Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome

Mendelian MONDO:0000133 Pathograph 20 Primary Immunodeficiency Disease

Immunodeficiency-centromeric instability-facial anomalies syndrome is a rare autosomal recessive primary immunodeficiency caused by defects in DNA methylation and chromatin regulators. The syndrome combines hypogammaglobulinemia and variable combined immunodeficiency with juxtacentromeric heterochromatin hypomethylation, chromosome instability, and craniofacial and neurodevelopmental manifestations.

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1
Mappings
1
Definitions
1
Inheritance
6
Pathophys.
23
Phenotypes
20
Pathograph
5
Genes
3
Treatments
4
Subtypes
1
Models
1
Deep Research
🔗

Mappings

MONDO
MONDO:0000133 immunodeficiency-centromeric instability-facial anomalies syndrome
skos:exactMatch Orphanet ORPHA:2268
Orphanet ORPHA:2268 lists MONDO:0000133 as an exact cross-reference for ICF syndrome.
📘

Definitions

1
Orphanet ICF syndrome definition
A rare autosomal recessive syndrome with combined immunodeficiency, panhypogammaglobulinemia, deficient memory B cells, centromeric instability, DNA hypomethylation around juxtacentromeric heterochromatin, and typical facial anomalies.
OTHER
Show evidence (2 references)
ORPHA:2268 SUPPORT Other
"A rare autosomal recessive syndrome with combined immunodeficiency characterized by the clinical triad of immunodeficiency, centromeric instability and facial anomalies (abbreviated ICF syndrome)."
Orphanet defines the clinical triad and inheritance pattern.
PMID:23486536 SUPPORT Human Clinical
"Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies."
A 44-patient clinical-genetic study supports the primary immunodeficiency and triad framing.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
ICF syndrome is inherited in an autosomal recessive pattern.
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:2268 SUPPORT Other
"Autosomal recessive"
Orphanet records autosomal recessive inheritance for ICF syndrome.
PMID:28713390 SUPPORT Human Clinical
"Immunodeficiency, centromeric instability, and facial anomaly (ICF) syndrome is a rare autosomal recessive genetic condition with severe immunodeficiency"
The clinical case report explicitly describes ICF syndrome as autosomal recessive.
◆

Subtypes

4
ICF syndrome type 1 (DNMT3B-related) MONDO:0009454
~50-60% DNMT3B link
DNMT3B-related ICF syndrome subtype, historically the most common molecular subtype and associated with hypomorphic DNMT3B variants.
Show evidence (1 reference)
PMID:23486536 SUPPORT Human Clinical
"Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX)."
The clinical cohort defines DNMT3B-mutated cases as ICF1 and gives their proportion in the 44-patient series.
ICF syndrome type 2 (ZBTB24-related) MONDO:0013553
~30% ZBTB24 link
ZBTB24-related ICF syndrome subtype with humoral and age-progressive cellular immune involvement.
Show evidence (1 reference)
PMID:23486536 SUPPORT Human Clinical
"Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX)."
The clinical cohort defines ZBTB24-mutated cases as ICF2 and supports the approximate 30% subtype frequency.
ICF syndrome type 3 (CDCA7-related) MONDO:0014828
CDCA7 link
CDCA7-related ICF syndrome subtype within the genetically heterogeneous ICF disease series.
Show evidence (1 reference)
PMID:31724723 SUPPORT Other
"The hallmark of this syndrome is hypomethylation of pericentromeric satellite repeats, with mutations in four genes: DNMT3B, ZBTB24, CDCA7 and HELLS, being linked to the disease."
The review identifies CDCA7 among the established ICF genes.
ICF syndrome type 4 (HELLS-related) MONDO:0014829
HELLS link
HELLS-related ICF syndrome subtype within the genetically heterogeneous ICF disease series.
Show evidence (1 reference)
PMID:31724723 SUPPORT Other
"The hallmark of this syndrome is hypomethylation of pericentromeric satellite repeats, with mutations in four genes: DNMT3B, ZBTB24, CDCA7 and HELLS, being linked to the disease."
The review identifies HELLS among the established ICF genes.
⚙

Pathophysiology

6
ICF Gene Network Disruption
Disease-causing variants in DNMT3B, ZBTB24, CDCA7, HELLS, and UHRF1 disrupt a gene network required for normal DNA methylation and heterochromatin regulation.
DNMT3B link ZBTB24 link CDCA7 link HELLS link UHRF1 link
DNA methylation link ↓ DECREASED
Downstream
Pericentromeric Satellite Hypomethylation
Show evidence (5 references)
ORPHA:2268 SUPPORT Other
"DNMT3B | DNA methyltransferase 3 beta | hgnc:2979 | Disease-causing germline mutation(s) in"
Orphanet lists DNMT3B as a disease-causing ICF syndrome gene.
ORPHA:2268 SUPPORT Other
"ZBTB24 | zinc finger and BTB domain containing 24 | hgnc:21143 | Disease-causing germline mutation(s) in"
Orphanet lists ZBTB24 as a disease-causing ICF syndrome gene.
ORPHA:2268 SUPPORT Other
"CDCA7 | cell division cycle associated 7 | hgnc:14628 | Disease-causing germline mutation(s) in"
Orphanet lists CDCA7 as a disease-causing ICF syndrome gene.
+ 2 more references
Pericentromeric Satellite Hypomethylation
ICF gene defects cause hypomethylation of pericentromeric satellite repeats and juxtacentromeric heterochromatin, especially around chromosomes 1, 16, and sometimes 9.
DNA methylation link ↓ DECREASED
pericentric heterochromatin link
Downstream
Centromeric Chromosome Instability
Show evidence (2 references)
PMID:31724723 SUPPORT Other
"The hallmark of this syndrome is hypomethylation of pericentromeric satellite repeats, with mutations in four genes: DNMT3B, ZBTB24, CDCA7 and HELLS, being linked to the disease."
The review identifies pericentromeric satellite hypomethylation as the ICF hallmark.
ORPHA:2268 SUPPORT Other
"Anomalies and rearrangements associated with DNA hypomethylation in the vicinity of the centromeres (the juxtacentromeric heterochromatin) of chromosomes 1 and 16 and sometimes 9, in mitogen-stimulated lymphocytes, is a hallmark of the syndrome."
Orphanet directly describes juxtacentromeric hypomethylation as a hallmark.
Centromeric Chromosome Instability
Hypomethylated juxtacentromeric heterochromatin produces characteristic chromosomal fragile sites, whole-arm deletions, triradials, multiradials, translocations, and other rearrangements in mitogen-stimulated lymphocytes.
chromosome segregation link ⚠ ABNORMAL
Downstream
Chromosome instability
Memory B-Cell Differentiation and Antibody Production Failure
Progressive Combined T-Cell Immune Defect
Show evidence (2 references)
PMID:39958354 SUPPORT Human Clinical
"Karyotype analysis showed fragile sites and entire arm deletions were detected on chromosomes 1 and 16 and triradials on chromosome 16."
Human ICF2 cytogenetic testing demonstrates the characteristic chromosome instability.
PMID:25330735 SUPPORT Human Clinical
"We also demonstrate impaired cell-proliferation and increased cell death of immune and non-immune cells as well as data suggesting a chromosome separation defect in addition to the known chromosome condensation defect."
Human ICF2 data support chromosome-separation/condensation defects.
Memory B-Cell Differentiation and Antibody Production Failure
Epigenetic dysregulation in lymphocytes impairs terminal B-cell differentiation and immunoglobulin production, leaving B-cell counts relatively preserved but memory B cells and circulating immunoglobulins deficient.
memory B cell link B cell link
B cell differentiation link ↓ DECREASED
Downstream
Hypogammaglobulinemia
Recurrent respiratory infections
Show evidence (2 references)
ORPHA:2268 SUPPORT Other
"The immunodeficiency is with panhypogammaglobulinemia, and a lack of memory (CD19+CD27+) B cells in the peripheral blood, although B and T-cell counts are normal."
Orphanet describes deficient immunoglobulin and memory B cells despite normal lymphocyte counts.
PMID:23486536 SUPPORT Human Clinical
"systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B- and T-cell compartments are both involved in ICF1 and ICF2"
The patient cohort supports involvement of both humoral and cellular immune compartments.
Progressive Combined T-Cell Immune Defect
In at least ICF2, the immune phenotype can extend beyond a B-cell defect to impaired lymphocyte proliferation, increased cell death, and age-progressive combined immunodeficiency.
T cell link lymphocyte link
T cell proliferation link ↓ DECREASED
Downstream
Cellular immunodeficiency
Show evidence (2 references)
PMID:25330735 SUPPORT Human Clinical
"we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course"
The ICF2 case report supports progressive combined immune involvement.
PMID:28713390 SUPPORT Human Clinical
"An intrinsic T cell defect has also been linked to the high frequency of opportunistic infections from pathogens such as with Pneumocystis jirovecii (PJ), but the exact mechanism has not been elucidated"
The clinical report supports T-cell dysfunction contributing to opportunistic infection susceptibility.
ZBTB24-CDCA7 Transcriptional Activation Failure
ZBTB24 zinc-finger dysfunction can reduce transcriptional activation of CDCA7 and other target genes, recapitulating centromeric methylation defects and reducing hematopoietic progenitor output in an ICF2 iPSC model.
ZBTB24 link CDCA7 link
regulation of DNA-templated transcription link ↓ DECREASED
Experimental models
Patient-derived ICF2 induced pluripotent stem cells The iPSC model recapitulates ZBTB24-dependent transcriptional activation failure and downstream centromeric hypomethylation.
Downstream
Pericentromeric Satellite Hypomethylation
Cellular immunodeficiency
Show evidence (1 reference)
PMID:39040103 SUPPORT In Vitro
"We validated that the mutated ZBTB24 protein loses its ability to directly activate expression of CDCA7 and other target genes in the patient-derived iPSCs."
The ICF2 iPSC model provides direct evidence of impaired ZBTB24 transcriptional activation of CDCA7 and target genes.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

23
Blood 3
Lymphopenia FREQUENT Decreased total lymphocyte count (HP:0001888)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0001888 | Lymphopenia | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Anemia FREQUENT Anemia (HP:0001903)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0001903 | Anemia | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Hypogammaglobulinemia VERY_FREQUENT Decreased circulating immunoglobulin concentration (HP:0004313)
Show evidence (2 references)
ORPHA:2268 SUPPORT Other
"HP:0004313 | Decreased circulating antibody level | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band; the HPO canonical label is decreased circulating immunoglobulin concentration.
PMID:23486536 SUPPORT Human Clinical
"Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies."
The patient cohort identifies agammaglobulinemia or hypoimmunoglobulinemia as a predominant feature.
Digestive 1
Malabsorption FREQUENT Malabsorption (HP:0002024)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0002024 | Malabsorption | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Ear 1
Low-set ears OCCASIONAL Low-set ears (HP:0000369)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0000369 | Low-set ears | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Eye 1
Hypertelorism OCCASIONAL Hypertelorism (HP:0000316)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0000316 | Hypertelorism | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Head and Neck 6
Macroglossia OCCASIONAL Macroglossia (HP:0000158)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0000158 | Macroglossia | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Macrocephaly FREQUENT Macrocephaly (HP:0000256)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0000256 | Macrocephaly | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Epicanthus OCCASIONAL Epicanthus (HP:0000286)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0000286 | Epicanthus | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Micrognathia VERY_FREQUENT Micrognathia (HP:0000347)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0000347 | Micrognathia | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Depressed nasal bridge FREQUENT Depressed nasal bridge (HP:0005280)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0005280 | Depressed nasal bridge | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Flat face OCCASIONAL Flat face (HP:0012368)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0012368 | Flat face | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Immune 2
Recurrent respiratory infections VERY_FREQUENT Recurrent respiratory infections (HP:0002205)
Show evidence (2 references)
ORPHA:2268 SUPPORT Other
"HP:0002205 | Recurrent respiratory infections | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
PMID:40585468 SUPPORT Human Clinical
"A male child with recurrent respiratory tract infections, ear discharge and facial anomalies."
The case report provides a human clinical example of recurrent respiratory infections.
Immunodeficiency VERY_FREQUENT Immunodeficiency (HP:0002721)
Show evidence (2 references)
ORPHA:2268 SUPPORT Other
"HP:0002721 | Immunodeficiency | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
PMID:39958354 SUPPORT Human Clinical
"The novel multi-exon deletion of ZBTB24 causes immunodeficiency, severe pneumonia and centromeric instability in the patient."
The ICF2 case report supports immunodeficiency and severe infection.
Nervous System 2
Intellectual disability FREQUENT Intellectual disability (HP:0001249)
Show evidence (2 references)
ORPHA:2268 SUPPORT Other
"HP:0001249 | Intellectual disability | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
PMID:23486536 SUPPORT Human Clinical
"ICF2 patients have a significantly higher incidence of intellectual disability"
The clinical cohort supports intellectual disability, especially in ICF2.
Global developmental delay FREQUENT Global developmental delay (HP:0001263)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0001263 | Global developmental delay | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Growth 1
Short stature VERY_FREQUENT Short stature (HP:0004322)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0004322 | Short stature | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
Other 6
Communicating hydrocephalus FREQUENT Communicating hydrocephalus (HP:0001334)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0001334 | Communicating hydrocephalus | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Umbilical hernia OCCASIONAL Umbilical hernia (HP:0001537)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0001537 | Umbilical hernia | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
Abnormality of neutrophils FREQUENT Abnormality of neutrophils (HP:0001874)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0001874 | Abnormality of neutrophils | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
Chromosome instability VERY_FREQUENT Abnormality of chromosome stability (HP:0003220)
Show evidence (2 references)
ORPHA:2268 SUPPORT Other
"HP:0003220 | Abnormality of chromosome stability | Very frequent (99-80%)"
Orphanet provides the disease-phenotype association and frequency band.
PMID:39958354 SUPPORT Human Clinical
"Karyotype analysis showed fragile sites and entire arm deletions were detected on chromosomes 1 and 16 and triradials on chromosome 16."
The ICF2 case report supports chromosomal instability in patient cells.
Cellular immunodeficiency FREQUENT Cellular immunodeficiency (HP:0005374)
Show evidence (2 references)
ORPHA:2268 SUPPORT Other
"HP:0005374 | Cellular immunodeficiency | Frequent (79-30%)"
Orphanet provides the disease-phenotype association and frequency band.
PMID:25330735 SUPPORT Human Clinical
"we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course"
The ICF2 report supports cellular immune involvement beyond isolated humoral deficiency.
Protruding tongue OCCASIONAL Protruding tongue (HP:0010808)
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"HP:0010808 | Protruding tongue | Occasional (29-5%)"
Orphanet provides the disease-phenotype association and frequency band.
🧬

