Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 132, Issue 3, Pages 656-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2013.06.013
Keywords
Combined immunodeficiency with multiple intestinal atresias; tetratricopeptide repeat domain 7A; whole-exome sequencing; thymus
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Funding
- Stanford University
- National Institutes of Health (NIH)
- NIH [5P01AI076210-04, 1R01AI00887-01,, 4U54AI082973-04]
- Manton Foundation
- Dubai Harvard Foundation for Medical Research
- Kuwait Foundation for the Advancement of Sciences [2010-1302-05]
- Fondazione Nocivelli
- University of Brescia
- MIUR [20104HBZ8E_002]
- Translational Investigator Service award from Boston Children's Hospital
- National Human Genome Research Institute of the NIH [K99HG007065]
- Damon Runyon Cancer Research Foundation (DRG) [2122-22]
- National Genome Research Institute
- NIH
- NIH/National Institute of Allergy and Infectious Diseases (NIAID)
- Boston Children's Hospital
- NIH/NIAID
- NIH/National Heart, Lung, and Blood Institute (NHLBI)
- Italian Ministry of University and Research
- Illumina
- Beckman Coulter
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Background: Combined immunodeficiency with multiple intestinal atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects. Objective: We sought to determine the underlying genetic causes of CID-MIA by analyzing the exomic sequences of 5 patients and their healthy direct relatives from 5 unrelated families. Methods: We performed whole-exome sequencing on 5 patients with CID-MIA and 10 healthy direct family members belonging to 5 unrelated families with CID-MIA. We also performed targeted Sanger sequencing for the candidate gene tetratricopeptide repeat domain 7A (TTC7A) on 3 additional patients with CID-MIA. Results: Through analysis and comparison of the exomic sequence of the subjects from these 5 families, we identified biallelic damaging mutations in the TTC7A gene, for a total of 7 distinct mutations. Targeted TTC7A gene sequencing in 3 additional unrelated patients with CID-MIA revealed biallelic deleterious mutations in 2 of them, as well as an aberrant splice product in the third patient. Staining of normal thymus showed that the TTC7A protein is expressed in thymic epithelial cells, as well as in thymocytes. Moreover, severe lymphoid depletion was observed in the thymus and peripheral lymphoid tissues from 2 patients with CID-MIA. Conclusions: We identified deleterious mutations of the TTC7A gene in 8 unrelated patients with CID-MIA and demonstrated that the TTC7A protein is expressed in the thymus. Our results strongly suggest that TTC7A gene defects cause CID-MIA.
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