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Genetic diagnosis of systemic autoinflammatory diseases and underlying primary immunodeficiency
Journal of Genetic Medicine 2022;19:57-62
Published online December 31, 2022;  https://doi.org/10.5734/JGM.2022.19.2.57
© 2022 Korean Society of Medical Genetics and Genomics.

Seung Hwan Oh*

Department of Laboratory Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
Seung Hwan Oh, M.D, Ph.D. https://orcid.org/0000-0002-1946-9939
Department of Laboratory Medicine, Pusan National University Yangsan Hospital, 20 Geumo-ro, Mulgeum-eup, Yangsan 50612, Korea.
Tel: +82-55-360-1870, Fax: +82-55-360-1880, E-mail: paracelsus@pusan.ac.kr
Received November 29, 2022; Accepted December 17, 2022.
cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Systemic autoinflammatory diseases (SAIDs) are characterized by unprovoked inflammatory episodes such as recurrent/periodic fever, serositis, skin lesions, abdominal symptoms, arthritis/arthralgia, and central nervous system involvement. Genetic diagnosis of SAIDs has been challenging because disease manifestations overlap among themselves and with other immunological disease categories, such as infection and autoimmune diseases. However, the advent of next-generation sequencing (NGS) technologies and expanding knowledge about the innate immunity and inflammation have made the routine genetic diagnosis of SAIDs possible. Here, we review the recurrent/periodic fevers, other recently identified autoinflammatory diseases, and type I interferonopathies, and discuss the clinical usefulness of NGS targeted sequencing for SAIDs, and recent advance of understandings for this heterogeneous disease group as for underlying primary immunodeficiency.
Keywords : Inflammation, Innate immunity, Genetic testing.
Introduction

Systemic autoinflammatory diseases (SAIDs) are characterized by unprovoked inflammatory episodes such as recurrent/periodic fever, serositis, skin lesions, abdominal symptoms, arthritis/arthralgia, and central nervous system involvement [1-4]. In this expanding and still ongoing disease category, genetic diagnosis has been challenging because disease manifestations overlap among themselves and with other immunological disease categories, such as infection and autoimmune diseases. Differential diagnosis with laboratory findings of this disease category has not been so helpful because their underlying pathophysiology shares a common immunological defect [5]. Prior to the dissemination of next-generation sequencing (NGS) technologies, the genetic diagnosis was limited to genes associated with prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). In the era of NGS, we can incorporate the expanded SAID-associated genes into our targeted panel gene list, and we are now hoping to adopt the routine genetic diagnosis in this challenging category of diseases and finally, provide a genetic characterization of many previously undiagnosed patients, and give an insight to the biological mechanisms of the innate immunity and autoinflammation. Recent diagnostic approaches of SAIDs can shorten the diagnostic odyssey and provide early access to the optimal treatment adapted to the underlying disease pathophysiology of the immune system. Here, we discuss the clinical usefulness of NGS targeted sequencing for SAIDs and recent advance of understandings for this heterogeneous disease group as for underlying primary immunodeficiency.

Genetic testing for 4 prototypic hereditary recurrent fevers (HRFs).

Genetic testing using Sanger sequencing as a first-line diagnostic tool was recommended for the patients with a clear clinical diagnosis of 4 prototypic HRFs. Genetic testing guidelines were suggested for two recessively inherited diseases [6]: Familial Mediterranean fever (FMF) associated with MEFV gene (MIM *608107) and mevalonate kinase deficiency (MKD) associated with MVK gene (MIM *251170), and two dominantly inherited diseases: tumor necrosis factor (TNF) receptor-associated periodic syndrome associated with TNFRSF1A gene (MIM *191190) and cryopyrin-associated periodic syndrome (CAPS) associated with NLRP3 gene (MIM *606416). This guideline recommended to screen mutational hot spots (exons 2, 3, 5, 10 of the MEFV gene; exons 2-11 of the MKV gene; exons 2-4 of the TNFRSF1A; exon 3 of the NLRP3). However, such a screening approach should always consider the possibility of the presence of a causal mutation outside the defined regions of interest. We can find genotype-phenotype information of these 4 prototypic HRFs in the well-organized registry for autoinflammatory diseases (Eurofever, https://www.printo.it/eurofever/index) [7]. Genetic diagnosis of these 4 prototypic HRFs could guide the therapy according to the specific defect in immunological process. Colchicine is the first-line therapeutic modality for FMF [8]. However, IL-1 or IL-6 blockade for MKD, and IL-1 blockade for CAPS are recommended [9-13].

