Helen J Kuht1, Gail D E Maconachie2, Jinu Han3, Line Kessel4, Maria M van Genderen5, Rebecca J McLean6, Michael Hisaund6, Zhanhan Tu1, Richard W Hertle7, Karen Gronskov8, Dayong Bai9, Aihua Wei10, Wei Li11, Yonghong Jiao12, Vasily Smirnov13, Jae-Hwan Choi14, Martin D Tobin15, Viral Sheth16, Ravi Purohit6, Basu Dawar6, Ayesha Girach6, Sasha Strul17, Laura May17, Fred K Chen18, Rachael C Heath Jeffery18, Abdullah Aamir6, Ronaldo Sano19, Jing Jin20, Brian P Brooks21, Susanne Kohl22, Benoit Arveiler23, Lluis Montoliu24, Elizabeth C Engle25, Frank A Proudlock6, Garima Nishad26, Prateek Pani26, Girish Varma27, Irene Gottlob28, Mervyn G Thomas29. 1. The University of Leicester Ulverscroft Eye Unit, Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom; Foveal Development Investigators Group. 2. The University of Leicester Ulverscroft Eye Unit, Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom; Academic Unit of Ophthalmology and Orthoptics, University of Sheffield, Sheffield, United Kingdom; Foveal Development Investigators Group. 3. Institute of Vision Research, Department of Ophthalmology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; Foveal Development Investigators Group. 4. Department of Ophthalmology, Rigshospitalet, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Foveal Development Investigators Group. 5. Department of Ophthalmology, University Medical Centre Utrecht, Utrecht, The Netherlands; Bartiméus Diagnostic Centre for Complex Visual Disorders, Zeist, The Netherlands; Foveal Development Investigators Group. 6. The University of Leicester Ulverscroft Eye Unit, Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom. 7. Department of Ophthalmology, The Rebecca D. Considine Research Institute and The Children's Vision Center, Akron Children's Hospital, Akron, Ohio; Department of Surgery, The Northeastern Ohio Medical University, Rootstown, Ohio; Foveal Development Investigators Group. 8. Department of Clinical Genetics, Rigshospitalet-Kennedy Center, Glostrup, Denmark; Foveal Development Investigators Group. 9. Department of Ophthalmology, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China; Foveal Development Investigators Group. 10. Department of Dermatology, Beijing Tongren Hospital, Capital Medical University, Beijing, China; Foveal Development Investigators Group. 11. Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute; Rare Disease Center, National Center for Children's Health; MOE Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, Capital Medical University, Beijing, China; Foveal Development Investigators Group. 12. Beijing Tongren Eye Centre, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Lab, Beijing, China; Foveal Development Investigators Group. 13. Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut de la Vision, Paris, France; Exploration de la Vision et Neuro-Ophtalmologie, CHU de Lille, Lille, France; Foveal Development Investigators Group. 14. Department of Neurology, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, South Korea; Foveal Development Investigators Group. 15. Department of Health Sciences, University of Leicester, Leicester, United Kingdom; Foveal Development Investigators Group. 16. The University of Leicester Ulverscroft Eye Unit, Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom; Academic Unit of Ophthalmology and Orthoptics, University of Sheffield, Sheffield, United Kingdom. 17. Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota; Foveal Development Investigators Group. 18. Centre for Ophthalmology and Visual Science (incorporating Lions Eye Institute), The University of Western Australia, Crawley, Australia; Foveal Development Investigators Group. 19. Retina and Vitreous Sector of Santa Casa de Misericórdia de São Paulo, São Paulo, Brazil; Foveal Development Investigators Group. 20. Sidney Kimmel Medical College of Thomas Jefferson University, Nemours Children's Health, Philadelphia, Pennsylvania; Nemours Children's Health, Wilmington, Delaware. 21. Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland; Foveal Development Investigators Group. 22. Centre for Ophthalmology, Institute for Ophthalmic Research, University Tübingen, Tübingen, Germany; Foveal Development Investigators Group. 23. Rare Diseases, Genetics and Metabolism, INSERM U1211, University of Bordeaux, Bordeaux, France; Molecular Genetics Laboratory, Bordeaux University Hospital, Bordeaux, France; Foveal Development Investigators Group. 24. National Centre for Biotechnology (CNB-CSIC) and CIBERER-ISCIII, Madrid, Spain; Foveal Development Investigators Group. 25. Departments of Neurology and Ophthalmology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; Howard Hughes Medical Institute, Chevy Chase, Maryland; Foveal Development Investigators Group. 26. International Institute of Information Technology, Hyderabad, India. 27. International Institute of Information Technology, Hyderabad, India; Foveal Development Investigators Group. 28. The University of Leicester Ulverscroft Eye Unit, Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom; Foveal Development Investigators Group; Cooper Neurological Institute, Cooper Medical School of Rowan University, Camden, New Jersey. 29. The University of Leicester Ulverscroft Eye Unit, Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom; Foveal Development Investigators Group. Electronic address: mt350@le.ac.uk.
Abstract
PURPOSE: To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). DESIGN: Multicenter, observational study. PARTICIPANTS: A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384). METHODS: Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans. MAIN OUTCOME MEASURES: Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA). RESULTS: The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH. CONCLUSIONS: We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.
PURPOSE: To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). DESIGN: Multicenter, observational study. PARTICIPANTS: A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384). METHODS: Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans. MAIN OUTCOME MEASURES: Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA). RESULTS: The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH. CONCLUSIONS: We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.
Authors: Je Hyun Seo; Young Suk Yu; Jeong Hun Kim; Ho Kyung Choung; Jang Won Heo; Seong-Joon Kim Journal: Ophthalmology Date: 2007-03-06 Impact factor: 12.079
Authors: M d'Addio; A Pizzigoni; M T Bassi; C Baschirotto; C Valetti; B Incerti; M Clementi; M De Luca; A Ballabio; M V Schiaffino Journal: Hum Mol Genet Date: 2000-12-12 Impact factor: 6.150
Authors: Sohaib R Rufai; Mervyn G Thomas; Ravi Purohit; Catey Bunce; Helena Lee; Frank A Proudlock; Irene Gottlob Journal: Ophthalmology Date: 2019-11-04 Impact factor: 12.079
Authors: Junwon Lee; Han Jeong; Dongju Won; Saeam Shin; Seung-Tae Lee; Jong Rak Choi; Suk Ho Byeon; Helen J Kuht; Mervyn G Thomas; Jinu Han Journal: Transl Vis Sci Technol Date: 2022-06-01 Impact factor: 3.048