Inborn errors of immunity: an expanding universe of disease and genetic architecture

ABSTRACT Inborn errors of immunity (IEIs) are generally considered to be rare monogenic disorders of the immune system that cause immunodeficiency, autoinflammation, autoimmunity, allergy

and/or cancer. Here, we discuss evidence that IEIs need not be rare disorders or exclusively affect the immune system. Namely, an increasing number of patients with IEIs present with severe

dysregulations of the central nervous, digestive, renal or pulmonary systems. Current challenges in the diagnosis of IEIs that result from the segregated practice of specialized medicine

could thus be mitigated, in part, by immunogenetic approaches. Starting with a brief historical overview of IEIs, we then discuss the technological advances that are facilitating the

immunogenetic study of IEIs, progress in understanding disease penetrance in IEIs, the expanding universe of IEIs affecting distal organ systems and the future of genetic, biochemical and

medical discoveries in this field. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your

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SIMILAR CONTENT BEING VIEWED BY OTHERS CELLULAR AND MOLECULAR MECHANISMS BREAKING IMMUNE TOLERANCE IN INBORN ERRORS OF IMMUNITY Article Open access 01 April 2021 GENE THERAPY FOR INBORN

ERRORS OF IMMUNITY: PAST, PRESENT AND FUTURE Article 25 November 2022 A HUMAN CASE OF GIMAP6 DEFICIENCY: A NOVEL PRIMARY IMMUNE DEFICIENCY Article 16 December 2020 REFERENCES * Tangye, S. G.

et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. _J. Clin. Immunol._ 40, 24–64 (2020).

PubMed  PubMed Central  Google Scholar  * Beck, D. B. et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. _N. Engl. J. Med._ 383, 2628–2638 (2020). CAS  PubMed

  PubMed Central  Google Scholar  * Bousfiha, A. et al. The 2022 update of IUIS phenotypical classification for human inborn errors of immunity. _J. Clin. Immunol._ 42, 1508–1520 (2022).

PubMed  Google Scholar  * Tangye, S. G. et al. Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee.

_J. Clin. Immunol._ 42, 1473–1507 (2022). THIS WORK PRESENTS THE MOST UP-TO-DATE REPORT OF THE CLASSIFICATION OF IEIS AND THEIR ASSOCIATED FEATURES. PubMed  PubMed Central  Google Scholar  *

Fischer, A. Gene therapy for inborn errors of immunity: past, present and future. _Nat. Rev. Immunol._ 23, 397–408 (2023). THIS ARTICLE REVIEWS THE DEVELOPMENT OF GENE THERAPIES FOR IEIS

AND DISCUSSES THE NEXT STEPS FOR THE FIELD. CAS  PubMed  Google Scholar  * von Verschuer, O. Twin research from the time of Francis Galton to the present-day. _Proc. R. Soc. Lond. B_ 128,

62–81 (1939). ADS  Google Scholar  * Boisson-Dupuis, S. The monogenic basis of human tuberculosis. _Hum. Genet._ 139, 1001–1009 (2020). PubMed  PubMed Central  Google Scholar  * Bruton, O.

C. Agammaglobulinemia. _Pediatrics_ 9, 722–728 (1952). CAS  PubMed  Google Scholar  * Ochs, H. D. & Hitzig, W. H. History of primary immunodeficiency diseases. _Curr. Opin. Allergy Clin.

Immunol._ 12, 577–587 (2012). THIS ARTICLE PRESENTS A COMPREHENSIVE HISTORY OF THE FIELD OF IEIS. CAS  PubMed  Google Scholar  * Bruton, O. C., Apt, L., Gitlin, D. & Janeway, C. A.

Absence of serum gamma globulins. _AMA Am. J. Dis. Child._ 84, 632–636 (1952). CAS  PubMed  Google Scholar  * Vetrie, D. et al. The gene involved in X-linked agammaglobulinaemia is a member

of the src family of protein-tyrosine kinases. _Nature_ 361, 226–233 (1993). CAS  PubMed  ADS  Google Scholar  * Hood, L. E., Hunkapiller, M. W. & Smith, L. M. Automated DNA sequencing

and analysis of the human genome. _Genomics_ 1, 201–212 (1987). CAS  PubMed  Google Scholar  * Benichou, B. & Strominger, J. L. Class II-antigen-negative patient and mutant B-cell lines

represent at least three, and probably four, distinct genetic defects defined by complementation analysis. _Proc. Natl Acad. Sci. USA_ 88, 4285–4288 (1991). CAS  PubMed  PubMed Central  ADS

