Biomolecules (Mar 2024)
Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes
- Rebekkah J. Hitti-Malin,
- Daan M. Panneman,
- Zelia Corradi,
- Erica G. M. Boonen,
- Galuh Astuti,
- Claire-Marie Dhaenens,
- Heidi Stöhr,
- Bernhard H. F. Weber,
- Dror Sharon,
- Eyal Banin,
- Marianthi Karali,
- Sandro Banfi,
- Tamar Ben-Yosef,
- Damjan Glavač,
- G. Jane Farrar,
- Carmen Ayuso,
- Petra Liskova,
- Lubica Dudakova,
- Marie Vajter,
- Monika Ołdak,
- Jacek P. Szaflik,
- Anna Matynia,
- Michael B. Gorin,
- Kati Kämpjärvi,
- Miriam Bauwens,
- Elfride De Baere,
- Carel B. Hoyng,
- Catherina H. Z. Li,
- Caroline C. W. Klaver,
- Chris F. Inglehearn,
- Kaoru Fujinami,
- Carlo Rivolta,
- Rando Allikmets,
- Jana Zernant,
- Winston Lee,
- Osvaldo L. Podhajcer,
- Ana Fakin,
- Jana Sajovic,
- Alaa AlTalbishi,
- Sandra Valeina,
- Gita Taurina,
- Andrea L. Vincent,
- Lisa Roberts,
- Raj Ramesar,
- Giovanna Sartor,
- Elena Luppi,
- Susan M. Downes,
- L. Ingeborgh van den Born,
- Terri L. McLaren,
- John N. De Roach,
- Tina M. Lamey,
- Jennifer A. Thompson,
- Fred K. Chen,
- Anna M. Tracewska,
- Smaragda Kamakari,
- Juliana Maria Ferraz Sallum,
- Hanno J. Bolz,
- Hülya Kayserili,
- Susanne Roosing,
- Frans P. M. Cremers
Affiliations
- Rebekkah J. Hitti-Malin
- Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
- Daan M. Panneman
- Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
- Zelia Corradi
- Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
- Erica G. M. Boonen
- Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
- Galuh Astuti
- Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
- Claire-Marie Dhaenens
- Univ. Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, F-59000 Lille, France
- Heidi Stöhr
- Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany
- Bernhard H. F. Weber
- Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany
- Dror Sharon
- Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
- Eyal Banin
- Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
- Marianthi Karali
- Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, 80138 Naples, Italy
- Sandro Banfi
- Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, 80138 Naples, Italy
- Tamar Ben-Yosef
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel
- Damjan Glavač
- Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
- G. Jane Farrar
- The School of Genetics and Microbiology, The University of Dublin Trinity College, D02 VF25 Dublin, Ireland
- Carmen Ayuso
- Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28049 Madrid, Spain
- Petra Liskova
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 08 Prague, Czech Republic
- Lubica Dudakova
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 08 Prague, Czech Republic
- Marie Vajter
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 08 Prague, Czech Republic
- Monika Ołdak
- Department of Histology and Embryology, Medical University of Warsaw, 02-004 Warsaw, Poland
- Jacek P. Szaflik
- Department of Ophthalmology, Medical University of Warsaw, SPKSO Ophthalmic University Hospital, 03-709 Warsaw, Poland
- Anna Matynia
- College of Optometry, University of Houston, Houston, TX 77004, USA
- Michael B. Gorin
- Jules Stein Eye Institute, Los Angeles, CA 90095, USA
- Kati Kämpjärvi
- Blueprint Genetics, 02150 Espoo, Finland
- Miriam Bauwens
- Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
- Elfride De Baere
- Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
- Carel B. Hoyng
- Department of Ophthalmology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Catherina H. Z. Li
- Department of Ophthalmology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Caroline C. W. Klaver
- Department of Ophthalmology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Chris F. Inglehearn
- Division of Molecular Medicine, Leeds Institute of Medical Research, St. James’s University Hospital, University of Leeds, Leeds LS9 7TF, UK
- Kaoru Fujinami
- Department of Ophthalmology, The Jikei University School of Medicine, Tokyo 105-8461, Japan
- Carlo Rivolta
- Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland
- Rando Allikmets
- Department of Ophthalmology, Columbia University, New York, NY 10027, USA
- Jana Zernant
- Department of Ophthalmology, Columbia University, New York, NY 10027, USA
- Winston Lee
- Department of Ophthalmology, Columbia University, New York, NY 10027, USA
- Osvaldo L. Podhajcer
- Laboratorio de Terapia Molecular y Celular (Genocan), Fundación Instituto Leloir, CONICET, Buenos Aires 1405, Argentina
- Ana Fakin
- Eye Hospital, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
- Jana Sajovic
- Eye Hospital, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
- Alaa AlTalbishi
- St John of Jerusalem Eye Hospital Group, East Jerusalem 91198, Palestine
- Sandra Valeina
- Department of Ophthalmology, Riga Stradins University, LV-1007 Riga, Latvia
- Gita Taurina
- Children’s Clinical University Hospital, LV-1004 Riga, Latvia
- Andrea L. Vincent
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, The University of Auckland, Grafton, Auckland 1023, New Zealand
- Lisa Roberts
- 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 (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
- Raj Ramesar
- 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 (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
- Giovanna Sartor
- Department of Pharmacy and Biotechnology, University of Bologna, 40127 Bologna, Italy
- Elena Luppi
- Department of Medical and Surgical Sciences, University of Bologna, 40127 Bologna, Italy
- Susan M. Downes
- Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, Oxford University, Oxford OX3 9DU, UK
- L. Ingeborgh van den Born
- The Rotterdam Eye Hospital, 3011 BH Rotterdam, The Netherlands
- Terri L. McLaren
- Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia
- John N. De Roach
- Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia
- Tina M. Lamey
- Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia
- Jennifer A. Thompson
- Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia
- Fred K. Chen
- Centre for Ophthalmology and Visual Science, The University of Western Australia, Nedlands, WA 6009, Australia
- Anna M. Tracewska
- Datana Solutions, 54-530 Wroclaw, Poland
- Smaragda Kamakari
- Ophthalmic Genetics Unit, OMMA Ophthalmological Institute of Athens, 115 25 Athens, Greece
- Juliana Maria Ferraz Sallum
- Department of Ophthalmology and Visual Sciences, Universidade Federal de São Paulo, São Paulo 04023-062, SP, Brazil
- Hanno J. Bolz
- Institute of Human Genetics, University Hospital of Cologne, 50937 Cologne, Germany
- Hülya Kayserili
- Department of Medical Genetics, Koc University School of Medicine (KUSOM), 34450 Istanbul, Turkey
- Susanne Roosing
- Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
- Frans P. M. Cremers
- Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
- DOI
- https://doi.org/10.3390/biom14030367
- Journal volume & issue
-
Vol. 14,
no. 3
p. 367
Abstract
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.
Keywords
