The landscape of submicroscopic structural variants at the OPN1LW/OPN1MW gene cluster on Xq28 underlying blue cone monochromacy

Author:

Wissinger Bernd1ORCID,Baumann Britta1,Buena-Atienza Elena1,Ravesh Zeinab1ORCID,Cideciyan Artur V.2ORCID,Stingl Katarina34ORCID,Audo Isabelle56ORCID,Meunier Isabelle7ORCID,Bocquet Beatrice7ORCID,Traboulsi Elias I.8ORCID,Hardcastle Alison J.9ORCID,Gardner Jessica C.9ORCID,Michaelides Michel910,Branham Kari E.11,Rosenberg Thomas12ORCID,Andreasson Sten13ORCID,Dollfus Hélène14,Birch David15,Vincent Andrea L.16ORCID,Martorell Loreto17ORCID,Català Mora Jaume18ORCID,Kellner Ulrich19ORCID,Rüther Klaus20,Lorenz Birgit2122ORCID,Preising Markus N.21,Manfredini Emanuela23,Zarate Yuri A.24ORCID,Vijzelaar Raymon25ORCID,Zrenner Eberhart26ORCID,Jacobson Samuel G.2,Kohl Susanne1ORCID

Affiliation:

1. Molecular Genetics Laboratory, Centre for Ophthalmology, University of Tuebingen, 72076 Tuebingen, Germany

2. Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104

3. University Eye Hospital, Centre for Ophthalmology, University of Tuebingen, 72076 Tuebingen, Germany

4. Center for Rare Eye Diseases, University of Tuebingen, 72076 Tuebingen, Germany

5. Sorbonne Université, INSERM, CNRS, Institut de la Vision, 75012 Paris, France

6. Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC 1423, 75571 Paris, France

7. National Reference Centre for Inherited Sensory Diseases, Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, 34091 Montpellier, France

8. Center for Genetic Eye Diseases, Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195

9. Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom

10. Moorfields Eye Hospital, University College London, London EC1V 2PD, United Kingdom

11. Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI 48109

12. Department of Ophthalmology, Kennedy Center, Rigshospitalet, 2600 Glostrup, Denmark

13. Department of Ophthalmology, University of Lund, 22362 Lund, Sweden

14. Centre de référence pour les Affections Rares en Génétique Ophtalmologique, Filière de santé maladies rares SENSGENE, Institut de Génétique médicale d’Alsace, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France

15. Retina Foundation of the Southwest, Dallas, TX 75231

16. Department of Ophthalmology, National Eye Centre, Faculty of Medical and Health Science, University of Auckland, Auckland 1023, New Zealand

17. Molecular Genetics Department, Hopital Sant Joan de Déu Barcelona, 08950 Esplugues de Llobregat, Spain

18. Unitat de Distròfies Hereditàries de Retina, Hospital Sant Joan de Déu Barcelona, 08950 Esplugues de Llobregat, Spain

19. Zentrum für Seltene Netzhauterkrankungen, AugenZentrum Siegburg, MVZ Augenärztliches Diagnostik- und Therapiecentrum Siegburg, 53721 Siegburg, Germany

20. Augenarztpraxis, 10117 Berlin, Germany

21. Department of Ophthalmology, Justus-Liebig-University Giessen, 35385 Giessen, Germany

22. Universitäts-Augenklinik, University of Bonn, 53127 Bonn, Germany

23. Dipartimento di Medicina di Laboratorio, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy

24. Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR 72202

25. MRC Holland b.v., Amsterdam 1057 DL, The Netherlands

26. Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, 72076 Tuebingen, Germany

Abstract

Blue cone monochromacy (BCM) is an X-linked retinal disorder characterized by low vision, photoaversion, and poor color discrimination. BCM is due to the lack of long-wavelength-sensitive and middle-wavelength-sensitive cone photoreceptor function and caused by mutations in the OPN1LW/OPN1MW gene cluster on Xq28. Here, we investigated the prevalence and the landscape of submicroscopic structural variants (SVs) at single-base resolution in BCM patients. We found that about one-third ( n = 73) of the 213 molecularly confirmed BCM families carry an SV, most commonly deletions restricted to the OPN1LW/OPN1MW gene cluster. The structure and precise breakpoints of the SVs were resolved in all but one of the 73 families. Twenty-two families—all from the United States—showed the same SV, and we confirmed a common ancestry of this mutation. In total, 42 distinct SVs were identified, including 40 previously unreported SVs, thereby quadrupling the number of precisely mapped SVs underlying BCM. Notably, there was no “region of overlap” among these SVs. However, 90% of SVs encompass the upstream locus control region, an essential enhancer element. Its minimal functional extent based on deletion mapping in patients was refined to 358 bp. Breakpoint analyses suggest diverse mechanisms underlying SV formation as well as in one case the gene conversion-based exchange of a 142-bp deletion between opsin genes. Using parsimonious assumptions, we reconstructed the composition and copy number of the OPN1LW/OPN1MW gene cluster prior to the mutation event and found evidence that large gene arrays may be predisposed to the occurrence of SVs at this locus.

Funder

Deutsche Forschungsgemeinschaft

Blue Cone Monochromacy Family Foundation

UK Medical Research Council

National Institute for Health Research Biomedical Research Centre

LabEx LifeSenses

IHU FOReSIGHT

Fondation Fighting Blindness

Tistou and Charlotte Kerstan Foundation

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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