Clinical and molecular findings in actin-related inborn errors of immunity: the middle East and North Africa registry
BackgroundThe 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 compre...
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2025-08-01
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| author | Zahra Chavoshzadeh Shahrzad Fallah Vahide Zeinali Samin Sharafian Samaneh Delavari Mehrnaz Mesdaghi Reda Djidjik Brahim Belaid Aydan Ikinciogullari Sule Haskologlu Figen Dogu Ferah Genel Nesrin Gulez Safa Baris Safa Baris Safa Baris Ahmet Ozen Ahmet Ozen Ahmet Ozen Elif Karakoc-Aydiner Elif Karakoc-Aydiner Elif Karakoc-Aydiner Ayça Kiykim Zeynep Meric Necil Kutukculer Ayse Aygun Guzide Aksu Neslihan Edeer Karaca Mehmet Geyik Sevgi Keles Ismail Reisli Sukru Nail Guner Rachida Boukari Saliha Hakem Reda Belbouab Mohamed-Ridha Barbouche Imen Ben-Mustapha Najla Mekki Meriem Ben-Ali Ali Sobh Marwa Elnagdy Kamel Djenouhat Azzeddine Tahiat Hiba Mohammed Shendi Amna Alkuwaiti Gulnara Nasrullayeva Tariq Alfars Nashat Alsukaiti Michel Massaad Michel Massaad Cybel Mehawej Andre Megarbane Andre Megarbane Carla Irani Gehad Elghazali Salem Al-Tamemi Nisreen Khalifa Raed Alzyoud Sara Sebnem Kilic Gultekin Hulya Kose Hedieh Khodaverdy Bibi Shahin Shamsian Narges Eslami Tooba Momen Roya Sherkat Soheila Aleyasin Hossein Esmaeilzadeh Hamid Ahanchian Fereshte Salami Saba Fekrvand Loïc Dupre Loïc Dupre Hans D. Ochs Nima Rezaei Waleed Al-Herz Waleed Al-Herz Hassan Abolhassani Hassan Abolhassani |
| author_facet | Zahra Chavoshzadeh Shahrzad Fallah Vahide Zeinali Samin Sharafian Samaneh Delavari Mehrnaz Mesdaghi Reda Djidjik Brahim Belaid Aydan Ikinciogullari Sule Haskologlu Figen Dogu Ferah Genel Nesrin Gulez Safa Baris Safa Baris Safa Baris Ahmet Ozen Ahmet Ozen Ahmet Ozen Elif Karakoc-Aydiner Elif Karakoc-Aydiner Elif Karakoc-Aydiner Ayça Kiykim Zeynep Meric Necil Kutukculer Ayse Aygun Guzide Aksu Neslihan Edeer Karaca Mehmet Geyik Sevgi Keles Ismail Reisli Sukru Nail Guner Rachida Boukari Saliha Hakem Reda Belbouab Mohamed-Ridha Barbouche Imen Ben-Mustapha Najla Mekki Meriem Ben-Ali Ali Sobh Marwa Elnagdy Kamel Djenouhat Azzeddine Tahiat Hiba Mohammed Shendi Amna Alkuwaiti Gulnara Nasrullayeva Tariq Alfars Nashat Alsukaiti Michel Massaad Michel Massaad Cybel Mehawej Andre Megarbane Andre Megarbane Carla Irani Gehad Elghazali Salem Al-Tamemi Nisreen Khalifa Raed Alzyoud Sara Sebnem Kilic Gultekin Hulya Kose Hedieh Khodaverdy Bibi Shahin Shamsian Narges Eslami Tooba Momen Roya Sherkat Soheila Aleyasin Hossein Esmaeilzadeh Hamid Ahanchian Fereshte Salami Saba Fekrvand Loïc Dupre Loïc Dupre Hans D. Ochs Nima Rezaei Waleed Al-Herz Waleed Al-Herz Hassan Abolhassani Hassan Abolhassani |
| author_sort | Zahra Chavoshzadeh |
| collection | DOAJ |
| description | BackgroundThe 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.MethodsWe 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.ResultsA 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.ConclusionPatients 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. |
| format | Article |
| id | doaj-art-5aade0dafc1e4580889954e502d1be8e |
| institution | Kabale University |
| issn | 1664-8021 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj-art-5aade0dafc1e4580889954e502d1be8e2025-08-20T03:41:01ZengFrontiers Media S.A.Frontiers in Genetics1664-80212025-08-011610.3389/fgene.2025.15846811584681Clinical and molecular findings in actin-related inborn errors of immunity: the middle East and North Africa registryZahra Chavoshzadeh0Shahrzad Fallah1Vahide Zeinali2Samin Sharafian3Samaneh Delavari4Mehrnaz Mesdaghi5Reda Djidjik6Brahim Belaid7Aydan Ikinciogullari8Sule Haskologlu9Figen Dogu10Ferah Genel11Nesrin Gulez12Safa Baris13Safa Baris14Safa Baris15Ahmet Ozen16Ahmet Ozen17Ahmet Ozen18Elif Karakoc-Aydiner19Elif Karakoc-Aydiner20Elif Karakoc-Aydiner21Ayça Kiykim22Zeynep Meric23Necil Kutukculer24Ayse Aygun25Guzide Aksu26Neslihan Edeer Karaca27Mehmet Geyik28Sevgi Keles29Ismail Reisli30Sukru Nail Guner31Rachida