphatidylinositoldeficiency pages 1-3). - Seizure management in IGDs: In the 2024 cohort, levetiracetam achieved control in 38.5% of treated individuals; pyridoxine produced complete or partial responses in a minority (4 complete, 3 partial among 22 trials) (sidpra2024theclinicaland pages 10-11). No surgical interventions were reported (sidpra2024theclinicaland pages 10-11). - Translational insight: Trophoblast data suggest tissue-specific vulnerabilities to GPI-AP loss (UPR/WNT defects), potentially informing obstetric monitoring in pregnancies with known fetal IGDs, though clinical translation to CHIME requires further evidence (alvarezsanchez2024thegpianchorbiosynthesis pages 8-9, alvarezsanchez2024thegpianchorbiosynthesis pages 1-2, alvarezsanchez2024thegpianchorbiosynthesis pages 2-3).

Expert opinions and analysis from authoritative sources - Authoritative pathway reviews and cohort studies conclude that GPI biosynthesis is essential for viability; hypomorphic germline variants cause heterogeneous neurocutaneous phenotypes through reduced GPI-AP expression (wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). The Brain 2024 cohort provides high-quality natural history and genotype-stage insights across IGDs (sidpra2024theclinicaland pages 1-1, sidpra2024theclinicaland pages 10-11). The 2024 CMLS mechanistic study offers strong causal evidence linking GPI pathway loss to ER stress and WNT signaling failure in trophoblast differentiation, with plausible implications for human placental disease (alvarezsanchez2024thegpianchorbiosynthesis pages 8-9, alvarezsanchez2024thegpianchorbiosynthesis pages 1-2, alvarezsanchez2024thegpianchorbiosynthesis pages 2-3).

Relevant statistics and data (recent) - IGD cohort (n=83): DD/ID 90%; seizures 83%; hypotonia 72%; motor symptoms 64%; cerebral atrophy 75%; cerebellar atrophy 60%; callosal anomalies 57%; central tegmental tract diffusion restriction 60%; median seizure onset 6 months; multisystem involvement: GI 66%, cardiac 19%, renal 14% (sidpra2024theclinicaland pages 1-1). - IGD treatment signals: Levetiracetam control in 38.5% (15/39 as part of polytherapy); pyridoxine trialed in 22 with 4 complete and 3 partial responses (sidpra2024theclinicaland pages 10-11). - PIGL genotype: recurrent p.Leu167Pro in trans with null alleles (with frequent large deletions), requiring targeted CNV assessment (ceroni2018largedeletionin pages 1-2). - ALP biomarker: hyperphosphatasia documented in PIGL-related presentations (e.g., 968 U/L) (altassan2018hyperphosphatasiawithmental pages 1-2).

Gene/protein annotations with ontology terms - PIGL (HGNC:8962): - Function: GlcNAc-PI de-N-acetylase (GPI anchor biosynthetic process; GO:0006506/GO:0006505 context) acting in ER membrane (GO:0005789) (altassan2018hyperphosphatasiawithmental pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - Localization: Endoplasmic reticulum membrane/cytoplasmic face (GO:0005789) (altassan2018hyperphosphatasiawithmental pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - Representative affected GPI-APs (examples): ALPL/TNAP, CD55, CD59, CD24, FCGR3 (CD16), CD14 (wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7).

Phenotype associations (HPO terms; examples) - Intellectual disability (HP:0001249), Developmental delay (HP:0001263), Seizures (HP:0001250), Hypotonia (HP:0001252) (sidpra2024theclinicaland pages 1-1). - Ichthyosis (HP:0008064) with migratory pattern (clinical description) (ceroni2018largedeletionin pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - Coloboma (HP:0000589) (ceroni2018largedeletionin pages 1-2). - Hearing impairment/conductive hearing loss (HP:0000405/HP:0000407) (ceroni2018largedeletionin pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - Congenital heart disease (HP:0001627) (conte2023metaboliccardiomyopathiesand pages 17-19, ceroni2018largedeletionin pages 1-2). - Renal/urogenital anomalies (e.g., hydronephrosis HP:0000126) (ceroni2018largedeletionin pages 1-2). - Brain atrophy (HP:0012444), Cerebellar atrophy (HP:0001272), Corpus callosum abnormality (HP:0001273) (sidpra2024theclinicaland pages 1-1).

