Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 21 3 2022 06 18 344 354 EN Fatemeh Arab Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran Nima Rezaei Research Center for Immunodeficiencies, Children’s Medical Center Hospital, Tehran University of Medical Sciences, Tehran, Iran AND International Hematology/Oncology of Pediatrics’ experts (IHOPE), Universal Scientific Education and Research Network (USERN), Tehran, Iran Forough Taheri Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Hamideh Kouhpeikar Department of Hematology and Blood Bank, Tabas School of Nursing, Birjand University of Medical Sciences, Birjand, Iran Elham Rayzan International Hematology/Oncology of Pediatrics’ Experts (IHOPE), Universal Scientific Education and Research Network (USERN), Tehran, Iran Mona Mirbeyk Research Center for Immunodeficiencies, Children’s Medical Center Hospital, Tehran University of Medical Sciences, Tehran, Iran Davood Zare‐Abdollahi Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran Mohsen Ghadami Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran AND Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran AND Cardiac Primary Prevention Research Center, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran 2022 03 27 2022 05 08 Neutropenia congenita grave (SCN) is a rare disease with a genetically and clinically heterogeneous nature, usually diagnosed in childhood, with an elevated risk of infections such as otitis, skin infections, pneumonia, deep abscesses, and septicemia. Patients with SCN also have an increased risk of leukemia, and mutations in the ELANE and the HAX1 genes have been observed in those patients. This study was conducted to genetically screen six Iranian families with SCN who have at least one affected person. In the first step, all exons and intron boundaries of ELANE and HAX1 genes were sequenced in probands. Cases with no pathogenic mutations were tested through whole-exome sequencing (WES). Analysis showed five different variants in ELANE (c.377 C>T), HAX1 (c.130_131 insA), HYOU1 (c.69 G>C and c.2744 G>A) and SHOC2 (c.4 A>G) genes in four families. We found that two out of six families had mutations in ELANE and HAX1 genes. Moreover, we found two novel mutations at the HYOU1 gene that had not previously been reported, as well as a pathogenic mutation at SHOC2 with multiple phenotypes, that will contribute to determining the genetic basis for SCN. Our study revealed that WES could help diagnose SCN, improve the classification of neutropenia, and rule out other immunodeficiencies such as autoimmune neutropenia, primary immunodeficiency diseases, and inherited bone marrow failure syndromes. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/3493 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/3493/1844