Immune Dysregulation in Patients With Chromosome 18q Deletions—Searching for Putative Loci for Autoimmunity and Immunodeficiency

IntroductionAutoimmune disorders, IgA deficiency, and allergies seem to be common among individuals with 18q deletion syndrome [OMIM 601808]. We aimed to determine the prevalence, mechanism, and genetic background of autoimmunity, immune deficiency, and allergy in a cohort of patients with 18q deletions.Material and MethodsMedical registries and social media were used to recruit the patients. Microarray oligonucleotide comparative genomic hybridization (aCGH) (Agilent, Santa Clara, CA, USA) was performed in all patients to identify size and location of chromosome 18 deletion. Clinical evaluation and medical record collection were performed in each of the study participants. The history of autoimmune disorders, severe and/or recurrent infections, and symptoms of allergy were noted. Total immunoglobulin IgG, IgA, IgM, IgE, and IgG1-4 serum levels were measured using nephelometry and ELISA methods. Lymphocyte T subset phenotyping was performed in 24 subjects from 18q del cohort. To predict the most promising candidate genes, we used the ENDEAVOUR—a free web resource for gene prioritization.Results18q deletion was confirmed by means of array CGH analysis in 27 individuals, 15 (55.6%) females and 12 males, referred to the project by specialists in medical genetics, diabetology, or pediatric endocrinology between May 2015 and December 2019. The mean age at examination was 11.8 years (min–max: 4.0–33.5). Autoimmune disorders were present in 14/27 (51.8%) of the cohort. In eight of patients, symptoms of immune deficiency coexisted with autoimmunity. Allergy was reported in nine of 27 (33.4%) patients. Over 89% of patients presented with at list one type of immunoglobulin (IgA, IgM, IgG, IgE, and IgG1-4) deficiency and eight of 25 (32%) had abnormalities in at least two major immunoglobulin (IgG, IgA, IgM) measurements (CVID-like phenotype). Patients with 18q del exhibited a significantly decreased CD4, Treg FOXP3+, TregFOXP3+Helios+, and TemCD4 cell numbers in comparison with the control groups of 24 T1DM patients and 28 healthy controls.ConclusionsPatients with 18q deletions frequently suffer from autoimmune disorders, recurrent infections, and allergy due to immune dysregulation presenting with variable antibody deficiencies and T-regulatory cell deficiency (CD4+CD25+CD127lowFOXP3+). The spectrum of speculations regarding which gene might be responsible for such phenotype ranges from single gene haploinsufficiency to deletion of a cluster of immunogenes located distally to 18q21.

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Does Inhaled Corticosteroid Treatment Result in a Secondary Immune Deficiency Predisposing To Recurrent Infections?

Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry ◽

10.2174/1871523011202030217 ◽

2012 ◽

Vol 11 (3) ◽

pp. 217-220

Author(s):

Nerin N. Bahceciler

Keyword(s):

Immune Deficiency ◽

Corticosteroid Treatment ◽

Treatment Result ◽

Recurrent Infections ◽

Inhaled Corticosteroid

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Recognizing Primary Immune Deficiency in Clinical Practice

Clinical and Vaccine Immunology ◽

10.1128/cvi.13.3.329-332.2006 ◽

2006 ◽

Vol 13 (3) ◽

pp. 329-332 ◽

Cited By ~ 37

Author(s):

Hale Yarmohammadi ◽

Lissette Estrella ◽

John Doucette ◽

Charlotte Cunningham-Rundles

Keyword(s):

Immune Deficiency ◽

Clinical Practice ◽

Organ Dysfunction ◽

Primary Immunodeficiency ◽

Scoring System ◽

Clinical Information ◽

Chronic Illnesses ◽

Primary Immune Deficiency ◽

Recurrent Infections

ABSTRACT Primary immunodeficiency results in recurrent infections, organ dysfunction, and autoimmunity. We studied 237 patients referred for suspicion of immunodeficiency, using a scoring system based on clinical information. The 113 patients with immunodeficiency had higher scores and more episodes of chronic illnesses and were more likely to have neutropenia, lymphopenia, or splenomegaly.