Cell type involvement (CL; examples) - Neuron (CL:0000540), astrocyte (CL:0000127) (neurodevelopmental phenotypes) (sidpra2024theclinicaland pages 1-1). - Keratinocyte (CL:0000312) (ichthyosis) (ceroni2018largedeletionin pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - Trophoblast stem cell (CL:0008031), syncytiotrophoblast (CL:0000359) (alvarezsanchez2024thegpianchorbiosynthesis pages 8-9, alvarezsanchez2024thegpianchorbiosynthesis pages 2-3). - Granulocyte (CL:0000094), monocyte (CL:0000576) for diagnostic GPI-AP readouts (wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7).

Anatomical locations (UBERON; examples) - Brain (UBERON:0000955) and cerebellum (UBERON:0002037) (sidpra2024theclinicaland pages 1-1). - Eye/retina (UBERON:0000970) (coloboma) (ceroni2018largedeletionin pages 1-2). - Skin/epidermis (UBERON:0001003/0001002) (wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7, ceroni2018largedeletionin pages 1-2). - Ear (UBERON:0001690) (ceroni2018largedeletionin pages 1-2). - Heart (UBERON:0000948) (conte2023metaboliccardiomyopathiesand pages 17-19). - Kidney/urinary system (UBERON:0002113) (ceroni2018largedeletionin pages 1-2). - Placenta (UBERON:0001987) (alvarezsanchez2024thegpianchorbiosynthesis pages 2-3).

Chemical entities (CHEBI; examples) - N-acetylglucosaminyl-phosphatidylinositol (GlcNAc-PI) and glucosaminyl-PI (GlcN-PI) intermediates in GPI biosynthesis (altassan2018hyperphosphatasiawithmental pages 1-2, wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - CHIR99021 (GSK3 inhibitor; WNT activator) used in rescue experiments (alvarezsanchez2024thegpianchorbiosynthesis pages 8-9, alvarezsanchez2024thegpianchorbiosynthesis pages 9-11).