Genetic Associations

5
Biallelic DNMT3B pathogenic variants (Causative)
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:2268 SUPPORT Other
"DNMT3B | DNA methyltransferase 3 beta | hgnc:2979 | Disease-causing germline mutation(s) in"
Orphanet identifies DNMT3B as a disease-causing gene.
PMID:30406101 SUPPORT Other
"The autosomal recessive Immunodeficiency, Centromeric instability and Facial anomalies syndrome, type I (ICF-1), is associated to hypomorphic mutations in DNMT3B gene"
The review links ICF1 to hypomorphic DNMT3B mutations.
Biallelic ZBTB24 pathogenic variants (Causative)
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:2268 SUPPORT Other
"ZBTB24 | zinc finger and BTB domain containing 24 | hgnc:21143 | Disease-causing germline mutation(s) in"
Orphanet identifies ZBTB24 as a disease-causing gene.
PMID:39958354 SUPPORT Human Clinical
"These results indicated that this novel multi-exon deletion variant of ZBTB24 may be the genetic etiology of ICF2."
The ICF2 case report links a homozygous ZBTB24 deletion to ICF2.
Biallelic CDCA7 pathogenic variants (Causative)
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:2268 SUPPORT Other
"CDCA7 | cell division cycle associated 7 | hgnc:14628 | Disease-causing germline mutation(s) in"
Orphanet identifies CDCA7 as a disease-causing gene.
PMID:31724723 SUPPORT Other
"The hallmark of this syndrome is hypomethylation of pericentromeric satellite repeats, with mutations in four genes: DNMT3B, ZBTB24, CDCA7 and HELLS, being linked to the disease."
The review identifies CDCA7 as one of the established ICF genes.
Biallelic HELLS pathogenic variants (Causative)
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:2268 SUPPORT Other
"HELLS | helicase, lymphoid specific | hgnc:4861 | Disease-causing germline mutation(s) in"
Orphanet identifies HELLS as a disease-causing gene.
PMID:31724723 SUPPORT Other
"The hallmark of this syndrome is hypomethylation of pericentromeric satellite repeats, with mutations in four genes: DNMT3B, ZBTB24, CDCA7 and HELLS, being linked to the disease."
The review identifies HELLS as one of the established ICF genes.
Biallelic UHRF1 pathogenic variants (Causative)
Autosomal recessive inheritance
Show evidence (1 reference)
ORPHA:2268 SUPPORT Other
"UHRF1 | ubiquitin like with PHD and ring finger domains 1 | hgnc:12556 | Disease-causing germline mutation(s) in"
Orphanet identifies UHRF1 as a disease-causing gene in the ICF syndrome disease series.
💊

Treatments

3
Immunoglobulin replacement therapy
Action: Intravenous Immunoglobulin Therapy NCIT:C121331
IgG or intravenous immunoglobulin replacement is used to manage antibody deficiency and reduce infection burden, but it does not correct non-immune epigenetic disease manifestations.
Target Phenotypes: Hypogammaglobulinemia ↗ Recurrent respiratory infections ↗
Show evidence (2 references)
PMID:28713390 SUPPORT Human Clinical
"Early IgG replacement and antibiotic prophylaxis can significantly improve patient outcomes (10)."
The treatment report supports early immunoglobulin replacement as clinically beneficial supportive therapy.
PMID:40585468 SUPPORT Human Clinical
"Treatments like immunoglobulin supplementation or allogeneic stem cell transplantation can improve the chances of survival and enhance the quality of life."
The case report supports immunoglobulin supplementation as a management option.
Antimicrobial prophylaxis and treatment
Action: antimicrobial pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986
Agent: sulfamethoxazole ↗ trimethoprim ↗
Antibiotic or antimicrobial prophylaxis and treatment are used to prevent or manage recurrent and opportunistic infections, including Pneumocystis jirovecii infection risk.
Target Phenotypes: Recurrent respiratory infections ↗
Show evidence (1 reference)
PMID:28713390 SUPPORT Human Clinical
"Treatment options are limited and consist primarily of supportive therapy such as substitution of immunoglobulins, prophylactic sulfamethoxazole–trimethoprim therapy, or antibiotic therapy (6–8)."
The treatment report supports antimicrobial prophylaxis and antibiotic therapy as supportive management.
Hematopoietic stem cell transplantation
Action: hematopoietic stem cell transplantation MAXO:0000747
Allogeneic hematopoietic stem cell transplantation can reconstitute hematopoietic immune function and may cure the immunodeficiency component in selected patients, while chromosome instability and facial or neurologic manifestations remain outside its direct corrective effect.
Mechanism Target:
RESTORES Memory B-Cell Differentiation and Antibody Production Failure — HSCT replaces hematopoietic cells carrying the causal variant and can restore immune-cell and immunoglobulin function.
Show evidence (1 reference)
PMID:28713390 SUPPORT Human Clinical
"HSCT replaces all hematopoietic cells carrying the DNMT3B mutation and can thereby cure the immunodeficiency in ICF patients."
The full-text clinical report explicitly states the proposed immune-corrective mechanism of HSCT.
Target Phenotypes: Immunodeficiency ↗ Hypogammaglobulinemia ↗
Show evidence (2 references)
PMID:28713390 SUPPORT Human Clinical
"Early diagnosis and subsequent HSCT can prevent severe opportunistic infections and cure the immunodeficiency."
The report supports HSCT as an immune-directed curative treatment in selected ICF patients.
PMID:28713390 SUPPORT Human Clinical
"Centromeric instability and facial anomaly remain unaffected."
The report clarifies that HSCT targets immune dysfunction rather than all ICF manifestations.
🧫

Experimental Models

1
Patient-derived ICF2 induced pluripotent stem cells
Patient-derived iPSCs carrying a homozygous ZBTB24 p.Cys408Gly mutation model ICF2 methylation defects, loss of CDCA7 activation, and impaired hematopoietic differentiation.
Organism
human ↗
Pathograph links
ZBTB24-CDCA7 Transcriptional Activation Failure The iPSC model recapitulates ZBTB24-dependent transcriptional activation failure and downstream centromeric hypomethylation.
Show evidence (1 reference)
PMID:39040103 SUPPORT In Vitro
"Overall, the ICF2-iPSC model is highly relevant to explore the role of ZBTB24 in DNA methylation homeostasis and provides a tool to investigate the early molecular events linking ZBTB24 deficiency to the ICF2 clinical phenotype."
The paper directly frames the iPSC model as informative for early ZBTB24-to-phenotype mechanisms.
Show evidence (1 reference)
PMID:39040103 SUPPORT In Vitro
"Here, we generated a novel ICF2 disease model by deriving induced pluripotent stem cells (iPSCs) from peripheral CD34+-blood cells of a patient homozygous for the p.Cys408Gly mutation"
The study describes generation of a patient-derived ICF2 iPSC model.
{ }