Genetic Testing for The Expanding List of SAID-Associated Genes

Targeted sequencing using NGS technologies is the current method of choice for SAIDs with ambiguous phenotypes and locus heterogeneity. NGS targeted gene panels usually analyze coding sequences of hundreds of genes. Therefore, we can incorporate other recently described SAID-associated genes, such as adenosine deaminase 2 (ADA2, MIM *607575), nucleotide-binding oligomerization domain protein 2 (NOD2, MIM *605956), proline/serine/threonine phosphatase-interacting protein 1 (PSTPIP1, MIM *606347), and tumor necrosis factor-alpha-induced protein 3 (TNFAIP3, MIM *191163) genes. Deficiency of plasma adenosine deaminase 2 caused by homozygous or compound heterozygous mutations of the ADA2 gene has been identified in various systemic inflammatory diseases and immune deficiencies, manifesting fever, vasculitis, polyarteritis nodosa, recurrent stroke, and pure red cell aplasia [14-16]. Blau syndrome is a representative autoinflammatory granulomatous disease resulting from mutations of the recognition receptor NOD2, presenting with granulomatous polyarthritis, dermatitis and uveitis [17,18]. Pyogenic sterile arthritis, pyoderma gangrenosum and acne syndrome is a pleiotropic autosomal dominant autoinflammatory disease caused by mutations of CD2-binding protein PSTPIP1, which interacts with pyrin [19,20]. Haploinsufficiency of nuclear factor kappa B (NF-κB) regulatory protein A20 encoded by TNFAIP3, mediates a familial Behcet-like autoinflammatory syndrome, characterized by painful and recurrent mucosal ulceration affecting the oral mucosa, gastrointestinal tract, and genital areas. Several non-truncating TNFAIP3 mutations may provoke autoimmune conditions such as rheumatoid arthritis, SLE, and Sjogren associated non-Hodgkin lymphoma [21-23]. Therefore, expert practice guidelines from the International Society of Systemic Autoinflammatory Disease recommended including these 4 recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3) in its diagnostic scheme in addition to the 4 previously annotated HRF associated genes (MEFV, MVK, NLRP3, and TNFRSF1A) [22].

The locus specific database for SAIDs (Infevers, https://infevers.umai-montpellier.fr/web/index.php) deposited 43 additional genes into an expanding list of SAID-associated genes: ADAM17, ALPK1, AP1S3. CARD14, CDC42, CEBPE, COPA, ELF4, F12, IKBKG, IL1RN, IL36RN, LACC1, LPIN2, NCSTN, NLRC4, NLRP1, NLRP12, NLRP7, OTULIN, PLCG2, POMP, PSMA3, PSMB4, PSMB8, PSMB9, PSMB10, PSMG2, PSTPI1, RBCK1, RELA, RIPK1, SAMD9L, SH3BP2, SLC29A3, STING1, TNFAIP3, TNFRSF1A, TNFRSF11A, TRAP1, TRNT1, UBA1, WDR1. Most of them are associated with the players of the innate immune system, such as inflammasomes and IL-1β production (MVK, NLRP1, NLRP3, NLRC4, PSTPIP1), NF-κB signaling (NOD2, TNFAIP3, TNFRSF1A, TNFRSF11A, TRAP1), ubiquitination (UBA1), and type I interferon production (COPA, POMP, STING1) [5].

Type I Interferonopathy and Innate Immune System

Type I interferonopathy has been denoted and classified within the broader disease entity of SAIDs [5,24]. Aicardi-Goutieres syndrome (AGS) is the first defined Mendelian disease associated with type I interferon upregulation, characterized by inflammation and tissue damage in the central nervous system, brain calcification, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon. Mutations of the ADAR, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and TREX1 can cause dysfunction of nucleases involved in the immune system, resulting in inflammatory damage to brain, skin and other body systems that lead to the characteristic features of AGS [25]. Type I interferon (IFN-I) and their cognitive receptors and signaling pathways are the essential components of the innate immune system. Type I interferonopathy-associated genes can be grouped according to their functions as nucleic acid sensing (IFIH1, DDK58), nucleic acid signaling (STING1, COPA), nuclear acid metabolism (RNASEH2A, RNASEH2B, RNASEH2C, POLA1, BLM, ATM, DCLRE1C, SAMHD1, TREX1, DNASE2, ADAR1, SKIV2L PTPN1, LSM11, RNU7-1), proteasome (PSMB4, PSMB8, PSMB9, PSMB10, PSMD12, PSMA3, PSMG2, POMP), mitochondrial integrity (NGLY1, ATAD3A), and post interferon receptor signaling pathways (ISG15, JAK1, STAT1, STAT2, USP18).

