Materiały źródłowe

• #1 22q11.2 deletion syndrome | MedLink Neurology

  https://www.medlink.com/articles/22q11-2-deletion-syndrome

  DiGeorge and velocardiofacial syndrome (22q11.2 deletion syndrome) is the most common microdeletion disorder in humans and, hence, one of the most common multiple malformation syndromes, with an estimated prevalence of 1 in 2000 to 1 in 4000. […] It is characterized by craniofacial anomalies, conotruncal heart disease, thymic aplasia or hypoplasia, hypocalcemia, and psychiatric illness. […] The initial evidence for involvement of genes on chromosome 22 in the etiology of DiGeorge syndrome included a family with a chromosome 2;22 translocation. […] Subsequently, cytogenetically visible interstitial deletions of 22q11 were detected in approximately 25% of patients with DiGeorge syndrome. […] Southern blotting and DNA dosage analysis revealed microdeletions within 22q11 in DiGeorge syndrome patients.

• #2 Practical guidelines for managing adults with 22q11.2 deletion syndrome | Genetics in Medicine

  https://www.nature.com/articles/gim2014175

  22q11.2 Deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans, estimated to affect up to 1 in 2,000 live births. […] The multisystem nature and associated burden of morbidities means that adults with 22q11.2DS may be seen in virtually any medical practice. […] Chromosome 22q11.2 deletions are absent in large populations of healthy controls, implying a high collective penetrance for at least one major phenotypic feature. […] The available information on the adult phenotype and natural history of 22q11.2DS pertains primarily to neuropsychiatric, endocrine, cardiovascular, reproductive, and psychosocial issues. […] The elevated risk for psychotic illness in 22q11.2DS prompts questions about prevention, early signs, diagnosis, and treatment. […] The available data support the likelihood that all associated conditions in 22q11.2DS respond similarly to the idiopathic forms of these conditions, that is, to standard management strategies and treatments, whether surgical or medical.

• #3 DiGeorge syndrome – Wikipedia

  https://en.wikipedia.org/wiki/DiGeorge_syndrome

  DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. […] DiGeorge syndrome is typically due to the deletion of 30 to 40 genes in the middle of chromosome 22 at a location known as 22q11.2. […] About 90% of cases occur due to a new mutation during early development, while 10% are inherited. […] The exact mechanism that causes all of the associated features of the syndrome is unknown. […] Of the 30-50 genes in the deleted region, a number have been identified as possibly playing a role in the development of some of the signs and symptoms. […] Haploinsufficiency of the TBX1 gene (T-box transcription factor TBX1) is thought to be the cause of some of the symptoms observed. […] Research in mouse models has shown that deletion of Tbx1 leads to several defects similar to those seen in humans, mainly affecting development of the great arteries and the thymus.

• #3 DiGeorge syndrome – Wikipedia

  https://en.wikipedia.org/wiki/DiGeorge_syndrome

  The role of Tbx1 for correct formation and remodelling of the aortic arches has been extensively studied in various mouse models suggesting the key role of Tbx1 for cardiovascular development and the phenotypes seen in DiGeorge syndrome. […] In mice, haploinsufficiency of the Dgcr8 gene has been linked to improper regulation of the microRNA miR-338 and 22q11.2 deletion phenotypes. […] Mutations in the TANGO2 gene may cause defects in mitochondrial oxidation and increased endoplasmic reticulum stress and a reduction in Golgi volume density. […] 22q11.2DS has been associated with a higher risk of early onset Parkinson’s disease (PD).

• #4 DiGeorge syndrome (22q11.2 deletion syndrome) – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/digeorge-syndrome/symptoms-causes/syc-20353543

  DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a condition caused when a small part of chromosome 22 is missing. This deletion causes several body systems to develop poorly. […] The portions of chromosome 22 missing in DiGeorge syndrome affect the development of several body systems. As a result, the condition can cause several errors during fetal development. […] 22q11.2 deletion syndrome often causes heart problems that could lead to too little oxygen-rich blood. For example, problems may include a hole between the lower chambers of the heart, also known as a ventricular septal defect. Or there may be only one large vessel rather than two vessels leading out of the heart, also known as truncus arteriosus. Or there may be four problems with heart structure, also known as tetralogy of Fallot.

