Clinical and Molecular Assessment of Iranian Families with Severe Congenital Neutropenia, Identification of HYOU1 and SHOC2   as Potential Novel Gene Defects

Fatemeh Arab; Nima Rezaei; Forough Taheri; Hamideh Kouhpeikar; Elham Rayzan; Mona Mirbeyk; Davood  Zare‐Abdollahi; Mohsen Ghadami

doi:10.18502/ijaai.v21i3.9808

Fatemeh Arab Department of Medical Genetics, School 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
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 Department of Allergy and Clinical Immunology, Immunology, Asthma and Allergy Research Institute, Children’s Medical Center Hospital, Tehran University of Medical Sciences, 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

DOI: https://doi.org/10.18502/ijaai.v21i3.9808

Keywords: ELANE protein; HAX1 protein; HYOU1 protein; Severe congenital neutropenia; SHOC2 protein; Whole exome sequencing

Abstract

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.