  Google Scholar  * Lisowska-Grospierre, B., Fondaneche, M. C., Rols, M. P., Griscelli, C. & Fischer, A. Two complementation groups account for most cases of inherited MHC class II

deficiency. _Hum. Mol. Genet._ 3, 953–958 (1994). CAS  PubMed  Google Scholar  * Seidl, C., Saraiya, C., Osterweil, Z., Fu, Y. P. & Lee, J. S. Genetic complexity of regulatory mutants

defective for HLA class II gene expression. _J. Immunol._ 148, 1576–1584 (1992). CAS  PubMed  Google Scholar  * Gong, W. et al. A transcription map of the DiGeorge and velo-cardio-facial

syndrome minimal critical region on 22q11. _Hum. Mol. Genet._ 5, 789–800 (1996). CAS  PubMed  Google Scholar  * de Saint Basile, G. et al. Close linkage of the locus for X chromosome-linked

severe combined immunodeficiency to polymorphic DNA markers in Xq11-q13. _Proc. Natl Acad. Sci. USA_ 84, 7576–7579 (1987). ADS  Google Scholar  * Noguchi, M. et al. Interleukin-2 receptor

gamma chain mutation results in X-linked severe combined immunodeficiency in humans. _Cell_ 73, 147–157 (1993). CAS  PubMed  Google Scholar  * Puck, J. M. et al. The interleukin-2 receptor

gamma chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1. _Hum. Mol. Genet._ 2, 1099–1104 (1993). CAS  PubMed  Google Scholar  * Baehner, R. L. et al.

DNA linkage analysis of X chromosome-linked chronic granulomatous disease. _Proc. Natl Acad. Sci. USA_ 83, 3398–3401 (1986). CAS  PubMed  PubMed Central  ADS  Google Scholar  * Royer-Pokora,

B. et al. Cloning the gene for an inherited human disorder — chronic granulomatous disease — on the basis of its chromosomal location. _Nature_ 322, 32–38 (1986). CAS  PubMed  ADS  Google

Scholar  * Kwan, S. P. et al. Localization of the gene for the Wiskott–Aldrich syndrome between two flanking markers, TIMP and DXS255, on Xp11.22–Xp11.3. _Genomics_ 10, 29–33 (1991). CAS 

PubMed  Google Scholar  * Schwarz, K. et al. RAG mutations in human B cell-negative SCID. _Science_ 274, 97–99 (1996). CAS  PubMed  ADS  Google Scholar  * Hsu, A. P. et al. Mutations in

GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. _Blood_ 118, 2653–2655 (2011). CAS  PubMed  PubMed Central  Google

Scholar  * Zhang, Q. et al. Combined immunodeficiency associated with DOCK8 mutations. _N. Engl. J. Med._ 361, 2046–2055 (2009). CAS  PubMed  PubMed Central  Google Scholar  * Arai, T. et

al. Copy number variations due to large genomic deletion in X-linked chronic granulomatous disease. _PLoS ONE_ 7, e27782 (2012). CAS  PubMed  PubMed Central  ADS  Google Scholar  * Yamada,

M. et al. Determination of the deletion breakpoints in two patients with contiguous gene syndrome encompassing CYBB gene. _Eur. J. Med. Genet._ 53, 383–388 (2010). PubMed  Google Scholar  *

Lander, E. S. & Botstein, D. Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. _Science_ 236, 1567–1570 (1987). CAS  PubMed  ADS  Google Scholar

  * Mueller, R. F. & Bishop, D. T. Autozygosity mapping, complex consanguinity, and autosomal recessive disorders. _J. Med. Genet._ 30, 798–799 (1993). CAS  PubMed  PubMed Central 

Google Scholar  * Byun, M. et al. Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma. _J. Exp. Med._ 207, 2307–2312 (2010). CAS  PubMed 

PubMed Central  Google Scholar  * Bogunovic, D. et al. Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency. _Science_ 337, 1684–1688 (2012). CAS 

PubMed  PubMed Central  ADS  Google Scholar  * Zhang, X. et al. Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation. _Nature_ 517, 89–93 (2015). CAS 

PubMed  ADS  Google Scholar  * Ombrello, M. J. et al. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. _N. Engl. J. Med._ 366, 330–338 (2012). CAS  PubMed 

PubMed Central  Google Scholar  * Boisson, B. et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. _Nat. Immunol._ 13,

1178–1186 (2012). CAS  PubMed  PubMed Central  Google Scholar  * Morup, S. B. et al. Added value of reanalysis of whole exome- and whole genome sequencing data from patients suspected of

primary immune deficiency using an extended gene panel and structural variation calling. _Front. Immunol._ 13, 906328 (2022). PubMed  PubMed Central  Google Scholar  * Similuk, M. N. et al.