• #4 DiGeorge syndrome (22q11.2 deletion syndrome) – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/digeorge-syndrome/symptoms-causes/syc-20353543

  The four parathyroid glands in the neck regulate the levels of calcium and phosphorus in the body. 22q11.2 deletion syndrome can cause parathyroid glands to be smaller than usual and produce too little parathyroid hormone. This leads to hypoparathyroidism. This condition results in low levels of calcium and high levels of phosphorus in the blood. […] The thymus gland, which is beneath the breastbone, is where T cells a type of white blood cell mature. Mature T cells help fight infections. In children with 22q11.2 deletion syndrome, the thymus gland may be small or missing. This leads to poor immune function and frequent, severe infections. […] A common condition of 22q11.2 deletion syndrome is a cleft palate, which is an opening in the roof of the mouth, with or without a cleft lip. Other, less visible problems with the structure of the palate can make it hard to swallow or make certain sounds in speech.

• #5 DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis – UpToDate

  https://www.uptodate.com/contents/digeorge-22q11-2-deletion-syndrome-epidemiology-and-pathogenesis

  DiGeorge syndrome (DGS) is a constellation of signs and symptoms associated with defective development of the pharyngeal pouch system. Most cases are caused by a heterozygous chromosomal deletion at 22q11.2 (22q11.2 deletion syndrome [22qDS]); deletions in this chromosome are seen in other patients with similar syndromes, such as velocardiofacial syndrome (VCFS; also called Shprintzen syndrome). The classic triad of features of DGS on presentation is conotruncal cardiac anomalies, hypoplastic thymus, and hypocalcemia (resulting from parathyroid hypoplasia). […] Thymic hypoplasia in DGS results in a range of T cell deficits. The majority of patients with DGS have mild defects in T cell numbers and are not severely immunodeficient. However, there is a spectrum of T cell lymphopenia, and approximately 0.5 to 1 percent of patients with DGS have a complete absence of thymic tissue and profound immunodeficiency. This congenital athymia form, called complete DGS or 22qDS with congenital athymia, has a severe combined immunodeficiency (SCID) phenotype and is life threatening if not corrected with immune reconstitution (eg, by thymic tissue implantation or potentially hematopoietic cell transplantation in some instances). […] This topic reviews the epidemiology and pathogenesis of DGS.

• #6 DiGeorge Syndrome (22q11.2 Deletion Syndrome): What It Is, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/21182-digeorge-syndrome

  DiGeorge syndrome is a genetic condition caused by a missing piece of chromosome 22. Another name for DiGeorge syndrome is 22q11.2 deletion syndrome. Symptoms can affect your heart, immune system and other body systems, and cause distinct facial characteristics. Treatment to manage your symptoms is lifelong and there’s no cure for the condition. […] DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a genetic condition that can affect many parts of your body and causes heart abnormalities, an impaired immune system and developmental delays. If you’re diagnosed with DiGeorge syndrome, you’re missing a small piece of chromosome 22. Symptoms of DiGeorge syndrome can range from mild to severe. The most severe symptoms can be life-threatening. […] A missing part of chromosome 22 causes DiGeorge syndrome (22q11.2 deletion syndrome). Each chromosome holds thousands of genes. Genes are responsible for providing the instruction manual to help your body grow and function. The term 22q11.2 gives the specific location on the chromosome where genes are missing; segment 11 on the long arm (q) of chromosome 22. When you’re missing potentially thousands of genes, your body doesn’t have the instructions you need to develop as expected and you’ll experience symptoms.

• #7 DiGeorge Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK549798/

  DiGeorge syndrome (DGS) is a congenital disorder with a broad phenotypic presentation, which results predominantly from the microdeletion of chromosome 22 at a location known as 22q11.2. This mutation results in the failure of appropriate development of the pharyngeal pouches, which are responsible for the embryologic development of the middle and external ear, maxilla, mandible, palatine tonsils, thyroid, parathyroids, thymus, aortic arch, and cardiac outflow tract. […] About 90% of DGS cases are a result of a deletion in chromosome 22, more specifically on the long arm (q) at the 11.2 locus (22q11.2). Most of these mutations arise de novo with no genetic abnormalities noted in the genome of the parents of children with DGS. […] DGS results from microdeletion of 22q11.2, which encodes over 90 genes. Patients with DGS display a broad array of phenotypes, and the most common findings include cardiac anomalies, hypocalcemia, and hypoplastic thymus.

• #7 DiGeorge Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK549798/

  On a genetic basis, TBX1 has correlations with the most prominent phenotypes characteristic of DGS. Failure in embryologic development of the pharyngeal pouches, which is driven by TBX1, leads to absence or hypoplasia of the thymus and parathyroid glands. […] A 22q11.2 knockout mouse model has also been studied, with findings pertinent for molecular and behavioral changes seen in Parkinson’s disease, autism spectrum disorder, attention deficit hyperactivity disorder, and schizophrenia. […] These findings, as well as the neuromicrovascular pathology found in TBX1 knockout mice, suggest a molecular basis for the psychiatric pathologies associated with DGS.

