Biallelic germline variants in the hematologic malignancy predisposition gene DDX41 cause retinal dystrophy through dysregulation of retinal homeostasis

DDX41 encodes a DEAD-box ATPase RNA helicase essential for RNA splicing, innate immune signaling, and hematopoiesis. Monoallelic germline DDX41 pathogenic variants represent the most common inherited predisposition to adult-onset myeloid malignancies, but their role in retinal disorders has remained unexplored. Using next-generation sequencing, we identified nine distinct germline DDX41 variants in biallelic combinations across ten families with inherited retinal disease, including one family previously reported by Diness et al. (2018), in whom retinal involvement had not been recognized. Patient fibroblasts homozygous for the missense variant c.1187T > C (p.I396T) and Ddx41 I396T/I396T mouse retinas exhibited markedly reduced DDX41 protein levels. Electroretinography demonstrated early and severe visual dysfunction, establishing a direct requirement for DDX41 in retinal physiology. DDX41 is localized to nuclei of all major retinal cell types and to photoreceptor synapses. Biochemical assays showed that disease-associated variants disrupted RNA binding through misfolding and aggregation, causing loss of function. Transcriptomic and proteomic profiling of mutant retinas revealed dysregulation of pathways involved in photoreceptor maintenance, RNA processing, immune signaling, and adherens junctions. Immunofluorescence analysis demonstrated altered Müller glial organization, and reactive gliosis. Retinal interactome analysis further characterized DDX41-associated protein networks enriched in synaptic function, RNA processing, and membrane trafficking pathways. These findings identify DDX41 deficiency as a previously unrecognized cause of early-onset severe retinal dystrophy (EOSRD). Clinically, they extend the spectrum of DDX41‑related disease beyond hematologic malignancies, indicating that individuals with biallelic variants may present with early‑onset visual impairment. More broadly, this work underscores the essential role of RNA helicases in neural tissue integrity and shows that disruption of DDX41 impairs retinal homeostasis and visual function.

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Journal
Genome Medicine
Published
2026-10-31
DOI
https://doi.org/10.1186/s13073-026-01824-6
Primary Topic
Retinal Development and Disorders
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article
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article

Biallelic germline variants in the hematologic malignancy predisposition gene DDX41 cause retinal dystrophy through dysregulation of retinal homeostasis

Lucas Fares‐Taie, Hafiz Muhammad Jafar Hussain, Carlo Rivolta, Victor Michel et al.
Genome Medicine
Retinal Development and Disorders
article

Biallelic germline variants in the hematologic malignancy predisposition gene DDX41 cause retinal dystrophy through dysregulation of retinal homeostasis

Lucas Fares‐Taie, Hafiz Muhammad Jafar Hussain, Carlo Rivolta, Victor Michel, Jérôme E. Roger, Duanya Liu, Siying Lin, Isabelle S. Audo, Béatrice Bocquet, Isabelle Meunier, Pierre David, Zoéline Mars, Isabelle Perrault, María Pilar Martín-Gutiérrez, Karolina Kamińska, Anna M. Boguszewska‐Chachulska, Slawomir Jan Teper, Marie Sébert, Line Kessel, Takero Miyagawa, Sebastian M. Fica, Hélène Dollfus, Carmen Ayuso, Mark Edward Pennesi, Mathieu Quinodoz, Jean‐Michel Rozet, Matthieu P. A. Robert, Vincent A. Jung, Christina Zeitz, Abigail R. Moye, Gavin Arno, Christel Condroyer, Gema García‐García, Rui Sousa‐Luís, Karin Wadt, Frédéric Rieux‐Laucat, Stéphane Giraudier, Andrew R. Webster, Ewa Matczyńska, Pilar Barberán-Martínez, Rui Chen, Andrea Zanetti, José María Millán, Aline Antonio, Olivier Patat, Louise Gioja, Paul Yang, Frederic Tran Mau Them, Saoud Tahsin Swafiri, Meng Wang, Chiara Ida Guerrera, Li Yumei, Lidia Fernández-Caballero, Xuan Bao
article en

