This report provides an updated classification of inborn errors of immunity (IEIs) involving 508 different genes and 17 phenocopies. Of these, we report 67 novel monogenic defects and 2 phenocopies due to neutralizing anti-cytokine autoantibodies or somatic mutations, which either have been discovered since the previous update (published June 2022) or were reported earlier but have been recently confirmed and/or expanded. The new additions were made after rigorous review of new genetic descriptions of IEIs by the International Union of Immunological Societies (IUIS) Expert Committee using criteria established to define IEI. Although similar pathogenic variants in one gene, in terms of both classes of mutation (missense, nonsense, etc.) and impact on protein function, can result in a spectrum of phenotypic manifestations, they are herein classified according to the most consistently reported phenotype. In addition, because different variants in a single gene can result in recognizable diseases due to gain or loss of function, such cases are classified according to their clinical manifestations as a distinct entry in the same or a different table depending on the associated phenotype. This report will serve as a valuable resource for clinical immunologists and geneticists involved in the molecular diagnosis of individuals with heritable and acquired immunological disorders. Moreover, we expect this report to also serve as a valuable resource for all disciplines of medicine, since patients with IEIs may be first seen by rheumatologists, hematologists, allergists, dermatologists, neurologists, gastroenterologists, and pulmonologists, depending upon their spectrum of presenting clinical features. Finally, expanding the known monogenic and related causes of human immune diseases requires dissection of underlying cellular and molecular mechanisms, which reveals fundamental requirements for specific genes, pathways, processes, and even cell types. Such knowledge may not only contribute to improved patient diagnosis and management but also pave the way to the development and implementation of therapies that target the cause—rather than the symptoms—of these conditions.
Introduction
Inborn errors of immunity (IEIs) are, by definition, caused by damaging germline variants in single genes. IEIs present clinically as increased susceptibility to infections, autoimmunity, autoinflammation, allergy, bone marrow failure, and/or malignancy. Although individual IEIs are rare, collectively IEIs are not, and they represent a significant health burden (1). Indeed, a recent study reported that the incidence of IEIs in the USA was 6 per 10,000 people (2). Genetic variants underlie IEI by altering the encoded gene product, such as abolition (null) or reduction (hypomorphic) of protein expression, titration of the intrinsic function of the protein (gain of function [GOF] or loss of function [LOF]), or acquiring novel functions (neomorphic) (3, 4). Mechanisms of disease in IEIs depend on the nature of the variant and mode of inheritance. Thus, monoallelic variants can cause disease by haploinsufficiency, negative dominance, or GOF. In contrast, biallelic genetic lesions (homozygous, compound heterozygous) cause autosomal recessive (AR) traits by loss of expression, LOF, GOF, or neomorphic function of the encoded protein. X-linked recessive traits arise from LOF or GOF variants on the X chromosome, either in hemizygosity in males or in a homozygous state in females.
The careful genetic dissection and functional study of individual IEIs has aided in confirming or contrasting the knowledge obtained from mouse models or has offered novel insights on protein function within different immune pathways and specific immune cells (5, 6). Thus, by linking defined monogenic defects with clinical phenotypes of immune dysregulation, IEIs represent elegant models of the human immune system and have thus been referred to as “experiments of nature” (7). IEIs have also revealed mechanisms of disease pathogenesis and enabled the implementation of gene- or pathway-specific therapies for the treatment of rare and common conditions and established fundamental aspects of human immunology (8, 9, 10). Thus, the study of IEIs has driven profound advances in molecular medicine and human biology.
Since 1970, an international expert committee comprising pediatric and adult clinical immunologists, clinician/scientists, and researchers in basic immunology—initially under the auspices of the World Health Organization and currently the International Union of Immunological Societies (IUIS)—has provided the clinical and research communities with an update of genetic causes of immune deficiency and dysregulation (https://iuis.org/committees/iei/).
IEIs are currently categorized into 10 tables, with subtables segregating groups of disorders into overlapping phenotypes. These tables describe combined immunodeficiencies (Table 1; 3 subtables); combined immunodeficiencies with syndromic features (Table 2; 9 subtables); predominantly antibody deficiencies (Table 3; 3 subtables); diseases of immune dysregulation (Table 4; 7 subtables); congenital defects of phagocytes (Table 5; 4 subtables); defects in intrinsic and innate immunity (Table 6; 9 subtables); autoinflammatory diseases (Table 7; 3 subtables); complement deficiencies (Table 8); bone marrow failure (Table 9); and phenocopies of IEIs (Table 10) (Fig. 1, A and B) (4).
