Clinical and Molecular Findings in Actin-related Inborn Errors of Immunity: The Middle East and North Africa Registry

Zahra Chavoshzadeh¹Shahrzad Fallah^1*Vahide Zeinali²Samin Sharafian¹Samaneh Delavari³Mehrnaz Mesdaghi²Reda Djidjik⁴Brahim Belaid⁴Kamile Aydan Ikinciogullari⁵Şule Haskoloğlu⁵Figen Dogu⁵Ferah Genel⁶Nesrin Gulez⁶Safa Baris⁷Ahmet Ozen⁷Elif Karakoc-Aydiner⁷Ayca Kiykim⁸Zeynep Meric⁸Necil Kutukculer⁹Ayse Aygun⁹Guzide Aksu⁹Edeer Neslihan⁹Mehmet Geyik⁹Sevgi Keles¹⁰Ismail Reisli¹⁰Sukru Nail¹⁰RACHIDA BOUKARI⁴Saliha Hakem⁴Reda Belbouab⁴Mohamed-Ridha Barbouche¹¹Imen Ben- Mustapha¹¹NAJLA MEKKI¹¹Meriem Ben-Ali¹¹Ali Sobh¹²Marwa Elnagdy¹²Kamel Djenouhat⁴Azzeddine Tahiat⁴Hiba Shendi¹³Amna Alkuwaiti¹⁴Gulnara Nasrullayeva¹⁵Tariq Al Farsi¹⁶Nashat Alsukaiti¹⁶Michel J. Massaad¹⁷Cybel Mehawej¹⁸André Mégarbané¹⁸Carla Irani¹⁹Gehad Elghazali¹⁶Salem Al-Tamemi²⁰Nisreen Khalifa²¹Raed Alzyoud²²Sara Sebnem Kilic²³Hulya Kose²³Hedieh Khodaverdy¹Bibi Shahin Shamsian¹Nima Eslami¹Tooba Momen²⁴Roya Sherkat²⁴Soheila Aleyasin²⁵Hossein Esmaeilzadeh²⁵Hamid Ahanchian²⁶Fereshte Salami³Saba Fekrvand³Loïc Dupre²⁷Hans D Ochs²⁸Nima Rezaei³Waleed Al-Herz²¹Hassan Abolhassani^29*

• ¹Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Alborz, Iran
• ²Shahid Beheshti University of Medical Sciences, Tehran, Tehran, Iran
• ³Tehran University of Medical Sciences, Tehran, Tehran, Iran
• ⁴University of Algiers, Algiers, Algiers, Algeria
• ⁵Faculty of Medicine, Ankara University, Ankara, Sakarya, Türkiye
• ⁶Dr.Behçet Uz Children's Hospital, University of Health Sciences, Konak, Izmir, Türkiye
• ⁷School of Medicine, Marmara University, Maltepe, Istanbul, Türkiye
• ⁸Faculty of Medicine, Istanbul University, Istanbul, Istanbul, Türkiye
• ⁹Ege University, Bornova, İzmir, Türkiye
• ¹⁰Necmettin Erbakan University, Karatay, Konya, Türkiye
• ¹¹Pasteur Institute of Tunis, Tunis, Tunisia
• ¹²Mansoura University, Mansoura, Dakahlia, Egypt
• ¹³Department of Pediatrics, Tawam Hospital, Al Ain, United Arab Emirates
• ¹⁴Tawam Hospital, Al Ain, Abu Dhabi, United Arab Emirates
• ¹⁵Azerbaijan Medical University, Baku, Azerbaijan
• ¹⁶United Arab Emirates University, Al-Ain, Abu Dhabi, United Arab Emirates
• ¹⁷American University of Beirut Medical Center, Beirut, Beyrouth, Lebanon
• ¹⁸Lebanese American University, Beirut, Beirut, Lebanon
• ¹⁹Saint Joseph University, Beirut, Beirut, Lebanon
• ²⁰Sultan Qaboos University Hospital, Muscat, Oman
• ²¹Kuwait University, Kuwait City, Kuwait
• ²²Queen Rania al-Abdullah Center for Environmental Science & Technology, Jordan University of Science and Technology, Irbid, Irbid, Jordan
• ²³Bursa Uludağ University, Bursa, Bursa, Türkiye
• ²⁴Isfahan University of Medical Sciences, Isfahan, Isfahan, Iran
• ²⁵Shiraz University of Medical Sciences, Shiraz, Fars, Iran
• ²⁶Mashhad University of Medical Sciences, Mashhad, Razavi Khorasan, Iran
• ²⁷Medical University of Vienna, Vienna, Vienna, Austria
• ²⁸University of Washington, Seattle, Washington, United States
• ²⁹Department of Medical Biochemistry and Biophysics, Karolinska Institutet (KI), Stockholm, Sweden

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.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 (42.1%), the most prevalent manifestations throughout the lifespan were infection in respiratory tracts (72.1%). 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, with significantly improved survival in patients with defects in WAS, DOCK8 and DOCK2. Overall mortality was 23.0%, mainly due to sepsis and malignancy.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.