Identification and Characterization of a Germline Mutation in CARD11 From a Chinese Case of B Cell Expansion With NF-κB and T Cell Anergy

Abstract

B cell expansion with NF-κB and T cell anergy (BENTA) is a rare primary immunodeficiency disorder caused by gain-of-function (GOF) mutations in the <i>CARD11</i> gene. Affected patients present with persistent B cell lymphocytosis in early childhood paired with lymphadenopathy and splenomegaly. Until now only six activating mutations from 14 patients have been reported in <i>CARD11</i>. Here we report a patient from China with polyclonal B cell lymphocytosis and frequent infections in early life. A heterozygous mutation (c.377G>A, G126D) in exon 5 of <i>CARD11</i> gene (NM_032415) was identified by whole exome sequencing. <i>In vitro</i> functional studies showed that the G126D mutation is associated with increased expression of CARD11 and NF-κB activation in Hela cells. Flow cytometry analysis indicated NK cell activity and CD107a degranulation of the patient were decreased. RNA sequencing analysis showed that a number of genes in NF-κB pathway increased while those involved in NK cell activity and degranulation were down-regulated. In summary, our work identified a <i>de novo</i> germline GOF mutation in <i>CARD11</i> with functional evidence of BENTA.