Clinical exome sequencing of 1000 families with complex immune phenotypes: toward comprehensive genomic evaluations. _J. Allergy Clin. Immunol._ 150, 947–954 (2022). CAS  PubMed  PubMed

Central  Google Scholar  * Boisson-Dupuis, S. et al. Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant. _Sci. Immunol._ 3,

eaau8714 (2018). PubMed  PubMed Central  Google Scholar  * Bastard, P. et al. A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes. _J. Exp. Med._

219, e20220028 (2022). CAS  PubMed  PubMed Central  Google Scholar  * Duncan, C. J. A. et al. Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the

Arctic. _J. Exp. Med._ 219, e20212427 (2022). CAS  PubMed  PubMed Central  Google Scholar  * Constantinescu, A. E. et al. A framework for research into continental ancestry groups of the UK

Biobank. _Hum. Genomics_ 16, 3 (2022). PubMed  PubMed Central  Google Scholar  * Gurdasani, D., Barroso, I., Zeggini, E. & Sandhu, M. S. Genomics of disease risk in globally diverse

populations. _Nat. Rev. Genet._ 20, 520–535 (2019). CAS  PubMed  Google Scholar  * Manolio, T. A. Using the data we have: improving diversity in genomic research. _Am. J. Hum. Genet._ 105,

233–236 (2019). CAS  PubMed  PubMed Central  Google Scholar  * Meyts, I. et al. Exome and genome sequencing for inborn errors of immunity. _J. Allergy Clin. Immunol._ 138, 957–969 (2016).

CAS  PubMed  PubMed Central  Google Scholar  * Austin-Tse, C. A. et al. Best practices for the interpretation and reporting of clinical whole genome sequencing. _npj Genom. Med._ 7, 27

(2022). PubMed  PubMed Central  Google Scholar  * Bucciol, G., Van Nieuwenhove, E., Moens, L., Itan, Y. & Meyts, I. Whole exome sequencing in inborn errors of immunity: use the power but

mind the limits. _Curr. Opin. Allergy Clin. Immunol._ 17, 421–430 (2017). PubMed  Google Scholar  * Gruber, C. & Bogunovic, D. Incomplete penetrance in primary immunodeficiency: a

skeleton in the closet. _Hum. Genet._ 139, 745–757 (2020). THIS ARTICLE REVIEWS DECADES OF REPORTS TO PRESENT FOUR PRINCIPLES OF INCOMPLETE PENETRANCE IN PRIMARY IMMUNODEFICIENCIES TO HELP

CATEGORIZE AND EXPLAIN THESE OCCURRENCES. PubMed  PubMed Central  Google Scholar  * Bustamante, J., Boisson-Dupuis, S., Abel, L. & Casanova, J. L. Mendelian susceptibility to

mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity. _Semin. Immunol._ 26, 454–470 (2014). CAS  PubMed  PubMed Central  Google Scholar  *

Felgentreff, K. et al. Ligase-4 deficiency causes distinctive immune abnormalities in asymptomatic individuals. _J. Clin. Immunol._ 36, 341–353 (2016). CAS  PubMed  PubMed Central  Google

Scholar  * Riballo, E. et al. Cellular and biochemical impact of a mutation in DNA ligase IV conferring clinical radiosensitivity. _J. Biol. Chem._ 276, 31124–31132 (2001). CAS  PubMed 

Google Scholar  * Mizoguchi, Y. & Okada, S. Inborn errors of STAT1 immunity. _Curr. Opin. Immunol._ 72, 59–64 (2021). CAS  PubMed  Google Scholar  * Dupuis, S. et al. Impaired response

to interferon-α/β and lethal viral disease in human STAT1 deficiency. _Nat. Genet._ 33, 388–391 (2003). CAS  PubMed  Google Scholar  * Sakata, S. et al. Autosomal recessive complete STAT1

deficiency caused by compound heterozygous intronic mutations. _Int. Immunol._ 32, 663–671 (2020). CAS  PubMed  Google Scholar  * Vairo, D. et al. Severe impairment of IFN-γ and IFN-α

responses in cells of a patient with a novel STAT1 splicing mutation. _Blood_ 118, 1806–1817 (2011). CAS  PubMed  Google Scholar  * Chapgier, A. et al. A partial form of recessive STAT1

deficiency in humans. _J. Clin. Invest._ 119, 1502–1514 (2009). CAS  PubMed  PubMed Central  Google Scholar  * Kong, X. F. et al. A novel form of human STAT1 deficiency impairing early but

not late responses to interferons. _Blood_ 116, 5895–5906 (2010). CAS  PubMed  PubMed Central  Google Scholar  * Kristensen, I. A., Veirum, J. E., Moller, B. K. & Christiansen, M. Novel