Boukari32Saliha Hakem33Reda Belbouab34Mohamed-Ridha Barbouche35Imen Ben-Mustapha36Najla Mekki37Meriem Ben-Ali38Ali Sobh39Marwa Elnagdy40Kamel Djenouhat41Azzeddine Tahiat42Hiba Mohammed Shendi43Amna Alkuwaiti44Gulnara Nasrullayeva45Tariq Alfars46Nashat Alsukaiti47Michel Massaad48Michel Massaad49Cybel Mehawej50Andre Megarbane51Andre Megarbane52Carla Irani53Gehad Elghazali54Salem Al-Tamemi55Nisreen Khalifa56Raed Alzyoud57Sara Sebnem Kilic Gultekin58Hulya Kose59Hedieh Khodaverdy60Bibi Shahin Shamsian61Narges Eslami62Tooba Momen63Roya Sherkat64Soheila Aleyasin65Hossein Esmaeilzadeh66Hamid Ahanchian67Fereshte Salami68Saba Fekrvand69Loïc Dupre70Loïc Dupre71Hans D. Ochs72Nima Rezaei73Waleed Al-Herz74Waleed Al-Herz75Hassan Abolhassani76Hassan Abolhassani77Department of Allergy and Clinical Immunology, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, IranDepartment of Allergy and Clinical Immunology, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, IranResearch Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran, IranDepartment of Allergy and Clinical Immunology, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, IranResearch Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, IranDepartment of Allergy and Clinical Immunology, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, IranDepartment of Medical Immunology, Beni Messous University Hospital Center, Faculty of Pharmacy, University of Health Sciences, Algiers, AlgeriaDepartment of Medical Immunology, Beni Messous University Hospital Center, Faculty of Pharmacy, University of Health Sciences, Algiers, AlgeriaDepartment of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, TürkiyeDepartment of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, TürkiyeDepartment of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, TürkiyeDepartment of Pediatric Immunology and Allergy, University of Health Sciences Dr. Behcet Uz Children’s Hospital, Izmir, TürkiyeDepartment of Pediatric Immunology and Allergy, University of Health Sciences Dr. Behcet Uz Children’s Hospital, Izmir, TürkiyeDivision of Allergy and Immunology, Marmara University School of Medicine, Istanbul, TürkiyeThe Isil Berat Barlan Center for Translational Medicine, Marmara University School of Medicine, Istanbul, TürkiyeIstanbul Jeffrey Modell Foundation Diagnostic Center for Primary Immune Deficiencies, Istanbul, TürkiyeDivision of Allergy and Immunology, Marmara University School of Medicine, Istanbul, TürkiyeThe Isil Berat Barlan Center for Translational Medicine, Marmara University School of Medicine, Istanbul, TürkiyeIstanbul Jeffrey Modell Foundation Diagnostic Center for Primary Immune Deficiencies, Istanbul, TürkiyeDivision of Allergy and Immunology, Marmara University School of Medicine, Istanbul, TürkiyeThe Isil Berat Barlan Center for Translational Medicine, Marmara University School of Medicine, Istanbul, TürkiyeIstanbul Jeffrey Modell Foundation Diagnostic Center for Primary Immune Deficiencies, Istanbul, Türkiye0Department of Pediatric Allergy and Immunology, Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Türkiye0Department of Pediatric Allergy and Immunology, Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Türkiye1Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Türkiye1Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Türkiye1Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Türkiye1Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Türkiye1Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Türkiye2Division of Pediatric Allergy and Immunology, Meram Medical Faculty, Necmettin Erbakan University, Konya, Türkiye2Division of Pediatric Allergy and Immunology, Meram Medical Faculty, Necmettin Erbakan University, Konya, Türkiye2Division of Pediatric Allergy and Immunology, Meram Medical Faculty, Necmettin Erbakan University, Konya, Türkiye3Department of Pediatrics, University Hospital of Mustapha Pacha, University of Algiers, Algiers, Algeria3Department of Pediatrics, University Hospital of Mustapha Pacha, University