# Whole Exome Sequencing of Adult Patients With Evans Syndrome Reveals Pathogenic Variants Associated With Autoimmunity

Étienne Crickx, Jehane Fadlallah, Morgane Cheminant, Jérémie Rosain, Jérémie Dion, Marion Malphettes, Benoit Faucher, Louis Terriou, Odile Souchaud-Debouverie, Thibault Comont, et al.

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## To cite this version:

Étienne Crickx, Jehane Fadlallah, Morgane Cheminant, Jérémie Rosain, Jérémie Dion, et al. Whole Exome Sequencing of Adult Patients With Evans Syndrome Reveals Pathogenic Variants Associated With Autoimmunity. American Journal of Hematology, 2025, American Journal of Hematology, 100 (9), pp.1700-1704. 10.1002/ajh.27767. hal-05348643

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CORRESPONDENCE

# Whole Exome Sequencing of Adult Patients With Evans Syndrome Reveals Pathogenic Variants Associated With Autoimmunity

Etienne Crickx¹,² ID | Jehane Fadlallah³ | Morgane Cheminant⁴ | Jérémie Rosain⁵,⁶,⁷ | Jérémie Dion⁸ |

Marion Malphettes³ ID | Benoit Faucher⁹ | Louis Terriou¹⁰ | Odile Souchaud-Debouverie¹¹ | Thibault Comont⁸ ID |

Felipe Suarez⁴ | Julie Graveleau¹² | Jérôme Hadjadj¹,¹³ | Thomas Moulinet¹⁴ ID | Anne-Marie Ronchetti¹⁵ | Mikael Ebbo⁹ |

Marie-Claude Stolzenberg¹ | Camille Brunaud¹ | Duong Ho-Nhat¹ | Cécile Masson¹⁶ | Mélodie Perin¹⁶ ID |

Gaelle Richard-Colmant¹⁷ | Lise Willems¹⁸ | Gwénola Maigné¹⁹ | Marielle Roux-Sauvat²⁰ | Laurent Gilardin²¹ ID |

Marie Gousseff²² ID | Adrien Bigot²³ | Antoine Froissart²⁴ | Guillaume Moulis²⁵,²⁶ | Mathieu Puyade¹¹ | Antoine Dossier²⁷ |

David Boutboul¹⁸ ID | Delphine Gobert¹³ | Clément Gourguechon²⁸ | Bertrand Godeau² | Lionel Galicier⁹ |

Jean-Francois Viallard²⁹ | Sylvain Audia³⁰ ID | Claire Fieschi³ | Olivier Hermine⁴ | Marc Michel² ID |

Matthieu Mahévas² ID | Frédéric Rieux-Laucat¹

**Correspondence:** Etienne Crickx (etienne.crickx@aphp.fr)

**Received:** 13 January 2025 | **Revised:** 6 June 2025 | **Accepted:** 9 June 2025

**Funding:** This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM) and by government grants managed by the Agence Nationale de la Recherche as part of the "Investment for the Future" program (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01, Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010), the Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), the Agence Nationale de la Recherche (ANR-22-ce15-0047-02 BREAK-ITP), the Fondation pour la recherche Médicale (FRM: EQU202103012670). E.C. was supported by a poste d'accueil AP-HP.

**Keywords:** autoimmune neutropenia | Evans syndrome | immune thrombocytopenia | primary immune deficiencies and/or dysregulations | warm autoimmune hemolytic anemia | whole-exome sequencing

To the Editor,

Evans syndrome (ES) is defined as the sequential or simulta-
neous association of immune thrombocytopenia (ITP) with
autoimmune hemolytic anemia (AIHA) and/or autoimmune
neutropenia (AIN). A previous study conducted in children
with ES revealed that 40% had pathogenic variants [1] in genes
involved in primary immune deficiencies and/or dysregulations
(PIDDs), a group of genetic diseases where autoimmune cytope-
nia are the most common form of autoimmunity [2]. In adult pa-
tients, ES is secondary to an underlying condition in 20%–50%,
mainly hematologic malignancies or systemic lupus [3, 4]. In
this study, we aimed to assess the prevalence of constitutional
genetic variants in a cohort of patients with adult-onset ES, and
to describe clinical and biological features associated with a ge-
netic diagnosis.

