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. 2025 Aug 8:16:1584681.
doi: 10.3389/fgene.2025.1584681. eCollection 2025.

Clinical and molecular findings in actin-related inborn errors of immunity: the middle East and North Africa registry

Zahra Chavoshzadeh #  1 , Shahrzad Fallah #  1 , Vahide Zeinali  2 , Samin Sharafian  1 , Samaneh Delavari  3 , Mehrnaz Mesdaghi  1 , Reda Djidjik  4 , Brahim Belaid  4 , Aydan Ikinciogullari  5 , Sule Haskologlu  5 , Figen Dogu  5 , Ferah Genel  6 , Nesrin Gulez  6 , Safa Baris  7   8   9 , Ahmet Ozen  7   8   9 , Elif Karakoc-Aydiner  7   8   9 , Ayça Kiykim  10 , Zeynep Meric  10 , Necil Kutukculer  11 , Ayse Aygun  11 , Guzide Aksu  11 , Neslihan Edeer Karaca  11 , Mehmet Geyik  11 , Sevgi Keles  12 , Ismail Reisli  12 , Sukru Nail Guner  12 , Rachida Boukari  13 , Saliha Hakem  13 , Reda Belbouab  13 , Mohamed-Ridha Barbouche  14 , Imen Ben-Mustapha  15 , Najla Mekki  15 , Meriem Ben-Ali  15 , Ali Sobh  16 , Marwa Elnagdy  17 , Kamel Djenouhat  18 , Azzeddine Tahiat  18 , Hiba Mohammed Shendi  19 , Amna Alkuwaiti  19 , Gulnara Nasrullayeva  20 , Tariq Alfars  21 , Nashat Alsukaiti  21 , Michel Massaad  22   23 , Cybel Mehawej  24 , Andre Megarbane  24   25 , Carla Irani  26 , Gehad Elghazali  21 , Salem Al-Tamemi  27 , Nisreen Khalifa  28 , Raed Alzyoud  29 , Sara Sebnem Kilic Gultekin  30 , Hulya Kose  30 , Hedieh Khodaverdy  1 , Bibi Shahin Shamsian  31 , Narges Eslami  1 , Tooba Momen  32 , Roya Sherkat  33 , Soheila Aleyasin  34 , Hossein Esmaeilzadeh  34 , Hamid Ahanchian  35 , Fereshte Salami  3 , Saba Fekrvand  3 , Loïc Dupre  36   37 , Hans D Ochs  38 , Nima Rezaei  3 , Waleed Al-Herz  39   40 , Hassan Abolhassani  3   41
Affiliations

Clinical and molecular findings in actin-related inborn errors of immunity: the middle East and North Africa registry

Zahra Chavoshzadeh et al. Front Genet. .

Abstract

Background: The majority of monogenic inborn errors of immunity presenting as actinopathies were reported originally from the Middle East and North Africa (MENA) countries indicating a high prevalence of these entities in the region. However, their prognosis is unclear due to rarity and lack of comprehensive treatment outcomes.

Methods: We evaluated clinical, immunological, and genetic abnormalities associated with 15 genetic entities of actinopathies. Based on the function of mutant genes in actin-regulatory pathways, patients were classified into CDC42- and RAC2-related subcategories.

Results: A total of 503 individuals (29.5% females) from 17 countries were considered with a median age of 120 months. Although most patients presented initially with allergic phenotypes (37.7%), the most prevalent manifestations throughout the lifespan were infection in respiratory tracts (72.2%). Primary clinical diagnosis was mainly combined immunodeficiencies (48.3%) and the majority of cases were molecularly assigned to the CDC42 pathway (64.8%). The most common genetic defects were reported within the DOCK8 (n = 209) followed by the WAS (n = 94) and the CARMIL2 (n = 15) genes. Hematopoietic stem cell transplantation (HSCT) was conducted on 24.0% of patients, which significantly improved survival in patients with defects in WAS, DOCK8 and DOCK2. Overall mortality was 23.0%, mainly due to sepsis and malignancy.

Conclusion: Patients with defects in RAC2-associated regulators of actin usually present with late-onset symptoms due to normal immune profiles, but a higher rate of EBV and HPV infections, autoimmune cytopenia, asthma, and lymphoproliferation compared to defects in the CDC42 pathway. The severity of mutations in patients of the CDC42 group helps to estimate the prognosis of the disease and prioritization of HSCT.

Keywords: actinopathies; eosinophilia; genetic; immune dysregulation; inborn errors of immunity; primary immunodeficiency; thrombocytopenia.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

FIGURE 1
FIGURE 1
(A) An illustration of countries from the MENA region and the prevalence and number of actin-related inborn errors of immunity cases contributed to the study originated from 17 countries. (B) The frequency of first presentations in actin-related inborn errors of immunity patients. (C) Percentage of different pathogens isolated from infected patients with actinopathies.
FIGURE 2
FIGURE 2
(A) Schematic pathway of actin-remodeling in the leukocyte via two main pathways. An opportunity for fresh actin polymerization to generate membrane protrusions at the leading edge is created by the collapse of the cortical actin network to the side of cells occupied by microtubule organizing centers by two main pathways associated with The Rho family of tiny G-proteins, which includes RAC2 (blue colors) and Cell division control protein 42 homolog (CDC42, red colors). Activated CDC42 pathway generates filopodia by inducing the WAVE complex and the RAC2 pathway promotes lamellipodia via ARP2/3 complex. Few genes also are known with an important role in the recycling and transcription of monomers of actins (green colors) (B) The frequency of genes, (C) inheritance pattern (AR: autosomal recessive, XR: X-lined recessive, AD: autosomal dominant) and (D) the most frequent variants associated with monogenic actin-related inborn errors of immunity mainly associated with defects in RAC2 and CDC42 GTPase pathways.
FIGURE 3
FIGURE 3
Survival analysis of monogenic actin-related inborn errors of immunity patients in the MENA region based on (A) genetic defects, (B) severity of mutations (nonsense or frameshift variants assigned as severe, while in-frame deletion/insertion, splicing, or missense mutations depicted as mild) and (C) hematopoietic stem cell transplantation.
See this image and copyright information in PMC

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