Variants in CFAP410 cause a range of retinal and skeletal phenotypes

Ryan E Schmidt; Amy E Pohodich; David Birch; Kaylie Jones; Byron L Lam; Emily H Jung; Nieraj Jain; Michalis Georgiou; Omar A Mahroo; Andrew R Webster; Michel Michaelides; Benjamin Bakall; Alessandro Iannaccone; Ajoy Vincent; Deepika C Parameswarappa; Elise Heon; Hendrik P N Scholl; Lucas Janeschitz-Kriegl; Elias I Traboulsi; Wadih Zein; Brian P Brooks; Catherine Cukras; Robert Hufnagel; Tomas S Aleman; Mohamed M Sylla; Stephen H Tsang; Michelle Alabek; Jose Sahel; Michael B Gorin; Maria M van Genderen; Katarina Stingl; Milda Reith; Susanne Kohl; Rebeca Azevedo Souza Amaral; Juliana Maria Ferraz Sallum; Andrea L Vincent; Sarah Hull; Jacque L Duncan; James V M Hanson; Matthias Tedeus; Jordi Maggi; Urs Graf; Samuel Koller; Wolfgang Berger; Christina Gerth-Kahlert; Molly Marra; Lesley A Everett; Paul Yang; Mark E Pennesi

doi:10.1038/s41525-025-00489-1

Variants in CFAP410 cause a range of retinal and skeletal phenotypes

NPJ Genom Med. 2025 Apr 17;10(1):32. doi: 10.1038/s41525-025-00489-1.

Authors

Ryan E Schmidt¹, Amy E Pohodich¹, David Birch², Kaylie Jones², Byron L Lam³, Emily H Jung⁴, Nieraj Jain⁵, Michalis Georgiou^{6

7}, Omar A Mahroo^{6

7}, Andrew R Webster^{6

7}, Michel Michaelides^{6

7}, Benjamin Bakall^{8

9}, Alessandro Iannaccone^{10

11

12}, Ajoy Vincent¹³, Deepika C Parameswarappa¹³, Elise Heon¹³, Hendrik P N Scholl^{14

15}, Lucas Janeschitz-Kriegl^{14

15}, Elias I Traboulsi¹⁶, Wadih Zein¹⁷, Brian P Brooks¹⁷, Catherine Cukras¹⁷, Robert Hufnagel¹⁷, Tomas S Aleman¹⁸, Mohamed M Sylla¹⁹, Stephen H Tsang¹⁹, Michelle Alabek²⁰, Jose Sahel²⁰, Michael B Gorin²¹, Maria M van Genderen^{22

23}, Katarina Stingl²⁴, Milda Reith²⁴, Susanne Kohl²⁴, Rebeca Azevedo Souza Amaral²⁵, Juliana Maria Ferraz Sallum²⁵, Andrea L Vincent^{26

27}, Sarah Hull^{26

27}, Jacque L Duncan²⁸, James V M Hanson²⁹, Matthias Tedeus³⁰, Jordi Maggi³¹, Urs Graf³¹, Samuel Koller³¹, Wolfgang Berger^{31

32

33}, Christina Gerth-Kahlert²⁹, Molly Marra¹, Lesley A Everett¹, Paul Yang¹, Mark E Pennesi^{34

35}

Affiliations

¹ Casey Eye Institute, Oregon Health Science University, Portland, OR, USA.
² Retina Foundation of the Southwest, Dallas, TX, USA.
³ Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA.
⁴ Department of Ophthalmology, Duke University School of Medicine, Durham, NC, USA.
⁵ Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA.
⁶ UCL Institute of Ophthalmology, University College London, London, London, UK.
⁷ Genetics Service, Moorfields Eye Hospital, London, London, UK.
⁸ Associated Retina Consultants, Phoenix, AZ, USA.
⁹ University of Arizona, College of Medicine-Phoenix, Phoenix, AZ, USA.
¹⁰ Duke Eye Center, Duke University School of Medicine, Durham, NC, USA.
¹¹ Ophthalmology Astellas Pharma US, Northbrook, IL, USA.
¹² Kittner Eye Center, University of North Carolina Chapel Hill, Chapel Hill, NC, USA.
¹³ Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children; University of Toronto, Toronto, ON, Canada.
¹⁴ Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland.
¹⁵ Department of Ophthalmology, University of Basel, Basel, Switzerland.
¹⁶ Center for Genetic Eye Diseases, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.
¹⁷ Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁸ Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
¹⁹ Department of Ophthalmology, Colombia University, Edward S. Harkness Eye Institute, NewYork-Presbyterian Hospital, New York, NY, USA.
²⁰ Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
²¹ Department of Ophthalmology and Human Genetics, University of California, Los Angeles, CA, USA.
²² Department of Ophthalmology University Medical Center Utrecht, Utrecht, The Netherlands.
²³ Bartiméus Diagnostic Center for complex visual disorders, Zeist, The Netherlands.
²⁴ Center for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
²⁵ Department of Ophthalmology, Universidade Federal de São Paulo, São Paulo, Brazil.
²⁶ Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
²⁷ Eye Department, Greenlane Clinical Centre, Te Toka Tumai Auckland, Te Whatu Ora-Health New Zealand, Auckland, New Zealand.
²⁸ Department of Ophthalmology, University of California, San Francisco, CA, USA.
²⁹ Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland.
³⁰ Schulthess Clinic, Zurich, Switzerland.
³¹ Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland.
³² Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
³³ Neuroscience Center Zurich (ZNZ), University and ETH Zurich, Zurich, Switzerland.
³⁴ Casey Eye Institute, Oregon Health Science University, Portland, OR, USA. pennesim@ohsu.edu.
³⁵ Retina Foundation of the Southwest, Dallas, TX, USA. pennesim@ohsu.edu.

Abstract

Ciliopathies are associated with a range of phenotypes including retinal degeneration and skeletal abnormalities. We present a retrospective study of 49 patients with variants in Cilia and Flagella Associated Protein 410 (CFAP410) from multiple ophthalmic centers across the world. Common clinical features included early-onset reduced visual acuity, photophobia, and delayed light-to-dark adaptation. A cone-rod dystrophy pattern was observed roughly two times more commonly than rod-cone dystrophy. A minority of patients (22.4%) presented with skeletal abnormalities consistent with axial spondylometaphyseal dysplasia (SMDAX). Patients with the most severe ophthalmic and skeletal phenotypes had disease-associated variants within conserved leucine-rich regions of CFAP410, and the structural effects of these variants were modelled using ChimeraX. This report furthers our understanding of CFAP410-associated clinical phenotypes such as retinal dystrophy and skeletal dysplasia.

Abstract

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