We consecutively included from November 2021 to November
2023 patients that had been diagnosed with adult onset
(≥18 years) ES (defined as an association of two or more
autoimmune cytopenia among ITP, wAIHA and/or AIN),
and identified in France throughout the network of the na-
tional reference center for adults' autoimmune cytopenias
(CeReCAI). The first cytopenia could have happened before
the age of 18 years. ITP and AIHA were diagnosed according to
international consensus guidelines (Supporting Information);
AIN was defined as an acquired neutropenia <1×10⁹/L with
positive monoclonal antibody immobilization of granulocyte-
specific antigens (MAIGA) test and/or a complete response to
corticosteroid treatment (neutrophil count > 1.5×10⁹/L), and
after the exclusion of non-immunological causes. We excluded
patients with a systemic lupus and patients with indolent

For affiliations refer to page.
B-cell malignancies at ES onset. Patients underwent whole-exome sequencing (WES), except those with confirmed prior genetic diagnosis. Written and informed consent was obtained from all patients. This study was conducted in compliance with the Declaration of Helsinki principles and was approved by the Institutional Review Boards Île de France (CPP-IDF2-DC-2014-2272015-03-03-AF) and the samples collection was declared to the French ministry of research with the reference DC-2014-2272.

We identified 122 patients with adult-onset ES in 25 centers (Figure S1). Two patients were excluded (diagnosis of mantle cell lymphoma and pyruvate kinase deficiency, respectively). The remaining 120 patients (37% female, median age 33 years [range 18–80] at ES diagnosis) were included in the study (Table S1). The delay between first and second cytopenia was 12 months in median [range 0–528], and 19 patients (16%) had less than 18 years at first cytopenia. Patients had ITP (98%) and/or wAIHA (72%) and/or AIN (48%).

None of the patients included were related, and consanguinity at first or second degree was found in 6/69 patients (9%). A familial history of immunopathologic manifestations (inflammatory and/or auto-immune disease) among the first-degree relatives was found in 24 (20%) patients (Table S2). A history of severe and/or recurrent infections was present in 31 patients (26%) and 30 patients had humoral immune deficiency (25%), including 20 (17%) with CVID-like disease. Organomegaly was present in 64 patients (53%) and comprised adenomegaly in 40%, splenomegaly in 31%, and hepatomegaly in 10%. Overall, 40 patients (33%) had associated immunopathologic manifestations affecting various organs (Table S2) and 37 (31%) had ANA (titer ≥1/160). Thirteen patients (11%) had malignancies, 10 before ES diagnosis (all in remission but the patient with the CMML) and 3 after ES diagnosis. After a median follow-up of 4 years [range 1–41] after ES diagnosis, four patients had died. The treatments given for ES are detailed in Table S3.

Before inclusion, 32 patients (27%) already had genetic testing for PIDD (Figure S1), either by NGS sequencing (N=26) or targeted Sanger sequencing (N=6), leading to 3 genetic diagnoses: 1 patient with a familial history of CGD and a *CYBB* heterozygous variant, 1 patient with a heterozygous del(6q23.3) resulting in deletion of exons 2–9 of *TNFAIP3*, and 1 patient with an *SLC29A3* G437R homozygous variant.

WES was performed in 118 patients (117 patients without prior genetic diagnosis and the patient with *SLC29A3* variant to search for a potential second variant; Figure S1). A total of 14.497.054 variants was obtained, including 12.299.342 single nucleotide polymorphisms (SNP) and 2.202.000 insertions/deletions. After focusing analysis on a panel of 709 genes involved in PIDDs, inherited platelet disorders, congenital hemolytic anemia, and neutropenia (Table S4), we identified 567 novel/rare variants of interest that were predicted deleterious in silico (CADD score ≥20) (Figures S2 and S3) in 117 patients (99.2%). After further analysis of WES, we identified 11 pathogenic variants among the 118 patients (Table 1), including 9 that could be linked to ES, namely, heterozygous variants in *NFKB1* (*N*=3), *CTLA4* (*N*=2), *STAT3* (*N*=1), *PTPN2* (*N*=1), *DDX41* (*(*N*=1), previously described in a family with lymphoid malignancies

and autoimmunity [5]), and a homozygous variant in *PIK3CG* (*N*=1). The clinical features of these patients and their pedigree are shown in Figure S4. In addition, one patient with a long-lasting history of thrombocytopenia and deafness that also had bona fide ITP as well as AIHA had a heterozygous pathogenic variant in *MYH9*, and another patient had compound heterozygous pathogenic variants in *GBA* and was therefore diagnosed with type 1 Gaucher disease, a condition that could explain her thrombocytopenia, neutropenia, and splenomegaly (Table 1).

