Common Variable Immunodeficiency with Genetic Defects Identified by Whole Exome Sequencing

Abstract

Common variable immunodeficiency (CVID) belongs to the primary immunodeficiency disorders (PIDs), presenting a profound heterogeneity in phenotype and genotype, with monogenic or complex causes. Recurrent respiratory infections are the most common clinical manifestations. CVID patients can also develop various autoimmune and lymphoproliferative complications. Genetic testing such as whole exome sequencing (WES) can be utilized to investigate likely genetic defects, helping for better clinical management. We described the clinical phenotypes of three sporadic cases of CVID, who developed recurrent respiratory infections with different autoimmune and lymphoproliferative complications. WES was applied to screen disease-causing or disease-associated mutations. Two patients were identified to have monogenic disorders, with compound heterozygous mutations in LRBA for one patient and a frameshift insertion in NFKB1 for another. The third patient was identified to be a complex form of CVID. Two novel mutations were identified, respectively, in LRBA and NFKB1. A combination of clinical and genetic diagnosis can be more extensively utilized in the clinical practice due to the complexity and heterogeneity of CVID.

Rituximab and antimetabolite treatment of granulomatous and lymphocytic interstitial lung disease in common variable immunodeficiency

“…GLILD is an interstitial lung disease that occurs in approximately 20% to 30% of patients with CVID and in an increasing number of monogenic CVID-like primary immunodeficiencies (PIDs) involving mutations in genes such as LRBA, CTLA4, RAG1, BIRC4, NFKB1, and KMT2D. [3][4][5][6][7][8][9][10][11] We reported the typical pathologic findings in GLILD, including peribronchiolar/interstitial lymphocytic infiltration (lymphocytic interstitial pneumonia), granulomas and organizing pneumonia with a predominance of CD4 1 T lymphocytes, and variable numbers of CD8 1 T cells and B cells. 12 Patients with GLILD exhibit diffuse lymphadenopathy, splenomegaly, and multisystemic granulomas.…”

Castleman Disease in a Patient with Common Variable Immunodeficiency

“…Therefore, we hypothesize that the multicentric adenopathy with splenomegaly was a consequence of inappropriate treatment of CVID. The constant low levels of blood immunoglobulins most likely, as already reported, hyperstimulated the immune system causing a lymphoproliferative disorder with adenopathy and splenomegaly [13].…”

The impact of rare and low-frequency genetic variants in common variable immunodeficiency (CVID)

“…Multi-gene panel was designed as a result of meta-analysis that was accordant with the OMIM entries of CVIDs and our population based phenotypic and genomic database 10 , 12 , 17 .…”