The committee strives to publish an updated report every 2 years to consolidate advances and catalog current IEIs (4). A large array of genetic variants related to IEI has been reported recently. Rather than including every candidate gene published in the peer-reviewed scientific literature, the committee applies stringent criteria to classify gene defects as novel causes of IEIs (11). These criteria include the following:
- (1)
The candidate genotype is monogenic and is not found in individuals without the clinical phenotype (recognizing that some conditions have incomplete penetrance).
- (2)
Experimental studies establish that the genetic variant impairs, destroys, or alters expression or function of the gene product.
- (3)
The causal relationship between the candidate genotype and the clinical phenotype must be confirmed via a relevant cellular phenotype, including—where possible—rescue of a functional defect (11).
These criteria can be met by the publication of multiple cases from unrelated families, including detailed immunological data; or publication of very few—even single—cases with compelling mechanistic data, often revealed from complementary studies in animal or cell culture models. With the number of genes and conditions growing, the committee also considers it essential that the immunological phenotype is described in-depth beyond the clinical phenotype. We also considered whether sufficient justification was provided to exclude alternative candidate gene variants identified in single cases, the depth of the clinical descriptions of the affected individuals, and the level of immune and functional characterization. It is important to consider that for specific diseases, even though at this point they fulfill the criteria to be included in these tables, building evidence may argue against disease causality. Indeed, stringent criteria are being developed to remove certain genes or inheritance modes from this list in the future.
This 2024 IUIS IEI update is intended as a follow-up resource for clinicians and researchers, and it can guide the design of panels used for targeted gene sequencing to facilitate clinical genetic diagnoses of IEI. Here, we summarize data on the genetic cause of 67 novel IEIs, and 2 phenocopies of IEI due to either autoantibodies (n = 1) or somatic mutations (n = 1), that have been assessed since the previous update (12). This increases the number of genes associated with IEI to 508, causing 559 conditions (Fig. 1 A). This includes four chromosomal deletion syndromes (22q11.2 deletion syndrome [DS], chromosome 11q DS, 10p13-p14DS [Table 2, subtables 3 and 9], and 14q 32 DS [Table 2, subtable 4]), as well as KRAS, NRAS, and UBA1, for which disease is only described due to somatic variants (Table 10). Given the rapid pace of discovery, the current update will likely be outdated by the time of its publication.
One gene, several phenotypes
For this update, IEIs are classified according to the predominant clinical presentation. However, patients with pathogenic mutations in specific IEI-associated genes may have clinical presentations that differ from the predominant clinical presentation under which they have been classified in this document, thereby expanding the phenotypic spectrum of disease. In this regard, some previously reported genes and IEIs have been reclassified into a different table after panel discussion. Nevertheless, it is important to stress that the disease-causing effect of a genetic variant cannot be excluded solely because the description of the classic phenotype in this table does not fit with the clinical presentation of a given patient. Indeed, the presenting phenotype of many IEIs is gradually expanding and this must be taken into careful consideration. One example of this is mutations in the WD40 domain of COPA causing COPA syndrome with arthritis and alveolar hemorrhages as the main clinical manifestations (13). However, patients with mutations in the C-terminal domain can have a wide spectrum of clinical manifestations including autoimmunity and neuroinflammation (14). It is therefore challenging to exclude pathogenicity of a novel variant, even if the phenotype is not typical for the described gene defect as the mechanism of disease and phenotype may differ based on the location of the variant. Furthermore, several IEIs may have incomplete penetrance (i.e., JAK1 GOF, PLCG2 LOF, NLRC4 GOF, PTPN2, among others) increasing complexity of genomic analysis, given that diseased individuals may have healthy family members carrying the same variant. Different factors may contribute to incomplete penetrance, and these are still not fully understood. Monoallelic expression has recently been identified as an important contributor to incomplete penetrance and should be taken into consideration (15).
