Department of Genetics, Stanford University School of Medicine, Stanford, Calif.
A. Nocivelli Institute for Molecular Medicine, Pediatric Clinic, University of Brescia, and the Section of Genetics, Department of Pathology Spedali Civili, Brescia, Italy.
Department of Pathology, University of Brescia, Brescia, Italy.
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, Mass.
Department of Transfusion Medicine, Boston Children's Hospital, Boston, Mass.
Division of Hematology and Oncology, Boston Children's Hospital, Boston, Mass.
Department of Public Health and Pediatrics, University of Torino, Torino, Italy.
USC Patologia Neonatale, Ospedali Riuniti di Bergamo, Bergamo, Italy.
Division of Pediatric Hematology-Oncology, Spedali Civili Brescia, Brescia, Italy.
Department of Pediatrics, Al-Sabah Hospital, Kuwait City, Kuwait.
Department of Surgery, Ibn-Sina Hospital, Kuwait City, Kuwait.
New England Newborn Screening Program, University of Massachusetts Medical School, Worcester, Mass.
Department of Internal Medicine, Children's Hospital of Pittsburgh, Pittsburgh, Pa.
Division of Hematology-Oncology, Boston Children's Hospital, Boston, Mass.
Clinical Immunology and Allergology, Spedali Civili Brescia, Brescia, Italy.
Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif. Electronic address: knadeau@stanford.edu.
Department of Genetics, Stanford University School of Medicine, Stanford, Calif. Electronic address: mpsnyder@stanford.edu.
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, Mass; Harvard Stem Cell Institute, Harvard Medical School, Boston, Mass. Electronic address: Luigi.Notarangelo@childrens.harvard.edu.
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.
Zhang K, Kang L, Zhang H, Bai L, Pang H, Liu Q, Zhang X, Chen D, Yu H, Lv Y, Gao M, Liu Y, Gai Z, Wang D, Li X.Front Immunol. 2022 Oct 19;13:987666. doi: 10.3389/fimmu.2022.987666. eCollection 2022.PMID: 36341355 Free PMC article.