Source YAML

click to show 
name: Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome
category: Mendelian
creation_date: "2026-05-10T06:09:11Z"
updated_date: "2026-05-10T06:09:11Z"
synonyms:
- ICF syndrome
- Immunodeficiency-centromeric instability-facial dysmorphism syndrome
description: >
  Immunodeficiency-centromeric instability-facial anomalies syndrome is a rare
  autosomal recessive primary immunodeficiency caused by defects in DNA
  methylation and chromatin regulators. The syndrome combines
  hypogammaglobulinemia and variable combined immunodeficiency with
  juxtacentromeric heterochromatin hypomethylation, chromosome instability, and
  craniofacial and neurodevelopmental manifestations.
disease_term:
  preferred_term: immunodeficiency-centromeric instability-facial anomalies syndrome
  term:
    id: MONDO:0000133
    label: immunodeficiency-centromeric instability-facial anomalies syndrome
parents:
- Primary Immunodeficiency Disease
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0000133
      label: immunodeficiency-centromeric instability-facial anomalies syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:2268
    mapping_justification: >
      Orphanet ORPHA:2268 lists MONDO:0000133 as an exact cross-reference for
      ICF syndrome.
external_assertions:
- name: Orphanet ICF syndrome disease record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:2268
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=2268
  description: >
    Orphanet's ORPHA:2268 structured record for ICF syndrome includes the exact
    MONDO cross-reference, definition, autosomal recessive inheritance,
    epidemiology, disease-causing genes, natural-history onset, and HPO
    phenotype annotations used in this entry.
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0000133 | Exact"
    explanation: Orphanet maps ORPHA:2268 to the same MONDO identifier used by this entry.
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:242860 | Broader"
    explanation: Orphanet lists OMIM:242860 among the external cross-references for the ICF syndrome disease series.
definitions:
- name: Orphanet ICF syndrome definition
  definition_type: OTHER
  description: >
    A rare autosomal recessive syndrome with combined immunodeficiency,
    panhypogammaglobulinemia, deficient memory B cells, centromeric
    instability, DNA hypomethylation around juxtacentromeric heterochromatin,
    and typical facial anomalies.
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare autosomal recessive syndrome with combined immunodeficiency characterized by the clinical triad of immunodeficiency, centromeric instability and facial anomalies (abbreviated ICF syndrome)."
    explanation: Orphanet defines the clinical triad and inheritance pattern.
  - reference: PMID:23486536
    reference_title: "Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies."
    explanation: A 44-patient clinical-genetic study supports the primary immunodeficiency and triad framing.
inheritance:
- name: Autosomal recessive inheritance
  description: ICF syndrome is inherited in an autosomal recessive pattern.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance for ICF syndrome.
  - reference: PMID:28713390
    reference_title: "Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunodeficiency, centromeric instability, and facial anomaly (ICF) syndrome is a rare autosomal recessive genetic condition with severe immunodeficiency"
    explanation: The clinical case report explicitly describes ICF syndrome as autosomal recessive.
has_subtypes:
- name: ICF1
  display_name: ICF syndrome type 1 (DNMT3B-related)
  subtype_term:
    preferred_term: immunodeficiency-centromeric instability-facial anomalies syndrome 1
    term:
      id: MONDO:0009454
      label: immunodeficiency-centromeric instability-facial anomalies syndrome 1
  subtype_frequency: "~50-60%"
  description: >
    DNMT3B-related ICF syndrome subtype, historically the most common molecular
    subtype and associated with hypomorphic DNMT3B variants.
  genes:
  - preferred_term: DNMT3B
    term:
      id: hgnc:2979
      label: DNMT3B
  evidence:
  - reference: PMID:23486536
    reference_title: "Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX)."
    explanation: The clinical cohort defines DNMT3B-mutated cases as ICF1 and gives their proportion in the 44-patient series.
- name: ICF2
  display_name: ICF syndrome type 2 (ZBTB24-related)
  subtype_term:
    preferred_term: immunodeficiency-centromeric instability-facial anomalies syndrome 2
    term:
      id: MONDO:0013553
      label: immunodeficiency-centromeric instability-facial anomalies syndrome 2
  subtype_frequency: "~30%"
  description: >
    ZBTB24-related ICF syndrome subtype with humoral and age-progressive
    cellular immune involvement.
  genes:
  - preferred_term: ZBTB24
    term:
      id: hgnc:21143
      label: ZBTB24
  evidence:
  - reference: PMID:23486536
    reference_title: "Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX)."
    explanation: The clinical cohort defines ZBTB24-mutated cases as ICF2 and supports the approximate 30% subtype frequency.
- name: ICF3
  display_name: ICF syndrome type 3 (CDCA7-related)
  subtype_term:
    preferred_term: immunodeficiency-centromeric instability-facial anomalies syndrome 3
    term:
      id: MONDO:0014828
      label: immunodeficiency-centromeric instability-facial anomalies syndrome 3
  description: >
    CDCA7-related ICF syndrome subtype within the genetically heterogeneous ICF
    disease series.
  genes:
  - preferred_term: CDCA7
    term:
      id: hgnc:14628
      label: CDCA7
  evidence:
  - reference: PMID:31724723
    reference_title: "DNA methylation in disease: Immunodeficiency, Centromeric instability, Facial anomalies syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The hallmark of this syndrome is hypomethylation of pericentromeric satellite repeats, with mutations in four genes: DNMT3B, ZBTB24, CDCA7 and HELLS, being linked to the disease."
    explanation: The review identifies CDCA7 among the established ICF genes.
- name: ICF4
  display_name: ICF syndrome type 4 (HELLS-related)
  subtype_term:
    preferred_term: immunodeficiency-centromeric instability-facial anomalies syndrome 4
    term:
      id: MONDO:0014829
      label: immunodeficiency-centromeric instability-facial anomalies syndrome 4
  description: >
    HELLS-related ICF syndrome subtype within the genetically heterogeneous ICF
    disease series.
  genes:
  - preferred_term: HELLS
    term:
      id: hgnc:4861
      label: HELLS
  evidence:
  - reference: PMID:31724723
    reference_title: "DNA methylation in disease: Immunodeficiency, Centromeric instability, Facial anomalies syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The hallmark of this syndrome is hypomethylation of pericentromeric satellite repeats, with mutations in four genes: DNMT3B, ZBTB24, CDCA7 and HELLS, being linked to the disease."
    explanation: The review identifies HELLS among the established ICF genes.
prevalence:
- population: Worldwide
  percentage: "<1 / 1,000,000"
  notes: >
    ICF syndrome is ultra-rare. Orphanet records worldwide point prevalence
    below one per million, and the 2013 cohort paper reports collection of 44
    patients for genotype-phenotype comparison.
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
    explanation: Orphanet records a worldwide point-prevalence band below one per million.
  - reference: PMID:23486536
    reference_title: "Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we compared clinical and genetic data of 44 ICF patients."
    explanation: The cohort size is consistent with an ultra-rare disease.
progression:
- phase: Childhood-onset recurrent infection phase
  age_range: Childhood, often infancy or early childhood
  notes: >
    The immunodeficiency often presents early with recurrent pulmonary and
    gastrointestinal infections; prognosis is strongly influenced by infection
    burden and treatment.
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Childhood"
    explanation: Orphanet records childhood onset.
  - reference: PMID:28713390
    reference_title: "Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ICF patients suffer from recurrent gastrointestinal and pulmonary infections in early childhood due to the agammablobulinemia resulting in failure to thrive"
    explanation: The clinical report supports early-childhood infectious morbidity.
- phase: Age-progressive combined immune dysfunction
  age_range: Childhood through later disease course
  notes: >
    Although ICF is often recognized as a humoral immunodeficiency, cellular
    immune defects, impaired proliferation, and cell death may become more
    apparent with age in ICF2.
  evidence:
  - reference: PMID:25330735
    reference_title: Combined immunodeficiency develops with age in Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course"
    explanation: The ICF2 report supports progression from a B-cell framing to combined immune dysfunction.
pathophysiology:
- name: ICF Gene Network Disruption
  description: >
    Disease-causing variants in DNMT3B, ZBTB24, CDCA7, HELLS, and UHRF1 disrupt
    a gene network required for normal DNA methylation and heterochromatin
    regulation.
  genes:
  - preferred_term: DNMT3B
    term:
      id: hgnc:2979
      label: DNMT3B
  - preferred_term: ZBTB24
    term:
      id: hgnc:21143
      label: ZBTB24
  - preferred_term: CDCA7
    term:
      id: hgnc:14628
      label: CDCA7
  - preferred_term: HELLS
    term:
      id: hgnc:4861
      label: HELLS
  - preferred_term: UHRF1
    term:
      id: hgnc:12556
      label: UHRF1
  biological_processes:
  - preferred_term: DNA methylation
    term:
      id: GO:0006304
      label: DNA modification
    modifier: DECREASED
  downstream:
  - target: Pericentromeric Satellite Hypomethylation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31724723
      reference_title: "DNA methylation in disease: Immunodeficiency, Centromeric instability, Facial anomalies syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The hallmark of this syndrome is hypomethylation of pericentromeric satellite repeats, with mutations in four genes: DNMT3B, ZBTB24, CDCA7 and HELLS, being linked to the disease."
      explanation: The review directly links the canonical ICF genes to pericentromeric satellite hypomethylation.
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DNMT3B | DNA methyltransferase 3 beta | hgnc:2979 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists DNMT3B as a disease-causing ICF syndrome gene.
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ZBTB24 | zinc finger and BTB domain containing 24 | hgnc:21143 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists ZBTB24 as a disease-causing ICF syndrome gene.
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CDCA7 | cell division cycle associated 7 | hgnc:14628 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists CDCA7 as a disease-causing ICF syndrome gene.
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HELLS | helicase, lymphoid specific | hgnc:4861 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists HELLS as a disease-causing ICF syndrome gene.
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "UHRF1 | ubiquitin like with PHD and ring finger domains 1 | hgnc:12556 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists UHRF1 as a disease-causing ICF syndrome gene.
- name: Pericentromeric Satellite Hypomethylation
  description: >
    ICF gene defects cause hypomethylation of pericentromeric satellite repeats
    and juxtacentromeric heterochromatin, especially around chromosomes 1, 16,
    and sometimes 9.
  biological_processes:
  - preferred_term: DNA methylation
    term:
      id: GO:0006304
      label: DNA modification
    modifier: DECREASED
  cellular_components:
  - preferred_term: pericentric heterochromatin
    term:
      id: GO:0005721
      label: pericentric heterochromatin
  downstream:
  - target: Centromeric Chromosome Instability
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26161907
      reference_title: Genome-Wide DNA Methylation Analysis Identifies Novel Hypomethylated Non-Pericentromeric Genes with Potential Clinical Implications in ICF Syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Immunodeficiency, centromeric instability and facial anomalies syndrome (ICF) is a rare autosomal recessive disease, characterized by severe hypomethylation in pericentromeric regions of chromosomes (1, 16 and 9), marked immunodeficiency and facial anomalies."
      explanation: Patient-derived cell methylation data connect pericentromeric hypomethylation with the ICF phenotype.
  evidence:
  - reference: PMID:31724723
    reference_title: "DNA methylation in disease: Immunodeficiency, Centromeric instability, Facial anomalies syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The hallmark of this syndrome is hypomethylation of pericentromeric satellite repeats, with mutations in four genes: DNMT3B, ZBTB24, CDCA7 and HELLS, being linked to the disease."
    explanation: The review identifies pericentromeric satellite hypomethylation as the ICF hallmark.
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Anomalies and rearrangements associated with DNA hypomethylation in the vicinity of the centromeres (the juxtacentromeric heterochromatin) of chromosomes 1 and 16 and sometimes 9, in mitogen-stimulated lymphocytes, is a hallmark of the syndrome."
    explanation: Orphanet directly describes juxtacentromeric hypomethylation as a hallmark.
- name: Centromeric Chromosome Instability
  description: >
    Hypomethylated juxtacentromeric heterochromatin produces characteristic
    chromosomal fragile sites, whole-arm deletions, triradials, multiradials,
    translocations, and other rearrangements in mitogen-stimulated lymphocytes.
  biological_processes:
  - preferred_term: chromosome segregation
    term:
      id: GO:0007059
      label: chromosome segregation
    modifier: ABNORMAL
  downstream:
  - target: Chromosome instability
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2268
      reference_title: "ICF syndrome (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003220 | Abnormality of chromosome stability | Very frequent (99-80%)"
      explanation: Orphanet lists abnormal chromosome stability as a very frequent ICF phenotype.
  - target: Memory B-Cell Differentiation and Antibody Production Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Chromosome instability in mitogen-stimulated lymphocytes disrupts B-cell immunoglobulin isotype switching and immune-cell regulation.
    evidence:
    - reference: PMID:28713390
      reference_title: "Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This is especially seen in mitogen-stimulated lymphocytes where whole arm deletions, translocations, and multibranched chromosomes cause an abnormal gene regulation of B cell immunoglobulin isotype switching, lymphocyte activation, and migration"
      explanation: The ICF clinical report links lymphocyte chromosome rearrangements to abnormal regulation of B-cell isotype switching and lymphocyte functions.
  - target: Progressive Combined T-Cell Immune Defect
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Chromosome instability in mitogen-stimulated lymphocytes perturbs lymphocyte activation and proliferation.
    evidence:
    - reference: PMID:28713390
      reference_title: "Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This is especially seen in mitogen-stimulated lymphocytes where whole arm deletions, translocations, and multibranched chromosomes cause an abnormal gene regulation of B cell immunoglobulin isotype switching, lymphocyte activation, and migration"
      explanation: The same lymphocyte chromosomal-instability mechanism supports downstream lymphocyte activation defects that contribute to the combined cellular immune phenotype.
  evidence:
  - reference: PMID:39958354
    reference_title: "Case report: Novel multi-exon homozygous deletion of ZBTB24 causes immunodeficiency, centromeric instability, and facial anomalies syndrome 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Karyotype analysis showed fragile sites and entire arm deletions were detected on chromosomes 1 and 16 and triradials on chromosome 16."
    explanation: Human ICF2 cytogenetic testing demonstrates the characteristic chromosome instability.
  - reference: PMID:25330735
    reference_title: Combined immunodeficiency develops with age in Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also demonstrate impaired cell-proliferation and increased cell death of immune and non-immune cells as well as data suggesting a chromosome separation defect in addition to the known chromosome condensation defect."
    explanation: Human ICF2 data support chromosome-separation/condensation defects.
- name: Memory B-Cell Differentiation and Antibody Production Failure
  description: >
    Epigenetic dysregulation in lymphocytes impairs terminal B-cell
    differentiation and immunoglobulin production, leaving B-cell counts
    relatively preserved but memory B cells and circulating immunoglobulins
    deficient.
  cell_types:
  - preferred_term: memory B cell
    term:
      id: CL:0000787
      label: memory B cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: B cell differentiation
    term:
      id: GO:0030183
      label: B cell differentiation
    modifier: DECREASED
  downstream:
  - target: Hypogammaglobulinemia
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2268
      reference_title: "ICF syndrome (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0004313 | Decreased circulating antibody level | Very frequent (99-80%)"
      explanation: Orphanet lists decreased circulating antibody level as a very frequent phenotype.
  - target: Recurrent respiratory infections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Hypogammaglobulinemia and impaired immune memory reduce respiratory pathogen control.
    evidence:
    - reference: PMID:28713390
      reference_title: "Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "ICF patients suffer from recurrent gastrointestinal and pulmonary infections in early childhood due to the agammablobulinemia resulting in failure to thrive"
      explanation: The clinical report links agammaglobulinemia to recurrent pulmonary and gastrointestinal infections.
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The immunodeficiency is with panhypogammaglobulinemia, and a lack of memory (CD19+CD27+) B cells in the peripheral blood, although B and T-cell counts are normal."
    explanation: Orphanet describes deficient immunoglobulin and memory B cells despite normal lymphocyte counts.
  - reference: PMID:23486536
    reference_title: "Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B- and T-cell compartments are both involved in ICF1 and ICF2"
    explanation: The patient cohort supports involvement of both humoral and cellular immune compartments.
- name: Progressive Combined T-Cell Immune Defect
  description: >
    In at least ICF2, the immune phenotype can extend beyond a B-cell defect to
    impaired lymphocyte proliferation, increased cell death, and age-progressive
    combined immunodeficiency.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: lymphocyte
    term:
      id: CL:0000542
      label: lymphocyte
  biological_processes:
  - preferred_term: T cell proliferation
    term:
      id: GO:0042098
      label: T cell proliferation
    modifier: DECREASED
  downstream:
  - target: Cellular immunodeficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39958354
      reference_title: "Case report: Novel multi-exon homozygous deletion of ZBTB24 causes immunodeficiency, centromeric instability, and facial anomalies syndrome 2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Immunodeficiency, centromeric instability, and facial anomalies syndrome (ICF) is a rare genetic disease characterized by hypogammaglobulinemia, T cell immune deficiency with age, pericentromeric hypomethylation, facial abnormalities, and intellectual disability."
      explanation: The ICF2 report directly identifies age-associated T-cell immune deficiency.
  evidence:
  - reference: PMID:25330735
    reference_title: Combined immunodeficiency develops with age in Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course"
    explanation: The ICF2 case report supports progressive combined immune involvement.
  - reference: PMID:28713390
    reference_title: "Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An intrinsic T cell defect has also been linked to the high frequency of opportunistic infections from pathogens such as with Pneumocystis jirovecii (PJ), but the exact mechanism has not been elucidated"
    explanation: The clinical report supports T-cell dysfunction contributing to opportunistic infection susceptibility.
- name: ZBTB24-CDCA7 Transcriptional Activation Failure
  subtypes:
  - ICF2
  description: >
    ZBTB24 zinc-finger dysfunction can reduce transcriptional activation of
    CDCA7 and other target genes, recapitulating centromeric methylation defects
    and reducing hematopoietic progenitor output in an ICF2 iPSC model.
  genes:
  - preferred_term: ZBTB24
    term:
      id: hgnc:21143
      label: ZBTB24
  - preferred_term: CDCA7
    term:
      id: hgnc:14628
      label: CDCA7
  biological_processes:
  - preferred_term: regulation of DNA-templated transcription
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    modifier: DECREASED
  downstream:
  - target: Pericentromeric Satellite Hypomethylation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Mutated ZBTB24 loses transcriptional activation of CDCA7 and other DNA-methylation-homeostasis target genes.
    evidence:
    - reference: PMID:39040103
      reference_title: "A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "ICF2-iPSCs recapitulate the methylation defects associated with ZBTB24 deficiency, including centromeric hypomethylation."