• #8 Pathology Outlines – DiGeorge syndrome

  https://www.pathologyoutlines.com/topic/thyroiddigeorge.html

  DiGeorge syndrome is a chromosomal disorder due to 22q11.2 deletion, characterized by failure of development of the third to fourth pharyngeal pouches and fourth branchial arch, which leads to a combination of congenital heart disease, parathyroid abnormalities (hypocalcemia) and thymic abnormalities (immunodeficiency) […] The occurrence of 22q11.2 deletions is related to the genomic architecture of the chromosome 22q11.2 region with several common rearrangement breakpoints […] The characteristic deletion of chromosome 22q11.2 is at least 10 times more common than the next most frequent human deletion syndrome, suggesting that this region is inherently unstable […] The deletion typically arises via unequal meiotic crossover / exchange, facilitated by asynchronous replication at the site of the deletion

• #8 Pathology Outlines – DiGeorge syndrome

  https://www.pathologyoutlines.com/topic/thyroiddigeorge.html

  TBX1 is the main gene responsible for DiGeorge phenotype […] TBX1 is a transcription factor normally expressed in the pharyngeal pouches, which give rise to the face, neck (parathyroids and thymus) and upper thorax […] Over 90% of the deletions occur de novo, while 6% – 10% of new cases are inherited from an affected parent […] Risk of recurrence in the offspring is up to 50% in each pregnancy.

• #9 Orphanet: 22q11.2 deletion syndrome

  https://www.orpha.net/en/disease/detail/567

  A rare chromosomal anomaly which causes a congenital malformation disorder that is typically characterized by cardiac defects, palatal anomalies, facial dysmorphism, developmental delay and immune deficiency. […] In most cases, the syndrome is due to a 3 million base pair (Mb) deletion on the chromosomal region 22q11.2 that is flanked by low copy number repeats. The deletion is due to a non-allelic meiotic recombination during spermatogenesis or oogenesis. In ~15% of cases, the deletion is nested within the 3 Mb DiGeorge critical region and varies in size. Most deletions include the TBX1 gene that has been shown to be implicated in cardiac, parathyroid, thymus and facial structure development. The variable expression of the 22q11.2 phenotype is thought to be due to genetic modifiers on either the other 22q11.2 allele or on other chromosomes.

• #10 DiGeorge Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/886526-overview

  The syndrome is caused by a microdeletion of band 22q11.2. The long arm of chromosome 22 (at q11) is prone to a microdeletion because of the presence of eight nonallelic, flanking, low-copy repeat DNA (deoxyribonucleic acid) sequence clusters (LCR22) labeled AH. Clusters AD are near the centromere. These repeat sequences lead to meiotic nonallelic crossing over between the 2 copies of chromosome 22 during spermatogenesis or oogenesis. […] The most common deletion present in 85% of individuals is 3 million base pair (Mb) in size, extends from A to D, and encompasses approximately 40 genes and 4 micro RNAs. Among them is the TBX1 gene, suspected to play a major role in many of the typical features of this syndrome. […] Among other genes mapped in the deleted region that have been implicated in the pathogenesis of 22q11.2DS include HIRA (a transcriptional corepressor of cell cycle dependent histone gene transcription and mammalian homologue of the yeast Hir1p and Hir2p proteins) and UFD1L (homologue of a highly conserved yeast gene involved in the degradation of ubiquitinated proteins).

• #10 DiGeorge Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/886526-overview

  DiGeorge syndrome (DGS) is one of a group of phenotypically similar disorders including velocardiofacial syndrome (VCFS, or Shprintzen syndrome) and conotruncal anomaly face (CTAF) syndrome that share a microdeletion of chromosome 22q11.2, a region known as the DGS critical region. […] The 22q11.2 deletion results in a range of embryonic developmental disruptions involving the head, neck, brain, skeleton, and kidneys. Portions of the heart, head and neck, thymus, and parathyroids derive from the third and fourth pharyngeal pouches, and this developmental field is disrupted due to the chromosomal microdeletion. This, in turn, leads to hypocalcemia, variable T-cell deficiency, and cardiac outflow defects. A combined T- and B-cell deficiency in part results from lack of T-helper cell function as typically seen in cases of complete 22q11.2DS.

