Exome sequencing diagnoses x-linked moesin-associated immunodeficiency in a primary immunodeficiency case
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Description
Background: We investigated the molecular etiology of a young male proband with confirmed immunodeficiency of unknown cause, presenting with recurrent bacterial and Varicella zoster viral infections in childhood and persistent lymphopenia into early adulthood. Aim: To identify causative functional genetic variants related to an undiagnosed primary immunodeficiency. Method: Whole genome microarray copy number variant (CNV) analysis was performed on the proband followed by whole exome sequencing (WES) and trio analysis of the proband and family members. A >4 kbp deletion identified by repeated CNV analysis of exome sequencing data along with three damaging missense single nucleotide variants were validated by Sanger sequencing in all family members. Confirmation of the causative role of the candidate gene was performed by qPCR and Western Blot analyses on the proband, family members and a healthy control. Results: CNV identified our previously reported interleukin 25 amplification in the proband; however, the variant was not validated to be a candidate gene for immunodeficiency. WES trio analysis, data filtering and in silico prediction identified a novel, damaging (SIFT: 0; Polyphen 1; Grantham score: 101) and disease-causing (MutationTaster) single base mutation in the X chromosome (c.511C > T p.Arg171Trp) MSN gene not identified in the UCSC Genome Browser database. The mutation was validated by Sanger sequencing, confirming the proband was hemizygous X-linked recessive (–/T) at this locus and inherited the affected T allele from his non-symptomatic carrier mother (C/T), with other family members (father, sister) confirmed to be wild type (C/C). Western Blot analysis demonstrated an absence of moesin protein in lymphocytes derived from the proband, compared with normal expression in lymphocytes derived from the healthy control, father and mother. qPCR identified significantly lower MSN mRNA transcript expression in the proband compared to an age- and sex-matched healthy control subject in whole blood (p = 0.02), and lymphocytes (p = 0.01). These results confirmed moesin deficiency in the proband, directly causative of his immunodeficient phenotype. Conclusion: These findings confirm X-linked moesin-associated immunodeficiency in a proband previously undiagnosed up to 24 years of age. This study also highlights the utility of WES for the diagnosis of rare or novel forms of primary immunodeficiency disease.
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ID Code: | 120124 | ||||||||||||
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Item Type: | Contribution to Journal (Journal Article) | ||||||||||||
Refereed: | Yes | ||||||||||||
ORCID iD: |
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Measurements or Duration: | 9 pages | ||||||||||||
Keywords: | Lymphopaenia, MSN, X-MAID, X-linked moesin-associated immunodeficiency, moesin, whole exome sequencing | ||||||||||||
DOI: | 10.3389/fimmu.2018.00420 | ||||||||||||
ISSN: | 1664-3224 | ||||||||||||
Pure ID: | 33363198 | ||||||||||||
Divisions: | Past > QUT Faculties & Divisions > Faculty of Health Past > Institutes > Institute of Health and Biomedical Innovation Current > Schools > School of Biomedical Sciences |
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Copyright Owner: | Consult author(s) regarding copyright matters | ||||||||||||
Copyright Statement: | This work is covered by copyright. Unless the document is being made available under a Creative Commons Licence, you must assume that re-use is limited to personal use and that permission from the copyright owner must be obtained for all other uses. If the document is available under a Creative Commons License (or other specified license) then refer to the Licence for details of permitted re-use. It is a condition of access that users recognise and abide by the legal requirements associated with these rights. If you believe that this work infringes copyright please provide details by email to qut.copyright@qut.edu.au | ||||||||||||
Deposited On: | 24 Jul 2018 03:29 | ||||||||||||
Last Modified: | 11 Jul 2024 16:45 |
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