RESUMEN
Primary immune deficiencies are usually attributed to genetic defects and, therefore, frequently referred to as inborn errors of immunity (IEI). We subjected the genomic DNA of 333 patients with clinical signs of IEI to next generation sequencing (NGS) analysis of 344 immunity-related genes and, in some instances, additional genetic techniques. Genetic causes of the disease were identified in 69/333 (21%) of subjects, including 11/18 (61%) of children with syndrome-associated IEIs, 45/202 (22%) of nonsyndromic patients with Jeffrey Modell Foundation (JMF) warning signs, 9/56 (16%) of subjects with periodic fever, 3/30 (10%) of cases of autoimmune cytopenia, 1/21 (5%) of patients with unusually severe infections and 0/6 (0%) of individuals with isolated elevation of IgE level. There were unusual clinical observations: twins with severe immunodeficiency carried a de novo CHARGE syndrome-associated SEMA3E c.2108C>T (p.S703L) allele; however, they lacked clinical features of CHARGE syndrome. Additionally, there were genetically proven instances of Netherton syndrome, Х-linked agammaglobulinemia, severe combined immune deficiency (SCID), IPEX and APECED syndromes, among others. Some patients carried recurrent pathogenic alleles, such as AIRE c.769C>T (p.R257*), NBN c.657del5, DCLRE1C c.103C>G (p.H35D), NLRP12 c.1054C>T (p.R352C) and c.910C>T (p.H304Y). NGS is a powerful tool for high-throughput examination of patients with malfunction of immunity.
Asunto(s)
Agammaglobulinemia/genética , Síndrome CHARGE/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades de Inmunodeficiencia Primaria/genética , Inmunodeficiencia Combinada Grave/genética , Adolescente , Agammaglobulinemia/inmunología , Agammaglobulinemia/patología , Síndrome CHARGE/inmunología , Síndrome CHARGE/patología , Niño , Preescolar , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Endonucleasas/deficiencia , Endonucleasas/genética , Endonucleasas/inmunología , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Enfermedades de Inmunodeficiencia Primaria/inmunología , Enfermedades de Inmunodeficiencia Primaria/patología , Federación de Rusia/epidemiología , Semaforinas/genética , Semaforinas/inmunología , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/patología , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Proteína AIRERESUMEN
BACKGROUND: X-linked lymphoproliferative disease type I (XLP I) is caused by mutations in the SH2D1A gene and characterized mainly by hypogammaglobulinemia and abnormal response to Epstein-Barr virus with a high predisposition to B-cell non-Hodgkin lymphoma development. OBSERVATIONS: In this article, we describe the experience of 2 centers in Belarus and in Russia that follow 3 male patients who were diagnosed with XLP I after lymphoma development and treatment. Three novel mutations c.51G>C (p.E17D), c.192G>T (p.W64C), and c.53insA (p.K18KfsX67) were found in 3 males patients with XLP I. Two of them did not have any signs of immunodeficiency before B-cell non-Hodgkin lymphoma development. CONCLUSIONS: We propose SH2D1A mutational screening be considered in male patients with or without hypogammaglobulinemia who received rituximab treatment for lymphoma and did not recover immunoglobulin G in a year after B-depleting therapy.