Novel XLF/Cernunnos mutation linked to severe combined immunodeficiency,
microcephaly and abnormal T and B cell receptor repertoires
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.