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

June 15, 2021

Smirnov V1,2,3, Grunewald O4, Muller J5,6, Zeitz C3, Obermaier CD7, Devos A8, Pelletier V9, Bocquet B10,11, Andrieu C12, Bacquet JL9, Lebredonchel E8, Mohand-Saïd S3,12, Defoort-Dhellemmes S2, Sahel JA3,12,13,14, Dollfus H9, Zanlonghi X15, Audo I3,12,16, Meunier I10,11, Boulanger-Scemama E13, Dhaenens CM4,*


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.