Adoption of Targeted NGS Panel Sequencing for SAIDs

SAID is a rapidly expanding disease category that is associated with the innate immune dysregulation, encompassing hereditary recurrent/periodic fevers, other recently defined SAIDs, and type I interferonopathies. Since they share the immunological pathways and interactions, genetic diagnostic approaches are challenging. Therefore, adoption of NGS technology in this complicated disease category, having locus heterogeneity and various expressivity, is mandatory. NGS panel testings, including primary immunodeficiency panel and hemophagocytic lymphohistiocytosis panel, are now routinely performed in Korea. There were some retrospective studies and case reports to reveal the genetic cause of SAIDs [26,27]. So far, SAID NGS panel testing is not widely performed. As for SAIDs, the list of panel genes should be periodically updated because they are still expanding rapidly. The SAID panel should include classical 4 HRF-associated genes and additional SAIDs-associated genes. The inclusion of type I interferonopathy-associated genes in the panel is also recommended. Table 1 shows the representative SAID gene panel in Korea. After the adoption of this NGS panel for 18 months, they could identify the causative mutations of classical HRF-associated genes and other SAID-associated genes in the patients with recurrent fever and/or systemic inflammatory diseases (Table 2).

Conclusion

Genetic diagnosis of autoinflammatory diseases has been challenging so far. However, the advent of NGS technologies and expanding knowledge about the innate immunity and inflammation have made the routine genetic diagnosis of SAIDs possible. Here we reviewed the classical recurrent hereditary fevers and recently defined SAIDs, and type I inteferonopathies with their corresponding molecular mechanisms of the innate immunity. Now is the time to adopt the targeted NGS panel testing in the routine genetic diagnosis of SAIDs in Korea.

Conflict of interest

I declare that I do not have any conflicts of interests.

Acknowledgements

This study was supported by a 2021 research grant from Pusan National University Yangsan Hospital.

