Variants in CFAP410 cause a range of retinal and skeletal phenotypes

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.

PMID: 40246852
PMCID: PMC12006490
DOI: 10.1038/s41525-025-00489-1

Variants in CFAP410 cause a range of retinal and skeletal phenotypes

Ryan E Schmidt et al. NPJ Genom Med. 2025.

. 2025 Apr 17;10(1):32.

doi: 10.1038/s41525-025-00489-1.

Authors

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.

PMID: 40246852
PMCID: PMC12006490
DOI: 10.1038/s41525-025-00489-1

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.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

Figures

**Fig. 1. Wild type CFAP410 protein.**
A The Leucine Rich Repeat region (residues 19-84) is highlighted in red. Image generated by ChimeraX. B The LRRCT (Leucine Rich Repeat C-Terminal region) highlighted in red. Image generated by ChimeraX.

**Fig. 2. Fourteen representative patients with *CFAP410*-associated retinal dystrophy in order from least (top of the table) to most advanced (bottom of the table) cone-rod or cone dystrophy.**
Rankings were made based on ophthalmic exam, visual symptoms, electroretinogram findings, fundus photography, fundus autofluorescence, and OCT (optical coherence tomography) imaging. Results of genetic testing, age of symptom onset, and age at most recent exam are also included.

**Fig. 3. Five representative patients with *CFAP410*-associated retinal dystrophy in order from least (top of the table) to most advanced (bottom of the table) rod-cone or rod dystrophy.**
Rankings were made based on ophthalmic exam, visual symptoms, electroretinogram findings, fundus photography, fundus autofluorescence, and OCT (optical coherence tomography) imaging. Results of genetic testing, age of symptom onset, and age at most recent exam are also included.

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References

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Variants in CFAP410 cause a range of retinal and skeletal phenotypes

Affiliations

Variants in CFAP410 cause a range of retinal and skeletal phenotypes

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

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References

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