title: Novel and recurrent AID mutations underlie prevalent autosomal recessive form of HIGM in consanguineous patients.
abstract: Immunoglobulin class switch recombination deficiencies (Ig-CSR-D) are characterized by normal or elevated serum IgM level and absence of IgG, IgA, and IgE. Most reported cases are due to X-linked CD40L deficiency. Activation-induced cytidine deaminase deficiency is the most frequent autosomal recessive form, whereas CD40 deficiency is more rare. Herein, we present the first North African study on hyper IgM (HIGM) syndrome including 16 Tunisian patients. Phenotypic and genetic studies allowed us to determine their molecular basis. Three CD40LG mutations have been identified including two novels (c.348_351dup and c.782_*2del) and one already reported mutation (g.6182G>A). No mutation has been found in another patient despite the lack of CD40L expression. Interestingly, three AICDA mutations have been identified in 11 patients. Two mutations were novel (c.91T>C and c.389A>C found in one and five patients respectively), and one previously reported splicing mutation (c.156+1T>G) was found in five patients. Only one CD40-deficient patient, bearing a novel mutation (c.109T>G), has been identified. Thus, unlike previous reports, AID deficiency is the most frequent underlying molecular basis (68%) of Ig-CSR-D in Tunisian patients. This finding and the presence of specific recurrent mutations are probably due to the critical role played by inbreeding in North African populations.
authors.affiliation: Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), Institut Pasteur de Tunis and University Tunis El Manar, Tunis, Tunisia.
authors.forename: Hanen
authors.initials: H
authors.lastname: Ouadani
authors.affiliation: Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), Institut Pasteur de Tunis and University Tunis El Manar, Tunis, Tunisia.
authors.forename: Imen
authors.initials: I
authors.lastname: Ben-Mustapha
authors.affiliation: Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), Institut Pasteur de Tunis and University Tunis El Manar, Tunis, Tunisia.
authors.forename: Meriem
authors.initials: M
authors.lastname: Ben-ali
authors.affiliation: Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), Institut Pasteur de Tunis and University Tunis El Manar, Tunis, Tunisia.
authors.forename: Leila
authors.initials: L
authors.lastname: Ben-khemis
authors.affiliation: Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), Institut Pasteur de Tunis and University Tunis El Manar, Tunis, Tunisia.
authors.forename: Beya
authors.initials: B
authors.lastname: Larguèche
authors.affiliation: Department of Pediatrics, Tahar Sfar Hospital, Mahdia, Tunisia.
authors.forename: Raoudha
authors.initials: R
authors.lastname: Boussoffara
authors.affiliation: Department of Pneumology "D", Abderahman Mami Hospital, Ariana, Tunisia.
authors.forename: Sonia
authors.initials: S
authors.lastname: Maalej
authors.affiliation: Department of Pediatrics, Mongi Slim Hospital, Marsa, Tunisia.
authors.forename: Ilhem
authors.initials: I
authors.lastname: Fetni
authors.affiliation: Department of Pediatrics, Sahloul Hospital, Sousse, Tunisia.
authors.forename: Saida
authors.initials: S
authors.lastname: Hassayoun
authors.affiliation: Department of Pediatrics, Hedi Chaker Hospital, Sfax, Tunisia.
authors.forename: Abdelmajid
authors.initials: A
authors.lastname: Mahfoudh
authors.affiliation: Department of Pediatrics, Bone Marrow Transplantation Center, Tunis, Tunisia.
authors.forename: Fethi
authors.initials: F
authors.lastname: Mellouli
authors.affiliation: Laboratory of Biology, Abderahman Mami Hospital, Ariana, Tunisia.
authors.forename: Sadok
authors.initials: S
authors.lastname: Yalaoui
authors.affiliation: Laboratory of Immunology, Habib Bourguiba Hospital, Sfax, Tunisia.
authors.forename: Hatem
authors.initials: H
authors.lastname: Masmoudi
authors.affiliation: Department of Pediatrics, Bone Marrow Transplantation Center, Tunis, Tunisia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bejaoui
authors.affiliation: Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), Institut Pasteur de Tunis and University Tunis El Manar, Tunis, Tunisia. ridha.barbouche@pasteur.rns.tn.
authors.forename: Mohamed-Ridha
authors.initials: MR
authors.lastname: Barbouche
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D019013:CD40 Antigens / Q000235:genetics; D023201:CD40 Ligand / Q000235:genetics; D002648:Child; D003241:Consanguinity; D003564:Cytidine Deaminase / Q000172:deficiency / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D053306:Hyper-IgM Immunodeficiency Syndrome / Q000235:genetics* / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D014416:Tunisia; D055815:Young Adult; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D019013:CD40 Antigens; D023201:CD40 Ligand; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
keywords: Activation-induced cytidine deaminase; CD40; CD40LG; Class switch recombination; Consanguinity; Hyper IgM syndrome