International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity

Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.

The new disorders (since 2015 [3]) represent an impressive spectrum of phenotypes. There are 354 distinct disorders with 344 different gene defects listed. The emerging dominance of next-generation sequencing has driven the rapid increase in the number of recognized disorders which has led to two major consequences. Often new inborn errors of immunity are initially described in a single kindred or a small number of kindreds. This may lead to incorrect assumptions about prevalence and phenotype. In fact, for most disorders, we have little idea of the prevalence within even the recognized population with the described phenotype. The second consequence of the rapid rise of nextgeneration sequencing is a striking expansion of the phenotypic spectrum associated with many diseases. Where once Fig. 1 Each publication of the World Health Organization and IUIS Primary Immunodeficiencies Committee was reviewed for the number of conditions listed and displayed graphically [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. The rapid increase in the twenty-first century relates to improved awareness and increasing use of sequencing. Assuming 20,000 coding genes in the human genome, inborn errors of immunity are implicated through mutations in 1.7% of these genes. There are now 330 specific disorders, 320 monogenic defects, 312 distinct genes (nine genes with both LOF and GOF and C4 deficiency requiring defects in both C4A and C4B). a The categorization of the inborn errors of immunity according the schema in the current manuscript. b The categorization of the inborn errors of immunity according to their inheritance

