Farrukh Sheikh1, Abbas Hawwari2,3, Safa Alhissi4, Sulaiman Al Gazlan5, Hasan Al Dhekri6, Agha M Rehan Khaliq5,7, Esteban Borrero4,8, Lina El-Baik4, Rand Arnaout5,7, Hamoud Al-Mousa6,7,9, Anas M Alazami10,11. 1. Department of Medicine, Allergy and Immunology section, King Faisal Specialist Hospital and Research Center, P.O Box 3354, MBC 46, Riyadh, 11211, Saudi Arabia. fsheikh96@kfshrc.edu.sa. 2. King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City Hospital, Ministry of National Guard Health Affairs, Mail Code 520, PO Box 6664, Al Hasa, 31982, Saudi Arabia. hawwariab@ngha.med.sa. 3. Department of Genetics, King Faisal Specialist Hospital and Research Center, P.O Box 3354, MBC 3, Riyadh, 11211, Saudi Arabia. hawwariab@ngha.med.sa. 4. Department of Genetics, King Faisal Specialist Hospital and Research Center, P.O Box 3354, MBC 3, Riyadh, 11211, Saudi Arabia. 5. Department of Medicine, Allergy and Immunology section, King Faisal Specialist Hospital and Research Center, P.O Box 3354, MBC 46, Riyadh, 11211, Saudi Arabia. 6. Department of Pediatrics, Allergy and Immunology section, King Faisal Specialist Hospital and Research Center, P.O Box 3354, MBC 58, Riyadh, 11211, Saudi Arabia. 7. Alfaisal University, P.O. Box 50927, Riyadh, 1153, Saudi Arabia. 8. SmartGenetics DNATICS S.A, 787 y Portugal Edf. 7sur, Tamesis, El Salvador. 9. Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, 11442, Saudi Arabia. 10. Department of Genetics, King Faisal Specialist Hospital and Research Center, P.O Box 3354, MBC 3, Riyadh, 11211, Saudi Arabia. amalazami@kfshrc.edu.sa. 11. Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, 11442, Saudi Arabia. amalazami@kfshrc.edu.sa.
Abstract
INTRODUCTION: Non-homologous end joining gene 1 (NHEJ1) defect is a rare form of primary immune deficiency. Very few cases have been described from around the world. PURPOSE: We are reporting the first family from the Arabian Gulf with three siblings presenting with combined immunodeficiency (CID), microcephaly, and growth retardation due to a novel NHEJ1 splice site mutation, in addition to a review of the previously published literature on this subject. METHODS: Patients' clinical, immunological, and laboratory features were examined. Samples were subjected to targeted next-generation sequencing (NGS). The pathogenic change in NHEJ1 was confirmed by Sanger sequencing, then further assessed at the RNA and protein levels. RESULTS: Patients were found to have a homozygous splice site mutation immediately downstream of exon 3 in NHEJ1 (c.390 + 1G > C). This led to two distinct mRNA products, one of which demonstrated skipping of the last 69 basepairs (bp) of exon 3 while the other showed complete skipping of the entire exon. Although both deletions were in-frame, immunoblotting did not reveal any NHEJ1 protein products in patient cells, indicating a null phenotype. CONCLUSION: Patients presenting with CID, microcephaly, and growth retardation should be screened for NHEJ1 gene mutations. We discuss our data in the context of one of our patients who is still alive at the age of 30 years, without transplantation, and who is the longest known survivor of this disease.
INTRODUCTION:Non-homologous end joining gene 1 (NHEJ1) defect is a rare form of primary immune deficiency. Very few cases have been described from around the world. PURPOSE: We are reporting the first family from the Arabian Gulf with three siblings presenting with combined immunodeficiency (CID), microcephaly, and growth retardation due to a novel NHEJ1 splice site mutation, in addition to a review of the previously published literature on this subject. METHODS:Patients' clinical, immunological, and laboratory features were examined. Samples were subjected to targeted next-generation sequencing (NGS). The pathogenic change in NHEJ1 was confirmed by Sanger sequencing, then further assessed at the RNA and protein levels. RESULTS:Patients were found to have a homozygous splice site mutation immediately downstream of exon 3 in NHEJ1 (c.390 + 1G > C). This led to two distinct mRNA products, one of which demonstrated skipping of the last 69 basepairs (bp) of exon 3 while the other showed complete skipping of the entire exon. Although both deletions were in-frame, immunoblotting did not reveal any NHEJ1 protein products in patient cells, indicating a null phenotype. CONCLUSION:Patients presenting with CID, microcephaly, and growth retardation should be screened for NHEJ1 gene mutations. We discuss our data in the context of one of our patients who is still alive at the age of 30 years, without transplantation, and who is the longest known survivor of this disease.
Authors: Vincent Cantagrel; Anne-Marie Lossi; Steven Lisgo; Chantal Missirian; Ana Borges; Nicole Philip; Carla Fernandez; Carlos Cardoso; Dominique Figarella-Branger; Anne Moncla; Susan Lindsay; William B Dobyns; Laurent Villard Journal: Hum Mutat Date: 2007-04 Impact factor: 4.878
Authors: Fiona Poyer; Raúl Jimenez Heredia; Wolfgang Novak; Petra Zeitlhofer; Karin Nebral; Michael N Dworzak; Oskar A Haas; Kaan Boztug; Leo Kager Journal: Front Immunol Date: 2022-06-24 Impact factor: 8.786
Authors: Maria J Recio; Nerea Dominguez-Pinilla; Melina Soledad Perrig; Carmen Rodriguez Vigil-Iturrate; Nerea Salmón-Rodriguez; Cristina Martinez Faci; María J Castro-Panete; Javier Blas-Espada; Marta López-Nevado; Raquel Ruiz-Garcia; Rebeca Chaparro-García; Luis M Allende; Luis Ignacio Gonzalez-Granado Journal: Front Immunol Date: 2019-01-07 Impact factor: 7.561