Genetic diversity in pediatric patients with inborn errors of immunity in Russia

To date, about 500 genetic defects are known to cause clinical manifestations of immunodeficiency. Genetic diagnosis is necessary to guide the management of patients with inborn errors of immunity (IEI) and plays an important role in genetic counselling of families. To find the genetic cause of IEI, 2395 probands were tested, in 1507 (65.7%) of them we identified 164 forms of IEI with defects in 143 single genes and abnormalities in 8 chromosomes. The majority of IEIs (89.1%) were monogenic, with 98.6% of them being of germline origin. Only 10.6% of IEIs were due to large chromosomal breaks. The most common monogenic forms of IEI with a confirmed genetic defect are Wiskott–Aldrich syndrome, X-linked chronic granulomatous disease, X-linked agammaglobulinemia, Nijmegen syndrome, hereditary angioedema types 1 and 2, ataxia-telangiectasia, Schwachman–Diamond syndrome, severe congenital neutropenia, X-linked severe combined immunodeficiency. Among IEIs associated with chromosomal abnormalities, del22.q11.2 syndrome (DiGeorge syndrome) predominates. These 10 forms of IEI were detected in 51% (775/1507) of all the probands with a confirmed genetic diagnosis. In our study, 6.4% (96/1507) of the probands had unique IEIs: a total of 80 different IEI entities associated with defects in 73 genes and 6 chromosomes (each entity affecting 1 or 2 patients). The majority of them were autosomal recessive IEIs (65%), 30% were autosomal dominant, and only 5% of the cases were X-linked. In addition, polygenic IEIs were identified in 0.3% of the probands and somatic mutations in wellknown genes (NRAS, KRAS, FAS, NLRP3) led to IEI in 0.9% of the probands. The frequency of familial cases among the probands with a confirmed genetic diagnosis was 9.6% (145/1507). Understanding the mechanisms of occurrence and inheritance of IEI in the heterogeneous Russian population will play an important role in the development of diagnostic and therapeutic strategies for patients and their families. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. Informed consent for genetic testing and for the publication of its results was obtained from the patients and/or from at least one parent of a child under the age of consent.