Introduction
In 1970, Drs. Fudenberg, Good, Hitzig, Kunkel, Roitt, Rosen, Rowe, Seligmann, and Soothill met under the auspices of the World Health Organization to classify the emerging "primary immune deficiencies." This august group focused on understanding whether immunodeficiencies could be categorized as B cell disorders or T cell disorders [1,2]. Their initial report identified 16 distinct immunodeficiencies and included the prophetic comment that "the variable immunodeficiency group probably lumps together a series of syndromes…. Included in this group are cases previously classified as 'congenital', non-sex linked or sporadic hypogammaglobulinemia, primary 'dysgammglobulinemia' of both childhood and adult life, and 'acquired' primary hypogammaglobulinemia. It is hoped that careful analysis of such patients…. will result in delineation of several homogeneous syndromes…". Indeed, the emergence of monogenic causes of hypogammaglobulinemia (Table 3) and disorders with variable immunoglobulin abnormalities associated with immune dysregulation (Table 4) have been the groups of immunodeficiencies most transformed by the advent of new technologies. Another group dramatically impacted by resetting of the clinical radar and new techniques has been the set of disorders associated with a limited spectrum of infectious susceptibility. The graphs in Fig. 1 define the transformation of the field over the interval during which next-generation sequencing came to prominence. The tremendous progress, energy, and enthusiasm in the field currently have led to a greater need than ever for a current cataloging of the disorders. "leaky" SCID, or still less profound combined immunodeficiency (CID) phenotypes. Both OS and leaky SCID can be associated with > 300 autologous T cells/μL of peripheral blood and reduced, rather than absent, proliferative responses when compared with typical SCID caused by null mutations. A spectrum of clinical findings including typical SCID, OS, leaky SCID, CID, granulomas with T lymphopenia, autoimmunity and CD4 T lymphopenia can be found in an allelic series of RAG1 and other SCID-associated genes. Total number of disorders in        Autoimmune cytopenias, enteropathy, interstitial lung disease,  Total number of disorders in Table 5: 39. New disorders: 9, WDR1, CFTR, SMARCD2, JAGN1, HYOU1, MKL1, DNAJC21, G6PD, CSF2RB. Removed: cyclic neutropenia was merged with elastase deficiency MDS myelodysplastic syndrome, IUGR intrauterine growth retardation, LAD leukocyte adhesion deficiency, AML acute myelogenous leukemia, CMML chronic myelomonocytic leukemia, N neutrophil, M monocyte, MEL melanocyte, L lymphocyte, NK natural killer, XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, GOF gain-of-function   Total number of disorders in Table 8: 30. New disorders: 1, CD55 MAC membrane attack complex, SLE systemic lupus erythematosus, XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, LOF loss-of-function, GOF gainof-function the phenotype of a given disorder was clear, the spectrum of manifestations often extends impressively once the ascertainment is not linked to a preconceived idea [20]. As a community, we recognize the importance of publishing cases and small series and to report specific mutations with clinical findings because publications are used to define likelihood of causality during bioinformatic analysis of next-generation sequencing results.
In 1999, the Committee on Primary Immunodeficiencies came under the auspices of the International Union of Immunological Societies (IUIS). The current committee met on February 23-24, 2017, in London to update the classification of human primary immunodeficiencies. Inclusion in this "master list" requires a body of literature supporting causality of a gene defect and a penetrance indicating clinical relevance [21]. Committee members vote on inclusion of each new disorder and this publications lists those included as of the February 2017 meeting. The landscape is changing so rapidly, and the number of primary immunodeficiencies growing so fast, that two major changes have been implemented. The published list will continue to serve as a reference; however, this list will now be available as a csv file on the IUIS website to enable sorting according to gene, disease name, or clinical/ laboratory feature. This file will also include the associated ICD10 codes in order to promote harmonization of utilization. The second major change is to the nomenclature. The term primary immunodeficiency has an important legacy-the abbreviations PID or PIDD are often used by patient organizations and are recognized around the world. However, this terminology does limit the conceptualization of disorders to those in which susceptibility to infection is the main manifestation. The improving recognition of immune dysregulation diseases, including the growing field of autoinflammatory disorders and interferonopathies, has mandated that a more encompassing terminology be used. This manuscript, therefore, utilizes "inborn errors of immunity" as the descriptor for the work and the categorization. In addition to embracing technology to remain updated, the companion publication "Update of the Phenotypical IUIS Classification for Primary Immunodeficiencies" will provide a phenotype-oriented approach to the IUIS categorization of disorders. Moreover, a new free application can be found as "PID phenotypical diagnosis" or "PID classification" from iTunes and Android app stores [22,23]. Information that is readily accessible is the new standard, and the IUIS Expert Committee on Primary Immunodeficiencies believes that improved access to information will positively impact patient care around the world.
The tables divide disease categories according to common phenotypes for ease of review and searching. Table 1 lists combined immunodeficiencies, Table 2 lists combined immunodeficiencies with syndromic features, Table 3 lists predominantly antibody deficiencies, Table 4 lists diseases of immune dysregulation, Table 5 lists defects of phagocyte number or function, Table 6 lists defects in intrinsic and innate immunity, Table 7 lists autoinflammatory diseases, Table 8 lists complement deficiencies, and Table 9 lists phenocopies of inborn errors of immunity. The division into phenotypes for the purpose of this list does not imply that the presentation is homogeneous. Each disorder is listed only once for the sake of simplicity although distinct modes of inheritance can be listed separately. There are nine genes for which both loss-of-function and gain-of-function variants have been identified: CFB, C3, CARD11, STAT1, STAT3, WAS, JAK1, IFIH1, and ZAP70. For these, the loss-of-function and gain-of-function aspects are listed. Within each table, there are additional sub-tables that segregate into coherent phenotypic sets. At the end of each table, the new disorders, added for this publication, are listed for easy reference. Other features important for navigation of the list include the use of OMIM links [24]. For additional information on a gene, the links can be accessed from within the online publication. For the second time, we also include non-inborn errors of immunity in Table 9, representing phenocopies of inborn errors which might be important to consider diagnostically.
The goal of the IUIS Expert Committee on Primary Immunodeficiencies is to increase awareness, facilitate recognition, promote optimal treatment, and support research in the field of immune deficiency disorders. Thus, the "IUIS PID Committee Report on Inborn Errors of Immunity" and "Update of the Phenotypical IUIS Classification for Primary Immunodeficiencies" publications are important resources for clinicians and researchers. In addition, these tables form the basis of lists used for sequencing panels and are used to monitor health utilization which will influence health services funding by federal or state governments and/or insurance companies in various global settings. The addition of ICD10 codes for the online version will promote a harmonization between the diagnostic tables and coding items that will facilitate bioinformatics research going forward.