• #10 DiGeorge Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/886526-overview

  The characteristic immunodeficiency in 22q11.2DS is a mild to moderate defect in T-cell lineage caused by thymic hypoplasia, typical of incomplete DGS. Nave T-cell production is usually reduced with resultant low TREC (T-cell receptor excision circles) detected by PCR. Only a small fraction of patients present with marked impairment of T-cell function associated with a complete absence of thymus/T-cells (complete DGS), and severe systemic infections, consistent with severe combined immunodeficiency phenotype. […] Impaired T-cell production may predispose patients with 22q11.2 deletion to autoimmune diseases.

• #11 DiGeorge syndrome (22q11 deletion)

  https://www.nhs.uk/conditions/digeorge-syndrome/

  DiGeorge syndrome is caused by a problem called 22q11 deletion. This is where a small piece of genetic material is missing from a person’s DNA. […] In around 1 in 10 cases (10%), the 22q11 deletion is passed on to a child by a parent who has DiGeorge syndrome, although they may not realise they have it if it’s mild.

• #12 22q11.2 deletion syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/22q11.2_deletion_syndrome_pathophysiology

  The main factor leading to DGS is the deletion of 22q11.2, which encodes over 90 genes. […] DiGeorge syndrome causes migration defects of neural crest-derived tissues, particularly affecting development of the third and fourth Branchial pouches (pharyngeal pouches). Also affected is the thymus gland; a mediastinal organ largely responsible for differentiation and induction of tolerance in T-cells. Impaired immune function results principally from this etiology. […] The deletion is bracketed by low copy number repeats (LCRs). Four discrete blocks of LCRs are found in this region and each block is comprised of multiple repeats. These blocks are named LCR A-D, with A being the most proximal. The deletion typically arises via unequal meiotic exchange, facilitated by asynchronous replication at the site of the deletion. The asynchronous replication can be associated with mispairing of the LCR and subsequent unequal crossing over. This mechanism predicts that duplications and deletions would be found in equal numbers. The characteristic deletion of chromosome 22q11.2 is at least 10 times more common than the next most frequent human deletion syndrome, suggesting that these repeat blocks are inherently unstable. The LCRs on chromosome 22q11.2 are larger and more complex and have higher homology than any of the other LCRs in the genome associated with human chromosomal deletion syndromes.

• #13 22q11.2 deletion syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/22q112-deletion-syndrome/

  22q11.2 deletion syndrome is a disorder caused by the deletion of a small piece of chromosome 22. The deletion occurs near the middle of the chromosome at a location designated q11.2. […] Most people with 22q11.2 deletion syndrome are missing a sequence of about 3 million DNA building blocks (base pairs) on one copy of chromosome 22 in each cell. This region contains 30 to 40 genes, many of which have not been well characterized. A small percentage of affected individuals have shorter deletions in the same region. This condition is described as a contiguous gene deletion syndrome because it results from the loss of many genes that are close together. […] Researchers are working to identify all of the genes that contribute to the features of 22q11.2 deletion syndrome. They have determined that the loss of a particular gene on chromosome 22, TBX1, is probably responsible for many of the syndrome’s characteristic signs (such as heart defects, a cleft palate, distinctive facial features, hearing loss, and low calcium levels). Some studies suggest that a deletion of this gene may contribute to behavioral problems as well. The loss of another gene, COMT, in the same region of chromosome 22 may also help explain the increased risk of behavioral problems and mental illness. The loss of additional genes in the deleted region likely contributes to the varied features of 22q11.2 deletion syndrome.

• #14

  https://link.springer.com/article/10.1007/s10875-022-01418-y

  22q11.2 microdeletion syndrome results from a deletion of chromosomal material within the 22q11.21 band, found at the proximal part of the long arm of chromosome 22. […] The 3 most common deletion sizes are 3 Mb (approximately 45 functional genes), 2 Mb, and 1.5 Mb (24 genes). […] Evidence in mouse models suggests that the impact of a Tbx1 mutation on thymic development is determined by the time point of the deletion. […] The diagnosis requires a severe deficiency of nave T cells and is traditionally defined as either CD45RA+CD3+ T cells co-expressing CD62L <50 cells/mm3 or CD45RA+ CD4+ T cells <50 cells/mm3 on two separate occasions in the absence of other explainable causes, such as SCID. [...] Characteristic immunologic features of congenital athymia resemble SCID and include profound T cell deficiency with risk of recurrent, severe, or opportunistic infections.

