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

Vasily M Smirnov ,Jean Muller,Hélène Dollfus,Béatrice Bocquet,Xavier Zanlonghi,Valérie Pelletier,Jean-Louis Bacquet,Isabelle Audo,Carolin D Obermaier,Isabelle Meunier,Christina Zeitz,Olivier Grunewald,Elodie Lebredonchel,Aurore Devos,Élise Boulanger-Scemama ,Claudia Andrieu ,Sabine Defoort‐Dhellemmes ,José‐Alain Sahel ,Saddek Mohand‐Saïd ,Claire‐Marie Dhaenens

doi:10.3390/ijms22126410

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.

Highlights

Cone and cone-rod dystrophies constitute a heterogeneous group of inherited retinal disorders primarily affecting cone photoreceptors
All were classified as pathogenic or likely pathogenic according to the ACMG (American College of Medical Genetics and Genomics) criteria [18]
We identified two novel missense variants, c.1474T>A, p.(Trp492Arg) and c.1513A>G, p.(Met505Val), in exons 17 and 18, respectively, located in the region surrounded by the TTLL and cofactor interaction domain (CID) domains

Summary

Introduction

Cone and cone-rod dystrophies constitute a heterogeneous group of inherited retinal disorders primarily affecting cone photoreceptors. In cone dystrophies (COD), alterations are generally restricted to the cones, but can extend to the rod photoreceptors at a later stage [1]. COD begins in late childhood or early adult life with visual loss, abnormal colour vision, photophobia and central scotoma [2]. The fundus is variably altered, ranging from no alteration to bull’s eye maculopathy. The optic discs show a variable degree of temporal pallor [2].

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