TABLES

Representative periodic fever/autoinflammatory disease panel gene list

Genes Reference transcript MIM * MIM # Associated disease Mode of inheritance
ACP5 NM_001111035.2 171640 607944 Spondyloenchondrodysplasia with immune dysregulation AR
ADA2 NM_001282225.2 607575 615688 Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome AR
ADAM17 NM_003183.5 603639 614328 Inflammatory skin & bowel disease, neonatal, 1 AR
ADAR NM_001111.4 146920 615010 Aicardi-Goutieres syndrome 6 AR
127400 Dyschromatosis symmetrica hereditaria AD
ASAH1 NM_177924.4 613468 228000 Farber lipogranulomatosis AR
CARD14 NM_024110.4 607211 173200 Pityriasis rubra pilaris AD
602723 Psoriasis 2 AD
DNASE2 NM_001375.2 126350 619858 Autoinflammatory-pancytopenia syndrome AR
ELANE NM_001972.3 130130 162800 Neutropenia, cyclic AD
202700 Neutropenia, severe congenital 1, autosomal dominant AD
HAX1 NM_006118.3 605998 610738 Neutropenia, severe congenital 3, autosomal recessive AR
IFIH1 NM_022168.4 606951 615846 Aicardi-Goutieres syndrome 7 AD
619773 Immunodeficiency 95 AR
IL10RA NM_001558.3 146933 613148 Inflammatory bowel disease 28, early onset AR
IL10RB NM_000628.4 123889 612567 Inflammatory bowel disease 25, early onset AR
IL1RN NM_173841.2 147679 612852 Interleukin 1 receptor antagonist deficiency AR
IL36RN NM_012275.2 605507 614204 Psoriasis 14, pustular AR
LPIN2 NM_014646.2 605519 609628 Majeed syndrome AR
MEFV NM_000243.2 608107 134610 Familial Mediterranean fever, AD AD
249100 Familial Mediterranean fever, AR AR
608068 Neutrophilic dermatosis, acute febrile AD
MVK NM_000431.3 251170 260920 Hyper-IgD syndrome AR
610377 Mevalonate kinase deficiency AR
NLRP1 NM_033004.3 606636 617388 Autoinflammation with arthritis and dyskeratosis AD, AR
NLRP12 NM_144687.3 609648 611762 Familial cold autoinflammatory syndrome 2 AD
NLRP3 NM_004895.4 606416 607115 CINCA syndrome AD
617772 Deafness, autosomal dominant 34, with or without inflammation AD
120100 Familial cold inflammatory syndrome 1 AD
191900 Muckle-Wells syndrome AD
NOD2 NM_022162.2 605956 186580 Blau syndrome AD
PLCG2 NM_002661.5 600220 614878 Autoinflammation, antibody deficiency, and immune dysregulation syndrome AD
614468 Familial cold autoinflammatory syndrome 3 AD
PSMB8 NM_148919.4 177046 256040 Proteasome-associated autoinflammatory syndrome 1 and digenic forms AR
PSTPIP1 NM_003978.4 606347 604416 Pyogenic sterile arthritis, pyoderma gangrenosum, and acne AD
RNASEH2A NM_006397.2 606034 610333 Aicardi-Goutieres syndrome 4 AR
RNASEH2B NM_024570.3 610326 610181 Aicardi-Goutieres syndrome 2 AR
RNASEH2C NM_032193.3 610330 610329 Aicardi-Goutieres syndrome 3 AR
SAMHD1 NM_015474.3 606754 612952 Aicardi-Goutieres syndrome 5 AR
SH3BP2 NM_003023.4 602104 118400 Cherubism AD
SLC29A3 NM_018344.5 612373 602782 Histiocytosis-lymphadenopathy plus syndrome AR
TNFAIP3 NM_006290.3 191163 616744 Autoinflammatory syndrome, familial, Behcet-like 1 AD
TNFRSF11A NM_003839.3 603499 612301 Osteopetrosis, autosomal recessive 7 AR
TNFRSF1A NM_001065.3 191190 142680 Periodic fever, familial AD
TREX1 NM_033629.5 606609 2235750 Aicardi-Goutieres syndrome 1, dominant and recessive AD, AR
STING1 (TMEM173) NM_198282.4 612374 615934 STING-associated vasculopathy, infantile-onset AD
WDR1 NM_017491.5 604734 150550 Periodic fever, immunodeficiency, and thrombocytopenia syndrome AR

MIM *, gene/locus MIM number; MIM #, phenotype MIM number; AD, autosomal dominant; AR, autosomal recessive.


An example of genetic variations detected by targeted sequencing for SAIDs which was conducted at one university hospital in South Korea for 18 months

No. Reasons of genetic testing Test results Genes Sequence variations (HGVS) Classification (ACMG) dbSNP Reference
1 Recurrent fever, family history Detected PSTPIP1 NM_003978.4:c.769G>A (p.Glu257Lys) LP N/A [28]
2 FUO, meningitis, papilledema ND
3 Recurrent fever, oral ulcer, abdominal pain, diarrhea Detected TNFAIP3 NM_006290.3:c.547C>T (p.Arg183*) P rs1423560438 [29,30]
4 Recurrent fever, synovitis (hip joint) ND
5 Recurrent fever ND
6 Recurrent fever, FUO ND
7 FUO Detected NLRP3 NM_004895.4:c.2582A>G (p.Tyr861Cys) LP rs180177452 [31]
8 Recurrent fever, skin rash ND
9 FUO, skin rash, pancytopenia ND
10 Recurrent fever, oral ulcer ND
11 Recurrent fever, vomiting ND
12 FUO, arthralgia Inconclusive MEFV NM_000243.2:c.250G>A (p.Glu84Lys) VUS rs150819742 [32]
13 Periodic fever, oral ulcer ND
14 Recurrent fever, cellulitis ND
15 Recurrent fever Inconclusive TREX1 NM_033629.4:c.-26-1G>A VUS rs749323787 N/A
16 Recurrent fever, oral ulcer ND
17 Periodic fever, conjunctivitis, periorbital edema, febrile convulsion ND

SAID, systemic autoinflammatory disease; HGVS, Human Genome Variation Society; ACMG, American College of Medical Genetics; FUO, fever of unknown origin; ND, not detected; LP, likely pathogenic; VUS, a variant of uncertain significance; N/A, not applicable.


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