Redefining or broadening of the clinical phenotype can also occur simply by the description of additional patients. Examples include AR MYD88 and IRAK4 deficiencies, which have been associated with susceptibility to invasive pyogenic bacterial infections, but recently have been found to cause severe viral infections (including coronaviruses and influenza) in some affected individuals (16). Alternatively, gene dose can impact disease phenotype and severity, in diseases that are classically described as AR disorders. An example of this phenomenon is mutations in RAG1, in which biallelic LOF mutations classically cause SCID, but patients with biallelic hypomorphic mutations can present later in life with combined immunodeficiency or milder immune dysregulation depending on residual RAG activity (17, 18). These findings challenge the assumption that IEIs are inevitably ultrarare and severe diseases affecting primarily children. Rather, they may include more common disorders that can present across the lifespan or even exclusively after exposure to specific microorganisms (19). Because of the expanding phenotypes, we have updated tables with less restrictive titles, and we foresee that current classifications will need to be reconsidered as the spectrum of disease associated with individual genes can be diverse and as several signaling pathways often illicit disease in a concerted action.
Clinically and phenotypically distinct IEI can arise due to variants in the same gene that have divergent molecular mechanisms such as LOF, GOF, and neomorphic or multimorphic function. Examples of this are mutations in IRF4, with one new entry causing AD combined immunodeficiency (Table 1, subtable 3) due to a mutation resulting in a neomorphic function (20) and two entries in Table 6, subtable 9, causing either Whipple disease by haploinsufficiency or antibody deficiency by another AD neomorphic variant (20, 21, 22). Similarly, CARD11 has three entries in three different tables as different inheritance patterns and pathogenic mechanisms lead to distinct phenotypes. OTULIN also appears three times—all in Table 7, subtable 3—due to distinct mechanisms of disease (heterozygous dominant negative or haploinsufficiency; AR LOF) that still manifest with similar clinical phenotypes. STAT1 and STAT3 have different entries in different tables because mutations in these genes lead to dramatically different phenotypes by GOF or LOF. This also emphasizes the crucial need to undertake in-depth in vitro functional validation of any novel variant considered to be potentially pathogenic. As a result, in this current update, >40 genes have more than one entry either in the same table or in different tables. Considering this complexity, counting IEI has become increasingly difficult. To improve clarity, for this version, we decided to count the number of monogenic IEI conditions and, separately, the number of genes causative of disease. If mutations in a gene cause disease with a similar phenotype yet follow an AR/AD inheritance pattern, they were counted as one condition (e.g., AD or AR LOF variants in AICDA, STAT1, or AIRE). If the diseases caused by a pathogenic variant in a single gene following AR/AD inheritance present as distinct phenotypes, they are counted as two different conditions (e.g., AD or AR variants in CARD11, PIK3R1; GOF or LOF variants in STAT1 or STAT3). With evolving genetic and pathophysiological insight, the number of IEI may change in the future as some conditions might be considered a spectrum of one disease rather than truly different conditions. As a result, comparing the numbers with previous versions would not be accurate as the criteria for counting are continuously evolving.
The discovery of novel IEI continues to demonstrate that distinct variants or zygosity in the same gene can cause disparate clinical conditions. In the current update, UNC93B1 is an example. Whereas AR UNC93B1 LOF was identified previously as an IEI underlying herpes simplex encephalitis, recent findings link heterozygous UNC93B1 GOF variants to childhood-onset systemic lupus erythematosus (SLE) (23, 24); furthermore, mouse models have revealed a gene dosage effect of Unc93b1 GOF variants (25).
