Novel TTLL5 Variants Associated with Cone-Rod Dystrophy and Early-Onset Severe Retinal Dystrophy

Authors

Smirnov V^1,2,3, Grunewald O⁴, Muller J^5,6, Zeitz C³, Obermaier CD⁷, Devos A⁸, Pelletier V⁹, Bocquet B^10,11, Andrieu C¹², Bacquet JL⁹, Lebredonchel E⁸, Mohand-Saïd S^3,12, Defoort-Dhellemmes S², Sahel JA^3,12,13,14, Dollfus H⁹, Zanlonghi X¹⁵, Audo I^3,12,16, Meunier I^10,11, Boulanger-Scemama E¹³, Dhaenens CM^4,*

Université de Lille, Faculté de Médecine, 59037 Lille, France
CHU Lille, Service d’Exploration Fonctionnelle de la Vision et de Neuro-Ophtalmologie, Hôpital Salengro, 59037 Lille, France
Sorbonne Université, INSERM, CNRS, Institut de la Vision, 75012 Paris, France
Univ. Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, 59045 Lille, France
Laboratoire de Génétique Médicale, Institut de Génétique Médicale d’Alsace (IGMA), INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg UMRS_1112, 67000 Strasbourg, France
Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Institut de Génétique Médicale d’Alsace (IGMA), 67000 Strasbourg, France
Praxis für Humangenetik Tuebingen & Center for Genomics and Transcriptomics, CeGaT GmbH, 72076 Tuebingen, Germany
Univ. Lille, CHU Lille, Service de Toxicologie et Génopathies, 59037 Lille, France
Centre de Référence pour les Affections Rares en Génétique Ophtalmologiques, Hopitaux Universitaires de Strasbourg, 67000 Strasbourg, France
National Reference Centre for Inherited Sensory Diseases, University of Montpellier, Montpellier University Hospital, Sensgene Care Network, ERN-EYE Network, 34295 Montpellier, France
Institute for Neurosciences of Montpellier (INM), INSERM, University of Montpellier, INSERM, 34295 Montpellier, France
Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 1423, 75012 Paris, France
Fondation Ophtalmologique Adolphe de Rothschild, 75019 Paris, France
Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Service d’Ophtalmologie, CHU de Rennes, 35000 Rennes, France
Institute of Ophthalmology, University College London, London EC1V 9EL, UK

*Author to whom correspondence should be addressed.

Abstract

Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5-associated patients might be due to the presence of additional gene defects.

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