      explanation: Patient-derived iPSCs support centromeric hypomethylation downstream of ZBTB24 deficiency.
  - target: Cellular immunodeficiency
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced hematopoietic differentiation from patient-derived iPSCs may contribute to immune-cell deficits.
    evidence:
    - reference: PMID:39040103
      reference_title: "A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Upon hematopoietic differentiation, ICF2-iPSCs showed decreased vitality and a lower percentage of CD34+/CD43+/CD45+ progenitors."
      explanation: The iPSC model links ZBTB24 deficiency to impaired hematopoietic progenitor generation.
  evidence:
  - reference: PMID:39040103
    reference_title: "A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We validated that the mutated ZBTB24 protein loses its ability to directly activate expression of CDCA7 and other target genes in the patient-derived iPSCs."
    explanation: The ICF2 iPSC model provides direct evidence of impaired ZBTB24 transcriptional activation of CDCA7 and target genes.
phenotypes:
- category: Craniofacial
  name: Macroglossia
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Macroglossia
    term:
      id: HP:0000158
      label: Macroglossia
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000158 | Macroglossia | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- category: Neurological
  name: Macrocephaly
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000256 | Macrocephaly | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- category: Craniofacial
  name: Epicanthus
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000286 | Epicanthus | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- category: Craniofacial
  name: Hypertelorism
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000316 | Hypertelorism | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- category: Craniofacial
  name: Micrognathia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000347 | Micrognathia | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- category: Craniofacial
  name: Low-set ears
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000369 | Low-set ears | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- category: Neurological
  name: Intellectual disability
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001249 | Intellectual disability | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
  - reference: PMID:23486536
    reference_title: "Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ICF2 patients have a significantly higher incidence of intellectual disability"
    explanation: The clinical cohort supports intellectual disability, especially in ICF2.
- category: Neurological
  name: Global developmental delay
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001263 | Global developmental delay | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- category: Neurological
  name: Communicating hydrocephalus
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Communicating hydrocephalus
    term:
      id: HP:0001334
      label: Communicating hydrocephalus
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001334 | Communicating hydrocephalus | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- category: Abdominal
  name: Umbilical hernia
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001537 | Umbilical hernia | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- category: Hematologic
  name: Abnormality of neutrophils
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormality of neutrophils
    term:
      id: HP:0001874
      label: Abnormality of neutrophils
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001874 | Abnormality of neutrophils | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- category: Hematologic
  name: Lymphopenia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Lymphopenia
    term:
      id: HP:0001888
      label: Decreased total lymphocyte count
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001888 | Lymphopenia | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- category: Hematologic
  name: Anemia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001903 | Anemia | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- category: Gastrointestinal
  name: Malabsorption
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Malabsorption
    term:
      id: HP:0002024
      label: Malabsorption
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002024 | Malabsorption | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- category: Respiratory
  name: Recurrent respiratory infections
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002205 | Recurrent respiratory infections | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
  - reference: PMID:40585468
    reference_title: "Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome identified by whole-exome sequencing (WES): a case report from a developing country."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A male child with recurrent respiratory tract infections, ear discharge and facial anomalies."
    explanation: The case report provides a human clinical example of recurrent respiratory infections.
- category: Immune
  name: Immunodeficiency
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Immunodeficiency
    term:
      id: HP:0002721
      label: Immunodeficiency
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002721 | Immunodeficiency | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
  - reference: PMID:39958354
    reference_title: "Case report: Novel multi-exon homozygous deletion of ZBTB24 causes immunodeficiency, centromeric instability, and facial anomalies syndrome 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The novel multi-exon deletion of ZBTB24 causes immunodeficiency, severe pneumonia and centromeric instability in the patient."
    explanation: The ICF2 case report supports immunodeficiency and severe infection.
- category: Cellular
  name: Chromosome instability
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Chromosome instability
    term:
      id: HP:0003220
      label: Abnormality of chromosome stability
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003220 | Abnormality of chromosome stability | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
  - reference: PMID:39958354
    reference_title: "Case report: Novel multi-exon homozygous deletion of ZBTB24 causes immunodeficiency, centromeric instability, and facial anomalies syndrome 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Karyotype analysis showed fragile sites and entire arm deletions were detected on chromosomes 1 and 16 and triradials on chromosome 16."
    explanation: The ICF2 case report supports chromosomal instability in patient cells.
- category: Immune
  name: Hypogammaglobulinemia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004313 | Decreased circulating antibody level | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band; the HPO canonical label is decreased circulating immunoglobulin concentration.
  - reference: PMID:23486536
    reference_title: "Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies."
    explanation: The patient cohort identifies agammaglobulinemia or hypoimmunoglobulinemia as a predominant feature.
- category: Growth
  name: Short stature
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004322 | Short stature | Very frequent (99-80%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- category: Craniofacial
  name: Depressed nasal bridge
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005280 | Depressed nasal bridge | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- category: Immune
  name: Cellular immunodeficiency
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cellular immunodeficiency
    term:
      id: HP:0005374
      label: Cellular immunodeficiency
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005374 | Cellular immunodeficiency | Frequent (79-30%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
  - reference: PMID:25330735
    reference_title: Combined immunodeficiency develops with age in Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course"
    explanation: The ICF2 report supports cellular immune involvement beyond isolated humoral deficiency.
- category: Craniofacial
  name: Protruding tongue
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Protruding tongue
    term:
      id: HP:0010808
      label: Protruding tongue
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010808 | Protruding tongue | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
- category: Craniofacial
  name: Flat face
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Flat face
    term:
      id: HP:0012368
      label: Flat face
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012368 | Flat face | Occasional (29-5%)"
    explanation: Orphanet provides the disease-phenotype association and frequency band.
genetic:
- name: Biallelic DNMT3B pathogenic variants
  gene_term:
    preferred_term: DNMT3B
    term:
      id: hgnc:2979
      label: DNMT3B
  association: Causative
  relationship_type: CAUSATIVE
  subtype: ICF1
  features: >
    DNMT3B pathogenic variants cause ICF1 by reducing de novo DNA methyltransferase
    function and disturbing pericentromeric, subtelomeric, and gene-body DNA
    methylation.
  inheritance:
  - name: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DNMT3B | DNA methyltransferase 3 beta | hgnc:2979 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies DNMT3B as a disease-causing gene.
  - reference: PMID:30406101
    reference_title: "DNMT3B Functions: Novel Insights From Human Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The autosomal recessive Immunodeficiency, Centromeric instability and Facial anomalies syndrome, type I (ICF-1), is associated to hypomorphic mutations in DNMT3B gene"
    explanation: The review links ICF1 to hypomorphic DNMT3B mutations.
- name: Biallelic ZBTB24 pathogenic variants
  gene_term:
    preferred_term: ZBTB24
    term:
      id: hgnc:21143
      label: ZBTB24
  association: Causative
  relationship_type: CAUSATIVE
  subtype: ICF2
  features: >
    ZBTB24 pathogenic variants cause ICF2, impair transcriptional activation of
    downstream target genes such as CDCA7, and recapitulate centromeric
    hypomethylation in patient-derived iPSCs.
  inheritance:
  - name: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ZBTB24 | zinc finger and BTB domain containing 24 | hgnc:21143 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies ZBTB24 as a disease-causing gene.
  - reference: PMID:39958354
    reference_title: "Case report: Novel multi-exon homozygous deletion of ZBTB24 causes immunodeficiency, centromeric instability, and facial anomalies syndrome 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results indicated that this novel multi-exon deletion variant of ZBTB24 may be the genetic etiology of ICF2."
    explanation: The ICF2 case report links a homozygous ZBTB24 deletion to ICF2.
- name: Biallelic CDCA7 pathogenic variants
  gene_term:
    preferred_term: CDCA7
    term:
      id: hgnc:14628
      label: CDCA7
  association: Causative
  relationship_type: CAUSATIVE
  subtype: ICF3
  features: >
    CDCA7 pathogenic variants cause ICF3 as part of the ICF DNA-methylation
    and chromatin-maintenance gene network.
  inheritance:
  - name: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CDCA7 | cell division cycle associated 7 | hgnc:14628 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies CDCA7 as a disease-causing gene.
  - reference: PMID:31724723
    reference_title: "DNA methylation in disease: Immunodeficiency, Centromeric instability, Facial anomalies syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The hallmark of this syndrome is hypomethylation of pericentromeric satellite repeats, with mutations in four genes: DNMT3B, ZBTB24, CDCA7 and HELLS, being linked to the disease."
    explanation: The review identifies CDCA7 as one of the established ICF genes.
- name: Biallelic HELLS pathogenic variants
  gene_term:
    preferred_term: HELLS
    term:
      id: hgnc:4861
      label: HELLS
  association: Causative
  relationship_type: CAUSATIVE
  subtype: ICF4
  features: >
    HELLS pathogenic variants cause ICF4 as part of the ICF DNA-methylation and
    chromatin-maintenance gene network.
  inheritance:
  - name: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HELLS | helicase, lymphoid specific | hgnc:4861 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies HELLS as a disease-causing gene.
  - reference: PMID:31724723
    reference_title: "DNA methylation in disease: Immunodeficiency, Centromeric instability, Facial anomalies syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The hallmark of this syndrome is hypomethylation of pericentromeric satellite repeats, with mutations in four genes: DNMT3B, ZBTB24, CDCA7 and HELLS, being linked to the disease."
    explanation: The review identifies HELLS as one of the established ICF genes.
- name: Biallelic UHRF1 pathogenic variants
  gene_term:
    preferred_term: UHRF1
    term:
      id: hgnc:12556
      label: UHRF1
  association: Causative
  relationship_type: CAUSATIVE
  features: >
    Orphanet records UHRF1 as an additional disease-causing germline gene for
    the ICF syndrome disease series; this entry does not assign a numbered
    MONDO subtype because the local MONDO subtype series currently enumerates
    ICF1-ICF4.
  inheritance:
  - name: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:2268
    reference_title: "ICF syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "UHRF1 | ubiquitin like with PHD and ring finger domains 1 | hgnc:12556 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies UHRF1 as a disease-causing gene in the ICF syndrome disease series.
diagnosis:
- name: Molecular genetic testing
  description: >
    Sequencing or exome testing can identify biallelic pathogenic variants in
    ICF syndrome genes and establish the molecular subtype.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:40585468
    reference_title: "Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome identified by whole-exome sequencing (WES): a case report from a developing country."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing was performed. A homozygous missense variant DNMT3B was identified, and the patient was diagnosed with ICF"
    explanation: The case report supports exome sequencing as a diagnostic route for ICF syndrome.
- name: Cytogenetic analysis of centromeric instability
  description: >
    Karyotype or related cytogenetic testing can demonstrate fragile sites,
    whole-arm deletions, triradials, multiradials, and rearrangements affecting
    chromosomes 1, 16, and sometimes 9.
  evidence:
  - reference: PMID:39958354
    reference_title: "Case report: Novel multi-exon homozygous deletion of ZBTB24 causes immunodeficiency, centromeric instability, and facial anomalies syndrome 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Karyotype analysis showed fragile sites and entire arm deletions were detected on chromosomes 1 and 16 and triradials on chromosome 16."
    explanation: The case report supports karyotype analysis for detecting characteristic chromosome instability.
- name: Immunologic evaluation
  description: >
    Immunologic workup should assess immunoglobulin concentrations, B cells,
    memory B cells, T-cell involvement, and infection susceptibility.
  evidence:
  - reference: PMID:28713390
    reference_title: "Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further immunological workup revealed agammaglobulinemia in the presence of B cells."
    explanation: The case report supports immunologic testing for ICF syndrome immune defects.
treatments:
- name: Immunoglobulin replacement therapy
  description: >
    IgG or intravenous immunoglobulin replacement is used to manage antibody
    deficiency and reduce infection burden, but it does not correct non-immune
    epigenetic disease manifestations.
  treatment_term:
    preferred_term: Intravenous Immunoglobulin Therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
  target_phenotypes:
  - preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  - preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:28713390
    reference_title: "Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early IgG replacement and antibiotic prophylaxis can significantly improve patient outcomes (10)."
    explanation: The treatment report supports early immunoglobulin replacement as clinically beneficial supportive therapy.
  - reference: PMID:40585468
    reference_title: "Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome identified by whole-exome sequencing (WES): a case report from a developing country."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatments like immunoglobulin supplementation or allogeneic stem cell transplantation can improve the chances of survival and enhance the quality of life."
    explanation: The case report supports immunoglobulin supplementation as a management option.
- name: Antimicrobial prophylaxis and treatment
  description: >
    Antibiotic or antimicrobial prophylaxis and treatment are used to prevent or
    manage recurrent and opportunistic infections, including Pneumocystis
    jirovecii infection risk.
  treatment_term:
    preferred_term: antimicrobial pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sulfamethoxazole
      term:
        id: CHEBI:9332
        label: sulfamethoxazole
    - preferred_term: trimethoprim
      term:
        id: CHEBI:45924
        label: trimethoprim
  target_phenotypes:
  - preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:28713390
    reference_title: "Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment options are limited and consist primarily of supportive therapy such as substitution of immunoglobulins, prophylactic sulfamethoxazole–trimethoprim therapy, or antibiotic therapy (6–8)."
    explanation: The treatment report supports antimicrobial prophylaxis and antibiotic therapy as supportive management.
- name: Hematopoietic stem cell transplantation
  description: >
    Allogeneic hematopoietic stem cell transplantation can reconstitute
    hematopoietic immune function and may cure the immunodeficiency component
    in selected patients, while chromosome instability and facial or neurologic
    manifestations remain outside its direct corrective effect.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: MAXO:0000747
      label: hematopoietic stem cell transplantation
  target_mechanisms:
  - target: Memory B-Cell Differentiation and Antibody Production Failure
    treatment_effect: RESTORES
    description: >
      HSCT replaces hematopoietic cells carrying the causal variant and can
      restore immune-cell and immunoglobulin function.
    evidence:
    - reference: PMID:28713390
      reference_title: "Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "HSCT replaces all hematopoietic cells carrying the DNMT3B mutation and can thereby cure the immunodeficiency in ICF patients."
      explanation: The full-text clinical report explicitly states the proposed immune-corrective mechanism of HSCT.
  target_phenotypes:
  - preferred_term: Immunodeficiency
    term:
      id: HP:0002721
      label: Immunodeficiency
  - preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:28713390
    reference_title: "Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early diagnosis and subsequent HSCT can prevent severe opportunistic infections and cure the immunodeficiency."
    explanation: The report supports HSCT as an immune-directed curative treatment in selected ICF patients.
  - reference: PMID:28713390
    reference_title: "Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Centromeric instability and facial anomaly remain unaffected."
    explanation: The report clarifies that HSCT targets immune dysfunction rather than all ICF manifestations.
experimental_models:
- name: Patient-derived ICF2 induced pluripotent stem cells
  description: >
    Patient-derived iPSCs carrying a homozygous ZBTB24 p.Cys408Gly mutation
    model ICF2 methylation defects, loss of CDCA7 activation, and impaired
    hematopoietic differentiation.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  modeled_mechanisms:
  - target: ZBTB24-CDCA7 Transcriptional Activation Failure
    description: >
      The iPSC model recapitulates ZBTB24-dependent transcriptional activation
      failure and downstream centromeric hypomethylation.
    evidence:
    - reference: PMID:39040103
      reference_title: "A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Overall, the ICF2-iPSC model is highly relevant to explore the role of ZBTB24 in DNA methylation homeostasis and provides a tool to investigate the early molecular events linking ZBTB24 deficiency to the ICF2 clinical phenotype."
      explanation: The paper directly frames the iPSC model as informative for early ZBTB24-to-phenotype mechanisms.
  evidence:
  - reference: PMID:39040103
    reference_title: "A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we generated a novel ICF2 disease model by deriving induced pluripotent stem cells (iPSCs) from peripheral CD34+-blood cells of a patient homozygous for the p.Cys408Gly mutation"
    explanation: The study describes generation of a patient-derived ICF2 iPSC model.
notes: >-
  Bounded deep research used Asta retrieval
  (research/Immunodeficiency_Centromeric_Instability_Facial_Anomalies_Syndrome-deep-research-asta.md)
  and cache-backed PubMed/Orphanet evidence. The entry intentionally treats
  UHRF1 as an Orphanet-supported disease gene without assigning a numbered ICF
  subtype because the local MONDO subtype series currently exposes ICF1-ICF4.
📚

