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

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.

CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms

“…Genomic DNA was extracted from leukocytes using a FlexiGene kit (Qiagen). We used dedicated large IRD gene panels including 230 genes associated with generalized retinal and macular dystrophies to screen for pathogenic variants [ 44 ]. The design of this panel does not allow the analysis of the specific 5′ and 3′ exons of CRB1 isoform B.…”

Expanding the phenotype of TTLL5-associated retinal dystrophy: a case series

“…However, P1 presented at a later age and was found to have peripheral sectoral atrophy seen on SW-AF, while a previously reported patient with the c.3354G>A:p.(Trp1118*) variant presented at a young age and was found to have a hyperautofluorescent ring surrounding central macular atrophy on SW-AF. In contrast, the c.1450C>T:p.(Arg-484Cys) missense variant identified in P1 occurs within close proximity of the c.1474T>A:p.(Trp492Arg) missense variant that was recently reported in a study by Smirnov et al [9] The patient who possessed this variant was found to have sectoral atrophy on examination with an onset of symptoms in his mid-forties, similarly to P1, suggesting that this area within the c-MTBD may have a genotype-phenotype correlation with sectoral atrophy.…”

“…The reason for the difference in phenotype severity between these patients is unclear, especially given that nonsense mutations are expected to lead to loss of function secondary to nonsense mediated decay [11]. However, the homozygous stop-gain variant found in P3, c.2029C>T:p.(Arg677*), is located in close proximity to the homozygous stop-gain variant c.1920G>A:p. (Trp640*) identified in a recently described patient diagnosed with a more severe early onset phenotype, both of which occur within the CID [9]. These findings suggest that mutations located around this locus may be associated with more advanced disease.…”

“…In this study, three patients with recessive mutations in TTLL5 showed three unique phenotypes: sectoral CORD, CORD, and COD. The age of onset among these three patients was variable, as were presenting symptoms, suggesting that TTLL5-mediated retinal dystrophy may be more phenotypically varied than previously reported [1,6,8,9]. P2 demonstrated relatively preserved retinal architecture with the exception of disruption of the ellipsoid zone band in the distribution of the hypoautofluorescent ring around the fovea and thinning of the outer nuclear layers (B).…”

“…To date, nineteen cases of TTLL5-associated retinal dystrophy have been reported across sixteen different families [1,6,8,9]. In all cases, disease was inherited in an autosomal recessive pattern, and the majority of patients were diagnosed with CORD.…”