Autosomal Recessive Agammaglobulinemia - first case with a novel TCF3 mutation from Pakistan

Qureshi, Sonia; Sheikh, Muhammad Dawood Amir

doi:10.1016/j.clim.2018.07.016

Cited by 18 publications

(16 citation statements)

References 8 publications

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“… 5 , 6 , 7 The data on PIDs in Pakistan is currently confined to a few case reports, case series, and editorials; there are no detailed reports on the spectrum of PIDs seen in the country. 8 , 9 , 10 , 11 …”

Section: Introductionmentioning

confidence: 99%

The spectrum of primary immunodeficiencies at a tertiary care hospital in Pakistan

Qureshi

Mir

Junejo

et al. 2020

World Allergy Organization Journal

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Background Primary Immunodeficiency Disorders (PIDs) are well-known disorders in the West. but the recognition and diagnosis of these disorders is challenging in developing countries. We present the spectrum of PIDs seen at a tertiary care center in Pakistan, identified using clinical case definitions and molecular methods. Methods A retrospective chart review of children suspected to have PID was conducted at the Aga Khan University Hospital (AKUH) Karachi, Pakistan from 2010 to 2016. Data on demographics, clinical features, family history of consanguinity, sibling death, details of laboratory workup done for PID and molecular tests targeted panel next generation sequencing (NGS) or whole exome sequencing (WES) performed at the Geha laboratory at Boston Children’s Hospital, USA was collected. The study was exempted from the Ethical Review Committee of AKUH. Results A total of 43 children visited the hospital with suspected PID during the study period. Genetic testing was performed in 31/43 (72.1%) children. A confirmed diagnosis of PID was established in 20/43 (46.5%) children. A pathogenic gene variant was identified in 17(85%) of the 20 confirmed cases (Table 1). Twelve (60%) of the confirmed cases of PID were male. The most common presenting symptom was recurrent diarrhea 11/20 (55%). The mean (±S.D) age of the cases at the time of diagnosis was 4.2 (±4.1) years. Chronic granulomatous disease (CGD) was the most common 6/20 (30%) disorder, followed by severe combined immunodeficiency (SCID) 3/20 (15%), leukocyte adhesion deficiency (LAD) 3/20 (15%), agammaglobulinemia/hypogammaglobulinemia 3/20 (15%), and Hermansky-Pudlak Syndrome (HPS) 2/20 (10%). Wiskott-Aldrich Syndrome, Immunodeficiency Centromeric Instability and Facial Anomalies Syndrome (ICF 2), Trichohepatoenteric syndrome (TRES), and C3 deficiency were each diagnosed once {1/20 (4.3%) each} (Table 1). Of these 20 confirmed cases, almost all 19/20 (95%) had a family history of consanguinity. Sibling death was reported in 5/20 (25%) of these cases. Five out of the 20 (25%) children died over the 7-year period for various reasons. Conclusion PIDs are not uncommon in Pakistan; their diagnosis may be missed or delayed due to the overlapping of clinical features of PID with other diseases and a lack of diagnostic facilities. There is a need to build capacity for early recognition and diagnosis of PIDs to decrease morbidity and mortality.

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Section: Introductionmentioning

confidence: 99%

The spectrum of primary immunodeficiencies at a tertiary care hospital in Pakistan

Qureshi

Mir

Junejo

et al. 2020

World Allergy Organization Journal

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“…The pathogenic mutations identified in these families (a nonsense mutation [Q270X] and a deletion of exons 5‐11) abolished expression of both isoforms of E2A. The index patients presented with recurrent pneumonias accompanied by meningitis, B‐cell acute lymphoblastic leukemia (B‐ALL), 47 or chronic diarrhea 47,48 . Somatic mutations of TCF3 were previously reported in patients with Burkitt lymphoma 50 …”

