Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families

Ben-Ali, Meriem; Kechout, Nadia; Mekki, Najla; Yang, Jing; Chan, Koon Wing; Barakat, Abdelhamid; Aadam, Zahra; Gamara, Jouda; Gargouri, L.; Larguèche, Beya; BelHadj-Hmida, Nabil; Nedri, Amel; Ameur, Houcine Ben; Mellouli, Fethi; Boukari, Rachida; Béjaoui, Mohamed; Bousfiha, Aziz; Ben‐Mustapha, Imen; Lau, Yu Lung; Barbouche, Mohamed‐Ridha

doi:10.1007/s10875-019-00706-4

Cited by 7 publications

(7 citation statements)

References 29 publications

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“…Agammaglobulinemia is the most profound primary antibody deficiency that results from early termination of B-cell development, which leads to the absence of mature circulating B-cells and very low or absent serum immunoglobulin levels. To date, defects in BTK, IGHM, IGLL1, CD79A, CD79B, BLNK, and PIK3R1 have been reported to cause agammaglobulinemia 1 .…”

Section: Introductionmentioning

confidence: 99%

Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency

Saettini

Poli

Vengoechea

et al. 2021

Blood

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Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated three novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound heterozygous variants in the gene for Folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and PI3K/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy or copy number variants [CNV] in two patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.

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Section: Introductionmentioning

confidence: 99%

Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency

Saettini

Poli

Vengoechea

et al. 2021

Blood

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“…Prior research has identified mutations in genes such as BTK, IGHM, IGLL1, CD79A, CD79B, BLNK, and PIK3R1 as causative for agammaglobulinemia. 3 The coordination of cell growth and division, alongside nutrient and energy management, is essential for the appropriate development and functioning of immune cells. FNIP1, which interacts with folliculin, is critical for B-cell development and metabolic equilibrium.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Immunologic Features of a Patient With Homozygous FNIP1 Variant

Ulaş,

Naiboğlu,

Özyilmaz

et al. 2024

Journal of Pediatric Hematology/Oncology

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Agammaglobulinemia represents the most profound primary antibody deficiency, stemming from early cessation of B-cell development. Deficiency in folliculin-interacting protein 1 (FNIP1) is a novel inborn error of immunity characterized by a severe defect in B-cell development, agammaglobulinemia, variable neutropenia, and hypertrophic cardiomyopathy. FNIP1 plays a critical role in B-cell development and metabolic homeostasis, establishing a metabolic checkpoint that ensures pre-B cells possess sufficient metabolic capacity to undergo division while concurrently limiting lymphogenesis due to abnormal growth. Disruption of FNIP1 functionality affects the fundamental metabolic regulators adenosine monophosphate-activated protein kinase and mTOR, culminating in a severe B-cell deficiency alongside hypogammaglobulinemia, hypertrophic cardiomyopathy, preexcitation syndrome, and intermittent neutropenia. This case report presents an 11-month-old male patient with FNIP1 deficiency who, in addition to classical features, exhibited posterior cerebellar hypoplasia.

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“…The major genetic cause of B-cell deficiency is X-linked agammaglobulinemia due to mutations in BTK encoding for Bruton's tyrosine kinase. Mutations in other genes involved in B-cell development or function can also cause antibody deficiency including IGHM, IGLL1, CD79A, CD79B, BLNK, PIK3R1 and FNIP [34][35][36].…”

Section: Autoinflammatory Diseasesmentioning

confidence: 99%

Functional Genetics in Inborn Errors of Immunity

Rey-Jurado

Poli

2021

Future Rare Dis.

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Inborn errors of immunity are genetic defects of the immune system, causing increased susceptibility to infection, autoinflammation, autoimmunity and immune dysregulation. Next-generation sequencing has enabled exponential identification of novel inborn errors of immunity due to mutations in genes encoding for proteins that participate in the immune response. However, genomic sequencing often yields multiple variants in potential candidate genes, hence functional validation of these genetic defects becomes paramount to achieve diagnosis and discovery. Genome-editing technologies such as CRISPR-Cas9 have allowed exponential advances on discovery of new primary immunodeficiencies, enabling appropriate diagnosis and treatment. This review summarizes the heterogeneous clinical presentation of primary immunodeficiencies and contextualizes the rationale for functional validation studies to achieve diagnosis and discovery, subsequently leading to the application of directed therapies.

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Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families

Cited by 7 publications

References 29 publications

Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency

Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency

Clinical and Immunologic Features of a Patient With Homozygous FNIP1 Variant

Functional Genetics in Inborn Errors of Immunity

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