Exome-first Approach Identified Novel Homozygous Dedicator of Cytokinesis 8 (DOCK8) Mutations in Three Unrelated Iranian Pedigrees Suspected with Hyper-IgE Syndrome

  • Ali Aghebati-Maleki Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences (ZUMS), Zanjan, Iran
  • Tina Shahani Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences (ZUMS), Zanjan, Iran
  • Tooba Momen Department of Allergy and Clinical Immunology, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
  • Soheila Alyasin Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  • Majid Changi-Ashtiani School of Mathematics, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
  • Alireza Biglari Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences (ZUMS), Zanjan, Iran
  • Mohammad Shahrooei Clinical and Diagnostic Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium AND Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran
  • Asiyeh Sadat Javanian Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran
  • Suzan Amini Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran
  • Xavier Bossuyt Clinical and Diagnostic Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium AND Department of Laboratory Medicine, University Hospitals Leuven, Herestraat 49, Leuven, Belgium
  • Hassan Rokni-Zadeh Mail Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences (ZUMS), Zanjan, Iran
Keywords:
Dedicator of cytokinesis 8, Exome-first approach, Hyper IgE syndrome, Whole exome sequencing

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.

References

1. Donabedian H, Gallin JI. The Hyperimmunoglobulin E Recurrent-Infection (Job's) Syndrome. A Review of the NIH Experience and the Literature. Medicine (Baltimore)1983; 62(4):195-208.
2. Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, et al. Dominant-Negative Mutations in the DNA-Binding Domain of STAT3 Cause Hyper-IgE Syndrome. Nature 2007; 448(7157):1058-62.
3. Sanal O, Jing H, Ozgur T, Ayvaz D, Strauss-Albee DM, Ersoy-Evans S, et al. Additional Diverse Findings Expand the Clinical Presentation of DOCK8 Deficiency. J Clin Immunol 2012;32(4):698-708.
4. Aydin SE, Kilic SS, Aytekin C, Kumar A, Porras O, et al. DOCK8 Deficiency: Clinical and Immunological Phenotype and Treatment Options - AReview of 136 Patients. J Clin Immunol 2015;35(2):189-98.
5. Woellner C, Schaffer AA, Puck JM, Renner ED, Knebel C, Holland SM, et al. The Hyper IgE Syndrome and Mutations in TYK2. Immunity 2007;26(5):535.
6. Renner ED, Puck JM, Holland SM, Schmitt M, Weiss M, Frosch M, et al. Autosomal Recessive Hyperimmunoglobulin E Syndrome: ADistinct Disease Entity. J Pediatr 2004;144(1):93-9.
7. Xu S, Li Q, Wu J, Chen G, Zhu B, Gu W. Identification of IL2RG and CYBB Mutations in Two Chinese Primary Immunodeficiency Patients by Whole-Exome Sequencing. Immunological Investigations 2018;47(3):221-8.
8. Kearney CJ, Randall KL, Oliaro J. DOCK8 Regulates Signal Transduction Events to Control Immunity. Cell Mol Immunol 2017;14(5):406-11.
9. Zhang Q, Jing H, Su HC. Recent Advances in DOCK8 Immunodeficiency Syndrome. J Clin Immunol 2016;36(5):441-9.
10. Shirkani A, Shahrooei M, Azizi G, Rokni-Zadeh H, Abolhassani H, Farrokhi S, et al. Novel Mutation of ZAP-70-Related Combined Immunodeficiency: First Case from the National Iranian Registry and Review of the Literature. Immunological Investigations 2017;46(1):70-9.
11. Frans G, van der Werff Ten Bosch J, Moens L, Gijsbers R, Changi-Ashtiani M, Rokni-Zadeh H, et al. Functional Evaluation of an IKBKG Variant Suspected to Cause Immunodeficiency without Ectodermal Dysplasia. J Clin Immunol 2017;37(8):801-10.
