A novel confirmed humoral immunodeficiency associated with <i>QARS1</i> mutation

Introduction: QARS1 (OMIM #615760) encodes glutaminyl-tRNA synthetase, an enzyme involved in normal brain development. Patients with QARS1 mutations typically present with the classical triad of early-onset epilepsy, progressive microcephaly, and developmental delay. More than 25 patients have been described in the literature, and none have been reported to have associated inborn errors of immunity. Herein, we describe two siblings with QARS1 mutations who exhibited confirmed humoral immunodeficiency, characterized by recurrent infections, hypogammaglobulinemia, and poor specific antibody responses. Aim: To describe the associated clinical and laboratory evidence of humoral immunodeficiency in patients with QARS1 mutations. Results: Patients’ charts were reviewed. The first patient is a 10-year-old boy who was born to nonconsanguineous parents. At 9 months of age, he developed intractable seizures, leading to profound developmental delay and hypotonia. Whole exome sequencing revealed a pathogenic homozygous variant in QARS1, c.1058G&gt;T p.(Gly353Val). At 9 years of age, he was admitted to the pediatric intensive care unit with septic shock and multi-organ failure secondary to influenza A infection. Investigations showed low IgG level and poor tetanus-specific antibody response despite optimized vaccination. The second patient is a 5-year-old boy and the younger sibling of the proband. Shortly after his birth, Sanger sequencing confirmed the same homozygous QARS1 variant. At 4 months of age, he developed his first seizure and was started on antiseizure medications. At 45 months of age, he was hospitalized due to EBV-associated lymphadenopathy, EBV viremia, and cellulitis caused by Methicillin-Resistant Staphylococcus aureus (MRSA). Immunological assessment revealed persistently low tetanus-specific antibody response despite booster vaccinations. To rule out known genetic causes of humoral immunodeficiency, whole genome sequencing was performed and identified only the previously known QARS1 variant. Discussion: The published literature on QARS1 mutations has not reported associated immunodeficiency or included immunological evaluations in affected patients. To the best of our knowledge, this paper is the first to examine immunological symptoms in patients with QARS1 mutations and highlight clinically significant hypogammaglobulinemia. Both patients showed significant clinical improvement and maintained adequate trough IgG levels on SCIG. We believe that our study emphasizes the importance of thorough immune system evaluation in patients with QARS1 mutations, as early intervention reduces morbidity and mortality and improves quality of life. Statement of novelty: We report two patients with a pathogenic QARS1 mutation who presented with a novel manifestation of humoral immunodeficiency.