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Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families

  • Meriem Ben-Ali
  • Nadia Kechout
  • Najla Mekki
  • Jing Yang
  • Koon Wing Chan
  • Abdelhamid Barakat
  • Zahra Aadam
  • Jouda Gamara
  • Lamia Gargouri
  • Beya Largueche
  • Nabil BelHadj-Hmida
  • Amel Nedri
  • Houcine Ben Ameur
  • Fethi Mellouli
  • Rachida Boukari
  • Mohamed Bejaoui
  • Aziz Bousfiha
  • Imen Ben-Mustapha
  • Yu-Lung Lau
  • Mohamed-Ridha BarboucheEmail author
Original Article
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Abstract

Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency characterized by absent peripheral B cells, severe hypogammaglobulinemia, and absent BTK gene mutations. In ARA, mutations occur in genes encoding the pre-B cell receptor (pre-BCR) or downstream signaling proteins. In this work, we used candidate gene and whole-exome sequencing to investigate the molecular basis of ARA in 6 patients from 4 consanguineous North-African families. Sanger sequencing of candidate genes encoding the pre-BCR components (ΙGΗΜ, CD79A, CD79B, IGLL1, and VPREB1) was initially performed and determined the genetic defect in five patients. Two novel mutations in IGHM (p.Val378Alafs*1 and p.Ile184Serfs*21) were identified in three patients from two unrelated kindred and a novel nonsense mutation was identified in CD79A (p.Trp66*) in two siblings from a third kindred. Whole-exome sequencing (WES) was performed on the sixth patient who harbored a homozygous stop mutation at position 407 in the RAG2 gene (p.Glu407*). We concluded that conventional gene sequencing, especially when multiple genes are involved in the defect as is the case in ARA, is costly and time-consuming, resulting in delayed diagnosis that contributes to increased morbidity and mortality. In addition, it fails to identify the involvement of novel and unsuspected gene defects when the phenotype of the patients is atypical. WES has the potential to provide a rapid and more accurate genetic diagnosis in ARA, which is crucial for the treatment of the patients.

Keywords

AR-agammaglobulinemia consanguinity whole-exome sequencing 

Notes

Acknowledgments

We acknowledge the patients and their families for their cooperation. We thank Dr. Michel J Massaad for the critical review of the manuscript.

Funding Information

This work was supported by the Tunisian Ministry of Higher Education and Research and the Institut Pasteur International Network (RIIP).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Meriem Ben-Ali
    • 1
    • 2
  • Nadia Kechout
    • 3
    • 4
  • Najla Mekki
    • 1
    • 2
  • Jing Yang
    • 5
  • Koon Wing Chan
    • 5
  • Abdelhamid Barakat
    • 6
  • Zahra Aadam
    • 6
  • Jouda Gamara
    • 1
    • 2
  • Lamia Gargouri
    • 7
  • Beya Largueche
    • 1
    • 2
  • Nabil BelHadj-Hmida
    • 1
    • 2
  • Amel Nedri
    • 8
  • Houcine Ben Ameur
    • 8
  • Fethi Mellouli
    • 9
  • Rachida Boukari
    • 10
  • Mohamed Bejaoui
    • 9
  • Aziz Bousfiha
    • 11
  • Imen Ben-Mustapha
    • 1
    • 2
  • Yu-Lung Lau
    • 5
  • Mohamed-Ridha Barbouche
    • 1
    • 2
    Email author
  1. 1.Laboratory of Transmission, Control and Immunobiology of Infections, LR11IPT02 (LTCII)Institut Pasteur de TunisTunis-BelvédèreTunisia
  2. 2.Université Tunis El ManarTunisTunisia
  3. 3.Department of ImmunologyInstitut Pasteur d’AlgérieAlgiersAlgeria
  4. 4.Faculty of Medicine of AlgiersAlgiersAlgeria
  5. 5.Department of Paediatrics and Adolescent MedicineThe University of Hong KongHong KongChina
  6. 6.Laboratory of Molecular and Human Genetics, Department of Scientific ResearchInstitut Pasteur du MarocCasablancaMorocco
  7. 7.Department of PaediatricsHabib Bourguiba HospitalSfaxTunisia
  8. 8.Department of PaediatricsMedenine HospitalMedenineTunisia
  9. 9.National Bone Marrow Transplantation CenterTunisTunisia
  10. 10.Department of Pediatrics, CHU Mustapha-BachaFaculty of Medicine of AlgiersAlgiersAlgeria
  11. 11.Clinical Immunology Unit, Department of Pediatrics, Centre Hospitalier Universitaire Ibn RochdKing Hassan II UniversityCasablancaMorocco

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