• #14

  https://link.springer.com/article/10.1007/s10875-022-01418-y

  Numerous other gene defects as well as environmental exposures have been identified as causing DTD, also termed thymic hypoplasia. […] The thymus is responsible for the development of T lymphocytes in utero and after birth. […] In pediatric necropsy samples of individuals with DGS, thymic tissue was located in various locations along its descent pathway as high as the base of the skull, medial to the submandibular salivary glands, and adjacent to the thyroid gland. […] The quantitative number of T lymphocytes measured in the blood of individuals with 22q11.2del largely reflects the thymic output and thymic size, particularly in the neonatal period. […] An estimated 67-80% of individuals affected with 22q11.2del have some degree of T cell lymphopenia (TCL). […] Studies suggest that approximately 0.5% of those diagnosed with 22q11.2del have a severe immune deficiency with very few T cells due to the absence of a thymus at birth, termed congenital athymia.

• #14

  https://link.springer.com/article/10.1007/s10875-022-01418-y

  The thymus plays a fundamental role in establishing and maintaining central and peripheral immune tolerance. […] T cell disorders are often associated with autoimmune disease, and individuals with 22q11.2del are at increased risk for autoimmunity. […] The overall incidence of autoimmune disease is approximately 10%.

• #15 Three Phases of DiGeorge/22q11 Deletion Syndrome Pathogenesis during brain development: patterning, proliferation, and mitochondrial functions of 22q11 genes

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3770287/

  DiGeorge, or 22q11 Deletion Syndrome (22q11DS), the most common survivable human genetic deletion disorder, is caused by deletion of a minimum of 32 contiguous genes on human chromosome 22, and presumably results from diminished dosage of one, some, or all of these genes particularly during development. […] Our data suggests that a substantial number of 22q11 genes act specifically and in concert to mediate early morphogenetic interactions and subsequent cellular differentiation at phenotypically compromised sites—the limbs, heart, face and forebrain. […] When dosage of a broad set of these genes is diminished, early morphogenesis is altered, and initial 22q11DS phenotypes are established. […] Thereafter, functionally similar subsets of 22q11 genes especially those that influence the cell cycle or mitochondrial function remain expressed, particularly in the developing cerebral cortex, to regulate neurogenesis and synaptic development.

• #15 Three Phases of DiGeorge/22q11 Deletion Syndrome Pathogenesis during brain development: patterning, proliferation, and mitochondrial functions of 22q11 genes

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3770287/

  Subsequently, diminished dosage of a subset of these 22q11 genes particularly those that regulate the cell cycle disrupts neurogenesis in the cerebral cortex. […] Finally, a distinct subset of mitochondrial 22q11 genes may compromise postnatal synaptogenesis. […] Such combined, recurrent function of 22q11 genes could disrupt differentiation from early embryonic through late postnatal development, especially in the brain. […] This concatenation of dosage-sensitive changes in development, especially if modified by additional genetic or environmental factors, could explain the variable behavioral pathology, as well as peripheral dysmorphology, associated with 22q11DS.

• #15 Three Phases of DiGeorge/22q11 Deletion Syndrome Pathogenesis during brain development: patterning, proliferation, and mitochondrial functions of 22q11 genes

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3770287/

  When dosage of these genes is diminished, numbers, placement and connectivity of neurons and circuits essential for normal behavior may be disrupted. […] Such disruptions likely contribute to vulnerability for schizophrenia, autism, or attention deficit/hyperactivity disorder seen in most 22q11DS patients. […] Despite these obvious signs that diminished 22q11 gene dosage disrupts critical developmental mechanisms, little is known about how such changes in 22q11 gene function result in the constellation of 22q11DS phenotypes. […] Our work suggests that 22q11 genes operate as functionally related sets at distinct times during development. […] Diminished dosage of a substantial set of 22q11 genes expressed at sites of mesenchymal/epithelial interaction—which later become the 22q11DS phenotypic sites—likely compromises early morphogenesis in the brain, face, heart and limbs.

• #16 22q11.2 deletion syndrome | MedLink Neurology

  https://www.medlink.com/articles/22q11-2-deletion-syndrome

  Genetic factors play a major role in the phenotypic variability of a mouse model of DiGeorge syndrome. […] The transcription factor encoded by TBX1 is important to cardiac development and is often deleted in patients. […] It is also required for the elongation and elevation of palatal shelves and pharyngeal development. […] The catechol-O-methyltransferase gene is located within the region typically deleted in DiGeorge and velocardiofacial syndrome. […] Individuals hemizygous for the catechol-O-methyltransferase gene (such as those with a 22q11.2 deletion) and carrying a low activity allele on their nondeleted chromosome may be predisposed to the development of psychotic features. […] Expression studies performed in mice and humans show that most 22q11.2 genes are expressed in the brain during multiple stages of development.

