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Exome-First Approach Identified Novel Homozygous Dedicator of Cytokinesis 8 (Dock8) Mutations in Three Unrelated Iranian Pedigrees Suspected With Hyper-Ige Syndrome Publisher Pubmed



Aghebatimaleki A1 ; Shahani T1 ; Momen T2 ; Alyasin S3 ; Changiashtiani M4 ; Biglari A1 ; Shahrooei M5, 6 ; Javanian AS6 ; Amini S6 ; Bossuyt X5, 7 ; Roknizadeh H8
Authors
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Authors Affiliations
  1. 1. Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences (ZUMS), Zanjan, Iran
  2. 2. Child Growth and Development Research Center, Department of Allergy and Clinical Immunology, Isfahan University of Medical Sciences, Isfahan, Iran
  3. 3. Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  4. 4. Institute for Research in Fundamental Sciences (IPM), School of Mathematics, Tehran, Iran
  5. 5. Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, Ku Leuven, Leuven, Belgium
  6. 6. Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran
  7. 7. Department of Laboratory Medicine, University Hospitals Leuven, Herestraat 49, Leuven, Belgium
  8. 8. Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences (ZUMS), Zanjan, Iran

Source: Iranian Journal of Allergy, Asthma and Immunology Published:2020


Abstract

The prevalence of primary immunodeficiency (PID) is rather high in Iran compared to the world average, mainly due to the high rate of consanguineous marriage. Despite that, little genetic information is available about primary immunodeficiencies in Iran. Autosomal recessive hyper IgE syndrome (AR-HIES) is a severe type of immunodeficiency, mainly caused by mutations in the dedicator of cytokinesis 8 (DOCK8). Rapid and precise diagnoses of patients suffering from AR-HIES can help to manage the patients and reach properly the treatment decision. However, in regions with low financial resources and limited expertise, deep phenotyping is uncommon. Therefore, an exome-first approach is helpful to make a genetic-based diagnosis. In the present study, whole-exome sequencing (WES) was applied to detect causative mutations in three unrelated primary immunodeficient patients with poor clinical information. One of the cases was a deceased patient with suspected hyper IgE syndrome (HIES) whose parents were subjected to WES. As a result, three novel pathogenic variants were detected in the DOCK8 gene, including two splicing sites (c.4241+1G>T and c.4886+1G>T) and one-stop-gain (c.4201G>T, p.Glu1401Ter) variants. Sanger sequencing confirmed the mutations' segregation in corresponding families. Further immunological investigations confirmed that HIES in the studied probands. The presence of frontal bossing and broad nose in one of the studied cases, in addition to the typical clinical presentation of DOCK8-AR-HIES, is notable. This work suggests that an exome-first approach can be a valuable alternative strategy for precise diagnosis of primary immunodeficiency patients. © April 2020, Iran J Allergy Asthma Immunol. All rights reserved.
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