Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes-Reference-Cited by-同舟云学术

Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes

Published:2024-03-19 Issue:3 Volume:14 Page:367
ISSN:2218-273X
Container-title:Biomolecules
language:en
Short-container-title:Biomolecules

Author:

Hitti-Malin Rebekkah J.¹^ORCID,Panneman Daan M.¹,Corradi Zelia¹^ORCID,Boonen Erica G. M.¹^ORCID,Astuti Galuh¹,Dhaenens Claire-Marie²^ORCID,Stöhr Heidi³^ORCID,Weber Bernhard H. F.³⁴^ORCID,Sharon Dror⁵^ORCID,Banin Eyal⁵,Karali Marianthi⁶⁷^ORCID,Banfi Sandro⁶⁷⁸^ORCID,Ben-Yosef Tamar⁹,Glavač Damjan¹⁰¹¹^ORCID,Farrar G. Jane¹²,Ayuso Carmen¹³¹⁴^ORCID,Liskova Petra¹⁵¹⁶^ORCID,Dudakova Lubica¹⁵^ORCID,Vajter Marie¹⁵¹⁶^ORCID,Ołdak Monika¹⁷^ORCID,Szaflik Jacek P.¹⁸,Matynia Anna¹⁹²⁰²¹,Gorin Michael B.²⁰^ORCID,Kämpjärvi Kati²²,Bauwens Miriam²³²⁴^ORCID,De Baere Elfride²³²⁴^ORCID,Hoyng Carel B.²⁵,Li Catherina H. Z.²⁵,Klaver Caroline C. W.²⁵,Inglehearn Chris F.²⁶^ORCID,Fujinami Kaoru²⁷,Rivolta Carlo²⁸^ORCID,Allikmets Rando²⁹³⁰,Zernant Jana²⁹,Lee Winston²⁹,Podhajcer Osvaldo L.³¹,Fakin Ana³²³³,Sajovic Jana³²³³^ORCID,AlTalbishi Alaa³⁴,Valeina Sandra³⁵³⁶,Taurina Gita³⁶,Vincent Andrea L.³⁷³⁸^ORCID,Roberts Lisa³⁹^ORCID,Ramesar Raj³⁹^ORCID,Sartor Giovanna⁴⁰,Luppi Elena⁴¹⁴²^ORCID,Downes Susan M.⁴³⁴⁴^ORCID,van den Born L. Ingeborgh⁴⁵,McLaren Terri L.⁴⁶⁴⁷^ORCID,De Roach John N.⁴⁶⁴⁷,Lamey Tina M.⁴⁶⁴⁷^ORCID,Thompson Jennifer A.⁴⁶^ORCID,Chen Fred K.⁴⁷^ORCID,Tracewska Anna M.⁴⁸,Kamakari Smaragda⁴⁹,Sallum Juliana Maria Ferraz⁵⁰⁵¹^ORCID,Bolz Hanno J.⁵²,Kayserili Hülya⁵³^ORCID,Roosing Susanne¹^ORCID,Cremers Frans P. M.¹

Affiliation:

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

2. Univ. Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, F-59000 Lille, France

3. Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany

4. Institute of Clinical Human Genetics, University Hospital Regensburg, 93053 Regensburg, Germany

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

6. Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, 80138 Naples, Italy

7. Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania ‘Luigi Vanvitelli’, 80131 Naples, Italy

8. Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy

9. Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel

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

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

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

13. Department of Genetics, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28049 Madrid, Spain

14. Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain

15. Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 08 Prague, Czech Republic

16. Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 08 Prague, Czech Republic

17. Department of Histology and Embryology, Medical University of Warsaw, 02-004 Warsaw, Poland

18. Department of Ophthalmology, Medical University of Warsaw, SPKSO Ophthalmic University Hospital, 03-709 Warsaw, Poland

19. College of Optometry, University of Houston, Houston, TX 77004, USA

20. Jules Stein Eye Institute, Los Angeles, CA 90095, USA

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

22. Blueprint Genetics, 02150 Espoo, Finland

23. Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium

24. Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium

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

26. Division of Molecular Medicine, Leeds Institute of Medical Research, St. James’s University Hospital, University of Leeds, Leeds LS9 7TF, UK

27. Department of Ophthalmology, The Jikei University School of Medicine, Tokyo 105-8461, Japan

28. Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland

29. Department of Ophthalmology, Columbia University, New York, NY 10027, USA

30. Department of Pathology & Cell Biology, Columbia University, New York, NY 10027, USA

31. Laboratorio de Terapia Molecular y Celular (Genocan), Fundación Instituto Leloir, CONICET, Buenos Aires 1405, Argentina

32. Eye Hospital, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia

33. Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia

34. St John of Jerusalem Eye Hospital Group, East Jerusalem 91198, Palestine

35. Department of Ophthalmology, Riga Stradins University, LV-1007 Riga, Latvia

36. Children’s Clinical University Hospital, LV-1004 Riga, Latvia

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

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

39. 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

40. Department of Pharmacy and Biotechnology, University of Bologna, 40127 Bologna, Italy

41. Department of Medical and Surgical Sciences, University of Bologna, 40127 Bologna, Italy

42. Unit of Medical Genetics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy

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

44. Oxford Eye Hospital, Oxford University NHS Foundation Trust, Oxford OX3 9DU, UK

45. The Rotterdam Eye Hospital, 3011 BH Rotterdam, The Netherlands

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

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

48. Datana Solutions, 54-530 Wroclaw, Poland

49. Ophthalmic Genetics Unit, OMMA Ophthalmological Institute of Athens, 115 25 Athens, Greece

50. Department of Ophthalmology and Visual Sciences, Universidade Federal de São Paulo, São Paulo 04023-062, SP, Brazil

51. Instituto de Genética Ocular, São Paulo 04552-050, SP, Brazil

52. Institute of Human Genetics, University Hospital of Cologne, 50937 Cologne, Germany

53. Department of Medical Genetics, Koc University School of Medicine (KUSOM), 34450 Istanbul, Turkey

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.

Funder

HRCI HRB Joint Funding Scheme

Stichting Oogfonds Nederland

Pro Retina Deutschland

Stichting tot Verbetering van het Lot der Blinden

Stichting voor Ooglijders

Stichting Blindenhulp

GA UK

Ministry of Health of the Czech Republic

Retina Australia

Australian National Health and Medical Research Council

WA Health