• #16 22q11.2 deletion syndrome | MedLink Neurology

  https://www.medlink.com/articles/22q11-2-deletion-syndrome

  Thus, the neuropsychiatric findings in individuals with DiGeorge and velocardiofacial syndrome may be the result of the deletion of multiple 22q11.2 genes. […] The embryology of the condition is caused by abnormal development of the third and fourth pharyngeal pouches and the fourth aortic arch. […] It is likely that the recognizable features in DiGeorge and velocardiofacial syndrome patients (unique facial features, congenital heart disease, thymus hypoplasia, parathyroid hypoplasia) result from either aberrant neural crest cell migration or from a disorder of cell interaction with pharyngeal pouch endoderm from which the affected structures are derived.

• #17 Neuroinflammation and Oxidative Stress in Individuals Affected by DiGeorge Syndrome

  https://www.mdpi.com/1422-0067/24/4/4242

  DiGeorge syndrome (DGS) is a rare genetic disease caused by microdeletions of the 22q11.2 region (DGS1). […] The specific aim of this descriptive report is to discuss the correlation between oxidative stress and neuroinflammation in DGS patients with microdeletions of the 22q11.2 region. […] The deleted chromosomic region maps various genes involved in mitochondrial metabolisms, such as DGCR8 and TXNRD2, that could lead to reactive oxygen species (ROS) increased production and antioxidant depletion. […] Furthermore, increased levels of ROS in mitochondria would lead to the destruction of the projection neurons in the cerebral cortex with consequent neurocognitive impairment. […] Finally, the increase in modified protein belonging to the family of sulfoxide compounds and hexoses, acting as inhibitors of the IV and V mitochondria complex, could result in direct ROS overproduction.

• #17 Neuroinflammation and Oxidative Stress in Individuals Affected by DiGeorge Syndrome

  https://www.mdpi.com/1422-0067/24/4/4242

  Neuroinflammation in DGS individuals could be directly related to the development of the syndrome’s characteristic psychiatric and cognitive disorders. […] The correlation between the imbalance of the redox state and the clinical DGS manifestations has not yet been established, but important findings have been revealed. […] It has been proposed that the under-connectivity of association cortices underlies behavioral deficits in several neurodevelopmental disorders, including DGS. […] Observing functional images, it has been demonstrated that association cortices are under-connected in the DGS. […] They also demonstrated that the use of antioxidants or the re-expression of Txnrd2 improved quantitative cellular deficits associated with LgDel layer 2/3 PN-selective under-connectivity.

• #18 22q11 deletion syndrome: current perspective | TACG

  https://www.dovepress.com/22q11-deletion-syndrome-current-perspective-peer-reviewed-fulltext-article-TACG

  Recently, it was shown that haploid 22q11 gene insufficiency, including but not limited to TBX1, disrupts orofacial and cranial nerve development by modifying retinoic acid-modulated anteriorposterior hindbrain differentiation. […] Recent studies showed that reduced doses of 22q11 genes could modify the initial forebrain patterning, subsequent cortical neurogenesis and migration, and the mitochondrial support of activity-dependent synapse formation and elimination in the early postnatal brain.

• #18 22q11 deletion syndrome: current perspective | TACG

  https://www.dovepress.com/22q11-deletion-syndrome-current-perspective-peer-reviewed-fulltext-article-TACG

  The diminished gene expression on 22q11.2 is responsible for the clinical findings associated with 22q11DS; however, little is known about how such changes lead to the phenotypes of 22q11DS. […] Numerous candidate genes have been linked with the 22q11DS phenotype. In 1999, murine models identified TBX1 as a candidate gene for this syndrome. TBX1 is the most important gene for 22q11DS. […] TBX1 haploinsufficiency contributes to the conotruncal and cardiac OFT anomalies that are observed commonly in 22q11DS. […] Various pathways downstream of TBX1 and modifiers of TBX1 activity seem to play an important role in the pathogenesis of 22q11DS. TBX1 regulates the expression of several growth factors and transcription factors, including FGF8, FGF10, PITX2, CHD7, VEFR3, EYA1, WNT5A, BMPER, and Otog-MyoD.

• #19 22Q11.2 Deletion Syndrome (Digeorge Syndrome, Velocardiofacial Syndrome) | 5-Minute Pediatric Consult

  https://peds.unboundmedicine.com/pedscentral/view/5-Minute-Pediatric-Consult/617617/all/22Q11_2_Deletion_Syndrome__Digeorge_Syndrome_Velocardiofacial_Syndrome_?q=Rubella

  22q11.2 deletion syndrome, formerly known as DiGeorge or velocardiofacial syndrome, is a multisystem disorder with variable severity and number of associated features, classically including developmental delay, learning difficulties, congenital cardiac anomalies, palatal abnormalities, especially velopharyngeal insufficiency, hypocalcemia, and subtle facial dysmorphism. […] A developmental defect of the 3rd and 4th pharyngeal arches may be part of the mechanism; molecular disturbances of neurodevelopment are yet to be identified.