References & Deep Research

Deep Research

1
Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome. Core d...
Asta Scientific Corpus Retrieval 18 citations 2026-05-09T23:11:15.138127

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome. Core d...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 18
  • Snippets retrieved: 20

Relevant Papers

[1] Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome

  • Authors: K. Gössling, Cyrill Schipp, U. Fischer, F. Babor, G. Koch et al.
  • Year: 2017
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/04dc7b970967766934f12292c0a007ebabe22652
  • DOI: 10.3389/fimmu.2017.00773
  • PMID: 28713390
  • PMCID: 5491950
  • Citations: 17
  • Summary: This report reports the case of a 1-year-old boy of Moroccan consanguineous parents, who was diagnosed at 4 months of age with ICF syndrome with a homozygous missense mutation in the DNMT3B gene and underwent hematopoietic stem cell transplantation (HSCT) from the HLA-matched healthy sister using a chemotherapeutic conditioning regimen.
  • Evidence snippets:
  • Snippet 1 (score: 0.602) > Immunodeficiency, centromeric instability, and facial anomaly (ICF) syndrome is a rare autosomal recessively inherited genetic condition. The majority of the affected individuals have mutations in the methyltransferase 3B gene (DNMT3B, OMIM 602900) on chromosome 20 leading to reduced DNA methylation of the pericentromeric regions of chromosomes 1, 9, and 16 (1,2). Epigenetic dysregulation rather than a single gene defect determines the clinical phenotype. Although all body cells carry the same mutation, various tissues are differently affected due to varying degrees of DNA methylation. This is especially seen in mitogen-stimulated lymphocytes where whole arm deletions, translocations, and multibranched chromosomes cause an abnormal gene regulation of B cell immunoglobulin isotype switching, lymphocyte activation, and migration (3). ICF patients suffer from recurrent gastrointestinal and pulmonary infections in early childhood due to the agammablobulinemia resulting in failure to thrive (4). An intrinsic T cell defect has also been linked to the high frequency of opportunistic infections from pathogens such as with Pneumocystis jirovecii (PJ), but the exact mechanism has not been elucidated (5). Typical clinical characteristics include the eponymous facial anomaly of epicanthic folds, hypertelorism, and a flat nasal bridge, as well as a delay in psychological and cognitive development. > Treatment options are limited and consist primarily of supportive therapy such as substitution of immunoglobulins, prophylactic sulfamethoxazole-trimethoprim therapy, or antibiotic therapy (6)(7)(8). Life expectancy of ICF patients is poor and prognosis is dependent on the frequency and severity of infections. A high proportion of reported ICF patients die at a young age (9). Early IgG replacement and antibiotic prophylaxis can significantly improve patient outcomes (10). An early sustainable therapy for the immunodeficiency can dramatically better the disease course.

[2] Case report: Novel multi-exon homozygous deletion of ZBTB24 causes immunodeficiency, centromeric instability, and facial anomalies syndrome 2

  • Authors: Yan Long, Chenghan Wang, Jie Xiao, Yunhua Huang, Xiaoting Ling et al.
  • Year: 2025
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/a41724adba116fbfb05757854039abb36941a3de
  • DOI: 10.3389/fimmu.2025.1517417
  • PMID: 39958354
  • PMCID: 11825828
  • Citations: 1
  • Summary: Results indicated that this novel multi-exon deletion variant of ZBTB24 may be the genetic etiology of ICF2, and this novel mutation expands the mutation spectrum of the ZBTB24 gene and improves the understanding of the molecular mechanisms underlying ICF.
  • Evidence snippets:
  • Snippet 1 (score: 0.565) > Immunodeficiency, centromeric instability, and facial anomalies syndrome (ICF) is a rare genetic disease characterized by hypogammaglobulinemia, T cell immune deficiency with age, pericentromeric hypomethylation, facial abnormalities, and intellectual disability. This study aimed to investigate the phenotype and immune function of a girl with ICF2, identify her genetic defect, and explore the potential pathogenic mechanisms of the disease. We identified a homologous deletion mutation in this girl, which involves exons 1-5 and part of introns 1 and 6 of the ZBTB24 gene (NG_029388.1: g.2831_18,995del). This ZBTB24 variant produces a severely truncated ZBTB24 protein that lacks the BTB, A-T hook and eight zinc fingers. The above changes may lead to abnormal transcriptional function of the ZBTB24 protein. Karyotype analysis showed fragile sites and entire arm deletions were detected on chromosomes 1 and 16 and triradials on chromosome 16. The novel multi-exon deletion of ZBTB24 causes immunodeficiency, severe pneumonia and centromeric instability in the patient. During the follow-up, the patient’s pneumonia continued to progress despite receiving intravenous immunoglobulin (IVIG) replacement and anti-infective therapy. These results indicated that this novel multi-exon deletion variant of ZBTB24 may be the genetic etiology of ICF2. The discovery of this novel mutation expands the mutation spectrum of the ZBTB24 gene and improves our understanding of the molecular mechanisms underlying ICF.
  • Snippet 2 (score: 0.510) > Immunodeficiency, centromeric instability, and facial anomalies syndrome (ICF) is a rare autosomal recessive genetic disease and one of the earliest congenital diseases discovered to be caused by DNA methylation defects (1,2). To date, only approximately 120 cases of ICF have been reported worldwide (3). ICF is characterized by a significant reduction in immunoglobulin levels that can lead to recurrent infections in respiratory and gastrointestinal systems, facial abnormalities (such as ocular hypertelorism, epicanthic folds, low-set ears, and flat nose) and intellectual disability (4). According to the molecular genetic evidence, ICF can be divided into five subtypes: about 60% of patients carry DNMT3B variants, known as ICF syndrome 1 (ICF1, OMIM 242860); nearly 30% of ICF individuals belong to ICF syndrome 2 (ICF2, OMIM 614069), caused by variants in ZBTB24; ICF syndrome 3 (ICF3, OMIM 616910) and ICF syndrome 4 (ICF4, OMIM 616911) are respectively associated with variants in CDCA7 and HELLS; Only very few cases of ICF with unknown causative genes are classified as ICF syndrome X (ICFX) (1,5). > The human ZBTB24 gene is located on chromosome 6q21 and contains 7 exons. The protein encoded by this gene is a member of the ZBTB family of transcriptional regulators. ZBTB24 is composed of a BTB (broad-complex, tram-track, and bric-a-brac) domain, an A-T hook domain, and eight C2H2-type zinc fingers (6). Previous study found that low expression of ZBTB24 was significantly associated with decreased yields and impaired differentiation of mature B lymphocytes, resulting in a higher incidence of hypogammaglobulinemia in ICF2 patients (7). Although ICF patients with different subtypes show similar clinical phenotypes, the clinical outcomes can vary depending on the severity and frequency of infection (5,8,9).