Novel IEIs
Since the last update in 2022 (12), novel gene defects have been found for most categories of IEI, including novel causes of:
Combined immunodeficiencies: IRF4 (AD neomorphic); NFATC1, PRIM1, POLD3, NUDCD3 (AR LOF); and FOXI3, PSMB10 (AD LOF) (20, 26, 27, 28, 29, 30, 31, 32) (Table 1, subtable 1);
Combined immunodeficiencies with syndromic features: IKZF2 (dominant negative); GINS4, SLC19A1, SGPL1, FLT3L, ITPR3, RECQL4 (AR LOF); PTCRA (AR LOF/hypomorphic); SMAD3 (AD); and STAT6 (AD GOF) (33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47) (Table 2, subtable 1);
B-cell deficiencies, agammaglobulinemia or hypogammaglobulinemia PAX5, PI4KA, KARS1 (48, 49, 50) (all AR LOF; Table 3, subtable 1);
Immune dysregulation: CD274 (PDL1), CBLB, SH2B3, ARPC5, NFATC2, DOCK11, RHBDF2, LACC1, NBEAL2, IL27RA, TNFSF9, DPP9, GIMAP6 (AR LOF); ERN1, PTPN2 (AD LOF); TRAF3 (AD haploinsufficiency); and TLR7, UNC93B1, PLCG1 (AD GOF) (23, 25, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72) (Table 4, subtable 1);
Neutropenia: DBF4, SRP19, SRPRA, CCR2 (73, 74, 75) (all AR LOF; Table 5, subtable 1);
Innate immune defects resulting in susceptibility to mycobacterial/bacterial (IRF1, MCTS1 [76, 77]) and viral (OAS1, OAS2, RNASEL, RIPK3, MD2, TLR4, GTF3A, IKBKE [78, 79, 80, 81, 82, 83]) infections (all AR LOF; Table 6, subtable 1);
Autoimmune/autoinflammatory disorders: PMVK, SHARPIN, LSM11, RNU71 (AR LOF);ALPK1, ARF1 (AD LOF);OTULIN (two entries, both AD); RELA (DN); and STAT4, LYN (AD GOF) (84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94). Heterozygous LOF variants in RELA have been previously described as causing mucocutaneous inflammation and fever but are included as a new disease in this update as novel descriptions of DN mutations are associated with an inflammatory phenotype driven by TLR7 upregulation and enhanced secretion of interferons (Table 7, subtable 1). Specific c.61G>C variants in NLRP3 are noted to cause keratitis fugax hereditaria (95, 96);
Bone marrow failure: DCLRE1B, DUT, RAD50 (97, 98, 99) (all AR LOF; Table 9, subtable 1);
Phenocopies of IEI: a somatic variant in JAK1 (AD GOF) (100) and autoantibodies against IL-27 (68) (Table 10, subtable 1).
New entries for each table are shown in bold in the Tables below.
Phenocopies of known IEIs confirm critical pathways for immune function
Some of these novel genetic findings link common clinical phenotypes that converge on a shared pathway. Examples in this update include the following:
PRIM1 encodes the catalytic subunit of the DNA primase as part of the DNA polymerase complex that includes POLA1 and POLD, mutations in which are associated with immunodeficiency and distinct syndromic features. Biallelic mutations in PRIM1 cause primordial dwarfism characterized by growth retardation, microcephaly, and developmental delay with B-cell deficiency, but unlike patients with defects in POLA1 and POLD have normal T-cell numbers with conserved proliferation (28).
GINS4 is a component of the DNA replication machinery of mammalian cells and forms part of multimeric/multiprotein “replisome” complexes (101). Biallelic mutations in GINS4 result in a clinical phenocopy of AR deficiency of MCM10, MCM4, or GINS1 genes (34, 102, 103) that encode key proteins involved in DNA replication (101).
Description of AR PMVK deficiency, which functions upstream of MVK, confirms the pathogenic effect of disturbed mevalonate metabolism, resulting in an autoinflammatory disease (87).
Recently described NUDCD3 deficiency builds on the crucial role of RAG-mediated recombination, with pathologic sequestration of RAG1 in the nucleoli in the absence of NUDCD3 (31).
IEIs define specific roles for known genes and reveal immune-specific functions of novel genes
The description of patients with IEIs and study of the pathogenic mechanism of IEIs can demonstrate nonredundant and redundant functions of a specific gene in human immunity, and reveal similarities and differences between functions of specific genes in mouse and human immunology. Examples are as follows:
NUDCD3 was mostly known as a chaperone protein, with only hints at a potential role in the immune system through interactome studies. We have now learned that it plays a crucial role in optimal localization of RAG1 necessary for recombination of T-cell and B-cell antigen receptors (31).
Studies in mice have established that FLT3L functions as a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) (104, 105). The identification of three patients with AR FLT3L deficiency confirmed that FLT3L is also required for B-cell and DC development in humans. However, unlike mice, human FLT3L is required for the development of monocytes but not NK cells (41).