12. Khatami S, Rokni-Zadeh H, Mohsen-Pour N, Biglari A, Changi-Ashtiani M, Shahrooei M, et al. Whole Exome Sequencing Identifies both Nuclear and Mitochondrial Variations in an Iranian Family with Non-Syndromic Hearing Loss. Mitochondrion 2018.
13. Su HC. Dedicator of Cytokinesis 8 (DOCK8) Deficiency. Curr Opin Allergy Clin Immunol 2010;10(6):515-20.
14. Stessman HA, Bernier R, Eichler EE. A Genotype-First Approach to Defining the Subtypes of a Complex Disease. Cell 2014;156(5):872-7.
15. Shi L, Li B, Huang Y, Ling X, Liu T, Lyon GJ, et al. "Genotype-First" Approaches on a Curious Case of Idiopathic Progressive Cognitive Decline. BMC Med Genomics 2014;7:66.
16. Gosso MF, Rohr C, Brun B, Mejico G, Madeira F, Fay F, et al. Exome-First Approach Identified Novel INDELs and Gene Deletions in Mowat-Wilson Syndrome Patients. Hum Genome Var 2018;5:21.
17. Yamamoto T, Shimojima K, Matsufuji M, Mashima R, Sakai E, Okuyama T. Aspartylglucosaminuria Caused by a Novel Homozygous Mutation in the AGA Gene was Identified by an Exome-First Approach in a Patient from Japan. Brain Dev 2017;39(5):422-5.
18. Jansen S, Hoischen A, Coe BP, Carvill GL, Van Esch H, Bosch DGM, et al. A Genotype-First Approach Identifies an Intellectual Disability-Overweight Syndrome Caused by PHIP Haploinsufficiency. Eur J Hum Genet 2018;26(1):54-63.
19. Kaplan S, Pinar G, Kaplan B, Aslantekin F, Karabulut E, Ayar B, et al. The Prevalence of Consanguineous Marriages and Affecting Factors in Turkey: A National Survey. J Biosoc Sci 2016;48(5):616-30.
20. Al-Herz W, Ragupathy R, Massaad MJ, Al-Attiyah R, Nanda A, Engelhardt KR, et al. Clinical, Immunologic and Genetic Profiles of DOCK8-Deficient Patients in Kuwait. Clin Immunol 2012;143(3):266-72.
21. Jalal Abbasi-Shavazi M, McDonald P, Hosseini-Chavoshi M. Modernization or Cultural Maintenance: The Practice of Consanguineous Marriage in Iran. J Biosoc Sci. 2008;40(6):911-33.
22. Biggs CM, Keles S, Chatila TA. DOCK8 deficiency: Insights into Pathophysiology, Clinical Features and Management. Clin Immunol 2017;181:75-82.
23. Ruusala A, Aspenstrom P. Isolation and Characterisation of DOCK8, AMember of the DOCK180-related Regulators of Cell Morphology. FEBS Lett 2004;572(1-3):159-66.
24. Chu EY, Freeman AF, Jing H, Cowen EW, Davis J, Su HC, et al. Cutaneous Manifestations of DOCK8 Deficiency Syndrome. Arch Dermatol 2012;148(1):79-84.
25. Atkinson C, Stutes S. The Evaluation and Management of DOCK8 Deficiency. Annals of Allergy, Asthma & Immunology 2018;121(5):S102.
26. Gatz SA, Benninghoff U, Schutz C, Schulz A, Honig M, Pannicke U, et al. Curative Treatment of Autosomal-Recessive Hyper-IgE Syndrome by Hematopoietic Cell Transplantation. Bone Marrow Transplant 2011;46(4):552-6.
27. Happel CS, Stone KD, Freeman AF, Shah NN, Wang A, Lyons JJ, et al. Food Allergies can Persist after Myeloablative Hematopoietic Stem Cell Transplantation in Dedicator of Cytokinesis 8-Deficient Patients. J Allergy Clin Immunol 2016;137(6):1895-8.
28. Cuellar-Rodriguez J, Freeman AF, Grossman J, Su H, Parta M, Murdock H, et al. Matched Related and Unrelated Donor Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency. Biol Blood Marrow Transplant 2015;21(6):1037-45.
Published
2020-04-16
How to Cite
1.
Aghebati-Maleki A, Shahani T, Momen T, Alyasin S, Changi-Ashtiani M, Biglari A, Shahrooei M, Javanian AS, Amini S, Bossuyt X, Rokni-Zadeh H. Exome-first Approach Identified Novel Homozygous Dedicator of Cytokinesis 8 (DOCK8) Mutations in Three Unrelated Iranian Pedigrees Suspected with Hyper-IgE Syndrome. Iran J Allergy Asthma Immunol. 19(2):193-199.
Section
Case Report(s)