Whole-exome sequencing of Two Siblings with X-Linked Agammaglobulinemia and Bronchiolitis Obliterans

Project Description: X-linked agammaglobulinemia (XLA) is an Inborn Errors of Immunity (IEI) characterized by pan-hypogammaglobulinemia and low numbers of B lymphocytes due to mutations in BTK gene. Usually, XLA patients are not susceptible to respiratory tract infections by viruses and do not present interstitial lung disease (ILD) such as bronchiolitis obliterans (BO) as a consequence of acute or chronic bacterial infections of the respiratory tract. Although many pathogenic variants have already been described in XLA, the heterogeneous clinical presentations in affected patients suggest a more complex genetic landscape underlying this disorder. We report two pediatric cases from male siblings with X-Linked Agammaglobulinemia and bronchiolitis obliterans, a phenotype not often observed in XLA phenotype. The whole-exome sequencing (WES) analysis showed a rare hemizygous missense variant NM_000061.2(BTK):c.1751G>A (p.Gly584Glu) BTK gene in both patients. We also identified a gain-of-function mutation in TGFB1 (rs1800471) previously associated with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. TGFB1 plays a key role in the regulation of immune processes and inflammatory response associated with pulmonary impairment.