Thus, in the whole cohort of 120 patients, 12 patients (10%) had a genetic diagnosis that could be linked to ES, and 2 patients (1.7%) had another relevant genetic diagnosis. Genetic diagnosis of ES allowed for family screening and identification of other patients with infectious and/or autoimmune diseases and pathogenic variants, particularly in families with *NFKB1* variants where many relatives were unaware of hypogammaglobulinemia despite several infectious events (Figure S4). Genetic diagnosis also allowed a patient with a *STAT3* gain of function variant to benefit from treatment with JAK inhibitors (Ruxolitinib, then Tofacitinib), resulting in normalized spleen size and complete response of autoimmune cytopenia.

Patients with genetic diagnosis were younger than patients without genetic diagnosis (median age 25 years [range 18–48] vs. 38 years [range 18–80], respectively, *p* < 0.01). When comparing both groups, patients with genetic diagnosis more frequently had a familial history of immunopathologic manifestation in first-degree relatives (50% vs. 16.7%, *p* < 0.01), but other clinical and biological features were not significantly different between both groups (Figure S5). Patients with first cytopenia during childhood had 16% of genetic diagnosis, versus 9% in other patients (NS).

This study reports a large cohort of patients with ES, revealing that 10% had a genetic diagnosis after complete genetic workup. As expected, this proportion was lower than that observed in pediatric cohorts [1]. Accordingly, patients with a genetic diagnosis in our cohort were younger, and we did not find pathogenic variants in patients aged ≥50 years.

The genetic testing benefited some patients, allowing for familial identification of asymptomatic hypogammaglobulinemia in the *NFKB1* families and genetic counseling, but also targeted therapy in a patient with *STAT3* GOF who was given JAK inhibitors with some success. Targeted therapies, such as abatacept in *CTLA4* haplo-insufficiency, mTOR inhibitors in ALPS patients, or JAK inhibitors in PIDD of JAK/STAT signaling [6] have been well documented in pediatric cases. WES also provided an alternative mechanism responsible for cytopenia in the patient diagnosed with Gaucher disease and in the patient with *MYH9* pathogenic variant, although the latter also had confirmed ES.