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Accurate, Fast and Cost-Effective Diagnostic Test for Monosomy 1p36 Using Real-Time Quantitative PCR

Disease Markers ◽

10.1155/2014/836082 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8

Author(s):

Pricila da Silva Cunha ◽

Heloisa B. Pena ◽

Carla Sustek D’Angelo ◽

Celia P. Koiffmann ◽

Jill A. Rosenfeld ◽

...

Keyword(s):

Real Time ◽

Diagnostic Test ◽

Quantitative Pcr ◽

Target Genes ◽

Cost Effective ◽

Qpcr Assay ◽

Deletion Syndrome ◽

Comparative Genomic ◽

Real Time Quantitative Pcr ◽

Subtelomeric Deletion

Monosomy 1p36 is considered the most common subtelomeric deletion syndrome in humans and it accounts for 0.5–0.7% of all the cases of idiopathic intellectual disability. The molecular diagnosis is often made by microarray-based comparative genomic hybridization (aCGH), which has the drawback of being a high-cost technique. However, patients with classic monosomy 1p36 share some typical clinical characteristics that, together with its common prevalence, justify the development of a less expensive, targeted diagnostic method. In this study, we developed a simple, rapid, and inexpensive real-time quantitative PCR (qPCR) assay for targeted diagnosis of monosomy 1p36, easily accessible for low-budget laboratories in developing countries. For this, we have chosen two target genes which are deleted in the majority of patients with monosomy 1p36:PRKCZandSKI. In total, 39 patients previously diagnosed with monosomy 1p36 by aCGH, fluorescentin situhybridization (FISH), and/or multiplex ligation-dependent probe amplification (MLPA) all tested positive on our qPCR assay. By simultaneously using these two genes we have been able to detect 1p36 deletions with 100% sensitivity and 100% specificity. We conclude that qPCR ofPRKCZandSKIis a fast and accurate diagnostic test for monosomy 1p36, costing less than 10 US dollars in reagent costs.

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A novel 5q11.2 deletion detected by microarray comparative genomic hybridisation in a child referred as a case of suspected 22q11 deletion syndrome

Human Genetics ◽

10.1007/s00439-004-1195-6 ◽

2004 ◽

Vol 116 (1-2) ◽

pp. 83-90 ◽

Cited By ~ 23

Author(s):

Katrina Prescott ◽

Kathryn Woodfine ◽

Paula Stubbs ◽

Maurice Super ◽

Bronwyn Kerr ◽

...

Keyword(s):

Deletion Syndrome ◽

Comparative Genomic Hybridisation ◽

Comparative Genomic ◽

22Q11 Deletion ◽

22Q11 Deletion Syndrome

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Immune Dysregulation and Autoimmune Disorders

10.1007/978-3-030-22009-9_301216 ◽

2021 ◽

pp. 2556-2556

Keyword(s):

Immune Dysregulation ◽

Autoimmune Disorders

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Structural diseases of the heart: syndromes affecting the cardiovascular system

ESC CardioMed ◽

10.1093/med/9780198784906.003.0162 ◽

2018 ◽

pp. 719-722

Author(s):

Sabine Klaassen

Keyword(s):