Section: Inborn Error Of Immunity Affecting Human B‐cell Developmentmentioning

confidence: 99%

“…AD, autosomal dominant; AR, autosomal recessive; BLNK, B-cell linker; BTK, Bruton tyrosine kinase; CD, cluster of differentiation; IGHM, immunoglobulin heavy constant mu; IGLL1, immunoglobulin lambda like polypeptide 1; IL7RA, alpha chain of the IL-7 receptor; JAK3, Janus activated kinase 3; NK, natural killer; SLC39A7, solute carrier family 39 member 7; TCF3, transcription factor 3; TOP2B, DNA topoisomerase II beta; γc, gamma common chain of the interleukin (IL)-2 receptor (IL2RG) pro-to pre-B-cell transition due to an intrinsic defect in the B-cell lineage. 34 Autosomal recessive agammaglobulinemia was also diagnosed in two unrelated kindreds harboring germline mutations in TCF3 47,48 ( These patients had undetectable peripheral blood B cells 52,53 ; analysis of BM from one patient revealed a block in development at the CLP to pro-B-cell stage. 53 Murine models engineered to carry an orthologous mutation showed reduced levels of multiple B-cell precursors in the BM, albeit to a lesser extent than in the single patient examined.…”

Section: X-linked Agammaglobulinemiamentioning

confidence: 99%

“…Autosomal recessive agammaglobulinemia was also diagnosed in two unrelated kindreds harboring germline mutations in TCF3 47,48 (Table 1). Alternative splicing of the TCF3 gene produces the proteins E12 and E47, two founding members of the basic helix‐loop‐helix (bHLH) family of transcription factors 49 .…”

Section: Inborn Error Of Immunity Affecting Human B‐cell Developmentmentioning

confidence: 99%

“…These findings demonstrated that E47 is actively involved in regulating B-cell development by preventing pro-B cells are unable to express a functional pre-BCR from developing further 51. Interestingly, depending on the nature of the variant, inborn errors in TCF3 can be pathogenic in either monoallelic or bi-allelic states.Indeed, despite the initial discovery that autosomal dominant variants in TCF3 cause agammaglobulinemia,51 the heterozygous relatives of individuals with homozygous TCF3 variants were healthy 47,48.…”

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Molecular requirements for human lymphopoiesis as defined by inborn errors of immunity

2021

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Hematopoietic stem cells (HSCs) are the progenitor cells that give rise to the diverse repertoire of all immune cells. As they differentiate, HSCs yield a series of cell states that undergo gradual commitment to become mature blood cells. Studies of hematopoiesis in murine models have provided critical insights about the lineage relationships among stem cells, progenitors, and mature cells, and these have guided investigations of the molecular basis for these distinct developmental stages. Primary immune deficiencies are caused by inborn errors of immunity that result in immune dysfunction and subsequent susceptibility to severe and recurrent infection(s). Over the last decade there has been a dramatic increase in the number and depth of the molecular, cellular, and clinical characterization of such genetically defined causes of immune dysfunction. Patients harboring inborn errors of immunity thus represent a unique resource to improve our understanding of the multilayered and complex mechanisms underlying lymphocyte development in humans. These breakthrough discoveries not only enable significant advances in the diagnosis of such rare and complex conditions but also provide substantial improvement in the development of personalized treatments. Here, we will discuss the clinical, cellular, and molecular phenotypes, and treatments of selected inborn errors of immunity that impede, either intrinsically or extrinsically, the development of B-or T-cells at different stages.

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Heterozygous TCF3‐related disease presenting as X‐linked agammaglobulinemia mimicry in a male toddler with B‐cell aplasia, agammaglobulinemia, and severe neutropenia

Bou‐Maroun,

Walkovich,

Frazier

et al. 2024

Pediatric Blood & Cancer

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Autosomal Recessive Agammaglobulinemia - first case with a novel TCF3 mutation from Pakistan

Cited by 18 publications

References 8 publications

The spectrum of primary immunodeficiencies at a tertiary care hospital in Pakistan

The spectrum of primary immunodeficiencies at a tertiary care hospital in Pakistan

Molecular requirements for human lymphopoiesis as defined by inborn errors of immunity

Heterozygous TCF3‐related disease presenting as X‐linked agammaglobulinemia mimicry in a male toddler with B‐cell aplasia, agammaglobulinemia, and severe neutropenia

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