Among the 12 patients with genetic diagnoses, the responsible variant was provided by WES in 9 patients, and by previous genetic testing in 3 patients. It is likely that performing WES after NGS panel testing has a lower diagnostic yield, but this approach led to the description of new variants (such as *PTPN2*) previously missed by the PIDD panel, and it is also possible that some of the variants of interest identified by WES could later be confirmed as causative.
<table><caption>TABLE 1 | Genetic diagnoses in the cohort of 120 adult patients with ES.</caption><thead><tr><th>Patient #</th><th>Gene</th><th>Gender</th><th>Evans syndrome onset (age)</th><th>cDNA mutation</th><th>Protein level mutation</th><th>CADD</th><th>Consequence</th><th>Zygosity</th><th>Allele frequency (GnomAD)</th><th>Clinical features</th></tr></thead><tbody><tr><td>1</td><td>CYBB</td><td>M</td><td>18</td><td>c.925G&gt;A</td><td>p.E309K</td><td>29</td><td>Loss of function</td><td>HTZ</td><td>8.27e-7</td><td>ITP+AIHA CGD</td></tr><tr><td>2</td><td>TNFAIP3</td><td>F</td><td>27</td><td>Del(6q23.3)</td><td>NA</td><td>.</td><td>Loss of function</td><td>HTZ</td><td>0</td><td>ITP+AIHA Rash, lupus like disease, granulomatosis</td></tr><tr><td>3</td><td>SLC29A3</td><td>M</td><td>26</td><td>c.1309G&gt;A</td><td>G437R</td><td>27</td><td>Loss of function</td><td>HMZ</td><td>3.47e-5</td><td>ITP+AIHA + AIN H syndrome, type 1 diabetes</td></tr><tr><td>4</td><td>STAT3</td><td>F</td><td>21</td><td>c.1082A&gt;G</td><td>Q361R</td><td>25</td><td>Gain of function</td><td>HTZ</td><td>0</td><td>ITP+AIHA + AIN Organomegaly, infections, Hypogammaglobulinemia</td></tr><tr><td>5</td><td>CTLA4</td><td>F</td><td>21</td><td>c.151C&gt;T</td><td>p.R51*</td><td>34</td><td>Stop gained</td><td>HTZ</td><td>0</td><td>ITP+AIHA Psoriasis, cervical cancer, Hypogammaglobulinemia</td></tr><tr><td>6</td><td>CTLA4</td><td>M</td><td>31</td><td>c.380A&gt;G</td><td>Y127C</td><td>26</td><td>Loss of function</td><td>HTZ</td><td>0</td><td>ITP+AIHA</td></tr><tr><td>7</td><td>NFKBI</td><td>M</td><td>48</td><td>c.1550delT</td><td>p.L517fs</td><td>.</td><td>Stop gained</td><td>HTZ</td><td>0</td><td>ITP+AIHA + AIN Hypogammaglobulinemia</td></tr><tr><td>8</td><td>NFKBI</td><td>F</td><td>24</td><td>c.928-2A&gt;G</td><td>F310_Q333del</td><td>34</td><td>Loss of function</td><td>HTZ</td><td>0</td><td>ITP+AIHA Hypogammaglobulinemia</td></tr><tr><td>9</td><td>NFKBI</td><td>F</td><td>29</td><td>c.899_900dupT</td><td>p.DF300fs</td><td>1</td><td>Stop gained</td><td>HTZ</td><td>0</td><td>ITP+AIHA Hypogammaglobulinemia</td></tr><tr><td>10</td><td>PTPN2</td><td>F</td><td>20</td><td>c.376T&gt;A</td><td>Y126N</td><td>28</td><td>Loss of function</td><td>HTZ</td><td>0</td><td>ITP+AIHA + AIN</td></tr><tr><td>11</td><td>DDX4I</td><td>M</td><td>31</td><td>c.490C&gt;T</td><td>R164W</td><td>23</td><td>Unknown</td><td>HTZ</td><td>1.47e-4</td><td>ITP+AIHA Nodular lymphocyte-predominant Hodgkin lymphoma DLBCL</td></tr><tr><td>12</td><td>PIK3CG</td><td>M</td><td>18</td><td>c.2207T&gt;C</td><td>V736A</td><td>24</td><td>Unknown</td><td>HMZ</td><td>2.48e-6</td><td>ITP+AIHA Crohn disease, alopecia areata</td></tr><tr><td>13</td><td>MYH9</td><td>M</td><td>30</td><td>c.4270G&gt;A</td><td>D1424N</td><td>29</td><td>Missense</td><td>HTZ</td><td>0</td><td>ITP+AIHA Deafness</td></tr></tbody></table>

(Continues)
<table><caption>TABLE 1 | (Continued)</caption><thead><tr><th>Patient #</th><th>Gene</th><th>Gender</th><th>Evans syndrome onset (age)</th><th>cDNA mutation</th><th>Protein level mutation</th><th>CADD</th><th>Consequence</th><th>Zygosity</th><th>Allele frequency (GnomAD)</th><th>Clinical features</th></tr></thead><tbody><tr><td>14</td><td>GBA</td><td>F</td><td>19</td><td>c.1226A&gt;G<br>c.[1448T&gt;C;<br>1483G&gt;C;<br>1497G&gt;C]</td><td>p.N409S<br>p.[L483P;<br>A495P;<br>V499<sub>-</sub>]</td><td>.</td><td>Loss of function</td><td>Compound HTZ</td><td>8.05e-06</td><td>ITP + AIN<br>Splenomegaly</td></tr></tbody></table>

Abbreviations: AIHA, autoimmune hemolytic anemia; AIN, autoimmune neutropenia; CADD, combined annotation-dependent depletion; cDNA, complementary DNA; CGD, chronic granulomatous disease; DLBCL, diffuse large B cell lymphoma; HMZ, homozygous; HTZ, heterozygous; ITP, immune thrombopenia; NA, not applicable.

