Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families
| Autor: | Yu-Lung Lau, Najla Mekki, Lamia Gargouri, Imen Ben-Mustapha, Rachida Boukari, Abdelhamid Barakat, Mohamed Bejaoui, Zahra Aadam, Jouda Gamara, Koon Wing Chan, Nabil BelHadj-Hmida, Aziz Bousfiha, Beya Larguèche, Houcine Ben Ameur, Jing Yang, Fethi Mellouli, Amel Nedri, Nadia Kechout, Mohamed-Ridha Barbouche, Meriem Ben-Ali |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Candidate gene Immunology Nonsense mutation Consanguinity Biology Gene mutation medicine.disease_cause Polymorphism Single Nucleotide 03 medical and health sciences symbols.namesake 0302 clinical medicine Agammaglobulinemia Exome Sequencing medicine Humans Immunology and Allergy Exome Exome sequencing Sanger sequencing Genetics Mutation Homozygote Infant Newborn Infant Sequence Analysis DNA CD79B Pedigree Phenotype 030104 developmental biology Codon Nonsense Child Preschool North America symbols Female 030215 immunology |
| Zdroj: | Journal of Clinical Immunology. 40:96-104 |
| ISSN: | 1573-2592 0271-9142 |
| DOI: | 10.1007/s10875-019-00706-4 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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