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Candidate modifier genes for immune function in 22q11.2 deletion syndrome
- Source :
- Molecular Genetics & Genomic Medicine, Vol 8, Iss 1, Pp n/a-n/a (2020), Molecular Genetics & Genomic Medicine
- Publication Year :
- 2019
- Publisher :
- Wiley, 2019.
-
Abstract
- Background The 22q11.2 deletion syndrome (22q11.2DS) is the most common contiguous microdeletion affecting humans and exhibits extreme phenotypic heterogeneity. Patients can manifest any combination of comorbidities including congenital heart disease, hypoparathyroidism, cleft palate, kidney abnormalities, neurodevelopmental disorders, and immune dysfunction. Immunodeficiency is present in the majority of patients with 22q11.2DS and is the second leading cause of death in these patients. Knowing the genetic determinants of immune dysfunction will aid in prognostication and potentially novel treatments. Methods We performed exome sequencing and gene‐based variant association analysis on 31 deeply phenotyped individuals with the canonical 3Mb 22q11.2 deletion to identify what genes outside the 22q11.2 locus may be modifying the immune dysregulated phenotype. Immunophenotyping was performed using preexisting medical data and a novel scoring system developed from numerous clinical laboratory values including immunoglobulin levels, lymphocyte transformation to antigens (LTA), lymphocyte transformation to mitogens (LTM), and peripheral blood flow cytometry. Immunophenotypic scoring was validated against newborn screening T‐cell receptor excision circle (TREC) results. Results Rare DNA variants in transcriptional regulators involved in retinoic acid signaling (NCOR2, OMIM *600848 and EP300, OMIM *602700) were found to be associated with immunophenotype. Conclusion The expression of TBX1, which seems to confer the major phenotypic features of 22q11.2DS, is regulated via retinoic acid signaling, and alterations in retinoic acid signaling during embryonic development can lead to phenocopies of 22q11.2DS. These observations support the hypothesis that genetic modifiers outside the microdeletion locus may influence the immune function in 22q11.2DS patients.<br />We performed deep phenotyping for immune status on 31 individuals with the canonical 3Mb 22q11.2 deletion followed by whole exome sequencing. DNA variants in transcriptional regulators involved in retinoic acid signaling (NCOR2, EP300) were found to be associated with immune status.
- Subjects :
- 0301 basic medicine
TBX1
22q11 Deletion Syndrome
lcsh:QH426-470
Retinoic acid
030105 genetics & heredity
Biology
medicine.disease_cause
Immunophenotyping
03 medical and health sciences
chemistry.chemical_compound
Immune system
immune dysregulation
retinoic acid
Genetics
medicine
Humans
Nuclear Receptor Co-Repressor 2
Lymphocytes
Molecular Biology
Genetics (clinical)
Immunodeficiency
Exome sequencing
Phenocopy
Genes, Modifier
Genetic heterogeneity
Original Articles
genetic modifiers
Immune dysregulation
medicine.disease
3. Good health
lcsh:Genetics
Phenotype
030104 developmental biology
chemistry
22q11.2 deletion syndrome
Immunology
Original Article
E1A-Associated p300 Protein
Subjects
Details
- ISSN :
- 23249269
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Molecular Genetics & Genomic Medicine
- Accession number :
- edsair.doi.dedup.....33c5e2764f010e07b8afe9c9643153db