Submission Details

The TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, was first reported in 2014 as a cause of autosomal recessive cone and cone-rod dystrophies (Sergouniotis, et al., 2014; PMID 24791901). We found TTL5-related disease is inherited in an autosomal recessive pattern, with biallelic disease-causing TTLL5 variants causing a range of retinopathies. To date, TTLL5-related retinopathies appear to be characterized by a cone-first phenotype, and include cone dystrophy, cone-rod dystrophy and early onset retinal dystrophy (PMID: 34203883). Some cases have been associated with male infertility, and at least one case with associated hearing loss has been described (PMID: 35365235). Because the cases with different diagnoses and syndromic features all exhibit a recessive mode of inheritance and share overlapping phenotypes consistent with a single spectrum of disease, and consistent with criteria outlined by the ClinGen Lumping and Splitting Working Group, these cases have been lumped into a single disease entity, TTLL5-related retinopathy.

This curation has scored six suspected disease-causing variants (five nonsense variants and one missense variant) that have been reported in six probands in three publications (PMIDs: 24791901, 34203883, 35365235). Homozygous variants in families from multiple countries were included in the curation (PMIDs: 34203883, 24791901) from both consanguineous and non-consanguineous families. While cases harbor apparent null variants, missense variants have also been associated with TTLL5-related disease (PMID: 20237254). More evidence is available in the literature, but the maximum score for genetic evidence has been reached.

The mechanism of pathogenicity appears to be loss of function, as multiple nonsense or frameshift mutations resulting in TTLL5-related disease are described in the literature (PMID 24791901, 34203883, 35365235). Deletions also appear to represent a mechanism of pathogenicity (PMID:34203883, 32783370), perhaps representing up to 20% of the mutational load in the gene. While precise genotype-phenotype correlations have not been described, mutational hot spots in two functional domains have emerged.

The TTLL5 gene was originally described (previously called STAMP; PMID 17116691) in 2007. Like other members of the superfamily, it is involved in post-translational modifications of α- and β-tubulin, key components of the axonemes. A mouse gene knockout was initially described with fertility defects and normal retinal function (PMID: 23558686); however, detailed study of the knockout mice revealed cone-rod dysfunction in older animals, including electroretinogram defects (PMID: 27162334). Expression of TTLL5 has also been validated in human retina (PMIDs: 24791901, 28173158). TTLL5 plays a role in glutamylation of RPGR, another major retinal dystrophy gene, and this function is apparently disrupted by human disease-causing mutations in TTLL5 (PMID: 27162334). Several studies have confirmed the physical interaction between TTLL5 and RPGR in vitro (PMID:27162334, 28173158). Multiple cell culture models support the role of TTLL5 in cellular ciliary structures, as TTLL5 localizes to ciliary structures in vitro (PMIDs: 27846257, 33833316, 35410372).

In summary, TTLL5 is definitively associated with autosomal recessive TTLL5-related retinopathy. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification has been approved by the ClinGen Retina GCEP on October 5th, 2023 (SOP Version 9).