Immune deficiencies, infection, and systemic immune disordersWhole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias
Section snippets
Human sample collection and DNA extraction
Patients with SCID-MIA and their direct family members were enrolled in our study after obtaining informed consent under institutional review board–approved protocol 04-09-113 (Children’s Hospital Boston) and ethics committee approval (Spedali Civili Brescia, Brescia, Italy). Genomic DNA was isolated with the automatic DNA extractor Maxwell 16 (Promega, Madison, Wis).
WES and data analysis
Whole-exome enrichment was performed with the Agilent SureSelect Human All Exon Kit 50M (Agilent Technologies, Santa Clara,
Clinical and immunologic features of patients
We analyzed a total of 8 unrelated patients with CID-MIA. Patient 1 (F1-A) was born to consanguineous parents of Arabic origin and was given a diagnosis of pyloric and anal atresias at birth. Surgery was complicated by Enterococcus faecalis bacteremia. Immunologic investigations at 15 days of life revealed moderate T-cell lymphopenia, with a marked decrease in CD8+ T-cell numbers, decreased in vitro proliferation to PHA, and severe hypogammaglobulinemia (Fig 1, A, and Table I). In spite of
Discussion
In this study we identified deleterious mutations in the TTC7A gene in 8 patients with CID-MIA belonging to unrelated families of distinct ethnic origin, indicating a strong genetic link.
While we were preparing our manuscript, Samuels et al27 reported on the occurrence of a homozygous 4-nt deletion (c.1000ΔAAGT) in 5 apparently unrelated French-Canadian patients with MIA and compound heterozygosity of exon 7 c.1000ΔAAGT + p.L823P (ie, exon 20 c.T2468C in our report) in 1 other affected patient.
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M.S. is funded by grants from Stanford University and the National Institutes of Health (NIH). L.D.N. is supported by NIH grants 5P01AI076210-04, 1R01AI00887-01, and 4U54AI082973-04 (also to S.-Y.P.) and the Manton Foundation. Both L.D.N. and W.A.-H. are supported by a grant from the Dubai Harvard Foundation for Medical Research and by Kuwait Foundation for the Advancement of Sciences (grant 2010-1302-05). S.G. is supported by Fondazione Nocivelli and the University of Brescia. F.F. is supported by MIUR (grant 20104HBZ8E_002). S.-Y.P. is supported by a Translational Investigator Service award from Boston Children’s Hospital. G.I.M.'s research reported in this publication was supported by the National Human Genome Research Institute of the NIH under award no. K99HG007065. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. D.H.P. is a Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-#2122-22).
Disclosure of potential conflict of interest: G. I. Mias has received grants from the National Institutes of Health (NIH) and the National Genome Research Institute. S. Lonardi is employed by the University of Brescia. J. Manis has received grants from NIH. G. Euskirchen receives part of her salary from NIH grants. S.-Y. Pai has received grants from NIH/National Institute of Allergy and Infectious Diseases (NIAID), has received a Translational Investigator Service internal award from Boston Children's Hospital, and has grants/grants pending from the Manton Foundation, NIH/NIAID, and NIH/National Heart, Lung, and Blood Institute (NHLBI). F. Facchetti has received the Bruto salary from the University of Brescia and has grants/grants pending from the Italian Ministry of University and Research. M. Snyder is a scientific advisory board member for Personalis and Genapsys; has consultant arrangements with Illumina; has received payment for lectures, including service on speakers' bureaus, from Illumina and Beckman Coulter; and has stock/stock options in Excelexis. L. D. Notarangelo has received grants from the NIH and the Dubai Harvard Foundation for Medical Research, is a board member for the Immune Disease Institute, is an advisory board member for Meyer Hospital, is employed by Boston Children's Hospital, and receives royalties from UpToDate. The rest of the authors declare that they have no relevant conflicts of interest.
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These authors contributed equally to this work.
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Dr Gallagher is currently affiliated with the Department of Biology, West Virginia University, Morgantown, WV.