STAT1 alleles in a patient with impaired resistance to mycobacteria. _J. Clin. Immunol._ 31, 265–271 (2011). PubMed  Google Scholar  * Chapgier, A. et al. Human complete Stat-1 deficiency is

associated with defective type I and II IFN responses in vitro but immunity to some low virulence viruses in vivo. _J. Immunol._ 176, 5078–5083 (2006). CAS  PubMed  Google Scholar  *

Dupuis, S. et al. Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. _Science_ 293, 300–303 (2001). CAS  PubMed  Google Scholar  * Sampaio, E. P. et al. A

novel STAT1 mutation associated with disseminated mycobacterial disease. _J. Clin. Immunol._ 32, 681–689 (2012). CAS  PubMed  PubMed Central  Google Scholar  * Tsumura, M. et al.

Dominant-negative STAT1 SH2 domain mutations in unrelated patients with Mendelian susceptibility to mycobacterial disease. _Hum. Mutat._ 33, 1377–1387 (2012). CAS  PubMed  PubMed Central 

Google Scholar  * Dorman, S. E. et al. Clinical features of dominant and recessive interferon γ receptor 1 deficiencies. _Lancet_ 364, 2113–2121 (2004). CAS  PubMed  Google Scholar  *

Rosain, J. et al. Mendelian susceptibility to mycobacterial disease: 2014–2018 update. _Immunol. Cell Biol._ 97, 360–367 (2019). PubMed  Google Scholar  * Fuchs, S. et al. Tyrosine kinase 2

is not limiting human antiviral type III interferon responses. _Eur. J. Immunol._ 46, 2639–2649 (2016). CAS  PubMed  Google Scholar  * Kreins, A. Y. et al. Human TYK2 deficiency:

mycobacterial and viral infections without hyper-IgE syndrome. _J. Exp. Med._ 212, 1641–1662 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Minegishi, Y. et al. Human tyrosine kinase

2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. _Immunity_ 25, 745–755 (2006). CAS  PubMed  Google Scholar  * Sarrafzadeh, S.

A. et al. A new patient with inherited TYK2 deficiency. _J. Clin. Immunol._ 40, 232–235 (2020). PubMed  Google Scholar  * Meuwissen, M. E. et al. Human USP18 deficiency underlies type 1

interferonopathy leading to severe pseudo-TORCH syndrome. _J. Exp. Med._ 213, 1163–1174 (2016). PubMed  PubMed Central  Google Scholar  * Martin-Fernandez, M. et al. Systemic type I IFN

inflammation in human ISG15 deficiency leads to necrotizing skin lesions. _Cell Rep._ 31, 107633 (2020). CAS  PubMed  PubMed Central  Google Scholar  * Casanova, J. L. & Abel, L. Lethal

infectious diseases as inborn errors of immunity: toward a synthesis of the germ and genetic theories. _Annu. Rev. Pathol._ 16, 23–50 (2021). THIS WORK PRESENTS A HISTORICAL ACCOUNT OF THE

GENETIC THEORY OF INFECTIOUS DISEASE, HIGHLIGHTING HOW THE STUDY OF RARE IEIS HAS SHAPED OUR CURRENT UNDERSTANDING. CAS  PubMed  Google Scholar  * Bolze, A. et al. Incomplete penetrance for

isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons. _Proc. Natl Acad. Sci. USA_ 115, E8007–E8016 (2018). CAS  PubMed  PubMed Central  Google

Scholar  * Kuehn, H. S. et al. FAS haploinsufficiency is a common disease mechanism in the human autoimmune lymphoproliferative syndrome. _J. Immunol._ 186, 6035–6043 (2011). CAS  PubMed 

Google Scholar  * Rodriguez-Cortez, V. C. et al. Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naive-to-memory B-cell transition.

_Nat. Commun._ 6, 7335 (2015). CAS  PubMed  ADS  Google Scholar  * Del Pino-Molina, L. et al. Impaired CpG demethylation in common variable immunodeficiency associates with B cell phenotype

and proliferation rate. _Front. Immunol._ 10, 878 (2019). PubMed  PubMed Central  Google Scholar  * Salzer, U. & Grimbacher, B. TACI deficiency — a complex system out of balance. _Curr.