[3] Combined immunodeficiency develops with age in Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2)

  • Authors: H. von Bernuth, Ethiraj Ravindran, Hang Du, Sebastian Fröhler, Karoline Strehl et al.
  • Year: 2014
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/6d6872b11128cf1a826dc119572dcb8faceeb2ea
  • DOI: 10.1186/s13023-014-0116-6
  • PMID: 25330735
  • PMCID: 4230835
  • Citations: 33
  • Influential citations: 1
  • Summary: The phenotype spectrum is extended by describing for the first time the development of a combined immune defect throughout the disease course as well as putative autoimmune phenomena such as granulomatous hepatitis and nephritis.
  • Evidence snippets:
  • Snippet 1 (score: 0.554) > The autosomal recessive immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome is characterized by immunodeficiency, intellectual deficit, and facial dysmorphism [1]. ICF 1 and 2 are caused by biallelic mutations in the DNA methyltransferase 3B gene DNMT3B (MIM602900, [2,3]) and in the zinc-finger-and BTBdomain containing 24 gene ZBTB24 (MIM614064, [4]), respectively. For ICF2, 16 patients from 13 families have been reported (Additional file 1: Table S1) [4][5][6][7][8][9][10][11][12][13]. ICF is considered primarily as a humoral immunodeficiency disease; however, this does not explain the high rate of opportunistic infections. Recently, an additional intrinsic T-cell deficiency in ICF has been discussed and a lymphocyte proliferation defect described in individual patients with ICF1 and ICF2 [5,8,9]. Mechanisms underlying the neurological phenotype of ICF remain to be elucidated. Here, we report the development of a combined immunodeficiency in a patient with ICF2 with age and demonstrate pathomechanisms that may contribute to the immunological and non-immunological phenotype. > The index patient was born hypotrophic at term without complications as the first child of non-consanguineous healthy, Caucasian parents of German descent after an uneventful pregnancy. She showed multiple facial anomalies, clubbing of fingers and toes, and fused teeth (Figure 1A). Language and motor development appeared initially normal, but intellectual disability became apparent by the second year of life. Her brain morphology was normal on MRI at 4 years-of-age, apart from a pineal cyst.

[4] Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome identified by whole-exome sequencing (WES): a case report from a developing country

  • Authors: Rahaf Joma, Shahed Radwan, S. Hannoun, Jawad Hasson, Banan M Aiesh
  • Year: 2025
  • Venue: Oxford Medical Case Reports
  • URL: https://www.semanticscholar.org/paper/4cd995ad962496c16fd41fd64913381c076dc934
  • DOI: 10.1093/omcr/omaf079
  • PMID: 40585468
  • PMCID: 12202303
  • Citations: 1
  • Summary: Treatments like immunoglobulin supplementation or allogeneic stem cell transplantation can improve the chances of survival and enhance the quality of life in ICF patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.538) > Immunodeficiency, centromeric instability, and facial anomalies (ICF) is an autosomal recessive disease characterized by immunodeficiency, centromeric instability, and facial anomalies. In 1978, it was described in patients with a variable primary immunodeficiency disease (PID) and centromere instability [1]. In the first year of life, patients with ICF syndrome usually require hospitalization due to severe recurrent respiratory tract and gastrointestinal infections. There are also growth delays, failures to thrive, psychomotor impairments, and mild facial dysmorphisms [2]. > ICF has been described in about 118 patients worldwide [3]. Chromosome breaks were observed in these patients due to distinctive rearrangements along the centromeres (the juxtacentromeric heterochromatin) of chromosomes 1 and 16, and occasionally 9 [1]. ICF type 1 accounts for approximately 50% of ICF patients who had mutations in the DNMT3B gene [2]. The remaining half may be caused by mutations in ZBTB24 (ICF2), CDCA7 (ICF3), or HELLS (ICF4). > Here, we report a novel homozygous mutation in DNMT3B gene in a Palestinian male child with ICF type 1. It is the first reported ICF case in Palestine. Whole-exome sequencing (WES) reported that the patient's variant was not described before, and it lies within the catalytic domain. > DNMT3B is the major de novo DNA methyltransferase expressed and active during the early stages of embryonic development. It is located on chromosome 20 at position 20q11.2 [4]. Recent observations suggest that DNMT3B acts as the main enzyme methylating intragenic regions of active genes [5]. However, complete loss of function of this gene leads to embryonic mortality in mice. Studies on murine models suggest that DNMT3B mutations do not affect the development of normal T cells at birth but modify their survival in the thymus by promoting their death through a p53-independent mechanism.
  • Snippet 2 (score: 0.465) > ICF is an autosomal recessive disease characterized by immunodeficiency, centromeric instability, and facial anomalies. ICF patients experience opportunistic infections such as bronchopneumonia and otitis, suffer from diarrhea, have low birth weight, and may experience cognitive impairment and developmental delays. This is mainly caused by a homozygous DNMT3B mutation [2]. Maraschio later named the illness ICF, using the diagnostic triad of facial dysmorphism, chromosomal abnormalities, and variable immunodeficiency. There are four categories of ICF, Figure 1. Facial anomalies (cleft lip and palate and f lat nasal bridge) for the child at the age of 4 months. and ICF type 1 (DNMT3B) is the most common, accounting for approximately 50% of all cases in which affected cases often lose their lives in the first or second decade of life [ 2]. Types 2, 3, and 4 are characterized by mutations in the ZBTB24, CDCA7, and HELLS genes, respectively. Eleven cases of ICF syndrome have been reported in the Middle East: five in Saudi Arabia [6], four in Lebanon [7], and two in Iran [4]. No cases have been reported in Palestine before. > Our case, who was later on diagnosed with type 1 ICF, had a history of NICU admission for one week due to feeding issues resulting from a cleft lip and palate. His growth parameters were below the 3 rd percentile and he has been experiencing frequent symptoms of high-grade fever, diarrhea, upper respiratory tract infections, and ear pain since early infancy. Meningitis, bilateral lung infiltration and pleural effusion, fever, and otitis media were reported in the presentation of Saudi cases [6]. The disease phenotype is characterized by recurring severe pulmonary or gastrointestinal infections in early childhood and micrognathia [3]. > At the age of six months, after receiving his vaccinations, he was admitted to the pediatric ward due to high-grade fever and was intubated on a mechanical ventilator for one month in the PICU due to aspiration pneumonia necessitating WES screening.

[5] DNA methylation in disease: Immunodeficiency, Centromeric instability, Facial anomalies syndrome

  • Authors: Maja Vukic, L. Daxinger
  • Year: 2019
  • Venue: Essays in Biochemistry
  • URL: https://www.semanticscholar.org/paper/1d4423827d37d4d130a29c2f18843409f92272a9
  • DOI: 10.1042/EBC20190035
  • PMID: 31724723
  • PMCID: 6923317
  • Citations: 47
  • Influential citations: 2
  • Summary: Recent progress in understanding the molecular interactions between these genes is discussed and current evidence for how aberrant DNA methylation may contribute to the abnormal phenotype present in ICF syndrome patients is considered.
  • Evidence snippets:
  • Snippet 1 (score: 0.521) > Described as a disorder of 'variable immunodeficiency, facial anomalies and centromeric heterochromatin instability' approximately 40 years ago, the ICF syndrome has fascinated scientists ever since. Aberrant DNA methylation is probably involved in the causation of the disease, but what types of changes in DNA methylation patterns lead to the phenotypic aspects of the disorder remains an open question. A great deal has been learned about the genetic defects underlying ICF syndrome and the genome-wide epigenetic consequences thereof. In addition, the molecular interactions between the four disease genes and their functions in cellular processes are beginning to be understood. Gaining further insights into these mechanisms through increasingly sophisticated genetics, biochemistry and genomics approaches will enable us to progress toward a fuller understanding of how the dysfunction of four different proteins can lead to the same disease phenotype.

[6] A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency

  • Authors: Vincenzo Lullo, Francesco Cecere, Saveria Batti, Sara Allegretti, Barbara Morone et al.
  • Year: 2024
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/b4cf5fec4fc8e63810ec38582d9d4b65cdeb1d80
  • DOI: 10.3389/fimmu.2024.1419748
  • PMID: 39040103
  • PMCID: 11260623
  • Citations: 2
  • Summary: The ICF2-iPSC model is highly relevant to explore the role of ZBTB24 in DNA methylation homeostasis and provides a tool to investigate the early molecular events linking ZBTB24 deficiency to the ICF2 clinical phenotype.
  • Evidence snippets:
  • Snippet 1 (score: 0.486) > Immunodeficiency, Centromeric and Facial anomalies syndrome is a rare autosomal recessive disease (1).It is a clinically heterogeneous disorder consisting of variable combined immunodeficiency and variable neurological impairments (2,3).The disease was primarily described as a humoral syndrome, but the broad altered clinical spectrum demonstrates a dysregulation of Tcell function (2,4). > DNA hypomethylation of pericentromeric satellites of chromosomes 1, 9 and 16 is the major molecular hallmark of ICF syndrome, and the basis for the chromosomal instability that is a principal cytological signature of this disease (5,6).ICF syndrome is also genetically heterogeneous.Four subtypes have been described, which are associated with mutations in specific causative genes: the DNA methyltransferase 3B gene (DNMT3B), the Zinc-finger and Broad-Complex, Tramtrack and Bric-a-brac domain-containing protein 24 (ZBTB24), the cell division cycle-associated protein 7 (CDCA7), and the Helicase lymphoid-specific (HELLS), for the ICF1-4 subtypes, respectively.No causative gene was identified for the few remaining patients (ICFX) (7)(8)(9).There is evidence that these genes contribute to generation and/or maintenance of DNA methylation profiles by interacting with each other in a coordinated manner.However, the precise molecular mechanism underlying these processes is still unclear (10)(11)(12)(13).While a subset of genomic regions displays hypomethylation in all disease subtypes, the whole genome methylation signature can distinguish the DNMT3Bmutated ICF1 patients from those of the ICF2-4 subtypes.Moreover, hypomethylation of alpha-satellite is specific to the ICF2-4 patients, while that of pericentromeric satellite repeats is common to all ICF subtypes (10). > DNMT3B and ZBTB24 are the most frequently mutated genes in ICF patients.

