A novel mutation in SLC39A7 identified in a patient with autosomal recessive agammaglobulinemia

Abstract

A novel mutation in SLC39A7 identified in a patient with autosomal recessive agammaglobulinemia To the Editor, ZIP7 deficiency is the most recently described congenital agammaglobulinemia with autosomal recessive inheritance (1). ZIP7, encoded by SLC39A7, is an endoplasmic reticulum-to-cytoplasm Zn 2+ transporter. Developing B cells are sensitive to altered Zn 2+ distribution which cause developmental blockade beyond the pre-B cell stage (2). Complete loss of ZIP7 in cell lines causes a reduction in cytoplasmic Zn 2+ and an increase in endoplasmic reticulum Zn 2+ concentration. Since the original report in 2019, no additional cases of ZIP7 deficiency have been published. Here we describe a patient evaluated for recurrent respiratory tract infections, meningitis, agammaglobulinemia and B cell lymphopenia, ultimately found to carry a novel SLC39A7 variant. We describe his clinical characteristics, immunological findings, and genetic investigations.The patient and his family members were interviewed, examined, treated and monitored at the University Clinic for Children's Disease in Skopje. Medical records were obtained from the electronic registry of the University Clinic. The mother of the patient has given written informed consent to conduct the study and for publication of data. All procedures were performed in accordance with the ethical standards of the Institutional Research Committee. Genomic DNA from the patient and his family members was isolated with the Gen Elute Blood Genomic DNA kit (Sigma-Aldrich) and subjected to whole-exome sequencing (WES) in the patient and targeted gene sequencing in the patient and available family members (3). WES was performed at the New York Genome Center and the Rockefeller University using an Illumina HiSeq 2500 sequencing system (Illumina). Exome capture was carried out with SureSelect human all exome kit (Agilent) in accordance with the manufacturer's instructions. Putative disease alleles found by WES were validated by dideoxy Sanger sequencing in the patient as well as in family members.Exons and flanking intronic regions of SLC39A7 were amplified by PCR. Amplicons were sequenced with the Big Dye Terminator cycle sequencing kit (Applied Biosystems) and targeted regions were analyzed by an ABI 3130 capillary sequencer (Applied Biosystems). Sequence variants were determined by comparing to the appropriate GenBank reference sequence to identify the position of mutations.The patient, a 14-year-old male and the third child in a Macedonian family with Albanian origin was born at term (Fig. 1). Birth weight and length were in the normal ranges and neonatal adaptation was uneventful. Consanguinity in the family was not reported. The patient received only BCG vaccination at birth indicated by a small scar on the left shoulder. He had suffered from recurrent upper and lower respiratory

Care of patients with inborn errors of immunity in thirty J Project countries between 2004 and 2021

“…Thus, taken 10 countries (with the exception of Bosnia & Herzegovina, Montenegro and Kosovo), the cumulative number of patients increased from max 100 to 5307 by the end of 2021 (Figure 1). A conceptual IEI-focused professional meeting series was started in 2004 and reached measurable results even in countries with low socioeconomic conditions including the Rep. of Moldova, Rep. of North Macedonia, Albania, and Kosovo (11,25,26). Over the past 18 years, 344 IEI-focused conferences were organized (Supplementary Table 1 and Figure 2A).…”

“…Altogether, 24,879 patients with various IEIs were reported (Table 1, Figure 3 and Supplementary Figure 3). Classification was made according to (11,524; 46,32%) followed by patients with combined immunodeficiencies with associated or syndromic feature (3,561; 14,31%). The percentages of patients with bone marrow failure and phenocopies of IEI were less than 1% each, respectively.…”

“…More than 450 IEIs have been described but many of them only in a few patients and families and data were obtained mostly from mice studies (7)(8)(9)(10)(11). Limitations to publish rare IEI cases in medical journals hamper the accumulation of substantial amount of clinical data.…”