Immune deficiencies, infection, and systemic immune disorders
Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias

https://doi.org/10.1016/j.jaci.2013.06.013Get rights and content

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.

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.

    These authors contributed equally to this work.

    Dr Gallagher is currently affiliated with the Department of Biology, West Virginia University, Morgantown, WV.

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