{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T13:55:24Z","timestamp":1781358924476,"version":"3.54.1"},"reference-count":23,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Human Genetics"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>Inborn errors of immunity (IEI) refer to a heterogeneous group of monogenic disorders caused by germline variants that disrupt immune function. Among these conditions, immunodeficiency 92 (IMD92), an extremely rare autosomal recessive disorder due to c Rel deficiency that results from pathogenic variants of the REL gene. c Rel is a key actor of the NF\u2010\u03baB pathway with major implications in the immune response. Up untill now, only two patients with confirmed pathogenic REL variants have been reported.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p>\n                      Here, a third case is described of a 5\u2010year\u2010old Moroccan child with combined immunodeficiency presenting with chronic diarrhea and recurrent opportunistic infections, alongside newly reported features including craniosynostosis, language delay, and epilepsy. Clinical exome sequencing, confirmed by Sanger sequencing, identified a novel homozygous frameshift variant (NM_001291746.4)\n                      <jats:italic>REL<\/jats:italic>\n                      :c.24del p.(Tyr9Ilefs*2). This variant introduces a very early premature stop codon. Western blot analysis of peripheral blood mononuclear cells demonstrated a severe reduction of c Rel protein expression with preserved p65 levels, confirming its functional impact.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This report expands the mutational spectrum of\n                      <jats:italic>REL<\/jats:italic>\n                      and further supports the critical, non\u2010redundant role of c\u2010Rel in human immune homeostasis. It also highlights the central role of next generation sequencing, particularly clinical exome approaches, in the diagnosis and evolving genetic classification of IEI, enabling earlier recognition, refined subclassification, and more personalized management of affected patients.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/ahg.70040","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T09:34:11Z","timestamp":1778578451000},"page":"240-248","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Biallelic\n                    <i>REL<\/i>\n                    Frameshift Variant p.(Tyr9Ilefs*2) Causing Immunodeficiency\u201092 With Profound c\u2010Rel Deficiency"],"prefix":"10.1111","volume":"90","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8220-3826","authenticated-orcid":false,"given":"Mohsine\u2010Ali","family":"El\u2010Hamri","sequence":"first","affiliation":[{"name":"Department of Medical Genetics National Institute of Hygiene  Rabat Morocco"},{"name":"Research Team in Genomics and Molecular Epidemiology of Genetic Diseases Genopath Centre Faculty of Medicine and Pharmacy of Rabat University Mohammed V  Rabat Morocco"},{"name":"Physiology and Physiopathology Team, Genomic of Human Pathologies Research Centre Mohammed V University in Rabat  Rabat Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zineb","family":"Sabky","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Institute of Hygiene  Rabat Morocco"},{"name":"Research Team in Genomics and Molecular Epidemiology of Genetic Diseases Genopath Centre Faculty of Medicine and Pharmacy of Rabat University Mohammed V  Rabat Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3373-2812","authenticated-orcid":false,"given":"Nada","family":"Benyahya","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Institute of Hygiene  Rabat Morocco"},{"name":"Research Team in Genomics and Molecular Epidemiology of Genetic Diseases Genopath Centre Faculty of Medicine and Pharmacy of Rabat University Mohammed V  Rabat Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9370-9435","authenticated-orcid":false,"given":"Oualid","family":"Abboussi","sequence":"additional","affiliation":[{"name":"Physiology and Physiopathology Team, Genomic of Human Pathologies Research Centre Mohammed V University in Rabat  Rabat Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4796-1872","authenticated-orcid":false,"given":"Jaber","family":"Lyahyai","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Institute of Hygiene  Rabat Morocco"},{"name":"Research Team in Genomics and Molecular Epidemiology of Genetic Diseases Genopath Centre Faculty of Medicine and Pharmacy of Rabat University Mohammed V  Rabat Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1921-5215","authenticated-orcid":false,"given":"Abdelaziz","family":"Seffiani","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Institute of Hygiene  Rabat Morocco"},{"name":"Research Team in Genomics and Molecular Epidemiology of Genetic Diseases Genopath Centre Faculty of Medicine and Pharmacy of Rabat University Mohammed V  Rabat Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576\u2010023\u201000656\u2010z"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1602820"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1134\/S1819712421020045"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2019.05.003"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1159\/000533894"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.11.7097"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203222"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207410"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2010.171"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci150143"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2020.06.029"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/11.3.361"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.050715"},{"key":"e_1_2_11_15_1","volume-title":"Severe Combined Immunodeficiency. 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