Evidence table | PMID | First author (year) | Study type | Key mechanistic/clinical finding | Relevance to CHIME/PIGL | URL | Publication date | |---|---|---|---|---|---|---| | | Sidpra (2024) | Multinational cohort (n=83 IGD) | Median age at seizure onset 6 months; high rates of developmental delay (90%), seizures (83%), hypotonia (72%); neuroimaging: cerebral atrophy 75%, cerebellar atrophy 60%, callosal anomalies 57%; synthesis-stage gene variants show shorter time-to-seizure vs transamidase/remodelling genes (cohort-level genotype signal) (sidpra2024theclinicaland pages 1-1) | Largest recent IGD cohort providing natural history benchmarks relevant to CHIME/PIGL (seizure onset, neuroimaging, multisystem involvement) | https://doi.org/10.1093/brain/awae056 | Mar 2024 | | | Álvarez-Sánchez (2024) | Mechanistic CRISPR KO study in mouse trophoblast stem cells / placentas | Pigl/Pigf loss → accumulation of misfolded GPI-AP precursors, robust ER stress / UPR (ATF4/ATF6/XBP1/Ddit3), increased mitochondrial respiration/ROS; downregulation of WNT ligands/receptors, reduced β-catenin and failed SynT-II differentiation; CHIR99021 (WNT activator) rescues β-catenin and SynT-II markers; Pigl/Pigf mutant transcriptomic signature segregates human preeclampsia samples (alvarezsanchez2024thegpianchorbiosynthesis pages 8-9) | Direct mechanistic link: PIGL deficiency → ER stress + impaired WNT/β-catenin signaling → defective syncytiotrophoblast differentiation; suggests tissue-specific consequences and relevance to placental disease | https://doi.org/10.1007/s00018-024-05284-2 | May 2024 | | | Ceroni (2018) | Genetic case report / series | PIGL encodes ER-localized GlcNAc-PI de-N-acetylase (step 2 of GPI biosynthesis); recurrent missense c.500T>C (p.Leu167Pro) frequently observed in CHIME patients, commonly in trans with a null allele (including large deletions involving 5'UTR/exon1) that may be missed by standard NGS; phenotype: ichthyosiform dermatosis, coloboma, ear anomalies, cardiac and renal anomalies, ID/epilepsy (ceroni2018largedeletionin pages 1-2) | Variant architecture and diagnostic note: p.Leu167Pro + null (often large deletions) is a recurrent CHIME genotype; emphasizes need to assay for copy-number/large deletions when one allele is not found | https://doi.org/10.1590/1678-4685-gmb-2017-0172 | Feb 2018 | | | Altassan (2018) | Case series / phenotype expansion report | Documents PIGL-related hyperphosphatasia with mental retardation (HPMRS-like) presentations; reports markedly elevated serum alkaline phosphatase (example ALP 968 U/L) with PIGL variants; links PIGL to both CHIME and Mabry/HPMRS phenotypes (altassan2018hyperphosphatasiawithmental pages 1-2) | Establishes ALP (hyperphosphatasia) as an important biochemical biomarker in some PIGL presentations and expands clinical phenotype spectrum | https://doi.org/10.1016/j.ymgmr.2018.01.007 | Jun 2018 | | | Wu (2020) | Review (GPI biosynthesis in human disease) | Summarizes PIGL function and structure (TM region aa2–22; de-N-acetylase domain aa44–168); documents common cellular readouts in IGDs: reduced CD59 and FLAER in fibroblasts, decreased CD24/CD16 on granulocytes and CD14 on monocytes; CHIME clinical features and many reported PIGL variants (wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7) | Provides molecular/domain annotation for PIGL, and practical diagnostic cellular assays (FLAER, CD55/CD59) used in IGD workups | https://doi.org/10.1186/s13023-020-01401-z | May 2020 | | | Patalan (2024) | Clinical review (Pediatria Polska) | Overview of inherited GPI deficiency disorders: ER-stage disruption (including PIGL) reduces GPI-AP presentation, can lead to degradation or release of abnormal GPI-APs; ALP abnormalities and multisystem involvement (neurological, cardiac, renal, GI, skin, sensory) emphasized; molecular testing recommended (patalan2024inheritedglycosylphosphatidylinositoldeficiency pages 1-3) | Recent clinical-summary supporting multisystem surveillance and use of molecular diagnostics for suspected CHIME/PIGL cases | https://doi.org/10.5114/polp.2024.146394 | Jan 2024 | | | Conte (2023) | Systematic review (cardiac involvement in carbohydrate-linked IMDs) | Highlights that several congenital glycosylation/GPI biosynthesis defects (including PIGL-CDG) present with cardiac defects/cardiomyopathy or structural cardiac anomalies and may contribute to childhood cardiac morbidity (conte2023metaboliccardiomyopathiesand pages 17-19) | Draws attention to cardiac surveillance as part of multisystem care in CHIME/PIGL patients and places PIGL-CDG among IMDs with cardiac risk | https://doi.org/10.3390/ijms24108632 | May 2023 |

Table: Table summarizing key mechanistic and clinical evidence (2018–2024) linking PIGL dysfunction to CHIME syndrome, with citations and source URLs for rapid reference.

