Clinical Manifestations and Genetic Findings in Three Patients with Chediak-Higashi Syndrome: Highlighting the Splice Site Variants

Shaghayegh  Tajik; Anne  Molitor; Zahra  Alizadeh; Mohammad Reza  Fazlollahi; Raphael  Carapito; Maryam  Akbari; Mohsen  Badalzadeh; Massoud  Houshmand; Mostafa  Moin; Seiamak  Bahram; Zahra  Pourpak

doi:10.18502/ijaai.v25i4.21743

Shaghayegh Tajik Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
Anne Molitor Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Institut Thématique Interdisciplinaire TRANSPLANTEX NG, Université de Strasbourg, Strasbourg, France
Zahra Alizadeh Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
Mohammad Reza Fazlollahi Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
Raphael Carapito Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Institut Thématique Interdisciplinaire TRANSPLANTEX NG, Université de Strasbourg, Strasbourg, France
Maryam Akbari Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
Mohsen Badalzadeh Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
Massoud Houshmand Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
Mostafa Moin Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
Seiamak Bahram Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Institut Thématique Interdisciplinaire TRANSPLANTEX NG, Université de Strasbourg, Strasbourg, France
Zahra Pourpak Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran

DOI: https://doi.org/10.18502/ijaai.v25i4.21743

Keywords: Chediak-Higashi syndrome; Inborn errors of immunity; LYST gene; Novel variant; Splice Site; Primary immunodeficiency; Whole exome sequencing

Abstract

Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by severe immunodeficiency, partial albinism, recurrent infections, and progressive neurologic dysfunction. Unless patients undergo successful hematopoietic cell transplantation (HCT), a majority of them die during childhood because of an accelerated phase of immune dysfunction and hemophagocytic lymphohistiocytosis (HLH). Herein, we aim to describe the laboratory diagnosis, clinical manifestations, and genetic findings in three patients with CHS.

Three patients with partial albinism associated with CHS were included in this study. Immunological screening tests were done. Leukocyte granules in peripheral blood smear (PBS) and hair shafts were examined. Subsequently, genetic analyses were performed by Whole Exome Sequencing (WES) followed by Sanger sequencing for all patients and their parents.

Initial immunology screening tests were within normal limits. Light microscopy studies of patients’ PBS showed giant granules in the leukocyte cytoplasm. Furthermore, there were evenly distributed melanin granules in the patients' hair shafts. Variant analysis of the LYST gene identified three splicing site defects: one known variant, c.7060-1G>A in intron 24, and two novel variants, c.2363+2T>C in intron 5, and c.10702-3A>G in intron 47.

Hair shaft assay and PBS are rapid and suitable tests in early diagnosis and differentiation in CHS patients. WES results revealed 2 novel splice site variants that might contribute to earlier and more accurate diagnosis. This facilitates early enrolment of CHS patients in the HCT protocol-the optimal treatment path-and enables prenatal diagnosis for affected families.