of Algiers, Algiers, Algeria3Department of Pediatrics, University Hospital of Mustapha Pacha, University of Algiers, Algiers, Algeria4Department of Microbiology, Immunology and Infectious Diseases, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain5Laboratory of Transmission, Control and Immunobiology of Infections, Department of Immunology, Institut Pasteur de Tunis and University Tunis El Manar, Tunis, Tunisia5Laboratory of Transmission, Control and Immunobiology of Infections, Department of Immunology, Institut Pasteur de Tunis and University Tunis El Manar, Tunis, Tunisia5Laboratory of Transmission, Control and Immunobiology of Infections, Department of Immunology, Institut Pasteur de Tunis and University Tunis El Manar, Tunis, Tunisia6Department of Pediatrics, Mansoura University Children’s Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt7Department of Biochemistry and Molecular Biology, Mansoura University Faculty of Medicine, Mansoura, Egypt8Laboratory of Immunology, Department of Medical Biology, Rouiba Hospital, University of Algiers, Algiers, Algeria8Laboratory of Immunology, Department of Medical Biology, Rouiba Hospital, University of Algiers, Algiers, Algeria9Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates9Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates0Department Immunology Research Laboratory, Azerbaijan Medical University, Baku, Azerbaijan1Department of Immunology, Sheikh Khalifa Medical City, PureLab, PureHealth, and Faculty of Medicine, United Arab Emirates University, Al Ain, United Arab Emirates1Department of Immunology, Sheikh Khalifa Medical City, PureLab, PureHealth, and Faculty of Medicine, United Arab Emirates University, Al Ain, United Arab Emirates2Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon3Division of Pediatric Infectious Diseases, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon4Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon4Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon5Institut Jerome Lejeune, Paris, France6Internal Medicine and Clinical Immunology, Hotel-Dieu de France Hospital, Saint Joseph University, Beirut, Lebanon1Department of Immunology, Sheikh Khalifa Medical City, PureLab, PureHealth, and Faculty of Medicine, United Arab Emirates University, Al Ain, United Arab Emirates7Department of Child Health, Sultan Qaboos University Hospital, University Medical City, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman8NBK Children’s Hospital, Kuwait City, Kuwait9Allergy, Immunology, and Rheumatology, Queen Rania Children’s Hospital, Amman, Jordan0Division of Pediatric Allergy and Immunology, Department of Pediatrics, Faculty of Medicine, Uludağ University, Bursa, Türkiye0Division of Pediatric Allergy and Immunology, Department of Pediatrics, Faculty of Medicine, Uludağ University, Bursa, TürkiyeDepartment of Allergy and Clinical Immunology, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran1Pediatric Congenital Hematologic Disorders Research Center, Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran, IranDepartment of Allergy and Clinical Immunology, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran2Department of Asthma, Allergy and Clinical Immunology, Child Growth and Development Research Center, Research Institute of Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran3Immunodeficiency Diseases Research Center, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran4Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran4Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran5Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, IranResearch Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, IranResearch Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran6Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), NSERM, CNRS, Toulouse University, Toulouse, France7Department of Dermatology, Medical University of Vienna, Vienna, Austria8Department of Pediatrics, Seattle Children’s Research Institute, University of