Study of patients with PTCRA variants taught us that, unexpectedly, the majority have remained healthy at ages 2–65 years, whereas others had severe infection, lymphoproliferation, or autoimmunity, developing during adolescence or adulthood. Further investigation of individuals with hypomorphic PTCRA variants showed that memory αβ T cells can develop in the absence of human pre-TCRα and that human pre-TCRα is largely redundant for αβ T-cell development. However, complete or partial deficiency can lead to late-onset clinical manifestations, with incomplete penetrance (40).
PSMB10 was previously described as an AR disease gene for the autoinflammatory disorders PRAAS5, but specific, sporadic heterozygous variants in the same gene are clearly associated rather with a SCID/Omenn phenotype. The distinct behavior of such variants is not yet understood in terms of pathomechanism (32).
Recently identified IEIs have also revealed critical roles for genes in new disease contexts. For instance, our previous update highlighted the role of the type I IFN pathway in host defense against SARS-CoV-2 with the identification of germline defects in this pathway or autoantibodies against type I IFNs associated with severe COVID-19 (12). Subsequent studies related to the COVID-19 pandemic have included children presenting with multisystemic inflammatory syndrome (MIS-C) after SARS-CoV-2 infection and uncovered AR deficiencies of OAS1, OAS2, or RNASEL in around 1% of patients with this severe inflammatory complication. These gene products function in the same signaling pathway to suppress inflammation after double-stranded RNA detection. Thus, AR OAS1, OAS2, and RNASEL deficiencies result in uncontrolled inflammatory cytokine production that can underlie inflammation in some patients (78).
The role of autoantibodies in susceptibility to infections is a growing field. The identification of neutralizing autoantibodies against different cytokines has explained some aspects of the complex phenotypes of immune dysregulation in previously described IEIs, such as those affecting the alternative NF-κB pathway (106). In this update, we include autoantibodies directed against IL-27 underlying EBV infections (68), which phenocopy AR variants in IL27RA encoding one component of the IL-27R complex.
Somatic mutations as a phenocopy of IEI
Advances in sequencing techniques and analysis have enabled the identification of somatic variants as a cause of human immune diseases. Since IEIs have been defined as being caused by monogenic germline mutations, somatic mutations associated with disease are classified in Table 10 along with the phenocopies of IEI. Several somatic disorders have no germline disease equivalent. This is the case for VEXAS (an acronym for vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome due to somatic mutation in UBA1 causing X-linked typically adult-onset immune dysregulation (107). In addition, there are diseases caused by either germline or somatic mutations including autoimmune lymphoproliferative syndrome due to FAS-FASL or RALD for which somatic mutations represent an important proportion of affected patients. All these disorders are included as phenocopies in Table 10. In this update, for several previously described AD autoinflammatory disorders, somatic mutations have been found to underlie a phenotype closely resembling that of germline variants affecting the same gene. Such is the case for somatic mutations in NLRP3, NOD2, TNFRSF1A, TNFAIP3, NLRC4, and MEFV (108, 109, 110, 111, 112, 113, 114) (indicated by ** in Tables 4 and 7). This growing list of immune disorders caused by somatic mutations underscores the need to consider variants detected at low allelic frequencies as possibly disease-causing, stressing the need for clinical laboratories to find ways to report these occurrences in addition to germline variants. We foresee that this list of somatic disorders resembling their IEI counterparts will increase with further advances in genetic sequencing and analysis techniques (115). In consideration of this, and to avoid redundancy, this committee has decided to denote such disorders throughout the manuscript to alert to the possibility of mosaicism as opposed to including them in Table 10 as different disorders.
Autoinflammation and immune dysregulation are at the forefront of novel discoveries blurring the borders between immunodeficiencies and rheumatology
Among the newly described genes, almost half (43%, 29/67) are either in the autoinflammatory or immune dysregulation tables. Autoimmune diseases affect around 10% of the population worldwide (116). These diseases have a complex etiology, where genetic and environmental factors interact, leading to a loss of tolerance against self-antigens, subsequent inflammation, and end-organ damage. B-cell dysregulation strongly contributes to the pathogenesis of several autoimmune diseases including SLE. The identification of new causes of monogenic lupus furthers our knowledge on how B cells are dysregulated and sheds light on new therapeutic targets. In this update, two novel gene defects are associated with monogenic lupus, namely, GOF variants in TLR7 (117) or UNC93B1 (23, 24). Remarkably, UNC93B1 is upstream of TLR7 and UNC93B1 GOF results in TLR7 hyperactivation, while TLR7 GOF variants result in aberrant survival of activated B cells. In addition, mutations in ERN1 (encoding IRE1α) disrupt XBP1 splicing and are associated with autoimmunity including SLE in one family member (66). In this update, we also include LACC1 as a monogenic cause of arthritis (64). Similar to COPA syndrome (118), monogenic arthritis due to biallelic LOF LACC1 variants is indistinguishable from polygenic arthritis. Thus, the identification of monogenic causes of arthritis may contribute to understanding pathophysiology and uncover new possibilities for precision medicine in rheumatology. As evidenced by the growing list of monogenic autoimmune disorders, the field of IEIs has become increasingly intertwined with rheumatology, underscoring the need to consider genetic analysis of patients with rheumatologic disease especially with, but not solely, onset in childhood. It is also important to note that the phenotypes of IEIs in general and specifically IEIs associated with autoimmunity and autoinflammation are increasingly overlapping.
