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Candidate modifier genes for immune function in 22q11.2 deletion syndrome
Catherina T Pinnaro1, Travis Henry2, Heather J Major1
1Stead Family Department of Pediatrics, Iowa City, IA, USA.
Molecular Genetics & Genomic Medicine
|December 13, 2019
Summary
Genetic variants outside the 22q11.2 deletion region influence immune dysfunction in 22q11.2DS patients. Rare variants in retinoic acid signaling genes, NCOR2 and EP300, are linked to altered immune phenotypes.
Area of Science:
- Genetics
- Immunology
- Human Diseases
Background:
- 22q11.2 deletion syndrome (22q11.2DS) is a common microdeletion disorder with varied symptoms.
- Immune dysfunction is a frequent and serious comorbidity in 22q11.2DS.
- Identifying genetic modifiers of immune dysfunction is crucial for patient prognostication and treatment development.
Purpose of the Study:
- To identify genes outside the 22q11.2 deletion locus that modify immune dysregulation in 22q11.2DS.
- To investigate the role of genetic variants in retinoic acid signaling pathways.
Main Methods:
- Exome sequencing and gene-based variant association analysis in 31 individuals with 22q11.2DS.
- Comprehensive immunophenotyping using clinical data and a novel scoring system.
- Validation of immunophenotypic scores against newborn screening T-cell receptor excision circle (TREC) results.
Main Results:
- Rare DNA variants in NCOR2 and EP300, transcriptional regulators of retinoic acid signaling, were associated with the immunophenotype.
- These genes are located outside the canonical 3Mb 22q11.2 deletion region.
Conclusions:
- Genetic modifiers outside the 22q11.2 deletion locus significantly influence immune function in 22q11.2DS patients.
- Alterations in retinoic acid signaling may play a key role in the immune dysregulation observed in 22q11.2DS.
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