Abstract

DDX41 encodes a DEAD-box ATPase RNA helicase essential for RNA splicing, innate immune signaling, and hematopoiesis. Monoallelic germline DDX41 pathogenic variants represent the most common inherited predisposition to adult-onset myeloid malignancies, but their role in retinal disorders has remained unexplored. Using next-generation sequencing, we identified nine distinct germline DDX41 variants in biallelic combinations across ten families with inherited retinal disease, including one family previously reported by Diness et al. (2018), in whom retinal involvement had not been recognized. Patient fibroblasts homozygous for the missense variant c.1187T > C (p.I396T) and Ddx41 I396T/I396T mouse retinas exhibited markedly reduced DDX41 protein levels. Electroretinography demonstrated early and severe visual dysfunction, establishing a direct requirement for DDX41 in retinal physiology. DDX41 is localized to nuclei of all major retinal cell types and to photoreceptor synapses. Biochemical assays showed that disease-associated variants disrupted RNA binding through misfolding and aggregation, causing loss of function. Transcriptomic and proteomic profiling of mutant retinas revealed dysregulation of pathways involved in photoreceptor maintenance, RNA processing, immune signaling, and adherens junctions. Immunofluorescence analysis demonstrated altered Müller glial organization, and reactive gliosis. Retinal interactome analysis further characterized DDX41-associated protein networks enriched in synaptic function, RNA processing, and membrane trafficking pathways. These findings identify DDX41 deficiency as a previously unrecognized cause of early-onset severe retinal dystrophy (EOSRD). Clinically, they extend the spectrum of DDX41‑related disease beyond hematologic malignancies, indicating that individuals with biallelic variants may present with early‑onset visual impairment. More broadly, this work underscores the essential role of RNA helicases in neural tissue integrity and shows that disruption of DDX41 impairs retinal homeostasis and visual function.

Genome Medicine
University of Copenhagen (DK), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Institut de la Vision (FR), University of Leicester (GB), Inserm (FR), Oregon Health & Science University (US), Medical University of Silesia (PL), Baylor College of Medicine (US), University of Basel (CH), Université de Montpellier (FR), University of California, Irvine (US), Université Paris Cité (FR), Université Paris-Saclay (FR), Centre hospitalier national d'ophtalmologie des Quinze-Vingts (FR), Instituto de Salud Carlos III (ES), Glostrup Hospital (DK), Copenhagen University Hospital (DK), Rigshospitalet (DK), Centre Hospitalier Universitaire de Toulouse (FR), Sorbonne Université (FR), University of Oxford (GB), Institut des Neurosciences Paris-Saclay (FR), St Mary's Hospital (GB), NIHR Moorfields Biomedical Research Centre (GB), Manchester University NHS Foundation Trust (GB), Centre Hospitalier Universitaire de Montpellier (FR), Assistance Publique – Hôpitaux de Paris (FR), Centre for Biomedical Network Research on Rare Diseases (ES), Retina Foundation of the Southwest (US), Hospital Universitario Fundación Jiménez Díaz (ES), Institute for Neurosciences of Montpellier (FR), Hôpital Saint-Louis (FR), Hôpitaux Universitaires de Strasbourg (FR), Genomed (Poland) (PL), Greenwood Genetic Center (US), Moorfields Eye Hospital (GB), Institut des Maladies Génétiques Imagine (FR), Institute of Molecular and Clinical Ophthalmology Basel (CH), Instituto de Investigación Sanitaria La Fe (ES), ERN EYE (FR), Laboratoire de Génétique Médicale (FR), Structure fédérative de recherche Necker (FR), Institut de recherche Saint-Louis (FR), Hématopoïèse normale et pathologique : Emergence, environnement et recherche translationnelle (FR), Laboratoire d'hématologie (FR), Instituto de Investigación Sanitaria Fundación Jiménez Díaz (ES), University College London (GB), Universidad Autónoma de Madrid (ES), Université de Strasbourg (FR)
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