Decreased or Absent B Cells in patients with Severe Reduction in All Serum Immunoglobulin Isotypes, a registry based study

Severe Reduction in All Serum Immunoglobulin Isotypes with Profoundly Decreased or Absent B Cells is a subgroup of inborn error of immunities (IEI). 80 to 90% carry mutations in X-chromosomal Bruton tyrosine kinase (BTK) and around 5–10% of the cases are autosomal recessive Agammaglobulinemia (ARA). Very few of Hypogammaglobulinemia with no B cells classified in other subgroups. All of these patients benefit from a genetic evaluation, especially in highly consanguine populations. 27 patients from 11 families with hypogamma-globinemia and no B-cells registered in Immunodeficiency Diseases Research Center registry, Isfahan University of Medical Sciences were phenotypically and genetically evaluated. The most prevalent genetic cause was mutations in BTK. The novel mutations in BTK gene includes c.176 G>A (p. Glu89Lys); c.115T>C (p. Tyr39His); c.685-686insTTAC (p. Asn229llefs5), in ARA includes a homozygous stop mutation in Immunoglobulin Heavy Constant Mu Chain (IGHM) gene, a frameshift mutation of B-Cell Antigen Receptor Complex-Associated Protein (CD79A), a bi-allelic stop-gain mutation in Transcription Factor 3 (TCF3), and in PIK3CD also in others IEI includes :novel homozygous silent mutations in Phosphoinositide-3-Kinase Regulatory Subunit (RASGRP1), homozygote SAMD9 mutation. We did not observe any phenotypically significant differences in XLA patients. The main clinical manifestation of ARA cases is, recurrent infections. However, patient with IGHM deficiency had earlier onset of the disease and more severe complications. In CD79A deficient case with 5 affected members and four deaths in her family, the symptoms started very early but managed properly according to the family history. Due to the late diagnosis of PIK3CD cases, more severe complications like bronchiectasis, neurologic sequels after poliomyelitis, and SLE nephropathy has been developed. Our novel SAMD9 had quite different phenotype and the novel RASPGR2 case with no B cells unfortunately managed as ARA before genetic diagnosis and has died of lymphoma as her 3 siblings. However, we observed that in families with more than one affected family member, the disease was better controlled in the second patient. Our study broadens the genetic spectrum of hypogammaglobulinemia with no B cells in Iran. This helps differentiate phenotypes and genotypes and manage patients appropriately.