Conclusions
In this update, the IUIS Expert Committee on IEI reports on 67 novel IEIs. These new gene defects bring the total number of IEIs to 559 (including four chromosomal deletion syndromes) resulting from variants in 508 genes (Fig. 1, A and B). The goals of the IUIS Expert Committee on IEI are to increase awareness, facilitate recognition, promote optimal treatment, and support research in the field of clinical immunology. The continuous increase in novel IEIs highlights the power of next-generation sequencing technologies with increased read depth also allowing for the detection of somatic mutations. Thorough and rigorous validation of candidate pathogenic variants enables us to (1) identify novel gene defects underlying human disease, (2) unveil mechanisms of disease pathogenesis, (3) define nonredundant functions of key genes in human immune cell development, host defense, and immune regulation, (4) expand the immunological and clinical phenotypes of IEIs, and (5) allow for future development of pathway- or gene-specific therapies. Collectively, the contributions of the researchers and scientists who discover novel IEIs will not only aid in diagnosing additional patients but also add to our fundamental knowledge of human immunology, as eloquently described in the inaugural Editorial for this journal by J.-L. Casanova (126).
Compliance with ethical standards
Ethics approval
This work is a summary of recently reported genetic variants that represent novel IEIs. No human research studies were performed to produce this summary. Thus, no approvals by appropriate institutional review boards or human research ethics committees were required to undertake the preparation of this report.
Consent to Publish
The authors consent to publish the content of this summary. However, as noted above, as this is a summary of recently reported genetic variants that represent novel IEIs, we did not require consent to publish from participants.
Acknowledgments
The members of the Inborn Errors of Immunity Committee would like to thank the International Union of Immunological Societies.
This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. S.G. Tangye is supported by an Investigator Grant (Level 3) awarded by the National Health and Medical Research Council of Australia. I. Meyts is a senior clinical investigator of FWO Vlaanderen (EBD-D8974-FKM) and also supported by Jeffrey Model Foundation. M.C. Poli is supported by ANID Regular Investigator Grant FONDECYT 1221802 and Jeffrey Modell Foundation.
Author contributions: M.C. Poli: conceptualization, data curation, formal analysis, methodology, and writing—original draft, review, and editing. I. Aksentijevich: conceptualization, investigation, and writing—review and editing. A.A. Bousfiha: writing—original draft, review, and editing. C. Cunningham-Rundles: resources and writing—review and editing. S. Hambleto: investigation and writing—review and editing. C. Klein: conceptualization, formal analysis, investigation, validation, and writing—review and editing. T. Morio: conceptualization, data curation, and validation. C. Picard: visualization and writing—original draft, review, and editing. A. Puel: writing—review and editing. N. Rezaei: conceptualization, data curation, investigation, methodology, supervision, validation, and writing—original draft, review, and editing. M.R.J. Seppänen: data curation, formal analysis, resources, validation, and writing—review and editing. R. Somech: data curation, formal analysis, investigation, supervision, and validation. H.C. Su: writing—review and editing. K.E. Sullivan: conceptualization, formal analysis, and writing—review and editing. T.R. Torgerson: data curation, investigation, and writing—review and editing. I. Meyts: conceptualization, data curation, formal analysis, investigation, methodology, supervision, validation, visualization, and writing—original draft, review, and editing. S.G. Tangye: conceptualization, data curation, investigation, project administration, supervision, and writing—original draft, review, and editing.
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