{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T14:05:13Z","timestamp":1779199513359,"version":"3.51.4"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T00:00:00Z","timestamp":1659052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30CA006927, P01AI138962"],"award-info":[{"award-number":["P30CA006927, P01AI138962"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Newborn screening for severe combined immunodeficiency (SCID) has not only accelerated diagnosis and improved treatment for affected infants, but also led to identification of novel genes required for human T cell development. A male proband had SCID newborn screening showing very low T cell receptor excision circles (TRECs), a biomarker for thymic output of nascent T cells. He had persistent profound T lymphopenia, but normal numbers of B and natural killer (NK) cells. Despite an allogeneic hematopoietic stem cell transplant from his brother, he failed to develop normal T cells. Targeted resequencing excluded known SCID genes; however, whole exome sequencing (WES) of the proband and parents revealed a maternally inherited X-linked missense mutation in <jats:italic>MED14 (MED14<jats:sup>V763A<\/jats:sup>)<\/jats:italic>, a component of the mediator complex. Morpholino (MO)-mediated loss of MED14 function attenuated T cell development in zebrafish. Moreover, this arrest was rescued by ectopic expression of cDNA encoding the wild type human <jats:italic>MED14<\/jats:italic> ortholog, but not by <jats:italic>MED14<jats:sup>V763A<\/jats:sup><\/jats:italic>, suggesting that the variant impaired MED14 function. Modeling of the equivalent mutation in mouse (<jats:italic>Med14<jats:sup>V769A<\/jats:sup>)<\/jats:italic> did not disrupt T cell development at baseline. However, repopulation of peripheral T cells upon competitive bone marrow transplantation was compromised, consistent with the incomplete T cell reconstitution experienced by the proband upon transplantation with bone marrow from his healthy male sibling, who was found to have the same <jats:italic>MED14<jats:sup>V763A<\/jats:sup><\/jats:italic> variant. Suspecting that the variable phenotypic expression between the siblings was influenced by further mutation(s), we sought to identify genetic variants present only in the affected proband. Indeed, WES revealed a mutation in the L1 cell adhesion molecule <jats:italic>(L1CAM<jats:sup>Q498H<\/jats:sup>)<\/jats:italic>; however, introducing that mutation <jats:italic>in vivo<\/jats:italic> in mice did not disrupt T cell development. Consequently, immunodeficiency in the proband may depend upon additional, unidentified gene variants.<\/jats:p>","DOI":"10.3389\/fimmu.2022.928252","type":"journal-article","created":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T10:03:19Z","timestamp":1659088999000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Investigation of the causal etiology in a patient with T-B+NK+ 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