Washington, Seattle, WA, United StatesResearch Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran9Department of Pediatrics, College of Medicine, Kuwait University, Kuwait City, Kuwait0Allergy and Clinical Immunology Unit, Pediatric Department, Al-Sabah Hospital, Kuwait City, KuwaitResearch Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran1Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SwedenBackgroundThe 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.MethodsWe 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.ResultsA 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.ConclusionPatients 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.https://www.frontiersin.org/articles/10.3389/fgene.2025.1584681/fullactinopathiesthrombocytopeniaeosinophiliainborn errors of immunityprimary immunodeficiencygenetic |
| spellingShingle | Zahra Chavoshzadeh Shahrzad Fallah Vahide Zeinali Samin Sharafian Samaneh Delavari Mehrnaz Mesdaghi Reda Djidjik Brahim Belaid Aydan Ikinciogullari Sule Haskologlu Figen Dogu Ferah Genel Nesrin Gulez Safa Baris Safa Baris Safa Baris Ahmet Ozen Ahmet Ozen Ahmet Ozen Elif Karakoc-Aydiner Elif Karakoc-Aydiner Elif Karakoc-Aydiner Ayça Kiykim Zeynep Meric Necil Kutukculer Ayse Aygun Guzide Aksu Neslihan Edeer Karaca Mehmet Geyik Sevgi Keles Ismail Reisli Sukru Nail Guner Rachida Boukari Saliha Hakem Reda Belbouab Mohamed-Ridha Barbouche Imen Ben-Mustapha Najla Mekki Meriem Ben-Ali Ali Sobh Marwa Elnagdy Kamel Djenouhat Azzeddine Tahiat Hiba Mohammed Shendi Amna Alkuwaiti Gulnara Nasrullayeva Tariq Alfars Nashat Alsukaiti Michel Massaad Michel Massaad Cybel Mehawej Andre Megarbane Andre Megarbane Carla Irani Gehad Elghazali Salem Al-Tamemi Nisreen Khalifa Raed Alzyoud Sara Sebnem Kilic Gultekin Hulya Kose Hedieh Khodaverdy Bibi Shahin Shamsian Narges Eslami Tooba Momen Roya Sherkat Soheila Aleyasin Hossein Esmaeilzadeh Hamid Ahanchian Fereshte Salami Saba Fekrvand Loïc Dupre Loïc Dupre Hans D. Ochs Nima Rezaei Waleed Al-Herz Waleed Al-Herz Hassan Abolhassani Hassan Abolhassani Clinical and molecular findings in actin-related inborn errors of immunity: the middle East and North Africa registry Frontiers in Genetics actinopathies thrombocytopenia eosinophilia inborn errors of immunity primary immunodeficiency genetic |
| title | Clinical and molecular findings in actin-related inborn errors of immunity: the middle East and North Africa registry |
| title_full | Clinical and molecular findings in actin-related inborn errors of immunity: the middle East and North Africa registry |
| title_fullStr | Clinical and molecular findings in actin-related inborn errors of immunity: the middle East and North Africa registry |
| title_full_unstemmed | Clinical and molecular findings in actin-related inborn errors of immunity: the middle East and North Africa registry |
| title_short | Clinical and molecular findings in actin-related inborn errors of immunity: the middle East and North Africa registry |
| title_sort | clinical and molecular findings in actin related inborn errors of immunity the middle east and north africa registry |
| topic | actinopathies thrombocytopenia eosinophilia inborn errors of immunity primary immunodeficiency genetic |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2025.1584681/full |
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clinicalandmolecularfindingsinactinrelatedinbornerrorsofimmunitythemiddleeastandnorthafricaregistry AT nimarezaei clinicalandmolecularfindingsinactinrelatedinbornerrorsofimmunitythemiddleeastandnorthafricaregistry AT waleedalherz clinicalandmolecularfindingsinactinrelatedinbornerrorsofimmunitythemiddleeastandnorthafricaregistry AT waleedalherz clinicalandmolecularfindingsinactinrelatedinbornerrorsofimmunitythemiddleeastandnorthafricaregistry AT hassanabolhassani clinicalandmolecularfindingsinactinrelatedinbornerrorsofimmunitythemiddleeastandnorthafricaregistry AT hassanabolhassani clinicalandmolecularfindingsinactinrelatedinbornerrorsofimmunitythemiddleeastandnorthafricaregistry |