A chromosomal deletion leading to BACH2 haploinsufficiency, hypogammaglobulinemia and recurrent infections without intestinal inflammation or autoimmunity

Abstract

Afzali et al. described 3 patients with heterozygous point mutations in the transcription factor BACH2, characterized by lymphocyte maturation defects, immunoglobulin deficiency and intestinal inflammation secondary to BACH2-related immunodeficiency and autoimmunity (BRIDA). Molecular testing suggested these mutations lead to disruption of protein stability. Mice with heterozygous Bach2 deficiency display similar lymphocyte defects, supporting that the disease-mechanism was BACH2 haploinsufficiency. We present a patient with recurrent infections and hypogammaglobulinemia with heterozygous chromosome 6 deletion encompassing the BACH2 gene, in absence of gastrointestinal or rheumatologic manifestations.A 3-year old boy with developmental delay, corpus callosum dysgenesis, dextrocardia, renal pyelectasis, abnormal ear canal shape and congenital hypotonia presented to immunology clinic for evaluation of recurrent infections. In his first 18 months he was isolated, but subsequently developed notable respiratory infections in daycare. Genetic testing identified a chromosome 6 deletion of 8.18Mb (6q14.3-q16); chr6:85227585-93409505, likely de novo, given no affected family members and mother’s chromosomal analysis revealed no translocation. Research WES showed no other variants of interest. 7 known disease genes lie within this region (Figure 1). MAP3K7 and TBX18 deletion were thought to explain the developmental and cardiac phenotypes.Table 1. (abstract: 96)Selected laboratory test results. Values below or above reference are indicated with blue and red respectively. Not shown: IL-2, IL-4, IL-5, IL-8, IL-12, IL-13, IL-17 were normal. Fecal blood testing at baseline was negative. T cell memory population percentages were normal. T cell proliferation studies were normal. Pre-SCIG = pre-subcutaneous IgG (SCIG) treatment. Post SCIG = post-SCIG treatment sample obtained after ~ 4 months of SCIG. n/a = sample not available.ParameterValue pre-SCIGValue post-SCIG UnitWBC19.6810.15 K cells/ulHgb12.211.9 K cells/ulPlatelet274279 K cells/ulANC13.114.05 K cells/ulALC4.724.98 K cells/ulIgG459871 mg/dLIgA4946 mg/dLIgM4039 mg/dLIgE7866 unit/mLC3n/a116 mg/dLC4n/a18 mg/dLC-reactive protein (CRP)0.4<0.06 mg/dLErythrocyte Secimentation Rate (ESR)101 mm/hrsIL2R27411154.1 pg/mLIFN-gamma<4.2<4.2 pg/mLIL-1020.13.6 pg/mLIL-68.4<2.0 pg/mLIL-1beta<6.5<6.5 pg/mLTNF-alpha2.3<1.7 pg/mLTotal T cells (CD3+)29543566 cells/ulCD4+ T cells (CD3+CD4+)19302229 cells/ulCD8+ T Cells (CD3+CD8+)9081167 cells/ulB cells (CD19+)10681051 cells/ulNK cells (CD3-/CD16+ or CD56+)751188 cells/ulNaïve CD4+ (CD45RA+CCR7+)83.774.1 %Naïve CD8+ (CD45RA+CCR7+)77.376 %Treg (CD4+ CD25hiCD127lo)5.68.8 %Naïve B cells (IgD+CD27-)88.4n/a %Unswitchedmem B cells (IgD+CD27+)4n/a %Switched mem B cells (IgD-CD27+)4.2n/a %Transitional B cells (CD24hiCD38hi)31.527.2 %Marginal Zone-like B cells (CD24hiCD38lo)614.5 %CD 19+CD21loCD38lo B cells2.81.6 %Plasmablasts (CD24loCD38hi)0.90.6 %Fecal calprotectin30n/a mcg/gFecal lactoferrinnegn/a mcg/mL [Display omitted] We assessed the impact of heterozygous BACH2 deletion on his immunophenotype. Detailed in Table 1, laboratory findings partially consistent with published BACH2 patients were hypogammaglobulinemia, decreased “Treg”% (CD25hiCD127lo, Foxp3 expression pending) and elevated transitional B cells. Contrary to patients previously described, he had no decreased memory B cells and had normal T cell proliferation. Prior patients had intestinal inflammation and one was ANCA+. Our patient’s cytokine panel showed mild elevations in sIL2R, IL-10 and IL-6, which resolved after SCIG initiation. Stool inflammatory markers were normal and evaluation by gastroenterology and rheumatology was reassuring. Of note, our patient is significantly younger than published patients, thus autoimmunity could develop with time. The frequency of patient’s infections improved since initiation of SCIG.In summary, we describe the first patient with immunodeficiency and clear BACH2 haploinsufficiency due to a chromosomal deletion, with recurrent infections and hypogammaglobulinemia in absence of intestinal inflammation or autoimmunity to date. He exhibits partially overlapping immunophenotype compared to described patients with BACH2 point mutations.