We did not find clinical or biological features associated with a genetic diagnosis, except the presence of immunopathologic manifestations in first-degree relatives. Nonetheless, given our results, ES diagnosis should probably prompt the physician to propose genetic testing in patients with features suggestive of PIDD such as hypogammaglobulinemia or significant family history. While adenomegalies at diagnosis were prevalent in this study, patients with SLE and indolent B-cell lymphoproliferations were excluded; therefore, the genetic diagnosis yield may be different in these populations.

Limitations of this study include a relatively low number of genetic diagnoses limiting statistical testing, and a potential recruitment bias that was limited by the inclusion of all patients with ES in the participating centers using local databases and independently of previous genetic testing. We also included some patients with a first cytopenia without ES during childhood, which may represent a particular population with more genetic variants, although genetic findings were not restricted to this population in our cohort.

In conclusion, our results suggest that genetic testing may be useful in adult-onset ES, in particular in patients aged <50 years and/or with a familial history of autoimmunity, by providing a modest but significant diagnostic yield with a potential impact on the management of patients and their relatives.

## Author Contributions

E.C., F.R.-L., and M.Mah. designed the study. E.C., D.H.-N., C.M., M.P., and M.-C.S. performed the experiments. E.C., J.F., M.C., J.R., J.D., M.Mal., B.F., L.T., O.S.-D., T.C., F.S., J.G., J.H., T.M., A.-M.R., M.E., G.R.-C., L.W., G.Ma., M.R.S., L.Ga., M.G., A.B., A.F., G.Mo., M.P., A.D., D.B., D.G., C.G., B.G., L.Gi., J.-F.V., S.A., C.F., O.H., M.Mi., M. Mah., and F.R.-L. contributed to data acquisition. EC, FRL, and M.Mah analyzed the data. All authors revised the manuscript and approved the final version.

## Affiliations

¹Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Université Paris Cité, Paris, France | ²Internal Medicine Department, Henri Mondor Hospital, AP-HP, Créteil, France | ³Clinical Immunopathology Department, Saint Louis Hospital, AP-HP, Paris, France | ⁴Haematology Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris Cité, Paris, France | ⁵Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France | ⁶Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Necker-Enfants Malades Hospital, Paris, France | ⁷Paris Cité University, Imagine Institute, Paris, France | ⁸Internal Medicine and Clinical Immunopathology Department, IUCT-Oncopole, Toulouse University Hospital, Université Paul Sabatier, Toulouse, France | ⁹Internal Medicine Department, Hôpital De La Timone, Aix-Marseille Université, Marseille, France | ¹⁰Hematology Department, Claude Huriez University Hospital, Lille, France | ¹¹Internal Medicine Department, Poitiers University Hospital, Poitiers Medicine University, Poitiers, France | ¹²Internal Medicine Department, Nantes University Hospital, Nantes, France | ¹³Sorbonne Université, Internal Medicine Department, Saint Antoine Hospital, AP-HP, Paris, France | ¹⁴Internal Medicine Department, Nancy University Hospital, Nancy, France | ¹⁵Hematology Department, CH Sud
Francilien Hospital, Corbeil Essonne, France | ¹⁶Bioinformatic Plateform, Imagine Institute, INSERM UMR 1163, Université Paris Cité, Paris, France | ¹⁷Internal Medicine Department, Croix-Rousse University Hospital, Lyon, France | ¹⁸Hematology Department, Cochin Hospital, AP-HP, Paris, France | ¹⁹Internal Medicine Department, Caen University Hospital, Caen, France | ²⁰Internal Medicine Department, Bourgoin-Jallieu Hospital, Bourgoin-Jallieu, France | ²¹Internal Medicine Department, Jean Verdier Hospital, AP-HP, Bondy, France | ²²Internal Medicine and Infectious Diseases Department, Vannes Hospital, Vannes, France | ²³Internal Medicine Department, Tours University Hospital, Tours, France | ²⁴Internal Medicine Department, Intercommunal de Créteil Hospital, Créteil, France | ²⁵Internal Medicine Department, Purpan University Hospital, Toulouse, France | ²⁶CIC 1436, Team PEPSS, Toulouse University Hhospital, Toulouse, France | ²⁷Internal Medicine Department, Bichat Hospital, AP-HP, Paris, France | ²⁸Hematology Department, Amiens University Hospital, Amiens, France | ²⁹Internal Medicine Department, Haut-Leveque Hospital, Pessac, France | ³⁰Internal Medicine Department, Dijon University Hospital, Dijon, France

