1. Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families
- Author
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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, and Meriem Ben-Ali
- Subjects
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 - 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.
- Published
- 2019