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1.
J Clin Immunol ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31696364

RESUMO

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.

2.
J Clin Immunol ; 36(3): 187-94, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26931785

RESUMO

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Agamaglobulinemia/genética , Expressão Gênica , Frequência do Gene , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação , Infecções Oportunistas/genética , Proteínas Tirosina Quinases/genética , Adulto , Tirosina Quinase da Agamaglobulinemia , Agamaglobulinemia/complicações , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/imunologia , Idade de Início , Argélia , Alelos , Linfócitos B/imunologia , Linfócitos B/patologia , Criança , Pré-Escolar , Estudos de Associação Genética , Aconselhamento Genético , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Heterozigoto , Humanos , Lactente , Masculino , Marrocos , Infecções Oportunistas/complicações , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/imunologia , Proteínas Tirosina Quinases/imunologia , Análise de Sequência de DNA , Tunísia
4.
J Clin Immunol ; 34(4): 452-8, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24596025

RESUMO

PURPOSE: Chronic granulomatous disease (CGD) is characterized by an inability of phagocytes to produce reactive oxygen species (ROS), which are required to kill some microorganisms. CGD patients are known to suffer from recurrent bacterial and/or fungal infections from the first year of life onwards. From 2009 to 2013, 12 cases of CGD were diagnosed in Morocco. We describe here these Moroccan cases of CGD. METHODS: We investigated the genetic, immunological and clinical features of 12 Moroccan patients with CGD from 10 unrelated kindreds. RESULTS: All patients were children suffering from recurrent bacterial and/or fungal infections. All cases displayed impaired NADPH oxidase activity in nitroblue tetrazolium (NBT), dihydrorhodamine (DHR) or 2',7' dichlorofluorescein diacetate (DCFH-DA) assays. Mutation analysis revealed the presence of four different mutations of CYBB in four kindreds, a recurrent mutation of NCF1 in three kindreds, and a new mutation of NCF2 in three patients from a single kindred. A large deletion of CYBB gene has detected in a patient. The causal mutation in the remaining one kindred was not identified. CONCLUSION: The clinical features and infectious agents found in these patients were similar to those in CGD patients from elsewhere. The results of mutation analysis differed between kindreds, revealing a high level of genetic and allelic heterogeneity among Moroccan CGD patients. The small number of patients in our cohort probably reflects a lack of awareness of physicians. Further studies on a large cohort are required to determine the incidence and prevalence of the disease, and to improve the description of the genetic and clinical features of CGD patients in Morocco.


Assuntos
Aspergilose/genética , Infecções Bacterianas/genética , Doença Granulomatosa Crônica/genética , Glicoproteínas de Membrana/genética , NADPH Oxidases/genética , Adolescente , Alelos , Aspergilose/complicações , Aspergilose/imunologia , Aspergilose/patologia , Infecções Bacterianas/complicações , Infecções Bacterianas/imunologia , Infecções Bacterianas/patologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Genes Recessivos , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , NADPH Oxidase 2 , Linhagem
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