Home / Deep Research / Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome

Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome

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

2026-05-09
Asta MONDO:0000133 Model: Asta Scientific Corpus Retrieval 18 citations

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.