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Exome Sequencing Diagnoses X-Linked Moesin-Associated Immunodeficiency in a Primary Immunodeficiency Case

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Exome Sequencing Diagnoses X-Linked Moesin-Associated Immunodeficiency in a Primary Immunodeficiency Case CASE REPORT published: 05 March 2018 doi: 10.3389/fimmu.2018.00420 Exome Sequencing Diagnoses X-Linked Moesin-Associated Immunodeficiency in a Primary Immunodeficiency Case Gabrielle Bradshaw, Robbie R. Lualhati, Cassie L. Albury, Neven Maksemous, Deidre Roos-Araujo, Robert A. Smith, Miles C. Benton, David A. Eccles, Rod A. Lea, Heidi G. Sutherland, Larisa M. Haupt and Lyn R. Griffiths* Genomics Research Centre, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia 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 Edited by: adulthood. Antonio Condino-Neto, University of São Paulo, Brazil Aim: To identify causative functional genetic variants related to an undiagnosed primary Reviewed by: immunodeficiency. Ivan K. Chinn, Baylor College of Medicine, Method: Whole genome microarray copy number variant (CNV) analysis was performed United States on the proband followed by whole exome sequencing (WES) and trio analysis of the Michel Massaad, proband and family members. A 4 kbp deletion identified by repeated CNV analysis of American University of Beirut > Medical Center, Lebanon exome sequencing data along with three damaging missense single nucleotide variants *Correspondence: were validated by Sanger sequencing in all family members. Confirmation of the caus- Lyn R. Griffiths ative role of the candidate gene was performed by qPCR and Western Blot analyses on [email protected] the proband, family members and a healthy control. Specialty section: Results: CNV identified our previously reported interleukin 25 amplification in the proband; This article was submitted to Primary Immunodeficiencies, however, the variant was not validated to be a candidate gene for immunodeficiency. a section of the journal WES trio analysis, data filtering and in silico prediction identified a novel, damaging (SIFT: Frontiers in Immunology 0; Polyphen 1; Grantham score: 101) and disease-causing (MutationTaster) single base Received: 01 December 2017 mutation in the X chromosome (c.511C T p.Arg171Trp) MSN gene not identified in Accepted: 15 February 2018 > Published: 05 March 2018 the UCSC Genome Browser database. The mutation was validated by Sanger sequen- Citation: cing, confirming the proband was hemizygous X-linked recessive (–/T) at this locus and Bradshaw G, Lualhati RR, Albury CL, inherited the affected T allele from his non-symptomatic carrier mother (C/T), with other Maksemous N, Roos-Araujo D, Smith RA, Benton MC, Eccles DA, family members (father, sister) confirmed to be wild type (C/C). Western Blot analysis Lea RA, Sutherland HG, Haupt LM demonstrated an absence of moesin protein in lymphocytes derived from the proband, and Griffiths LR (2018) compared with normal expression in lymphocytes derived from the healthy control, father Exome Sequencing Diagnoses X-Linked Moesin-Associated and mother. qPCR identified significantly lower MSN mRNA transcript expression in the Immunodeficiency in a Primary proband compared to an age- and sex-matched healthy control subject in whole blood Immunodeficiency Case. Front. Immunol. 9:420. (p = 0.02), and lymphocytes (p = 0.01). These results confirmed moesin deficiency in the doi: 10.3389/fimmu.2018.00420 proband, directly causative of his immunodeficient phenotype. Frontiers in Immunology | www.frontiersin.org 1 March 2018 | Volume 9 | Article 420 Bradshaw et al. WES Diagnoses Moesin-Associated (Primary) Immunodeficiency 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. Keywords: lymphopenia, whole exome sequencing, moesin, MSN, X-linked moesin-associated immunodeficiency INTRODUCTION aeruginosa infection. Neutropenia was first noted during that episode. Bone marrow aspirate showed normal myeloid matu­ Primary immunodeficiency disorders (PIDs) encompass a diverse ration, consistent with an immune etiology. No treatment was group of mostly inherited genetic disorders that compromise started at that stage. At 4 years of age, he had an episode of immune system function and predispose individuals to recur­ thrombocytopenia, with platelets falling to <5. A further bone rent infections and other immune disorders such as auto­ marrow aspirate was consistent with an immune mediated immunity, hematological disorders and lymphoid malignancies thrombocytopenia, and he responded rapidly to intravenous (1–3). As defined by the International Union of Immunological immunoglobulin. He had some further skin infections and