Opin. Immunol._ 71, 81–88 (2021). CAS  PubMed  Google Scholar  * Ameratunga, R. et al. Epistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary

immunodeficiency disorder and systemic lupus erythematosus. _Clin. Transl. Immunol._ 6, e159 (2017). Google Scholar  * O’Marcaigh, A. S., Puck, J. M., Pepper, A. E., De Santes, K. &

Cowan, M. J. Maternal mosaicism for a novel interleukin-2 receptor γ-chain mutation causing X-linked severe combined immunodeficiency in a Navajo kindred. _J. Clin. Immunol._ 17, 29–33

(1997). PubMed  Google Scholar  * Puck, J. M., Pepper, A. E., Bedard, P. M. & Laframboise, R. Female germ line mosaicism as the origin of a unique IL-2 receptor γ-chain mutation causing

X-linked severe combined immunodeficiency. _J. Clin. Invest._ 95, 895–899 (1995). CAS  PubMed  PubMed Central  Google Scholar  * Mensa-Vilaro, A. et al. Unexpected relevant role of gene

mosaicism in patients with primary immunodeficiency diseases. _J. Allergy Clin. Immunol._ 143, 359–368 (2019). CAS  PubMed  Google Scholar  * Aluri, J. & Cooper, M. A. Genetic mosaicism

as a cause of inborn errors of immunity. _J. Clin. Immunol._ 41, 718–728 (2021). THIS PAPER HIGHLIGHTS THE ROLE OF GENETIC MOSAICISM IN IEI DISEASE PATHOGENESIS. PubMed  PubMed Central 

Google Scholar  * Davis, B. R. et al. Somatic mosaicism in the Wiskott–Aldrich syndrome: molecular and functional characterization of genotypic revertants. _Clin. Immunol._ 135, 72–83

(2010). CAS  PubMed  Google Scholar  * Stewart, D. M., Candotti, F. & Nelson, D. L. The phenomenon of spontaneous genetic reversions in the Wiskott–Aldrich syndrome: a report of the

workshop of the ESID Genetics Working Party at the XIIth Meeting of the European Society for Immunodeficiencies (ESID). Budapest, Hungary October 4–7, 2006. _J. Clin. Immunol._ 27, 634–639

(2007). PubMed  Google Scholar  * Arredondo-Vega, F. X. et al. Adenosine deaminase deficiency with mosaicism for a “second-site suppressor” of a splicing mutation: decline in revertant T

lymphocytes during enzyme replacement therapy. _Blood_ 99, 1005–1013 (2002). CAS  PubMed  Google Scholar  * Okuno, Y. et al. Late-onset combined immunodeficiency with a novel IL2RG mutation

and probable revertant somatic mosaicism. _J. Clin. Immunol._ 35, 610–614 (2015). CAS  PubMed  Google Scholar  * Uzel, G. et al. Reversion mutations in patients with leukocyte adhesion

deficiency type-1 (LAD-1). _Blood_ 111, 209–218 (2008). CAS  PubMed  PubMed Central  Google Scholar  * Arostegui, J. I. et al. A somatic NLRP3 mutation as a cause of a sporadic case of

chronic infantile neurologic, cutaneous, articular syndrome/neonatal-onset multisystem inflammatory disease: novel evidence of the role of low-level mosaicism as the pathophysiologic

mechanism underlying mendelian inherited diseases. _Arthritis Rheum._ 62, 1158–1166 (2010). CAS  PubMed  Google Scholar  * Lasiglie, D. et al. Cryopyrin-associated periodic syndromes in

Italian patients: evaluation of the rate of somatic NLRP3 mosaicism and phenotypic characterization. _J. Rheumatol._ 44, 1667–1673 (2017). CAS  PubMed  Google Scholar  * Mensa-Vilaro, A. et

al. Late-onset cryopyrin-associated periodic syndrome due to myeloid-restricted somatic NLRP3 mosaicism. _Arthritis Rheumatol._ 68, 3035–3041 (2016). CAS  PubMed  Google Scholar  * Omoyinmi,

E. et al. Whole-exome sequencing revealing somatic NLRP3 mosaicism in a patient with chronic infantile neurologic, cutaneous, articular syndrome. _Arthritis Rheumatol._ 66, 197–202 (2014).

CAS  PubMed  Google Scholar  * Rowczenio, D. M. et al. Late-onset cryopyrin-associated periodic syndromes caused by somatic NLRP3 mosaicism-UK single center experience. _Front. Immunol._ 8,

1410 (2017). PubMed  PubMed Central  Google Scholar  * Tanaka, N. et al. High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular

syndrome: results of an International Multicenter Collaborative Study. _Arthritis Rheum._ 63, 3625–3632 (2011). CAS  PubMed  PubMed Central  Google Scholar  * Aluri, J. et al.

Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function. _Blood_ 137, 2450–2462 (2021). CAS  PubMed  PubMed Central  Google Scholar  * Lynch, M. Mutation and

human exceptionalism: our future genetic load. _Genetics_ 202, 869–875 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Martincorena, I. et al. Universal patterns of selection in

cancer and somatic tissues. _Cell_ 171, 1029–1041.e21 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Fadlallah, J. et al. Microbial ecology perturbation in human IgA deficiency.

