Mutations in the polyglutamylase gene TTLL5, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility.

Hereditary retinal degenerations encompass a group of genetic diseases characterized by extreme clinical variability. Following next-generation sequencing and autozygome-based screening of patients presenting with a peculiar, recessive form of cone-dominated retinopathy, we identified five homozygous variants [p.(Asp594fs), p.(Gln117*), p.(Met712fs), p.(Ile756Phe), and p.(Glu543Lys)] in the polyglutamylase-encoding gene TTLL5, in eight patients from six families. The two male patients carrying truncating TTLL5 variants also displayed a substantial reduction in sperm motility and infertility, whereas those carrying missense changes were fertile. Defects in this polyglutamylase in humans have recently been associated with cone photoreceptor dystrophy, while mouse models carrying truncating mutations in the same gene also display reduced fertility in male animals. We examined the expression levels of TTLL5 in various human tissues and determined that this gene has multiple viable isoforms, being highly expressed in testis and retina. In addition, antibodies against TTLL5 stained the basal body of photoreceptor cells in rat and the centrosome of the spermatozoon flagellum in humans, suggesting a common mechanism of action in these two cell types. Taken together, our data indicate that mutations in TTLL5 delineate a novel, allele-specific syndrome causing defects in two as yet pathogenically unrelated functions, reproduction and vision.

Biallelic variants in coenzyme Q10 biosynthesis pathway genes cause a retinitis pigmentosa phenotype.

The aim of this study was to investigate coenzyme Q10 (CoQ10) biosynthesis pathway defects in inherited retinal dystrophy. Individuals affected by inherited retinal dystrophy (IRD) underwent exome or genome sequencing for molecular diagnosis of their condition. Following negative IRD gene panel analysis, patients carrying biallelic variants in CoQ10 biosynthesis pathway genes were identified. Clinical data were collected from the medical records. Haplotypes harbouring the same missense variant were characterised from family genome sequencing (GS) data and direct Sanger sequencing. Candidate splice variants were characterised using Oxford Nanopore Technologies single molecule sequencing. The CoQ10 status of the human plasma was determined in some of the study patients. 13 individuals from 12 unrelated families harboured candidate pathogenic genotypes in the genes: PDSS1, COQ2, COQ4 and COQ5. The PDSS1 variant c.589 A > G was identified in three affected individuals from three unrelated families on a possible ancestral haplotype. Three variants (PDSS1 c.468-25 A > G, PDSS1 c.722-2 A > G, COQ5 c.682-7 T > G) were shown to lead to cryptic splicing. 6 affected individuals were diagnosed with non-syndromic retinitis pigmentosa and 7 had additional clinical findings. This study provides evidence of CoQ10 biosynthesis pathway gene defects leading to non-syndromic retinitis pigmentosa in some cases. Intronic variants outside of the canonical splice-sites represent an important cause of disease. RT-PCR nanopore sequencing is effective in characterising these splice defects.

Illness Perceptions, Psychiatric Manifestations, and Quality of Life in Patients with Inherited Retinal Dystrophies.

PURPOSE: We aimed to assess psychiatric manifestations, health-related quality of life (HRQoL), and associated illness perceptions in patients with inherited retinal dystrophies (IRD). METHODS: In 48 IRD patients, we assessed a wide range of psychological distress symptoms (Symptom Distress Checklist-90-R), depressive symptom severity (PHQ-9), generic HRQoL (WHOQOL-BREF), and Illness Perceptions (B-IPQ). Ninety-six alleged healthy participants matched for age, sex, and education served as healthy controls and 331 patients with rheumatological disorders served as disease controls. RESULTS: IRD patients exhibited elevated symptoms of phobic anxiety (p=0.049) and paranoid ideation (p=0.028) compared to healthy and disease controls and were less satisfied with their general health (p<0.001) compared to disease controls. They shared, however, similar levels on all other aspects of psychiatric manifestations and HRQoL. The majority of patients acknowledged the hereditary and chronic nature of the illness. They also attributed more symptoms to their disease (illness identity) compared to people with rheumatological disorders (p<0.001), and this attribution was associated with paranoid ideation (p<0.05) and phobic anxiety (p<0.001). CONCLUSIONS: Broadening our view of the psychological variables which should be assessed in IRD patients may help to better identify those psychological parameters which impair the patients' well-being and yet may be amenable to treatment. The design of psycho-educational therapies targeting illness representations may have a beneficial effect upon the IRD patients' psychological distress and HRQoL.

Genetic polymorphisms associated with retinal vein occlusion: a Greek case-control study and meta-analysis.

BACKGROUND: The genetic background of retinal vein occlusion (RVO) remains unclear. In the current study, we aimed to replicate polymorphisms related to thrombophilia/hypofibrinolysis in a Greek population and also systematically summarize current evidence available on the topic. MATERIALS AND METHODS: A total of 48 RVO patients and 53 controls were genotyped for factor V H1299R and V Leiden, ß-fibrinogen G455A, PAI-1 4G/5G, ACE I/D, HPA1, prothrombin G20210A, factor XIII Val34Leu, MTHFR A1298C and C677T polymorphisms. We examined the association between RVO and the above polymorphisms under a per-allele genetic model in a Greek unrelated case/control population. Additionally, searching PubMed up to January 2012, we identified existing evidence on these polymorphisms and performed meta-analyses. RESULTS: A total of three polymorphisms had nominally significant associations with RVO. These associations pertained to ACE D allele (odds ratio, OR, 2.08 [95% CI, 1.12-3.85], p = 0.02); factor XIII 34Leu allele (OR = 0.41 [95% CI, 0.18-0.95], p = 0.037] and MTHFR 677T variant (OR = 2.20 [95% CI 1.10-4.40], p = 0.026). We performed a meta-analysis on the associations between RVO and PAI-1 (n = 5), factor V Leiden (n = 21), MTHFR C677T (n = 19) and prothrombin G20210A (n = 21). We observed nominally significant associations only for PAI-1 (OR = 1.27 [95% CI, 1.02-1.60, p = 0.036]) (I(2) = 44.7%), and factor V Leiden (OR = 1.40 [95% CI, 1.07-1.84, p = 0.015]) (I(2) = 3.6%) using random effects model. CONCLUSIONS: Our results suggest that there may be an association between increased risk for RVO and ACE I/D, MTHFR C677T, PAI-1 4G/5G and factor V Leiden polymorphisms, whereas the Val34Leu variant may exert a protective effect.

Contrast sensitivity and color vision in eyes with retinitis pigmentosa and good visual acuity: correlations with SD-OCT findings.

BACKGROUND AND OBJECTIVE: To investigate the morphological substrate of the changes in visual function in eyes with retinitis pigmentosa and good visual acuity using spectral-domain optical coherence tomography (SD-OCT). PATIENTS AND METHODS: A total of 30 eyes of 17 patients with retinitis pigmentosa and visual acuity of 20/40 or better underwent contrast sensitivity and color vision testing. The retinal thickness at the fovea and macula and the length of the photoreceptor inner/outer segment (IS/OS) junction were assessed by SD-OCT. Structural-functional correlations were investigated. RESULTS: Contrast sensitivity correlated well with IS/OS length (Spearman r = 0.719, P < .001) and foveal thickness (r = 0.672, P < .001) and moderately with macular thickness (r = 0.422, P = .025). Moreover, color vision correlated significantly with IS/OS length (r = -0.725, P < .001) and foveal thickness (r = -0.661, P < .001). CONCLUSION: In eyes with retinitis pigmentosa and good visual acuity, the structural changes observed on OCT scans correspond well to subtle measures of central visual function, complementary to visual acuity testing.