Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing-a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

Australian Inherited Retinal Disease Registry and DNA Bank Department of Medical Technology and Physics Sir Charles Gairdner Hospital Nedlands WA 6009 Australia

Blueprint Genetics 02150 Espoo Finland

Center for Biomedical Network Research on Rare Diseases Instituto de Salud Carlos 3 28029 Madrid Spain

Center for Human Genetics and Pharmacogenomics Faculty of Medicine University of Maribor 2000 Maribor Slovenia

Center for Medical Genetics Ghent University Hospital 9000 Ghent Belgium

Centre for Ophthalmology and Visual Science The University of Western Australia Nedlands WA 6009 Australia

Children's Clinical University Hospital LV 1004 Riga Latvia

College of Optometry University of Houston Houston TX 77004 USA

Datana Solutions 54 530 Wroclaw Poland

Department of Biomolecular Medicine Ghent University 9000 Ghent Belgium

Department of Genetics Health Research Institute Fundación Jiménez Díaz University Hospital Universidad Autónoma de Madrid 28049 Madrid Spain

Department of Histology and Embryology Medical University of Warsaw 02 004 Warsaw Poland

Department of Human Genetics Radboud University Medical Center 6500 HB Nijmegen The Netherlands

Department of Medical and Surgical Sciences University of Bologna 40127 Bologna Italy

Department of Medical Genetics Koc University School of Medicine 34450 Istanbul Turkey

Department of Molecular Genetics Institute of Pathology Faculty of Medicine University of Ljubljana 1000 Ljubljana Slovenia

Department of Ophthalmology 1st Faculty of Medicine Charles University and General University Hospital Prague 128 08 Prague Czech Republic

Department of Ophthalmology and Visual Sciences Universidade Federal de São Paulo São Paulo 04023 062 SP Brazil

Department of Ophthalmology Columbia University New York NY 10027 USA

Department of Ophthalmology Hadassah Medical Center Faculty of Medicine The Hebrew University of Jerusalem Jerusalem 91120 Israel

Department of Ophthalmology Medical University of Warsaw SPKSO Ophthalmic University Hospital 03 709 Warsaw Poland

Department of Ophthalmology New Zealand National Eye Centre Faculty of Medical and Health Sciences The University of Auckland Grafton Auckland 1023 New Zealand

Department of Ophthalmology Radboud University Medical Center 6525 GA Nijmegen The Netherlands

Department of Ophthalmology Riga Stradins University LV 1007 Riga Latvia

Department of Ophthalmology The Jikei University School of Medicine Tokyo 105 8461 Japan

Department of Paediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague 128 08 Prague Czech Republic

Department of Pathology and Cell Biology Columbia University New York NY 10027 USA

Department of Pharmacy and Biotechnology University of Bologna 40127 Bologna Italy

Department of Precision Medicine University of Campania 'Luigi Vanvitelli' 80138 Naples Italy

Division of Molecular Medicine Leeds Institute of Medical Research St James's University Hospital University of Leeds Leeds LS9 7TF UK

Eye Clinic Multidisciplinary Department of Medical Surgical and Dental Sciences University of Campania 'Luigi Vanvitelli' 80131 Naples Italy

Eye Department Greenlane Clinical Centre Auckland District Health Board Auckland 1142 New Zealand

Eye Hospital University Medical Centre Ljubljana 1000 Ljubljana Slovenia

Faculty of Medicine University of Ljubljana 1000 Ljubljana Slovenia

Institute of Clinical Human Genetics University Hospital Regensburg 93053 Regensburg Germany

Institute of Human Genetics University Hospital of Cologne 50937 Cologne Germany

Institute of Human Genetics University of Regensburg 93053 Regensburg Germany

Institute of Molecular and Clinical Ophthalmology Basel 4031 Basel Switzerland

Instituto de Genética Ocular São Paulo 04552 050 SP Brazil

Jules Stein Eye Institute Los Angeles CA 90095 USA

Laboratorio de Terapia Molecular y Celular Fundación Instituto Leloir CONICET Buenos Aires 1405 Argentina

Nuffield Laboratory of Ophthalmology Nuffield Department of Clinical Neurosciences Oxford University Oxford OX3 9DU UK

Ophthalmic Genetics Unit OMMA Ophthalmological Institute of Athens 115 25 Athens Greece

Ophthalmology University of California Los Angeles David Geffen School of Medicine Los Angeles CA 90095 USA

Oxford Eye Hospital Oxford University NHS Foundation Trust Oxford OX3 9DU UK

Ruth and Bruce Rappaport Faculty of Medicine Technion Israel Institute of Technology Haifa 31096 Israel

St John of Jerusalem Eye Hospital Group East Jerusalem 91198 Palestine

Telethon Institute of Genetics and Medicine 80078 Pozzuoli Italy

The Rotterdam Eye Hospital 3011 BH Rotterdam The Netherlands

The School of Genetics and Microbiology The University of Dublin Trinity College D02 VF25 Dublin Ireland

Unit of Medical Genetics IRCCS Azienda Ospedaliero Universitaria di Bologna 40138 Bologna Italy

Univ Lille Inserm CHU Lille U1172 LilNCog Lille Neuroscience and Cognition F 59000 Lille France

University of Cape Town MRC Precision and Genomic Medicine Research Unit Division of Human Genetics Department of Pathology Institute of Infectious Disease and Molecular Medicine Faculty of Health Sciences University of Cape Town Cape Town 7925 South Africa

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