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Novel Variants of DOCK8 Deficiency in a Case Series of Iranian Patients

Author(s):

Sara Momtazmanesh, Elham Rayzan, Samaneh Zoghi, Sepideh Shahkarami, Rasol Molatefi, Iraj Mohammadzadeh, Javad Ghaffari, Hamidreza Mahmoudi, Jasmin Dmytrus, Anna Segarra-Roca, Ido Somekh, Maximilian Witzel, Fabian Hauck, Kaan Boztug, Christoph Klein and Nima Rezaei*   Pages 1 - 10 ( 10 )

Abstract:


Background: Dedicator of Cytokinesis 8 (DOCK8) deficiency, the most frequent cause of autosomal recessive hyper immunoglobulin (Ig)E syndrome, is a rare combined immunodeficiency.

Objective: In this study, we report seven patients with consanguineous parents with five novel variants within the DOCK8 gene.

Methods: For genetic analysis, we performed Whole Exome Sequencing (WES), or targeted sequencing by means of Next-generation sequencing (NGS) for some of the patients. For others, Sanger sequencing, Fluorescence-activated cell sorting (FACS), or polymerase chain reaction (PCR) was used.

Results: We report five novel variants within the DOCK8 gene: three deletions (deletion of exons 4-12, 24-30, and 22-27), one frameshift (LRG_196:g.189315dup;p.(Leu1052Profs*7)), and a splice region variant (LRG_196t1:c.741+5G>T). Patients presented with skin lesions, food allergy, candidiasis, otitis, recurrent respiratory infections, short stature, aortic aneurism, gynecomastia, and coarse facial features. Patients had leukocytosis, eosinophilia, lymphopenia, and monocytosis, elevated IgE, IgG, IgA , reduced IgM and IgA levels. Patients had a low percentage of CD3+ and CD4+ cells, and a high percentage of CD19+, CD27+CD19+, and recent thymic emigrants T cells. The percentage of natural killer cells was increased in one of the patients while it was decreased in another patient. One patient died due to disseminated intravascular coagulation after hematopoietic stem cell transplantation.

Conclusion: We reported novel variants within the DOCK8 gene and highlighted risk of aneurysms in these patients, which have been rarely reported in these patients.

Keywords:

Dedicator of cytokinesis 8, Job Syndrome, Hyperimmunoglobulinemia E Syndrome, Immunologic Deficiency Syndromes, Primary Immunodeficiency Diseases

Affiliation:

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Pediatric department of Bou-Ali educational Hospital, Ardabil university of medical sciences, Ardabil, Noncommunicable Pediatric Diseases Research Center, Amirkola Hospital, Babol University of Medical Sciences, Babol, Department of Allergy and Clinical Immunology, Bou Ali Sina Hospital, Mazandaran University of Medical Sciences, Sari, Mazandaran, Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran



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