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

BACKGROUND: Inherited retinal dystrophies describe a heterogeneous group of retinal diseases that lead to the irreversible degeneration of rod and cone photoreceptors and eventual blindness. Recessive loss-of-function mutations in Tubulin Tyrosine Ligase Like 5 (TTLL5) represent a recently described cause of inherited cone-rod and cone dystrophy. This study describes the unusual phenotypes of three patients with autosomal recessive mutations in TTLL5. Examination of these patients included funduscopic evaluation, spectral-domain optical coherence tomography, short-wavelength autofluorescence, and full-field electroretinography (ffERG). Genetic diagnoses were confirmed using whole exome capture. Protein modeling of the identified variants was performed to explore potential genotype-phenotype correlations. RESULTS: Genetic testing revealed five novel variants in TTLL5 in three unrelated patients with retinal dystrophy. Clinical imaging demonstrated features of sectoral cone-rod dystrophy and cone dystrophy, with phenotypic variability seen across all three patients. One patient also developed high-frequency hearing loss during a similar time period as the onset of retinal disease, potentially suggestive of a syndromic disorder. Retinal structure findings were corroborated with functional measures including ffERG findings that supported these diagnoses. Modeling of the five variants suggest that they cause different effects on protein function, providing a potential reason for genotype-phenotype correlation in these patients. CONCLUSIONS: The authors report retinal phenotypic findings in three unrelated patients with novel mutations causing autosomal recessive TTLL5-mediated retinal dystrophy. These findings broaden the understanding of the phenotypes associated with TTLL5-mediated retinal disease and suggest that mutations in TTLL5 should be considered as a potential cause of sectoral retinal dystrophy in addition to cone-rod and cone dystrophies.

Clinical characteristics and ultra-widefield fundus image analysis of two siblings with Bardet-Biedl syndrome type 1 p.Met390Arg variant.

PURPOSE: To present the case of two siblings with a genetic diagnosis of Bardet Biedl syndrome (BBS) type 1, yet different clinical profiles and disease manifestations. OBSERVATIONS: Sequencing analysis revealed a p.Met390Arg pathogenic variant in the BBS1 gene of both patients, as well as several additional variants of uncertain significance Patient 1 was 41 years old, had three primary (cone-rod dystrophy, hypogonadism, and truncal obesity) and three secondary (arterial hypertension, strabismus, and astigmatism) BBS features. He also had insulin resistance, as well as low levels of total testosterone and cortisol. Patient 2 was 43 years old, had two primary (cone-rod dystrophy and truncal obesity), and four secondary (arterial hypertension, diabetes mellitus, strabismus, and astigmatism) BBS features. Both patients had severe maculopathy; however, patient 1 had bone-spicules that extended up to the mid-periphery, in a perivenular pattern, and significant vascular attenuation with "ghost vessel" appearance towards the temporal periphery, a feature that was absent on patient 2. CONCLUSIONS AND IMPORTANCE: The intrafamilial phenotypic variability among our patients supports the hypothesis that BBS is a disease with genetic, hormonal, and environmental triggers interacting to produce phenotypic variability. Although our report may not establish a definite relationship between environmental and genetic influences, their role should be explored in future studies.