Expanding the clinical and immunological phenotypes of PAX1-deficient SCID and CID patients
Nalan Yakıcı, Alexandra Y. Kreins, Mehmet Cihangir Çatak, Royala Babayeva, Baran Erman, Heather Kenney, Hatice Güngör, Pablo A. Cea, Tomoki Kawai, Marita Bosticardo, Ottavia M. Delmonte, Stuart Adams, Yu-Tong Fan, Francesca Pala, Ayberk Türkyılmaz, Evey Howley, Austen Worth, Hakan Kot, Asena Pınar Sefer, Altan Kara, Alper Bulutoğlu, Sevgi Bilgic-Eltan, Melek Yorgun Altunbaş, Feyza Bayram Catak, İbrahim Serhat Karakuş, Emrah Karatay, Sidem Tekeoglu, Metin Eser, Davut Albayrak, Şenol Çitli, Ayça Kıykım, Elif Karakoç-Aydıner, Ahmet Özen, Sujal Ghosh, Holger Gohlke, Fazıl Orhan, Luigi D. Notarangelo, E. Graham Davies, Safa Barış
Abstract
Paired box 1 (PAX1) deficiency has been reported in a small number of patients diagnosed with otofaciocervical syndrome type 2 (OFCS2). We described six new patients who demonstrated variable clinical penetrance. Reduced transcriptional activity of pathogenic variants confirmed partial or complete PAX1 deficiency. Thymic aplasia and hypoplasia were associated with impaired T-cell immunity. Corrective treatment was required in 4/6 patients. Hematopoietic stem cell transplantation resulted in poor immune reconstitution with absent naïve T cells, contrasting with the superior recovery of T-cell immunity after thymus transplantation. Normal ex vivo differentiation of PAX1-deficient CD34+ cells into mature T-cell demonstrated the absence of a hematopoietic cell-intrinsic defect. New overlapping features with DiGeorge syndrome included primary hypoparathyroidism (n = 5) and congenital heart defects (n = 2), in line with PAX1 expression during early embryogenesis. Our results highlight new features of PAX1 deficiency, which are relevant to improving early diagnosis and identifying patients requiring corrective treatment.