[7] Genome-Wide DNA Methylation Analysis Identifies Novel Hypomethylated Non-Pericentromeric Genes with Potential Clinical Implications in ICF Syndrome

  • Authors: L. Simó-Riudalbas, Á. Díaz-Lagares, Sole Gatto, M. Gagliardi, A. Crujeiras et al.
  • Year: 2015
  • Venue: PLoS ONE
  • URL: https://www.semanticscholar.org/paper/d30862d85935e8cfb3f0b3cb43f009b99a1afe02
  • DOI: 10.1371/journal.pone.0132517
  • PMID: 26161907
  • PMCID: 4498748
  • Citations: 34
  • Influential citations: 2
  • Summary: The detection of DNA hypomethylation at BOLL, SYCP2 and NCRNA00221 may pave the way for the development of specific clinical biomarkers with the aim to facilitate the identification of ICF patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.484) > The immunodeficiency, centromeric instability and facial anomalies syndrome (ICF) is a rare recessive disorder, with less than 60 cases reported worldwide. ICF syndrome is characterized by two peculiar signs: a variable immunodeficiency and a recurrent instability of pericentromeric heterochromatin, which usually leads to chromosome breakage in mitogen-stimulated lymphocytes. The chromosomal abnormalities are found exclusively in hypomethylated pericentromeric regions of chromosome 1, 16 and less frequently in 9. Other ICF symptoms count in facial anomalies, psychomotor and mental retardation and developmental delay [1]. > The importance of ICF pathology, at the molecular level, relies on the fact that it is the only human disease showing mendelian inheritance of aberrant DNA methylation, caused by mutations in one of the three main DNA-methyltransferase genes, DNMT3B. Approximately 50% of the ICF cases, defined as ICF type1, present biallelic DNMT3B mutations located mainly in the catalytic domain of the protein, often leading to the impairment of its methyltransferase activity [2]. Among the rest of patients some carry nonsense mutations in zinc-finger and BTB domain-containing 24 gene (ZBTB24), designated as ICF2 patients, while a small group of them has still unknown etiology, and are designated as ICFX [2]. > The biochemical defects in DNMT3B-mediated de novo DNA methylation have been recently assessed by in vitro studies of the ICF-associated DNMT3B variants [3]. These results reveal that catalysis by DNMT3B is much more complex than expected. In that context, ICF mutations cause a broad spectrum of biochemical defects in DNMT3B function, including defects in homo-oligomerization, SAM binding, SAM utilization and DNA binding [3].

[8] Epigenetic alteration of microRNAs in DNMT3B-mutated patients of ICF syndrome

  • Authors: Sole Gatto, F. D. Ragione, A. Cimmino, M. Strazzullo, M. Fabbri et al.
  • Year: 2010
  • Venue: Epigenetics
  • URL: https://www.semanticscholar.org/paper/54a018a63f4a2347868225c427719904b2b05391
  • DOI: 10.4161/epi.5.5.11999
  • PMID: 20448464
  • Citations: 35
  • Influential citations: 1
  • Summary: A better understanding of how DNA methylation and histone code interact to regulate the class of microRNA genes is provided and enable us to predict molecular events possibly contributing to ICF condition.
  • Evidence snippets:
  • Snippet 1 (score: 0.463) > Immunodeficiency, Centromeric region instability, Facial anomalies (ICF; OMIM #242860) syndrome, due to mutations in the DNMT3B gene, is characterized by inheritance of aberrant patterns of DNA methylation and heterochromatin defects. Patients show variable agammaglobulinemia and a reduced number of T cells, making them prone to infections and death before adulthood. Other variable symptoms include facial dysmorphism, growth and mental retardation. Despite the recent advances in identifying the dysregulated genes, the molecular mechanisms, which underlie the altered gene expression causing ICF phenotype complexity, are not well understood. Held the recently-shown tight correlation between epigenetics and microRNAs (miRNAs), we searched for miRNAs regulated by DNMT3B activity, comparing cell lines from ICF patients with those from healthy individuals. We observe that eighty-nine miRNAs, some of which involved in immune function, development and neurogenesis, are dysregulated in ICF (LCLs) compared to wild-type cells. Significant DNA hypomethylation of miRNA CpG islands was not observed in cases of miRNA up-regulation in ICF cells, suggesting a more subtle effect of DNMT3B deficiency on their regulation; however, a modification of histone marks, especially H3K27 and H3K4 trimethylation, and H4 acetylation, was observed concomitantly with changes in microRNA expression. Functional correlation between miRNA and mRNA expression of their targets allow us to suppose a regulation either at mRNA level or at protein level. These results provide a better understanding of how DNA methylation and histone code interact to regulate the class of microRNA genes and enable us to predict molecular events possibly contributing to ICF condition.

[9] An acquired high-risk chromosome instability phenotype in multiple myeloma: Jumping 1q Syndrome

  • Authors: J. Sawyer, E. Tian, B. Walker, C. Wardell, J. Lukacs et al.
  • Year: 2018
  • Venue: Blood Cancer Journal
  • URL: https://www.semanticscholar.org/paper/866f98dd36ca70fc331f8c2a94998fc45daeaf0a
  • DOI: 10.1038/s41408-019-0226-4
  • PMID: 31399558
  • PMCID: 6689064
  • Citations: 37
  • Influential citations: 1
  • Summary: Strikingly, the acquired instability phenotype identified in patients with multiple myeloma demonstrates the same transient structural aberrations of 1q12 as those found in ICF syndrome, suggesting similar underlying pathological mechanisms.
  • Evidence snippets:
  • Snippet 1 (score: 0.449) > Patients with multiple myeloma (MM) accumulate adverse copy number aberrations (CNAs), gains of 1q21, and 17p deletions during disease progression. A subset of these patients develops heightened 1q12 pericentromeric instability and jumping translocations of 1q12 (JT1q12), evidenced by increased copy CNAs of 1q21 and losses in receptor chromosomes (RC). To understand the progression of these aberrations we analyzed metaphase cells of 50 patients with ≥4 CNAs of 1q21 by G-banding, locus specific FISH, and spectral karyotyping. In eight patients with ≥5 CNAs of 1q21 we identified a chromosome instability phenotype similar to that found in ICF syndrome (immunodeficiency, centromeric instability, and facial anomalies). Strikingly, the acquired instability phenotype identified in these patients demonstrates the same transient structural aberrations of 1q12 as those found in ICF syndrome, suggesting similar underlying pathological mechanisms. Four types of clonal aberrations characterize this phenotype including JT1q12s, RC deletions, 1q12-21 breakage-fusion-bridge cycle amplifications, and RC insertions. In addition, recurring transient aberrations include 1q12 decondensation and breakage, triradials, and 1q micronuclei. The acquired self-propagating mobile property of 1q12 satellite DNA drives the continuous regeneration of 1q12 duplication/deletion events. For patients demonstrating this instability phenotype, we propose the term “Jumping 1q Syndrome.”

[10] DNA Methylation in Mammalian Cells

  • Authors: P. Winata, M. William, V. Keena, Ken Takahashi, Y. Cheng
  • Year: 2018
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/05aca80c3bed9882bfa8235ca362b3116766d5d1
  • DOI: 10.5772/INTECHOPEN.72991
  • Citations: 1
  • Summary: This book chapter discusses the key epigenetic processes involved in mammalian cell development and disease progression, specifically in cancer.
  • Evidence snippets:
  • Snippet 1 (score: 0.444) > Germline and somatic mutations are mainly the result of cytosine methylation during cancer development [74]. Abnormal promoter methylation of the regulatory genes can lead to gene silencing and is an important mechanism of cancer progression [75]. Rare diseases such as immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF) [13] and mental retardation in young girls (Rett Syndrome) are the potential consequence of abnormal methylation alteration [76]. For example, ICF patients are found to be have a mutated DNMT3b gene that leads to the downregulation of satellite DNA methylation and chromosomal de-condensation. Methylation binding domains (MBDs, MeCP2) were found to be aberrantly methylated in Rett Syndrome patients, resulting in the interruption of the methylation signal [76]. Together this suggests methylation is not completed after embryonic development, requires maintenance and is essential in mammalian cells. Alternatively, the increasing methylation of mammalian cells may contribute to the risk of cancer development. Therefore, the balance of methylation is essential in maintaining healthy cellular function. > Many studies have indicated that the imbalance of DNA methylation occurs in the disease mechanism which leads to the discovery of pharmacological agents that reverse epigenetic abnormalities [77]. The interaction of DNA methylation and histone modification machinery were further investigated and proved to be an important contribution that led to disease development. Another group of epigenetic alterations caused by small RNAs also play a major role at different disease stages that could also be exploited to monitor treatment results [78].

[11] Immunodeficiency, Centromeric Instability and Facial Dysmorphism Syndrome: A Case Report

  • Authors: Alonazi Na, M. S, Alonazi A, E. H, J. B et al.
  • Year: 2019
  • Venue: Journal of Clinical Case Reports
  • URL: https://www.semanticscholar.org/paper/a731fd5856b567417a9164b019301f56f5ab9c30
  • DOI: 10.4172/2165-7920.10001201
  • Summary: An 18-month-old boy, who presented with colonic perforation, is reported, confirmed by whole-exome sequencing that revealed a homozygous c.2506G>A, (p.Val836Met) mutation in DNMT3B gene, which expands the clinical and immunological features of ICF syndrome.
  • Evidence snippets:
  • Snippet 1 (score: 0.431) > Immunodeficiency, Centromeric Instability and Facial Dysmorphism Syndrome: A Case Report

[12] [Primary immunodeficiency and autoimmune diseases].

  • Authors: G. Műzes, F. Sipos
  • Year: 2018
  • Venue: Orvosi hetilap
  • URL: https://www.semanticscholar.org/paper/14a8db6d56e353b48c82e510366b6fe608ff76bb
  • DOI: 10.1556/650.2018.31064
  • PMID: 29860882
  • Citations: 5
  • Summary: The case presented finally highlights that both the recognition of autoimmune diseases in association with Immunodeficiencies and the diagnosis of immunodefiency in those phenotypes with predominant autoimmunity could be challenging.
  • Evidence snippets:
  • Snippet 1 (score: 0.430) > Primary immunodeficiencies consist of a group of genetically heterogeneous immune disorders affecting distinct elements of the innate and adaptive immune system. Patients with primary immunodeficiency are more prone to develop not only recurrent infections, but non-infectious complications, like inflammatory or granulomatous conditions, lymphoproliferative and solid malignancies, autoinflammatory disorders, and a broad spectrum of autoimmune diseases. The concomitant appearance of primary immunodeficiency and autoimmunity appears to be rather paradoxical, therefore making the diagnosis of immunodeficiency patients with autoimmune complications challenging. Mutations of one or more genes playing a fundamental role in immunoregulation and/or immune tolerance network are thought to be responsible for primary immunodeficiencies. The diverse immunological abnomalities along with the compensatory and excessive sustained inflammatory response result in tissue damage and finally in manifestation of organ-, cell-specific or systemic autoimmune diseases. Several forms of primary immunodeficiency disorders are characterized by a variety of specific autoimmune phenomena. This overview addresses the spectrum of autoimmune diseases associated with primary immunodeficiencies, and explores the molecular and cellular mechanisms underlying abnormalities of the immune system. The case presented finally highlights that both the recognition of autoimmune diseases in association with immunodeficiencies and the diagnosis of immunodefiency in those phenotypes with predominant autoimmunity could be challenging. Orv Hetil. 2018; 159(23): 908-918.

[13] DNMT3B Functions: Novel Insights From Human Disease

  • Authors: M. Gagliardi, M. Strazzullo, M. R. Matarazzo
  • Year: 2018
  • Venue: Frontiers in Cell and Developmental Biology
  • URL: https://www.semanticscholar.org/paper/9bcde663fb498002b070559474b0de3eb814d419
  • DOI: 10.3389/fcell.2018.00140
  • PMID: 30406101
  • PMCID: 6204409
  • Citations: 90
  • Influential citations: 2
  • Summary: An overview of the most recent research aimed at deciphering the molecular mechanisms by which DNMT3B abnormalities are associated with the onset and progression of these pathologies is provided.
  • Evidence snippets:
  • Snippet 1 (score: 0.427) > DNA methylation plays important roles in gene expression regulation and chromatin structure. Its proper establishment and maintenance are essential for mammalian development and cellular differentiation. DNMT3B is the major de novo DNA methyltransferase expressed and active during the early stage of embryonic development, including implantation. In addition to its well-known role to methylate centromeric, pericentromeric, and subtelomeric repeats, recent observations suggest that DNMT3B acts as the main enzyme methylating intragenic regions of active genes. Although largely studied, much remains unknown regarding how these specific patterns of de novo CpG methylation are established in mammalian cells, and which are the rules governing DNMT3B recruitment and activity. Latest evidence indicates that DNMT3B recruitment is regulated by numerous mechanisms including chromatin modifications, transcription levels, non-coding RNAs, and the presence of DNA-binding factors. DNA methylation abnormalities are a common mark of human diseases involving chromosomal and genomic instabilities, such as inherited disease and cancer. The autosomal recessive Immunodeficiency, Centromeric instability and Facial anomalies syndrome, type I (ICF-1), is associated to hypomorphic mutations in DNMT3B gene, while its altered expression has been correlated with the development of tumors. In both cases, this implies that abnormal DNA hypomethylation and hypermethylation patterns affect gene expression and genomic architecture contributing to the pathological states. We will provide an overview of the most recent research aimed at deciphering the molecular mechanisms by which DNMT3B abnormalities are associated with the onset and progression of these pathologies.

