E Overwater1, K Floor2, D van Beek2, K de Boer3, T van Dijk2, Y Hilhorst-Hofstee4, A J M Hoogeboom5, K J van Kaam6, J M van de Kamp2, M Kempers7, I P C Krapels6, H Y Kroes8, B Loeys7, S Salemink7, C T R M Stumpel9, V J M Verhoeven10, E Wijnands-van den Berg11, J M Cobben12, J P van Tintelen13, M M Weiss2, A C Houweling2, A Maugeri2. 1. Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands; Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: e.overwater@vumc.nl. 2. Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. 3. Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands. 4. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. 5. Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. 6. Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands. 7. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. 8. Department of Clinical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 9. Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, The Netherlands. 10. Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands; Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands. 11. Department of Pediatrics, Medical Center Twente, Enschede, The Netherlands. 12. Department of Medical Genetics, St George's University Hospital London, London, United Kingdom; Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 13. Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands; Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Abstract
BACKGROUND: Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes. OBJECTIVE: The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients. Furthermore, we provide an overview of currently described mutations in ADAMTSL4, the main gene involved in isolated EL. METHODS: A NGS gene panel was analysed in 24 patients with EL. RESULTS: A genetic diagnosis was confirmed in 16 patients (67%). Of these, four (25%) had a heterozygous FBN1 mutation, 12 (75%) were homozygous or compound heterozygous for ADAMTSL4 mutations. The known European ADAMTSL4 founder mutation c.767_786del was most frequently detected. CONCLUSION: The diagnostic yield of our NGS panel was high. Causative mutations were exclusively identified in ADAMTSL4 and FBN1. With this approach the risk of misdiagnosis or delayed diagnosis can be reduced. The value and clinical implications of establishing a genetic diagnosis in patients with EL is corroborated by the description of two patients with an unexpected underlying genetic condition.
BACKGROUND: Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes. OBJECTIVE: The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients. Furthermore, we provide an overview of currently described mutations in ADAMTSL4, the main gene involved in isolated EL. METHODS: A NGS gene panel was analysed in 24 patients with EL. RESULTS: A genetic diagnosis was confirmed in 16 patients (67%). Of these, four (25%) had a heterozygous FBN1 mutation, 12 (75%) were homozygous or compound heterozygous for ADAMTSL4 mutations. The known European ADAMTSL4 founder mutation c.767_786del was most frequently detected. CONCLUSION: The diagnostic yield of our NGS panel was high. Causative mutations were exclusively identified in ADAMTSL4 and FBN1. With this approach the risk of misdiagnosis or delayed diagnosis can be reduced. The value and clinical implications of establishing a genetic diagnosis in patients with EL is corroborated by the description of two patients with an unexpected underlying genetic condition.
Authors: Eva Lenassi; Jill Clayton-Smith; Sofia Douzgou; Simon C Ramsden; Stuart Ingram; Georgina Hall; Claire L Hardcastle; Tracy A Fletcher; Rachel L Taylor; Jamie M Ellingford; William D Newman; Cecilia Fenerty; Vinod Sharma; I Chris Lloyd; Susmito Biswas; Jane L Ashworth; Graeme C Black; Panagiotis I Sergouniotis Journal: Genet Med Date: 2019-12-18 Impact factor: 8.822