_Sci. Transl Med._ 10, eaan1217 (2018). PubMed  Google Scholar  * Fiedorova, K. et al. Bacterial but not fungal gut microbiota alterations are associated with common variable

immunodeficiency (CVID) phenotype. _Front. Immunol._ 10, 1914 (2019). CAS  PubMed  PubMed Central  Google Scholar  * Jorgensen, S. F. et al. Altered gut microbiota profile in common variable

immunodeficiency associates with levels of lipopolysaccharide and markers of systemic immune activation. _Mucosal Immunol._ 9, 1455–1465 (2016). CAS  PubMed  Google Scholar  * Berbers, R.

M. et al. Low IgA associated with oropharyngeal microbiota changes and lung disease in primary antibody deficiency. _Front. Immunol._ 11, 1245 (2020). CAS  PubMed  PubMed Central  Google

Scholar  * Roser, M., Ritchie, H. & Dadonaite, B. Child and infant mortality. _Our World In Data_ https://ourworldindata.org/child-mortality (2019). * El-Brolosy, M. A. et al. Genetic

compensation triggered by mutant mRNA degradation. _Nature_ 568, 193–197 (2019). CAS  PubMed  PubMed Central  ADS  Google Scholar  * Ma, Z. et al. PTC-bearing mRNA elicits a genetic

compensation response via Upf3a and COMPASS components. _Nature_ 568, 259–263 (2019). CAS  PubMed  ADS  Google Scholar  * Telenti, A. & di Iulio, J. Regulatory genome variants in human

susceptibility to infection. _Hum. Genet._ 139, 759–768 (2020). CAS  PubMed  Google Scholar  * Thaventhiran, J. E. D. et al. Whole-genome sequencing of a sporadic primary immunodeficiency

cohort. _Nature_ 583, 90–95 (2020). CAS  PubMed  PubMed Central  ADS  Google Scholar  * Borel, C. et al. Biased allelic expression in human primary fibroblast single cells. _Am. J. Hum.

Genet._ 96, 70–80 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Gimelbrant, A., Hutchinson, J. N., Thompson, B. R. & Chess, A. Widespread monoallelic expression on human

autosomes. _Science_ 318, 1136–1140 (2007). CAS  PubMed  ADS  Google Scholar  * Jeffries, A. R. et al. Stochastic choice of allelic expression in human neural stem cells. _Stem Cell_ 30,

1938–1947 (2012). Google Scholar  * Gruber, C. N. et al. Complex autoinflammatory syndrome unveils fundamental principles of JAK1 kinase transcriptional and biochemical function. _Immunity_

53, 672–684.e11 (2020). THIS STUDY PROVIDES THE FIRST DEMONSTRATION OF ALLELIC BIAS IN GENE EXPRESSION, RESULTING IN A DISCREPANCY BETWEEN GENOTYPE AND ‘TRANSCRIPTOTYPE’, IN A PATIENT WITH

AN IEI. CAS  PubMed  PubMed Central  Google Scholar  * Reinius, B. & Sandberg, R. Random monoallelic expression of autosomal genes: stochastic transcription and allele-level regulation.

_Nat. Rev. Genet._ 16, 653–664 (2015). CAS  PubMed  Google Scholar  * Jeffries, A. R. et al. Random or stochastic monoallelic expressed genes are enriched for neurodevelopmental disorder

candidate genes. _PLoS ONE_ 8, e85093 (2013). PubMed  PubMed Central  ADS  Google Scholar  * Gunther, C. et al. Defective removal of ribonucleotides from DNA promotes systemic autoimmunity.

_J. Clin. Invest._ 125, 413–424 (2015). PubMed  Google Scholar  * Giordano, A. M. S. et al. DNA damage contributes to neurotoxic inflammation in Aicardi–Goutières syndrome astrocytes. _J.

Exp. Med._ 219, e20211121 (2022). CAS  PubMed  PubMed Central  Google Scholar  * Buckley, R. H. Conversations with founders of the field of human inborn errors of immunity. _J. Clin.

Immunol._ 40, 1–8 (2020). PubMed  Google Scholar  * Lutz, W. [About verruciform epidermodysplasia] [French]. _Dermatologica_ 92, 30–43 (1946). CAS  PubMed  Google Scholar  * Ramoz, N. et al.

Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. _Nat. Genet._ 32, 579–581 (2002). CAS  PubMed  Google Scholar  * de Jong, S. J. et al. The human

CIB1–EVER1–EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses. _J. Exp. Med._ 215, 2289–2310 (2018). PubMed  PubMed Central  Google Scholar  * Kambhampati, A.,

Payne, D. C., Costantini, V. & Lopman, B. A. Host genetic susceptibility to enteric viruses: a systematic review and metaanalysis. _Clin. Infect. Dis._ 62, 11–18 (2016). CAS  PubMed 

Google Scholar  * Lindesmith, L. et al. Human susceptibility and resistance to Norwalk virus infection. _Nat. Med._ 9, 548–553 (2003). CAS  PubMed  Google Scholar  * Nordgren, J. et al. Both

Lewis and secretor status mediate susceptibility to rotavirus infections in a rotavirus genotype-dependent manner. _Clin. Infect. Dis._ 59, 1567–1573 (2014). CAS  PubMed  PubMed Central 

Google Scholar  * Payne, D. C. et al. Epidemiologic association between FUT2 secretor status and severe rotavirus gastroenteritis in children in the United States. _JAMA Pediatr._ 169,

1040–1045 (2015). PubMed  PubMed Central  Google Scholar  * Thorven, M. et al. A homozygous nonsense mutation (428G– > A) in the human secretor (FUT2) gene provides resistance to

symptomatic norovirus (GGII) infections. _J. Virol._ 79, 15351–15355 (2005). CAS  PubMed  PubMed Central  Google Scholar  * Ciancanelli, M. J. et al. Infectious disease. Life-threatening

influenza and impaired interferon amplification in human IRF7 deficiency. _Science_ 348, 448–453 (2015). CAS  PubMed  PubMed Central  ADS  Google Scholar  * Lafaille, F. G. et al. Impaired

intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. _Nature_ 491, 769–773 (2012). CAS  PubMed  PubMed Central  ADS  Google Scholar  * d’Angelo, D. M., Di Filippo, P.,

Breda, L. & Chiarelli, F. Type I interferonopathies in children: an overview. _Front. Pediatr._ 9, 631329 (2021). PubMed  PubMed Central  Google Scholar  * Wu, D., Shen, M. & Yao,

Q. Cutaneous manifestations of autoinflammatory diseases. _Rheumatol. Immunol. Res._ 2, 217–225 (2021). PubMed  PubMed Central  Google Scholar  * Liu, Y. et al. Activated STING in a vascular

and pulmonary syndrome. _N. Engl. J. Med._ 371, 507–518 (2014). CAS  PubMed  PubMed Central  Google Scholar  * David, C. & Fremond, M. L. Lung inflammation in STING-associated

vasculopathy with onset n infancy (SAVI). _Cells_ 11, 318 (2022). CAS  PubMed  PubMed Central  Google Scholar  * Fremond, M. L. & Crow, Y. J. STING-mediated lung inflammation and beyond.

_J. Clin. Immunol._ 41, 501–514 (2021). PubMed  Google Scholar  * Staels, F. et al. Adult-onset ANCA-associated vasculitis in SAVI: extension of the phenotypic spectrum, case report and

review of the literature. _Front. Immunol._ 11, 575219 (2020). CAS  PubMed  PubMed Central  Google Scholar  * Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the

interleukin-10 receptor. _N. Engl. J. Med._ 361, 2033–2045 (2009). CAS  PubMed  PubMed Central  Google Scholar  * Avitzur, Y. et al. Mutations in tetratricopeptide repeat domain 7A result in

a severe form of very early onset inflammatory bowel disease. _Gastroenterology_ 146, 1028–1039 (2014). CAS  PubMed  Google Scholar  * Salzer, E. et al. Early-onset inflammatory bowel

disease and common variable immunodeficiency-like disease caused by IL-21 deficiency. _J. Allergy Clin. Immunol._ 133, 1651–1659.e12 (2014). CAS  PubMed  Google Scholar  * Li, Q. et al.

Variants in TRIM22 that affect NOD2 signaling are associated with very-early-onset inflammatory bowel disease. _Gastroenterology_ 150, 1196–1207 (2016). CAS  PubMed  Google Scholar  *

Parlato, M. et al. Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis. _EMBO Mol. Med._ 10, e8483 (2018). PubMed  PubMed Central 

Google Scholar  * Beck, D. B. et al. Estimated prevalence and clinical manifestations of UBA1 variants associated with VEXAS syndrome in a clinical population. _JAMA_ 329, 318–324 (2023).

