Coronin 1A deficiency identified by newborn screening for severe combined immunodeficiency

Schejter, Yael Dinur; Mandola, Amarilla B.; Reid, Brenda

doi:10.14785/lymphosign-2019-0001

Cited by 4 publications

(5 citation statements)

References 29 publications

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“…Despite advanced genetic testing of known SCID genes, up to 10% of infants with SCID remain without a proven genotype. In this regard, homozygous mutations in TRAC resulting in TCR-α chain constant deficiency were not previously reported in the context of positive NBS (Kwan et al 2014;Dinur et al 2019;Mandola et al 2019;Giżewska et al 2020;Kumrah et al 2020;Scott et al 2021).…”

Section: Discussionmentioning

confidence: 86%

A novel mutation in TRAC in a patient with abnormal newborn screening for severe combined immunodeficiency

et al. 2022

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Background: The T cell receptor (TCR) α subunit plays a key role in the TCR structure and its function. Biallelic mutations in the TCR-α subunit constant gene (TRAC) obliterated T cell receptor expression and results in immunodeficiency. TRAC deficiency presents at infancy or childhood with repeated viral and bacterial infections, enlarged liver, spleen, and lymph nodes as well as autoimmune features and lymphoma (OMIM #615387). Aim: To broaden the genotypic and phenotypic spectrum of TRAC deficiency. Methods: Case report of a patient with severe combined immunodeficiency (SCID) due to a novel autosomal recessive mutation in TRAC. Results: Our patient was identified at 13 days of life due to abnormal T cell receptor excision circle levels detected in newborn screening (NBS). Immune evaluation revealed profound lymphopenia, depressed responses to the mitogen PHA and a skewed T cell repertoire, all consistent with SCID. The patient was found to carry a novel homozygous mutation in the TRAC gene. Conclusion: A novel homozygous mutation in the TRAC gene caused profound T cell lymphopenia and aberrant in vitro mitogenic response, the hallmarks of SCID. Statement of Novelty: TCR-alpha chain (TRAC) deficiency is a rare and relatively new condition and not very well defined. We herein report a novel mutation in TRAC resulting in SCID.

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Section: Discussionmentioning

confidence: 86%

A novel mutation in TRAC in a patient with abnormal newborn screening for severe combined immunodeficiency

et al. 2022

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“…To date, there have been reports of 10 patients (from 6 kindreds) with coronin 1A deficiency (Shiow et al 2008;Moshous et al 2013;Stray-Pedersen et al 2014;Punwani et al 2015;Yee et al 2016;Dinur Schejter et al 2019). Here, we describe an 11th patient with a novel mutation in the WD4 repeat which is necessary for formation of the beta propeller motif.…”

Section: Discussionmentioning

confidence: 89%

“…Here, we describe an 11th patient with a novel mutation in the WD4 repeat which is necessary for formation of the beta propeller motif. Mutations affecting the N-terminal extension (R12L/del116p11) (Punwani et al 2015), WD repeat regions-WD2 (P83R/del116p11) (Shiow et al 2008), WD4 (R201C) (Dinur Schejter et al 2019), and C-terminal extension (Q360RfsX44) (Stray-Pedersen et al 2014) have each been associated with complete loss of coronin 1A protein expression, either through truncation codons leading to nonsense mediated decay of mRNA or possibly loss of the stabilizing coiled-coil domain. In cases where residual albeit low levels of coronin 1A were detected (V134M affecting WD3, and S401fs targeting the CE region), a somewhat milder immunological phenotype was described.…”

Section: Discussionmentioning

confidence: 99%

“…In all cases described so far, patients experienced recurrent infections, had markedly reduced naïve peripheral T cells, and impaired T cell responses to mitogens (Moshous et al 2013;Mace and Orange 2014). All but 3 patients showed failure to control Epstein-Barr virus (EBV) predisposing to B cell lymphoproliferation and lymphoma (Yee et al 2016;Dinur Schejter et al 2019). Interestingly, the thymus of coronin 1A deficient patients appears normal, indicating that loss of naïve T cells may be due to defects in cell survival.…”

Section: Introductionmentioning

confidence: 99%

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Successful hematopoietic stem cell transplantation in a patient with a novel mutation in coronin 1A

et al. 2019

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Introduction: Coronin 1A is part of a family of highly conserved actin regulatory proteins with key roles in T cell homeostasis and T cell receptor signaling. Null mutations in coronin 1A result in severe combined immunodeficiency, whereas hypomorphic mutations have been associated with a somewhat milder immunological phenotype. Nevertheless, all patients described so far have markedly reduced naïve peripheral T cells, impaired T cell responses to mitogens, and limited T cell receptor diversity. Interestingly, despite poor thymic output, thymus architecture appears normal. To date, only 2 cases of hematopoietic stem cell transplantation (HSCT) have been reported in coronin 1A deficiency. Aim: To describe the identification, transplantation course, and long term outcome of a Canadian Inuit patient diagnosed with coronin 1A deficiency. Methods: Patient chart review was performed in accordance with institutional research ethics approval. A combination of immunological investigations and molecular genetic analyses were utilized to identify a novel mutation in the tryptophan-aspartate repeat region of coronin 1A. Based on the patient’s profound T cell dysfunction, the decision was made to proceed with HSCT. Results: The patient presented with a history of recurrent urinary tract infections, otitis media, and developmental delay involving poor axial and peripheral muscle tone. Axillary lymphadenopathy was noted and subsequent thymus biopsy revealed aberrant CD7+ T cell deficiency. Lymphocyte responses to mitogens and T cell receptor excision circle levels were markedly reduced, consistent with the diagnosis of severe combined immunodeficiency. Whole exome sequencing and Sanger confirmation revealed a novel mutation in coronin 1A. HSCT using a HLA-matched unrelated donor resulted in long term engraftment and solid immune reconstitution. Conclusion: Very few patients with coronin 1A deficiency have been described to date, making it difficult to evaluate its natural history and management. Here, we describe the presentation, identification, transplantation, and outcome in our patient. Statement of novelty: We describe the successful hematopoietic stem cell transplantation course and outcome in a patient with a novel mutation in coronin 1A.

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“…Since the first patient with this T − B + NK + SCID was identified in 2009, 1 a series of patients with CORO1A protein deficiency have been reported and the disease’s spectrum has been expanded to include a milder phenotype that is caused by hypomorphic CORO1A mutations and leads to T-cell lymphopenia of variable severity, profound defects of naive T-cells, seemingly preserved B- and natural killer (NK) cell compartments, recurrent viral infections, and EBV-associated B-cell lymphoproliferation. 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 …”

Section: Introductionmentioning

confidence: 99%

Novel hemizygous CORO1A variant leads to combined immunodeficiency with defective platelet calcium signaling and cell mobility

Khoreva,

Butov,

Nikolaeva

et al. 2024

Journal of Allergy and Clinical Immunology: Global

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Coronin 1A deficiency identified by newborn screening for severe combined immunodeficiency

Cited by 4 publications

References 29 publications

A novel mutation in TRAC in a patient with abnormal newborn screening for severe combined immunodeficiency

A novel mutation in TRAC in a patient with abnormal newborn screening for severe combined immunodeficiency

Successful hematopoietic stem cell transplantation in a patient with a novel mutation in coronin 1A

Novel hemizygous CORO1A variant leads to combined immunodeficiency with defective platelet calcium signaling and cell mobility

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