Abstract
In a subset of inherited retinal degenerations (including cone, cone-rod, and macular dystrophies), cone photoreceptors are more severely affected than rods; ABCA4 mutations are the most common cause of this heterogeneous class of disorders. To identify retinal-disease-associated genes, we performed exome sequencing in 28 individuals with "cone-first" retinal disease and clinical features atypical for ABCA4 retinopathy. We then conducted a gene-based case-control association study with an internal exome data set as the control group. TTLL5, encoding a tubulin glutamylase, was highlighted as the most likely disease-associated gene; 2 of 28 affected subjects harbored presumedloss-of-function variants: c.[1586_1589delAGAG];[1586_1589delAGAG], p.[Glu529Valfs(∗)2];[Glu529Valfs(∗)2], and c.[401delT(;)3354G>A], p.[Leu134Argfs(∗)45(;)Trp1118(∗)]. We then inspected previously collected exome sequence data from individuals with related phenotypes and found two siblings with homozygous nonsense variant c.1627G>T (p.Glu543(∗)) in TTLL5. Subsequently, we tested a panel of 55 probands with retinal dystrophy for TTLL5 mutations; one proband had a homozygous missense change (c.1627G>A [p.Glu543Lys]). The retinal phenotype was highly similar in three of four families; the sibling pair had a more severe, early-onset disease. In human and murine retinae, TTLL5 localized to the centrioles at the base of the connecting cilium. TTLL5 has been previously reported to be essential for the correct function of sperm flagella in mice and play a role in polyglutamylation of primary cilia invitro. Notably, genes involved in the polyglutamylation and deglutamylation of tubulin have been associated with photoreceptor degeneration in mice. The electrophysiological and fundus autofluorescence imaging presented here should facilitate the molecular diagnosis in further families.
Highlights
In a subset of inherited retinal degenerations, cone photoreceptors are more severely affected than rods; ABCA4 mutations are the most common cause of this heterogeneous class of disorders
In order to use the UCL-exomes control samples, (1) we inferred ancestry on the basis of the exome sequencing data, and using a principal-component analysis, we excluded samples that did not cluster with the bulk of the UCL-exomes samples, which are predominantly of European origin (Figure 2A; 5 out of 28 case samples were removed); (2) we removed all samples with a history of retinal disease; and (3) when several samples were sequenced in a family, we kept a single sample per family to obtain unrelated control samples
We reviewed the exome sequencing data from these families with the aim of identifying additional individuals with most likely disease-causing variants in TTLL5; a 44-year-old man with an early-onset cone-rod dystrophy phenotype (Figure 1C; Table 2) was found to harbor a homozygous nonsense variant (c.[1627G>T];[1627G>T], p.[Glu543*];[Glu543*])
Summary
Biallelic Variants in TTLL5, Encoding a Tubulin Glutamylase, Cause Retinal Dystrophy. Gene-based p values were computed with two strategies: a binomial test for excess of rare variants in the case group and the more general gene-based testing procedure Sequence Kernel Association Test (SKAT).[11] In order to use the UCL-exomes control samples, (1) we inferred ancestry on the basis of the exome sequencing data, and using a principal-component analysis, we excluded samples that did not cluster with the bulk of the UCL-exomes samples, which are predominantly of European origin (Figure 2A; 5 out of 28 case samples were removed); (2) we removed all samples with a history of retinal disease; and (3) when several samples were sequenced in a family, we kept a single sample per family to obtain unrelated control samples. Two of 28 probands were found to harbor a pair of presumed loss-of-function
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