Combined Immunodeficiency Due to MALT1 Mutations, Treated by Hematopoietic Cell Transplantation

• DOI: 10.1007/s10875-014-0125-1
• Publication Date: 2015-01-27T07:42:06Z
• Authors: Divya Punwani; Haopeng Wang; Alice Y. Chan; Morton J. Cowan; Jacob Mallott; Uma Sunderam; Marianne Mollenauer; Rajgopal Srinivasan; Steven E. Brenner; Arend Mulder; Frans H. J. Claas; Arthur Weiss; Jennifer M. Puck
• Keywords: Medical microbiology; Primary Immunodeficiency

A male infant developed generalized rash, intestinal inflammation and severe infections including persistent cytomegalovirus. Family history was negative, T cell receptor excision circles were normal, engraftment of maternal cells absent. No defects found in multiple genes associated with combined immunodeficiency. 9/10 HLA matched unrelated hematopoietic transplant (HCT) led to mixed chimerism clinical resolution. We sought an underlying cause for this patient's immune deficiency dysregulation. Clinical laboratory features reviewed. Whole exome sequencing analysis genomic DNA from the patient, parents 2 unaffected siblings performed, revealing MALT1 variants. With a host-specific HLA-C antibody, we assessed expression function post-HCT autologous donor lymphocytes. Wild type cDNA added transformed patient B assess functional correction. The had compound heterozygous variants affecting exon 10 (isoform a, NM_006785.3), maternally inherited splice acceptor c.1019-2A > G, de novo deletion c.1059C leading frameshift premature termination. Autologous lymphocytes failed express lacked NF-κB signaling dependent upon CARMA1, BCL-10 signalosome. Transduction wild corrected observed defects. Our nonconsanguineous early onset profound immunodeficiency dysregulation due mutations extends immunologic phenotype reported prior families. cure achieved after nonmyeloablative conditioning HCT.