Single Gene ◽

Significant Proportion ◽

Signal Transduction Pathway ◽

Alagille Syndrome ◽

Mitogen Activated Protein Kinase ◽

Neurological Deficits ◽

Deletion Syndrome ◽

Gene Encoding ◽

Mitogen Activated Protein ◽

Craniofacial Features

Congenital heart disease (CHD) occurs in association with extracardiac anomalies or as part of an identified syndrome in 25–40% of cases. Approximately 30% of children with a chromosomal abnormality have CHD. Aneuploidy, or abnormal chromosomal number, accounts for a significant proportion of CHD. Of individuals born with trisomy 21, 50% have CHD, the most common being an atrioventricular septal defect (45%). In segmental aneuploidies, the so-called microdeletion syndromes, small submicroscopic chromosomal deletions can lead to CHD. The 22q11 deletion syndrome causes CHD with thymic and parathyroid hypoplasia (DiGeorge syndrome) and characteristic dysmorphic craniofacial features due to abnormal pharyngeal arch development. Williams–Beuren syndrome with renovascular anomalies, typical elfin facies, and neurological deficits, is characterized by cardiac involvement in the form of supravalvar aortic and peripheral pulmonic stenosis. Chromosome 1p36 deletion syndrome is the most common subterminal deletion syndrome. A substantial proportion of individuals with 1p36 deletion syndrome have CHD which may occur in the presence or absence of cardiomyopathy, most commonly left ventricular non-compaction cardiomyopathy. Single gene mutations may also cause syndromic CHD. Noonan syndrome and related disorders (‘RASopathies’) are caused by dominant gain-of-function mutations in one of the genes which encode proteins that function in the Ras/mitogen-activated protein kinase (RAS-MAPK) signal transduction pathway. Holt–Oram syndrome is associated with mutations in the transcription factor TBX5. Alagille syndrome is caused by mutations in JAG1, a gene encoding a ligand in the Notch signaling pathway. Heterotaxy syndrome, which means randomization of cardiac, pulmonary, or gastrointestinal situs, is frequently associated with CHD.

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An Interstitial 20q11.21 Microdeletion Causing Mild Intellectual Disability and Facial Dysmorphisms

Case Reports in Genetics ◽

10.1155/2013/353028 ◽

2013 ◽

Vol 2013 ◽

pp. 1-5 ◽

Cited By ~ 3

Author(s):

Ivan Y. Iourov ◽

Svetlana G. Vorsanova ◽

Oxana S. Kurinnaia ◽

Yuri B. Yurov

Keyword(s):

Intellectual Disability ◽

Single Gene ◽

Index Patient ◽

Genomic Region ◽

Comparative Genomic ◽

Mild Intellectual Disability ◽

Present Case Report ◽

Facial Dysmorphisms ◽

Genomic Variations ◽

Opitz Syndrome

We report a case of an interstitial chromosome 20q11.21 microdeletion in a 7-year-old male child presenting with mild intellectual disability and facial dysmorphisms. Array comparative genomic hybridization (CGH) has shown that the deletion resulted in the loss of 68 genes, among which 5 genes (COX4I2,MYLK2,ASXL1,DNMT3B, andSNTA1) are disease causing. The size of the deletion was estimated to span 2.6 Mb. Only three cases of deletions encompassing this chromosomal region have been reported. The phenotype of the index patient was found to resemble the mildest cases of Bohring-Opitz syndrome that is caused byASXL1mutations. Anin silicoevaluation of the deleted genomic region has shown that benign genomic variations have never been observed to affect theASXL1gene, in contrast to the other disease-causing genes. As a result, it was suggested thatASXL1loss is likely to be the main cause of the phenotypic manifestations. The present case report indicates that a loss of the disease-causing gene can produce a milder phenotype of a single gene condition.

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Immune dysregulation in patients with RAG deficiency and other forms of combined immune deficiency

Blood ◽

10.1182/blood.2019000923 ◽

2020 ◽

Vol 135 (9) ◽

pp. 610-619 ◽

Cited By ~ 1

Author(s):

Ottavia M. Delmonte ◽

Anna Villa ◽

Luigi D. Notarangelo

Keyword(s):

Immune Deficiency ◽

Cell Function ◽

Immune Dysregulation ◽

Therapeutic Interventions ◽

B Cell Tolerance ◽

Recombination Activating Genes ◽

Immune Deficiencies ◽

Severe Infections ◽

Rag Deficiency ◽

Combined Immune Deficiency

Abstract Traditionally, primary immune deficiencies have been defined based on increased susceptibility to recurrent and/or severe infections. However, immune dysregulation, manifesting with autoimmunity or hyperinflammatory disease, has emerged as a common feature. This is especially true in patients affected by combined immune deficiency (CID), a group of disorders caused by genetic defects that impair, but do not completely abolish, T-cell function. Hypomorphic mutations in the recombination activating genes RAG1 and RAG2 represent the prototype of the broad spectrum of clinical and immunological phenotypes associated with CID. The study of patients with RAG deficiency and with other forms of CID has revealed distinct abnormalities in central and peripheral T- and B-cell tolerance as the key mechanisms involved in immune dysregulation. Understanding the pathophysiology of autoimmunity and hyperinflammation in these disorders may also permit more targeted therapeutic interventions.

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