Key evidence with URLs and publication dates (selected quotes) - “PIGL is an endoplasmic reticulum localized enzyme that catalyzes the second step of glycosylphosphatidylinositol (GPI) biosynthesis” (Genet Mol Biol, Feb 2018; https://doi.org/10.1590/1678-4685-gmb-2017-0172) (ceroni2018largedeletionin pages 1-2). - “Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset… Median age at seizure onset was 6 months” (Brain, Mar 2024; https://doi.org/10.1093/brain/awae056) (sidpra2024theclinicaland pages 1-1). - “Impaired GPI-AP generation induces an excessive unfolded protein response (UPR) in the ER… Upon differentiation, the impairment of the GPI pathway hinders the induction of WNT signaling for early SynT-II development… CHIR99021 rescues” (CMLS, May 2024; https://doi.org/10.1007/s00018-024-05284-2) (alvarezsanchez2024thegpianchorbiosynthesis pages 8-9, alvarezsanchez2024thegpianchorbiosynthesis pages 1-2, alvarezsanchez2024thegpianchorbiosynthesis pages 9-11, alvarezsanchez2024thegpianchorbiosynthesis pages 2-3). - “Alkaline phosphatase (ALP) serum level abnormalities… PIGL p.Leu167Pro recurrently in trans with null alleles, including large deletions missed by standard sequencing” (Genet Mol Biol, Feb 2018; https://doi.org/10.1590/1678-4685-gmb-2017-0172) (ceroni2018largedeletionin pages 1-2). - “Cellular readouts… reduced CD59 and FLAER… decreased CD24/CD16 on granulocytes and CD14 on monocytes” (OJRD, May 2020; https://doi.org/10.1186/s13023-020-01401-z) (wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - “Markedly elevated ALP (e.g., 968 U/L) in PIGL-related disease” (Mol Genet Metab Rep, Jun 2018; https://doi.org/10.1016/j.ymgmr.2018.01.007) (altassan2018hyperphosphatasiawithmental pages 1-2).

References (DOIs/URLs; publication dates) - Sidpra et al., Brain 2024; https://doi.org/10.1093/brain/awae056; Mar 2024 (sidpra2024theclinicaland pages 10-11, sidpra2024theclinicaland pages 1-1). - Álvarez-Sánchez et al., CMLS 2024; https://doi.org/10.1007/s00018-024-05284-2; May 2024 (alvarezsanchez2024thegpianchorbiosynthesis pages 8-9, alvarezsanchez2024thegpianchorbiosynthesis pages 1-2, alvarezsanchez2024thegpianchorbiosynthesis pages 9-11, alvarezsanchez2024thegpianchorbiosynthesis pages 7-8, alvarezsanchez2024thegpianchorbiosynthesis pages 2-3, alvarezsanchez2024thegpianchorbiosynthesis pages 4-5, alvarezsanchez2024thegpianchorbiosynthesis pages 3-4, alvarezsanchez2024thegpianchorbiosynthesis pages 6-7). - Ceroni et al., Genet Mol Biol 2018; https://doi.org/10.1590/1678-4685-gmb-2017-0172; Feb 2018 (ceroni2018largedeletionin pages 1-2). - Altassan et al., Mol Genet Metab Rep 2018; https://doi.org/10.1016/j.ymgmr.2018.01.007; Jun 2018 (altassan2018hyperphosphatasiawithmental pages 1-2). - Wu et al., Orphanet J Rare Dis 2020; https://doi.org/10.1186/s13023-020-01401-z; May 2020 (wu2020theglycosylphosphatidylinositolbiosynthesis pages 5-7). - Patalan et al., Pediatria Polska 2024; https://doi.org/10.5114/polp.2024.146394; Jan 2024 (patalan2024inheritedglycosylphosphatidylinositoldeficiency pages 1-3). - Conte et al., Int J Mol Sci 2023; https://doi.org/10.3390/ijms24108632; May 2023 (conte2023metaboliccardiomyopathiesand pages 17-19).

Completion status All required components are addressed with recent, authoritative citations. Where mechanistic links are model-derived (trophoblast UPR/WNT), they are explicitly attributed to the 2024 study and not overgeneralized to all CHIME tissues (alvarezsanchez2024thegpianchorbiosynthesis pages 8-9, alvarezsanchez2024thegpianchorbiosynthesis pages 1-2).

References

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