Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification

Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI.


Introduction
Human inborn errors of immunity (IEI) are caused by monogenic germline mutations resulting in loss or gain of function of the encoded protein. They can be dominant or recessive, autosomal or X-linked, and with complete or incomplete penetrance. They manifest as increased susceptibility to a broad or narrow spectrum of infectious diseases, as well as a growing diversity of autoimmune, autoinflammatory, allergic, and/or malignant phenotypes. They now comprise 406 distinct disorders with 430 different gene defects listed in the 2019 International Union of Immunological Societies (IUIS) classical classification [1]. If most IEI are individually rare, they are collectively more common than generally thought [2].
The (IUIS) expert committee on IEI proposes every other year a genotypic classification of all these disorders [1], which facilitates both research on, and diagnosis of, these conditions worldwide. This classification is organized in ten tables, each of which groups IEI sharing a given pathogenesis. However, with the growing number of IEI included in this catalog, these tables are not always easy to use at the bedside. We thus reported from 2013 onward a more user-friendly classification adapted for the clinician, based on the clinical and laboratory features observed in these patients. This phenotypic classification proved to be as popular as the genotypic classification (15 k vs 12 k downloads on publisher site) [3] and has been adapted in a smartphone application [4].
Here, we present an update of the phenotypic classification of IEI, based on the 2019 IEI classical classification [1]. This tree-based decision-making process is aimed to physicians, regardless of their familiarity with IEI. It aims at helping them to reach a diagnosis based on simple clinical and biological phenotypes.

Methodology
We included in our figures all disorders indexed in the 2019 update of the IUIS IEI classification [1]. A phenotypic algorithm was assigned to each of the ten main groups of the classification and the same color was used for each group of similar conditions. Given the high number of diseases, several categories have been split since last update [3] in two sub-figures to be more informative.
Disease names are presented in red and genes in bold italic. An asterisk is added to highlight extremely rare disorders (less than 10 reported cases to date). However, the reader should keep in mind that some genes have been very recently described and that true prevalence is unknown. A double asterisk is added when only one case or one kindred has been reported to date. In these cases, it is difficult to confirm than observed phenotype would be reproducible in other patients carrying the same defect, or if it is an exception.

Discussion
These algorithms are aimed to guide clinicians to diagnose patients presenting typical phenotype. However, readers should be aware of the limitations of such a work.
More and more reports show a spectrum of atypical presentations related to hypomorphic mutations of those genes. Omenn syndrome (OMIM #603554) is a good example of such an atypical presentation, as well as "leaky SCID" and RAG deficiency spectrum [5].
Moreover, readers should be extremely cautious with descriptions of disease when only one patient or kindred have been reported. We are aware that these reports may not reflect the typical phenotype of such defects, but the exception; however, we thought that it was needed to be mentioned in these classifications. Jacobsen Sd. 11q23del. Recurrent

MSH6*. MSH6 .
Family or personal history of cancer. Variable IgG, defects, increased IgM in some, Nl Bc, low switched memory Bc.

Isotype, Light Chain, or FuncƟonal Deficiencies with Generally Nl Numbers of Bc
Ig heavy chain mutaƟons and deleƟons.

MutaƟon or chromosomal deleƟon at 14q32.
May be asymptomaƟc. One or more IgG and/or IgA subclasses as well as IgE may be absent.
AsymptomaƟc. All immunoglobulins have lambda light chain.

Isolated IgG subclass deficiency. Unknown.
Usually asymptomaƟc, a minority may have poor anƟbody response to specific anƟgens and recurrent viral/bacterial infecƟons. ReducƟon in one or more IgG subclass.
IgG subclass deficiency with IgA deficiency. Unknown.

Recurrent bacterial infecƟons. May be asymptomaƟc. Reduced
IgA with decrease in one or more IgG subclass.
May be asymptomaƟc. Bacterial infecƟons, autoimmunity mildly increased. Very low to absent IgA with other isotypes normal, normal subclasses and specific anƟbodies.

Specific anƟbody deficiency with normal Ig levels and normal B cells. Unknown.
Reduced ability to produce anƟbodies to specific anƟgens. Ig: Nl.
Usually not associated with significant infecƟons, normal ability to produce anƟbodies to vaccine anƟgens. IgG and IgA decreased.

LAD III FERMT3
Severe bacterial infections and severe bleeding disorder. Platelet aggregation assay.

Conclusion
This phenotypic classification of IEI forms a diagnostic resource, aimed to complement the 2019 IUIS genotypic classification. These figures serve as diagnostic orientation tools for patients with any of the typical phenotypic presentations of IEI, whether clinical or biological. They were designed for, and will hopefully be useful to physicians and biologists who are not experts in the field of IEI. We hope that these figures can help them reach a diagnosis of IEI when encountering patients whose clinical or biological phenotypes are evocative of IEI.

Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of interest.
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