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Novel XLF/Cernunnos mutation linked to severe combined immunodeficiency, microcephaly and abnormal T and B cell receptor repertoires
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  • Shirly Frizinsky,
  • Erez Rechavi,
  • Ortal Barel,
  • Yu-Nee Lee,
  • Amos Simon,
  • Atar Lev,
  • Tali Stauber,
  • Raz Somech
Shirly Frizinsky
Sheba Medical Center
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Erez Rechavi
Edmond and Lili Safra Children’s Hospital
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Ortal Barel
The Wohl Institute for Translational Medicine
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Yu-Nee Lee
Tel Aviv University Sackler Faculty of Medicine
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Amos Simon
Sheba Medical Center
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Atar Lev
Tel Aviv University Sackler Faculty of Medicine
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Tali Stauber
Sheba Hospital
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Raz Somech
Edmond and Lili Safra Children’s Hospital
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Abstract

Background: During the process of generating diverse T and B cell receptor (TCR and BCR, respectively) repertoires, double strand DNA breaks are produced. Subsequently, these breaks are corrected by a complexed system led mainly by the non-homologous end-joining (NHEJ). Mutations in proteins involved in this process, including the XLF/ Cernunnos gene, cause severe combined immunodeficiency syndrome (SCID) along with neurodevelopmental disease and susseptability to inoizing radiation. Objective: To provide new clinical and immunological insights on XLF/Cernunnos deficiency, arising from a newly diagnosed patient with severe immunodeficiency. Methods: A male infant, born to consanguineous parents, suspected of having primary immunodeficiency underwent immunological and genetic work up. This included a thorough assessment of T cell phenotyping and lymphocyte activation by mitogen stimulation tests, whole exome sequencing (WES), TCR repertoire Vβ repertoire via flow cytometry analysis and TCR and BCR via next generation sequencing (NGS). Results: Clinical findings included microcephaly, recurrent bacterial viral pneumonia and failure to thrive. Immune workup revealed lymphopenia, reduced T cell function and hypogammaglubolinemia. A skewed TCR Vβ repertoire, TCR gamma (TRG) repertoire and BCR repertoire were determined in the patient. Genetic analysis identified a novel autosomal recessive homozygous missense mutation in XLF/Cernunnos c. A580Ins.T; p. M194fs. The patient underwent a successful hematopoietic stem cell transplantation (HSCT). Conclusions: A novel XLF/Cernunnos mutation is reported in a patient presented with SCID phenotype that displayed clonally expanded T and B cells. An adjusted HSCT was safe to ensure full T cell immune reconstitution.

Peer review status:IN REVISION

08 Apr 2021Submitted to Clinical & Experimental Immunology
14 Apr 2021Assigned to Editor
14 Apr 2021Submission Checks Completed
14 Apr 2021Reviewer(s) Assigned
01 May 2021Review(s) Completed, Editorial Evaluation Pending
02 May 2021Editorial Decision: Revise Major