X-Linked Agammagobulinemia in a Large Series of North African Patients: Frequency, Clinical Features and Novel BTK Mutations

Zahra Aadam (1, 2) , Nadia Kechout (3) , Abdelhamid Barakat (1) , Koon-Wing Chan (4) , Meriem Ben-Ali (5) , Imen Ben-Mustapha (5) , Fethi Zidi (6) , Fatima Ailal (7) , Nabila Attal (3) , Fatouma Doudou (3) , Mohamed-Cherif Abbadi (3) , Chawki Kaddache (8) , Leila Smati (9) , Jalel Chemli (10) , Nabila Touri (8) , Tahar Gargah (11) , Ines Brini (12) , Amina Bakhchane (1) , Hicham Charoute (1) , Leïla Jeddane (7) , Sara El Atiqi (7) , Naima El Hafidi (13) , Mustapha Hida (14) , Rachid Saile (2) , Hanane Salih Alj (2) , Rachida Boukari (9) , Mohamed Bejaoui (15) , Jilali Najib (7) , Mohamed-Ridha Barbouche (5) , Yu-Lung Lau (4) , Fethi Mellouli (15) , Ahmed Aziz Bousfiha (7)

1 Institut Pasteur du Maroc
2 UH2MC - Université Hassan II [Casablanca]
3 Institut Pasteur d'Algérie
4 Department of Paediatrics and Adolescent Medicine [HKU]
5 LR11IPT02 - Laboratoire de Transmission, Contrôle et Immunobiologie des Infections - Laboratory of Transmission, Control and Immunobiology of Infection
6 Department of Pediatrics [Tozeur]
7 FSAC - Faculté des Sciences Aïn Chock [Casablanca]
8 CHU Blida - Centre Hospitalo-Universitaire de Blida
9 Faculté de médecine d'Alger
10 CHU Sahloul - Hôpital Universitaire Sahloul
11 Hôpital Charles Nicolle [Tunis]
12 Hôpital d'enfants de Tunis
13 Avicenne University Hospital [Rabat]
14 CHU HII - Centre Hospitalier Universitaire Hassan II
15 CNGMO - Centre National de Greffe de la Moëlle osseuse Tunis

X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) gene defect. XLA patients have absent or reduced number of peripheral B cells and a profound deficiency in all immunoglobulin isotypes. This multicenter study reports the clinical, immunological and molecular features of Bruton's disease in 40 North African male patients. Fifty male out of 63 (male and female) patients diagnosed with serum agammaglobulinemia and non detectable to less than 2 % peripheral B cells were enrolled. The search for BTK gene mutations was performed for all of them by genomic DNA amplification and Sanger sequencing. We identified 33 different mutations in the BTK gene in 40 patients including 12 missense mutations, 6 nonsense mutations, 6 splice-site mutations, 5 frameshift, 2 large deletions, one complex mutation and one in-frame deletion. Seventeen of these mutations are novel. This large series shows a lower frequency of XLA among male patients from North Africa with agammaglobulinemia and absent to low B cells compared with other international studies (63.5 % vs 85 %). No strong evidence for genotype-phenotype correlation was observed. This study adds to other reports from highly consanguineous North African populations, showing lower frequency of X-linked forms as compared to AR forms of the same primary immunodeficiency. Furthermore, a large number of novel BTK mutations were identified and could further help identify carriers for genetic counseling.

Keywords: BTK; XLA; novel mutations; north african population

Domains: Immunology; Biochemistry, Molecular Biology

Zahra Aadam, Nadia Kechout, Abdelhamid Barakat, Koon-Wing Chan, Meriem Ben-Ali, et al.. X-Linked Agammagobulinemia in a Large Series of North African Patients: Frequency, Clinical Features and Novel BTK Mutations. Journal of Clinical Immunology, 2016, 36 (3), pp.187-194. ⟨10.1007/s10875-016-0251-z⟩. ⟨pasteur-01374987⟩