Recurrent microdeletions at chromosome 2p11.2 are associated with thymic hypoplasia and features resembling DiGeorge syndrome

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:145

Article

Bernstock, Joshua D.^1,7,8  Totten, Arthur H.¹  Elkahloun, Abdel G.³  Johnson, Kory R.⁴  Hurst, Anna C.²  Goldman, Frederick¹  Groves, Andrew K.^5,6  Mikhail, Fady M.²  Atkinson, T. Prescott¹ 

[1] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA

[2] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA

[3] NHGRI, NIH, Bethesda, MD 20892 USA

[4] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA

[5] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA

[6] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[7] Brigham & Womens Hosp, Dept Neurosurg, 75 Francis St, Boston, MA 02115 USA

[8] Boston Childrens Hosp, Boston, MA USA

关键词: Thymus;    T-cell receptor excision circles;    DiGeorge syndrome;    knockout mice;    immunodeficiency;    FOXI3;   

DOI  :  10.1016/j.jaci.2019.09.020

来源: Elsevier

【 摘 要 】

Background: Thymic hypoplasia/aplasia occurs as a part of DiGeorge syndrome, which has several known genetic causes, and with loss-of-function mutations in forkhead box N1 (FOXN1). Objective: We sought to determine the cause of selective T-cell lymphopenia with inverted kappa/lambda ratio in several kindreds. Methods: Patients were identified through newborn screening for severe combined immunodeficiency using the T-cell receptor excision circle assay. Those found to have selective T-cell lymphopenia underwent testing with chromosomal microarray analysis. Three-week-old mice heterozygous for a loss-offunction mutation in forkhead box I3 (FOXI3), a candidate gene within the common deleted region found in patients, were compared with wild-type littermates. Assessments included body and organ weights, flow cytometric analysis of thymocytes and splenocytes, and histologic/transcriptomic analyses of thymic tissue. Results: Five kindreds with similar immunophenotypes that included selective T-cell lymphopenia had overlapping microdeletions at chromosome 2p11.2 that spanned FOXI3 and, in most cases, the immunoglobulin kappa light chain locus. Studies in a mouse knockout strain for FOXI3 revealed smaller body weights and relatively lower thymus weights in heterozygous compared with wild-type animals. Histology and flow cytometry on spleens and thymi from 3-week-old pups for T- and B-cell subsets and epithelial cells did not show any significant qualitative or quantitative differences. Transcriptomic analysis of thymic RNA revealed divergence in global transcriptomic signatures, and Ingenuity Pathway Analysis revealed predicted dysfunction in epithelial adherens junctions. Conclusions: Microdeletions at chromosome 2p11.2 are associated with T-cell lymphopenia and probable thymic hypoplasia in human subjects, and haploinsufficiency for FOXI3, a candidate gene within the deleted region, is the likely underlying cause.

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