## Ethics Statement

Written and informed consent for genetic testing was obtained from all patients. This study was conducted in compliance with the Declaration of Helsinki principles and was approved by the Institutional Review Boards of the ethic committee “Comité de Protection des Personnes” (CPP) of the Île de France (CPP IDF2 DC-2014-22722015-03-03 AF) and the samples collection was declared to the French ministry of research with the reference DC 2014-2272.

## Conflicts of Interest

M.Mah.: Research funds: GSK; Educational sessions: Amgen and Novartis. B.G.: Advisory boards: Amgen, Novartis, Grifols, and Sobi. M.Mi.: Advisory boards: Novartis, Amgen, UCB, Argenx, Alexion, and Sanofi. E.C.: Advisory boards: Novartis, UCB; Educational sessions: Amgen and Sanofi. G. Mo.: research grants: Amgen, Argenx, CSL Behring, Grifols, Novartis, Sanofi; Advisory boards: Alpine, Amgen, Argenx, CSL Behring, Grifols, Novartis, Sanofi, UCB pharma; Educational sessions: Amgen, Grifols, Novartis. T.C.: Advisory boards: BMS, Novartis; Educational sessions: BMS, Novartis, Takeda, Abbvie. S.A.: Congress support: Alexion, Amgen, GlaxoSmithKline, Grifols, LFB, Novartis; Consulting fees and lecture honorariums: Amgen, Argenx, GlaxoSmithKline, Grifols, Novartis, Swedish Orphan Biovitrum; Board meeting: Amgen, Argenx, GlaxoSmithKline, Novartis, Sanofi, SOBI; Research grants: Novartis. D.G.: Congress support: Amgen. Other authors declare no conflicts of interest.

## Data Availability Statement

Data are available from the corresponding author upon reasonable request.

## References

1. J. Hadjadj, N. Aladjidi, H. Fernandes, et al., “Pediatric Evans Syndrome Is Associated With a High Frequency of Potentially Damaging Variants in Immune Genes,” *Blood* 134, no. 1 (2019): 9–21.

2. A. Fischer, J. Provot, J.-P. Jais, et al., “Autoimmune and Inflammatory Manifestations Occur Frequently in Patients With Primary Immunodeficiencies,” *Journal of Allergy and Clinical Immunology* 140, no. 5 (2017): 1388–1393.

3. M. Michel, V. Chanet, A. Dechartres, et al., “The Spectrum of Evans Syndrome in Adults: New Insight Into the Disease Based on the Analysis of 68 Cases,” *Blood* 114, no. 15 (2009): 3167–3172.

4. B. Fattizzo, M. Michel, J. A. Giannotta, et al., “Evans Syndrome in Adults: An Observational Multicenter Study,” *Blood Advances* 5, no. 24 (2021): 5468–5478.

5. M. Lewinsohn, A. L. Brown, L. M. Weinel, et al., “Novel Germ Line DDX41 Mutations Define Families With a Lower Age of MDS/ AML Onset and Lymphoid Malignancies,” *Blood* 127, no. 8 (2016): 1017–1023.

6. M. Fischer, P. Olbrich, J. Hadjadj, et al., “JAK Inhibitor Treatment for Inborn Errors of JAK/STAT Signaling: An ESID/EBMT-IEWP Retrospective Study,” *Journal of Allergy and Clinical Immunology* 153, no. 1 (2024): 275–286.

## Supporting Information

Additional supporting information can be found online in the Supporting Information section.