• #20 DiGeorge or 22q11.2 deletion syndrome | Immune Deficiency Foundation

  https://primaryimmune.org/understanding-primary-immunodeficiency/types-of-pi/digeorge-or-22q112-deletion-syndrome

  DiGeorge syndrome, most frequently caused by a deletion at 22q11.2, is a PI caused by abnormal migration and development of certain cells and tissues during fetal development. […] DGS occurs in four main groups of children: The most common cause is due to a genetic defect called 22q11.2 deletion syndrome (22q11.2DS). In children with 22q11.2DS, a piece of chromosome 22 is missing. […] Most cases of 22q11.2 DS occur spontaneously. DGS is caused by a large deletion from chromosome 22. This deletion means that several genes from this region are not present in those with DGS. It appears that the variation in the symptoms of the disease is related to the amount of genetic material lost in the chromosomal deletion. Many of the manifestations of DGS have been linked to deletion of the T-box transcription factor 1 (TBX1) gene on chromosome 22q11, which plays a role in neural crest cell migration, pharyngeal arch (PA) development, and formation of the pharyngeal pouches. TBX1 interacts with many genetic molecular pathways leading to craniofacial defects and aberrant neural crest cell migration and survival.

• #21 The 22q11.2 deletion syndrome

  https://www.jstage.jst.go.jp/article/kjm1952/51/2/51_2_77/_article

  The 22g11.2 deletion syndrome (22q11DS) encompasses DiGeorge syndrome, velo-cardio-facial syndrome and conotruncal anomaly face syndrome and is due to a microdeletion of chromosome 22q11.2. […] The structures primarily affected in patients with 22g11DS are derivatives of the embryonic pharyngeal arches and pouches suggesting that haploinsufficiency of the gene(s) on the deleted region, spanning 2-3 Mb, is important in pharyngeal arch/pouch development. […] Extensive gene searches have been successful in identifying more than 30 genes in the deleted segment. […] Although standard positional cloning has failed to demonstrate a role for any of these genes in the syndrome, the use of experimental animal models and advanced genome manipulation technologies in mice have been providing an insight into the developmental role of some of these genes, including TBX1.

• #22

  https://jsurgmed.com/article/view/513859

  Aim: Congenital heart defects (CHD) are the most common major birth defects in humans. Conotruncal cardiac defects (CCD) and aortic arch anomalies, the outflow tract anomalies of the heart, usually accompany dysmorphic syndromes. Di George Syndrome, deletion of 22q11.2, is one of the typical examples for this entity. […] All patients having 22q11.2 deletion had at least one abnormality of the syndrome other than cardiac problems. Facial dysmorphism and growth retardation were the most common features. Cognitive disability, feeding problems, hypocalcemia, psychiatric problems, immunity differences were the other associated problems. […] We suggest that 22q11.2 deletion must be explored in all newborns with selective conotruncal cardiac defects and with non-conotruncal cardiac defects accompanying the other anomalies of the syndrome. All deletion positive patients must be evaluated for the accompanying features of the syndrome with genetic counselling.

• #23 22q11.2 deletion syndrome: Novel approaches to understand cardiopharyngeal pathogenesis |

  https://www.fondationleducq.org/network/22q11-2-deletion-syndrome-novel-approaches-to-understand-cardiopharyngeal-pathogenesis/

  DiGeorge Syndrome, or the 22q11.2 deletion syndrome, is the most frequent human congenital heart syndrome. […] New findings have linked some of the most common human congenital heart defects to a progenitor cell population named the cardiopharyngeal mesoderm (CPM), which as the name implies, forms not only the heart, but part of the face and neck. […] This Leducq networks multidisciplinary team will investigate the role of the Tbx1 gene, which is essential for development of the CPM cell population and the formation of the heart, relying upon models in the mouse and the sea squirt Ciona; mice recapitulate faithfully the human patient phenotype and Ciona has recently emerged as an excellent model for CPM biology. […] Investigators hope to gain novel insights concerning 22q11.2DS pathogenesis, and the mechanisms controlling cardiopharyngeal development.