[14] New insights into candidate genes for autism spectrum disorder in 8p23.1 duplication syndrome

  • Authors: M. M. Côrrea, Thiago Corrêa, C. Santos-Rebouças, Marino Miloca Rodrigues, G. Luca et al.
  • Year: 2022
  • Venue: Brazilian Journal of Case Reports
  • URL: https://www.semanticscholar.org/paper/7549630ec79b57d7221fb427280bd360a35590b2
  • DOI: 10.52600/2763-583x.bjcr.2023.3.1.16-23
  • Summary: Clinical and cytomolecular findings of an 8p23.1 duplication in a boy with mild facial dysmorphisms, cardiac anomalies and ASD are described, pointing out crucial interactions among BLK, GATA4, PINX1, and TNKS and genes associated with ASD.
  • Evidence snippets:
  • Snippet 1 (score: 0.425) > The 8p23.1 duplication syndrome is a rare condition, characterized by dysmorphisms, intellectual disability, congenital cardiac anomalies, and autism spectrum disorder (ASD). The current model for explaining the pathogenesis of this condition postulates that few dosage-sensitive genes within the duplication are sufficient for the core clinical features, although the molecular mechanisms leading to the ASD presentation remain to be solved. Herein, we described clinical and cytomolecular findings of an 8p23.1 duplication in a boy with mild facial dysmorphisms, cardiac anomalies and ASD. Therefore, we investigated the influence of duplicated genes on the pathophysiology of ASD in our patient. We identified four duplicated genes (BLK, GATA4, PINX1, TNKS) connected with proteins previously associated with ASD and involved in significant enriched pathways associated with human neurological conditions. Moreover, the candidate genes are highly expressed in brain regions associated to ASD, such as the hippocampus. Taken together, these results point out crucial interactions among BLK, GATA4, PINX1, and TNKS and genes associated with ASD. We indicate cellular networks perturbations encompassing neuronal development pathways related to our patient's condition. Thus, these findings bring new insights into the genetic basis of ASD in patients with 8p23.1 duplication syndrome.

[15] Clinical features and genetic analysis of a family with t(5;9) (p15;p24) balanced translocation leading to Cri-du-chat syndrome in offspring

  • Authors: Jing Zhao, Ping Chen, Yijia Ren, Shurong Li, Weiyi Zhang et al.
  • Year: 2025
  • Venue: Frontiers in Genetics
  • URL: https://www.semanticscholar.org/paper/5caf88001c66b473b6565f9e75eb6a4f1a8c4a0a
  • DOI: 10.3389/fgene.2025.1550937
  • PMID: 40406061
  • PMCID: 12094932
  • Citations: 1
  • Summary: This study reports a rare familial balanced translocation pedigree, particularly noting that the offspring can suffer from Cri-du-chat syndrome, which suggests a potential new genetic model for this syndrome.
  • Evidence snippets:
  • Snippet 1 (score: 0.425) > Using the Metascape database for GO enrichment analysis of the region containing 60 OMIM genes from 5p15.33p14.1 revealed the potential molecular mechanisms of the disease. The results showed that OMIM genes in the 5p15.33p14.1 region are mainly enriched in Na+/Cl-dependent neurotransmitter transporters, cell-cell adhesion mediated by cadherin, nephron epithelium development, and other signaling pathways (Figure 5A). Disease enrichment analysis showed that genes in this region are mainly associated with Cri-du-chat syndrome (Figure 5B) . Cri-du-chat syndrome is closely related to developmental abnormalities, neurological defects, and craniofacial malformations. Enrichment analysis supports the involvement of molecular mechanisms related to Wnt signaling, neurotransmitter transport, ubiquitination pathways, particularly through diseasegene associations from DisGeNET and GO functional enrichment. These results provide clues for revealing the molecular network of the disease and guide future research. > Using the Metascape database, GO enrichment analysis of 45 OMIM genes located in the 9p24.3-p22.3 region was performed. The results showed that OMIM genes in the 9p24.3-p22.3 region are mainly enriched in signaling pathways such as positive regulation of leukocyte activation, response to amine, cell population proliferation, positive regulation of cell development, etc. (Figure 5C). Disease enrichment analysis revealed that genes in this region are mainly associated with Chromosome 9p deletion syndrome (Figure 5D). This study, through multidimensional bioinformatics analysis, not only clarified the core biological functions of genes in the 9p24.3-p22.3 region, but also revealed their potential association mechanisms with major diseases, providing important theoretical basis and directional guidance for subsequent gene function validation, molecular mechanism research, and clinical translation. Balanced translocation carriers have the opportunity to produce phenotypically normal offspring, but they are at a higher risk of recurrent miscarriages and offspring with chromosomal abnormalities.

[16] Comprehensive Genetic Results for Primary Immunodeficiency Disorders in a Highly Consanguineous Population

  • Authors: W. Al-Herz, J. Chou, O. Delmonte, M. Massaad, Wayne Bainter et al.
  • Year: 2019
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/0794e0c675f21265b75b799555fd1d03da46d199
  • DOI: 10.3389/fimmu.2018.03146
  • PMID: 30697212
  • PMCID: 6340972
  • Citations: 47
  • Influential citations: 1
  • Summary: Genetic testing should be an integral part in the management of primary immunodeficiency patients and Studying inbred populations using sophisticated diagnostic methods can allow better understanding of the genetics of primary immune deficiencies disorders.
  • Evidence snippets:
  • Snippet 1 (score: 0.423) > n = 8), ICOS deficiency (n = 2), RFXANK resulting in MHC class II deficiency (n = 12 mutations), ZAP-70 (n = 1), IKBKB (n = 1). No cases of hyper-IgM syndrome (HIGM) due to X-linked CD40 ligand (CD40L) deficiency were reported. A patient with clinical features of Omenn syndrome (OS) who did not harbor defects in genes known to be associated with OS, had a homozygous 691 kb deletion at 5q33.1 encompassing the GM2A gene associated with GM2-gangliosidosis, which was detected by chromosomal microarray. Interestingly, large deletions were reported in all DOCK8 deficient patients and two patients with Artemis deficiency. All the diseases reported in this category have autosomal recessive (AR) pattern of transmission. > Among the 64 individuals who were diagnosed with combined immunodeficiencies (CID) with associated syndromic features, a molecular defect was identified in 54 patients (84%). The diagnosis of a DNA repair defect syndrome was made in 14 out of 64 patients (21.8%). Ten of them were diagnosed with ataxia telangiectasia, of whom six were confirmed to have ATM mutations while no genetic testing was attempted for the other four patients. Four patients had immunodeficiency with centromeric instability and facial anomalies (ICF) due to a mutation in either DNMT3B or ZBTB24, while two patients have no identifiable mutations in ICF-causing genes despite satisfying clinical, immunologic, and cytogenetic diagnostic criteria. No Nijmegen breakage or Bloom syndrome patients were identified. Eight out of 64 (12.5%) patients in this group carried the clinical diagnosis of hyper IgE syndrome (HIES). In four of them, the molecular diagnosis of STAT3 loss-of-function was obtained. No patients with TYK2 or PGM3 deficiency were identified. Three patients were diagnosed with Wiskott-Aldrich syndrome (WAS) on the basis of genetic testing and clinical phenotype, while 30 patients were diagnosed with DiGeorge syndrome and carried the typical 22q

[17] DNA methylation in human diseases

  • Authors: Samareh Younesian, M. Mohammadi, Ommolbanin Younesian, M. Momeny, S. H. Ghaffari et al.
  • Year: 2024
  • Venue: Heliyon
  • URL: https://www.semanticscholar.org/paper/cbdc00c131ed5ea9cb5032c222576abc10a93f14
  • DOI: 10.1016/j.heliyon.2024.e32366
  • PMID: 38933971
  • PMCID: 11200359
  • Citations: 23
  • Summary: The study of DNA methylation machinery is a phenomenal intersection that each of its ways can reveal the mysteries of various diseases, introduce new diagnostic and prognostic biomarkers, and propose a new patient-tailored therapeutic approach for diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.420) > To perform the literature review, our initial search consisted of an AND/OR combination of DNA methylation, DNA methyltransferases, Methyl-CpG-binding domain proteins, DNA-demethylating enzymes, diagnosis, prognosis, minimal residual disease, response, pathogenesis, survival, Imprinting disorders (Silver-Russell syndrome; Beckwith-Wiedemann syndrome; Prader-Willi syndrome; Angelman syndrome), Single-gene disorders (Immunodeficiency, centromeric instability, and facial anomalies syndrome; Hereditary sensory autonomic neuropathy 1E with dementia and hearing loss; Autosomal dominant cerebellar ataxia with deafness and narcolepsy, …), Autoimmune diseases (Systemic lupus erythematosus; Rheumatoid arthritis; Systemic sclerosis; Multiple sclerosis), Metabolic disorders (Type 2 diabetic Mellitus; Obesity), Hematological malignancies (Myeloproliferative neoplasms; myelodysplastic syndrome; Acute myeloid leukemia; T cell lymphoma; Adult T acute lymphoblastic leukemia), Solid tumors (Bladder cancer; Breast cancer; Colorectal cancer; Cervix cancer; Cancer of unknown primary; Glioblastomas; Gastric cancer; Hepatocellular carcinoma; Head and neck squamous cell carcinoma; Lung cancer; Non-small-cell lung cancer; Ovarian cancer; Prostate cancer; Pancreatic cancer; Small cell lung cancer), DNA methylation-based drugs (DNMT inhibitors; IDH1/2 inhibitors, …).We further extended our search domain by investigating scientific articles of electronic resources (Google Scholar, PubMed, Science Direct, Wiley, Scopus, and Springer) by the abbreviated form of the names.Ultimately, we investigated the results and selected the most relevant publications for review (Fig. 1).

[18] Contribution of common and rare damaging variants in familial forms of bipolar disorder and phenotypic outcome

  • Authors: Elisa Courtois, Mark-Daniel Schmid, Orly Wajsbrot, C. Barau, P. Le Corvoisier et al.
  • Year: 2020
  • Venue: Translational Psychiatry
  • URL: https://www.semanticscholar.org/paper/b9780e75a42c54e05c2688c0c0d0f3e5afa3a25b
  • DOI: 10.1038/s41398-020-0783-0
  • PMID: 32345981
  • PMCID: 7188882
  • Citations: 8
  • Summary: The results suggest that common and rare genetic variants both contribute to the familial aggregation of BD and this genetic architecture may explain the heterogeneity of clinical manifestations in multiplex families.
  • Evidence snippets:
  • Snippet 1 (score: 0.419) > This protein is required for genome-wide methylation 50 and it is responsible of immunodeficiency ventromeric region instability and facial anomalies (ICF) syndrome (MIM: 616910). The ICF syndrome is characterized by centromeric instability, as the cytogenetic hallmark, facial dysmorphism, and severe immunodeficiency, as well as developmental delay and intellectual deficit. In mice, HELLS was demonstrated as regulator of neural stem cell fate, affecting self-renewal and proliferation of neural progenitor cells 51 , suggesting a direct role in nervous system development. > The third gene frequently mutated in our cohort of individuals with BD is UPF2 (MIM: 605529), a core component of the nonsense-mediated mRNA decay (NMD) pathway, a surveillance pathway that eliminates mRNA with premature translation termination codon. In drosophila, Upf2 plays a role for proper development of synapse architecture and synaptic vesicle efficacy 52 . Moreover, copy number variants in this gene were found in intellectual disabilities syndrome with DiGeorge syndrome associated 53 and de novo point mutations have been identified in a patient with SZ 54 . Altogether, these observations suggest a role for UPF2 in nervous system development. > Few things are known about the last gene, WDR37. Its protein belongs to the WD40 repeat domain family that is characterized by diverse cellular function, as chromatin assembly, RNA processing, immunity, or development 55 . This interacting domain scaffolds protein-protein or protein-DNA interactions. Although WDR37 function is unknown, mice knockout for this gene show a larger brain than wild-type littermates 56 . Interestingly, 57 copy number variants including this gene have been reported in the DECIPHER v9.30 released (https://decipher.sanger.ac.uk/ ). Among associated phenotypes, we reported developmental delay, seizures, intellectual disabilities, and ASD. > In summary, we demonstrated that both common and rare variants contribute to phenotypic outcome in multiplex families of BD, and our data suggest that the difference between the affected and unaffected status of individuals within multiplex families might come from the balance between the two types of variants.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.