THIS STUDY USES A REVERSE GENETICS APPROACH TO DEFINE THE GENERAL POPULATION PREVALENCE AND PHENOTYPIC SPECTRUM OF AN IEI. CAS  PubMed  PubMed Central  Google Scholar  * Dowdell, K. C. et

al. Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome. _Blood_ 115, 5164–5169 (2010). CAS  PubMed  PubMed Central  Google

Scholar  * Walker, S. et al. Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome. _Blood_ 127, 948–951 (2016). PubMed  PubMed

Central  Google Scholar  * Campbell, T. M. et al. Respiratory viral infections in otherwise healthy humans with inherited IRF7 deficiency. _J. Exp. Med._ 219, e20220202 (2022). CAS  PubMed 

PubMed Central  Google Scholar  * Martin-Fernandez, M. et al. A partial form of inherited human USP18 deficiency underlies infection and inflammation. _J. Exp. Med._ 219, e20211273 (2022).

CAS  PubMed  PubMed Central  Google Scholar  * Gruber, C. et al. Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy. _J. Exp.

Med._ 217, e20192319 (2020). CAS  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported by National Institute of Allergy and Infectious Disease

grants R01 AI148963, R01 AI127372, R01 AI150300, R01 HD108467 and R01 AI151029 awarded to D.B. Y.T.A. was supported by T32 training grant T32 AI078892. The authors apologize to colleagues

whose work they could not cite or could only superficially discuss owing to space limitations. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Center for Inborn Errors of Immunity, Precision

Immunology Institute, Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA Yemsratch T. Akalu & Dusan Bogunovic Authors * Yemsratch T.

Akalu View author publications You can also search for this author inPubMed Google Scholar * Dusan Bogunovic View author publications You can also search for this author inPubMed Google

Scholar CONTRIBUTIONS Both authors contributed equally to all aspects of the article. CORRESPONDING AUTHOR Correspondence to Dusan Bogunovic. ETHICS DECLARATIONS COMPETING INTERESTS D.B. is

a founder and part owner of Lab11 Therapeutics. Y.T.A. declares no competing interests. PEER REVIEW PEER REVIEW INFORMATION _Nature Reviews Genetics_ thanks Esteban Ballestar, David Beck and

Cecilia Poli for their contribution to the peer review of this work. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in

published maps and institutional affiliations. RELATED LINKS AFRICAN GENOME VARIATION PROJECT: https://www.sanger.ac.uk/collaboration/african-genome-variation-project ALL OF US RESEARCH

PROGRAM: https://allofus.nih.gov INTERNATIONAL UNION OF IMMUNOLOGICAL SOCIETIES (IUIS) INBORN ERRORS OF IMMUNITY COMMITTEE: https://iuis.org/committees/iei MOUNT SINAI MILLION HEALTH

DISCOVERIES PROGRAM: https://icahn.mssm.edu/research/ipm/programs/mount-sinai-million UK BIOBANK: https://www.ukbiobank.ac.uk GLOSSARY * Agammaglobulinemia A rare disorder characterized by

complete or near-complete lack of serum antibodies and circulating B cells owing to early termination of B cell development. * Aicardi–Goutières syndrome (AGS). A rare type I

interferonopathy that affects the brain, immune system and skin. * Common variable immunodeficiency (CVID). The most common form of primary immunodeficiency characterized by antibody

deficiency, increased susceptibility to infection, autoimmune manifestations and impaired vaccine responses. * Chronic granulomatous disease A rare condition, mainly affecting phagocytic

cells of the immune system, that is characterized by an increased susceptibility to bacterial and fungal infections, as well as the development of granulomas. * Di George syndrome A primary

immune deficiency associated with susceptibility to infections, owing to an absent or poorly developed thymus. * Genetic theory of infectious disease A theory proposing that the genetic

background of the host is a determinant of resistance or susceptibility to a given microorganism. * Incomplete penetrance The occurrence of individuals having a disease-causing mutation who

develop partial or no disease. * Monoallelic expression The maintenance of expression of an autosomal gene from a single allele in a somatic cell over time. * Nonsense-mediated decay A

mechanism to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons. * Primary immune deficiencies A varied group of disorders that result from

genetic defects that impair the development and/or function of the immune system, mostly presenting as severe recurrent infections and occasionally with an increased incidence of

autoimmunity and malignancies. * Type I interferonopathy An inherited disorder involving a central role for dysregulation of the type I interferon pathway in disease pathogenesis. * Severe

combined immunodeficiency (SCID). A very rare life-threatening genetic disorder in which there is combined absence of T cell and B cell function. * Wiskott–Aldrich syndrome A rare X-linked

recessive immunodeficiency that is characterized by abnormal bleeding resulting from a reduced number of platelets in the blood. RIGHTS AND PERMISSIONS Springer Nature or its licensor (e.g.

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version of this article is solely governed by the terms of such publishing agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Akalu, Y.T., Bogunovic,

D. Inborn errors of immunity: an expanding universe of disease and genetic architecture. _Nat Rev Genet_ 25, 184–195 (2024). https://doi.org/10.1038/s41576-023-00656-z Download citation *

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