• #24 Endocrine aspects of the 22q11.2 deletion syndrome | Genetics in Medicine

  https://www.nature.com/articles/gim20015

  Hormonal disorders are common in patients with a 22q11.2 deletion. While hypoparathyroidism was the first endocrine disturbance documented in the DiGeorge syndrome, growth hormone deficiency, hypothyroidism, and hyperthyroidism are now known to occur in patients with a 22q11.2 deletion. […] Accurate assessment of the prevalence of hormonal disorders in the 22q11.2 is important not only for genetic counseling, but also to provide optimal clinical care to patients. Furthermore, elucidation of the pathophysiology of the hormonal disturbances may provide insights into the molecular mechanisms underlying the 22q11.2 deletion syndrome. […] The hypocalcemia in children with 22q11 deletions is invariably due to hypoparathyroidism, as originally described by DiGeorge in 1965 and documented by aplasia or hypoplasia of the parathyroid glands at surgery or autopsy. […] Hypoparathyroidism is most likely to present with symptoms of hypocalcemia—seizures, tremors, or tetany—in the neonatal period. […] Growth hormone deficiency remains an important, treatable cause of poor growth in this population.

• #25 Exploring pathway interactions to detect molecular mechanisms of disease: 22q11.2 deletion syndrome | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02953-6

  22q11.2 Deletion Syndrome (22q11DS) is a genetic disorder characterized by the deletion of adjacent genes at a location specified as q11.2 of chromosome 22, resulting in an array of clinical phenotypes including autistic spectrum disorder, schizophrenia, congenital heart defects, and immune deficiency. […] however, the exact and systemic molecular mechanisms between the deleted area and its resulting clinical phenotypic expression, for example that of neuropsychiatric diseases, are not yet fully understood. […] One major challenge of studying 22q11DS is to understand the molecular mechanisms between the deleted genes and the resulting disease phenotypes; previous research showed that the phenotypes vary widely among individuals, even though most patients share a common 3 Mb deletion. […] It is now suspected that multiple genes deleted within and outside the 22q11.2 region interact and target various cellular mechanisms, causing a range of clinical variation with different degrees of severity.

• #25 Exploring pathway interactions to detect molecular mechanisms of disease: 22q11.2 deletion syndrome | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02953-6

  Using the pathway interaction method, we were able to detect a molecular network that could possibly explain the development of neuropsychiatric diseases among the 22q11DS patients. […] We expect our pathway interaction method could be used for problems with similar contexts, where complex genetic mechanisms need to be identified to explain the resulting phenotypic plasticity. […] The differentiating feature of the Psychiatric Group over the Nonpsychiatric Group, i.e. the molecular signature of the 22q11DS patients who have experienced autism spectrum disorder and/or psychosis, compared to those who have not experienced such diseases, implies the involvement of NK cell functions and PI3K/Akt signalling pathway, as well as several genes such as CRKL, PDGFRB, and AKT1. […] We can summarize our findings as follows. […] The role of other genes, HLA-A, HRAS, and PAK2, whose connection was not clearly demonstrated by the disease subnetwork, may be illuminated in conjunction with GRAP2 or its close interaction partners.

• #25 Exploring pathway interactions to detect molecular mechanisms of disease: 22q11.2 deletion syndrome | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02953-6

  Challenges to understanding exact mechanisms of 22q11.2 Deletion Syndrome (22q11DS) originate from the high level of genotype-phenotype variability and the polygenic inheritance of the disease. […] Using the method, we were able to identify and explain possible involvement of pathways including the NK cell functions pathway and genes such as CRKL for the development of autism and/or psychosis in 22q11DS patients.

• #26 DiGeorge Syndrome | Concise Medical Knowledge

  https://www.lecturio.com/concepts/digeorge-syndrome/

  DiGeorge syndrome (DGS) is a condition caused by a microdeletion at location q11.2 of chromosome 22 (thus also called 22q11.2 deletion syndrome). There is a defective development of the third and fourth pharyngeal pouches, leading to thymic and parathyroid hypoplasia, causing T-cell immunodeficiency and hypocalcemia, respectively. Conotruncal anomalies presenting as congenital heart defects are also characteristic of the disease. […] Approximately 30-50 genes are affected by the 22q11.2 deletion. Disrupts the development of the 3rd and 4th pharyngeal pouches. Creates a defect in the embryonic development of the brain, neck, skeleton, and kidneys. […] TBX1 is the main gene responsible for the DiGeorge phenotype. It plays a vital role in organ formation and regulation, affecting the formation of the skull bones, mesenchyme of the face and palate, outflow tract of the heart, thymus, and parathyroid stroma. […] 22q11.2 deletions are associated with a higher risk of early onset Parkinson’s disease.

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