Societies, there are almost 300 single gene defects described paronychiae at this time, and continued to suffer repeated which are causative for the wide range of phenotypes (4), respiratory infections, although not requiring hospitalization. making PIDs a rapidly expanding field of medicine. Loss of At 6 years 6 months of age, he had his first episode of pneumonia function mutations in multiple genes coding for proteins that and had several hospitalizations. regulate the actin cytoskeleton are known to cause PID, the At this stage, a diagnosis of combined immunodeficiency was most well characterized form being Wiskott­Aldrich (WAS) made: he had persistent absolute lymphopenia, normal T­cell syndrome (5). This is a rare X chromosome­linked PID where receptor Vβ distribution, low numbers of T­cell receptor excision expression and function of the WAS protein results in failure circles (TRECs), no mutation in the common γ chain gene, low of Arp2/3­mediated actin polymerization causing a combined IgG, IgA, and IgM. He was negative for HIV by PCR. He started defect of innate and adaptive immunity associated with micro­ immunoglobulin replacement (IVIg) and G­CSF treatment in thrombocytopenia, eczema, blood cancers, and increased risk of early 2000 and has very much improved symptomatically since autoimmunity (5). then, however, lymphocyte counts have remained severely Next­generation DNA sequencing technologies such as decreased (Tables 1and 2). whole genome sequencing (WGS) and whole exome sequenc­ We previously investigated a functional molecular cause for ing (WES) have revolutionized the field of genomics by this undiagnosed immunodeficiency through whole genome enabling a high­throughput and increasingly cost­effective arrays. Briefly, analysis of Affymetrix 250K SNP microarray data method for complex and rare disease diagnosis (6). While of the case and a matched healthy control subject via a copy num­ WGS is the most comprehensive technique able to identify ber analysis tool identified hyperploidy of a region centromeric around 4 million variants within the entire genome, including to chromosome 14q11.2, mapped over the interleukin 25 (IL25) coding and non­coding regions, WES provides more focus gene (10). IL­25 (a member of the IL­17 family of cytokines) on only protein­coding exons, which harbor around 85% of induction in mice has been previously associated with a T­helper pathogenic mutations (7, 8). Currently, WES permits lower (Th) 2­like pathological immune response (11) and shown to operating costs (US$800 per sample compared to US$1,500 per regulate the development of autoimmune inflammation medi­ sample for WGS) with faster data generation and less complex ated by IL­17­producing cells (12, 13) and was deemed a plausible analysis, however, it is unable to identify structural variants candidate for further analyses. (6, 9). Here, we used WES to elucidate possible disease­causing Green et al. (10) paired genetic analysis with transcrip­ variants in a case diagnosed previously as immunodeficient of tional profiling and found a large number of genes associ­ unknown cause. ated with Th1/Th2 profiles to be differentially expressed in peripheral blood lymphocytes of the proband, indicative of a BACKGROUND Th2 bias confirmed by flow cytometric analysis. T­cells from the proband and control subject were cultured and activated The proband is a 24­year–old male. At age 7 weeks, he had boils in vitro with qPCR analysis demonstrating higher IL25 in his groin and axillae. At 18 months of age, he had a prolonged expression in the proband when compared to the control. The episode of bronchitis for which he received antibiotics but was skewed Th2 immunity hypothesized in the proband was in line not hospitalized. He suffered repeated upper respiratory tract with his susceptibility to infections normally cleared by Th1 infections and ear infections for the next few years. He had responses, such as Varicella and Pseudomonas. Further in vitro two episodes of chicken pox (Varicella) at around 18 months studies were performed in B­cell line models to measure the and 3 years. The first episode was severe, with widespread skin effect of IL­25 treatment on cellular proliferation and viability, lesions, but no secondary infection or hemorrhagic lesions. At however when proband and control lymphocytes were treated about 3 years of age, he had a persistent eye infection, which with exogenous IL­25, no differences were observed (data not progressed to periorbital cellulitis, secondary to Pseudomonas shown). Frontiers in Immunology | www.frontiersin.org 2 March 2018 | Volume 9 | Article 420 Bradshaw et al. WES Diagnoses
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