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

Abstract

Variants of the <i>TTLL5</i> 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 <i>TTLL5</i> patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of <i>TTLL5.</i> 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 <i>USH2A</i> variants, which might explain the observed rod involvement. Our study highlights the role of <i>TTLL5</i> 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 <i>TTLL5,</i> previously undetected by classical sequencing methods. In addition, variable phenotypes in <i>TTLL5</i>-associated patients might be due to the presence of additional gene defects.