B-Cells Absence in Patients Diagnosed As Inborn Errors of Immunity: A Registry-Based Study Publisher Pubmed

Summary: Study finds novel BTK gene mutations in hypogammaglobulinemia patients, expanding genetic insights for immune disorders in Iranians. #Immunology #Genetics

Khoshnevisan R¹ ; Hassanzadeh S¹ ; Klein C² ; Rohlfs M³ ; Grimbacher B^{4, 5, 6, 7, 8} ; Molavi N¹ ; Zamanifar A¹ ; Khoshnevisan A¹ ; Jafari M¹ ; Bagherpour B¹ ; Behnam M^{9, 10} ; Najafi S¹ ; Sherkat R¹
Source: Immunogenetics Published:2024

Abstract

Hypogammaglobulinemia without B-cells is a subgroup of inborn errors of immunity (IEI) which is characterized by a significant decline in all serum immunoglobulin isotypes, coupled with a pronounced reduction or absence of B-cells. Approximately 80 to 90% of individuals exhibit genetic variations in Bruton’s agammaglobulinemia tyrosine kinase (BTK), whereas a minority of cases, around 5–10%, are autosomal recessive agammaglobulinemia (ARA). Very few cases are grouped into distinct subcategories. We evaluated phenotypically and genetically 27 patients from 13 distinct families with hypogammaglobinemia and no B-cells. Genetic analysis was performed via whole-exome and Sanger sequencing. The most prevalent genetic cause was mutations in BTK. Three novel mutations in the BTK gene include c.115 T > C (p. Tyr39His), c.685-686insTTAC (p.Asn229llefs5), and c.163delT (p.Ser55GlnfsTer2). Our three ARA patients include a novel homozygous stop-gain mutation in the immunoglobulin heavy constant Mu chain (IGHM) gene, a novel frameshift mutation of the B-cell antigen receptor complex-associated protein (CD79A) gene, a novel bi-allelic stop-gain mutation in the transcription factor 3 (TCF3) gene. Three patients with agammaglobulinemia have an autosomal dominant inheritance pattern, which includes a missense variant in PIK3CD, a novel missense variant in PIK3R1 and a homozygous silent mutation in the phosphoinositide-3-kinase regulatory subunit (RASGRP1) gene. This study broadens the genetic spectrum of hypogammaglobulinemia without B-cells and presented a few novel variants within the Iranian community, which may also have implications in other Middle Eastern populations. Notably, disease control was better in the second affected family member in families with multiple cases. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024.