Genetic analysis of ocular tumour-associated genes using large genomic datasets: insights into selection constraints and variant representation in the population.

BACKGROUND: Large genomic databases enable genetic evaluation in terms of haploinsufficiency and prevalence of missense and synonymous variants. We explored these parameters in ocular tumour-associated genes. METHODS: A curated list of ocular tumour-associated genes was assessed using the genomic databases Genome Aggregation Database (gnomAD) and DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) and compared with breast and lung cancer-associated gene lists. Haploinsufficiency was determined based on specific criteria: probability of loss of function index ≥0.9 in gnomAD, upper CI O/E limit <0.35 for loss of function variants in gnomAD and/or a DECIPHER pHaplo ≥0.86. UniProt was used for further gene characterisation, and gene ontology Protein Analysis THrough Evolutionary Relationships was explored for common biological pathways. In addition, we identified genes with under-representation/over-representation of missense/synonymous variants. RESULTS: Fifty-seven genes were identified in association with ocular and extraocular tumours.Regarding haploinsufficiency, 41% of genes met the criteria for negative selection, with 57% categorised as tumour-suppressing and 39% as oncogenic. Most genes were involved in regulatory processes. Regarding triplosensitivity, 33% of genes reached significance and 83% of these were haploinsufficient. Analysis of variants revealed under-representation of missense variants in 23% of genes and over-representation of synonymous variants in 5% of genes. Ocular tumour-associated genes exhibited higher scores for haploinsufficiency and triplosensitivity compared with breast and lung cancer-associated genes. Pathway analysis revealed significant enrichment in cellular proliferation, differentiation and division. Encoded proteins of ocular tumour-associated genes were generally longer than the median of the UniProt database. CONCLUSION: Our findings highlight the importance of negative selection in ocular tumour genes, supporting cranial gene conservation. This study provides insights into ocular tumourigenesis and future research avenues.

Two cases of linagliptin-associated bullous pemphigoid resulting in sepsis and endocarditis.

We describe two patients, in their 70s, each presenting to the emergency department, with 6-week histories of progressively developing pruritic bullae. Both individuals had multiple comorbidities, including type 2 diabetes-for which they took linagliptin, chronic kidney disease, hypertension and prosthetic heart valves. Owing to systemic illness and endocarditis secondary to superadded bacterial infections, they both required intensive treatment and prolonged hospital admissions.Despite the beneficial effect of linagliptin on glycaemic control and its reported cardiovascular and renal safety profiles, we add our cases as evidence of the significant risk of developing bullous pemphigoid while taking this medication. Secondary infection of bullous pemphigoid increased the risk of developing endocarditis, particularly among individuals with a medical history of valve replacement surgery. Considering this, we advocate caution when prescribing this medication.

One-year surgical outcomes of the PreserFlo MicroShunt in glaucoma: a multicentre analysis.

BACKGROUND/AIMS: To evaluate the efficacy and safety of the PreserFlo MicroShunt glaucoma device in a multicentre cohort study. METHODS: All consecutive patients who received the microshunt with mitomycin-C (MMC) 0.4 mg/mL from May 2019 to September 2020 in three UK tertiary centres. Primary outcome at 1 year was a complete success, with failure defined as intraocular pressure (IOP) >21 mmHg or <20% reduction, IOP≤5 mmHg with any decreased vision on two consecutive visits, reoperation or loss of light perception vision. Secondary outcomes were IOP, best-corrected visual acuity, medications, complications, interventions and reoperations. We also performed subgroup analyses for severe glaucoma and assessed risk factors for failure. RESULTS: 104 eyes had 1-year follow-up. Complete and qualified success at 1 year were achieved in 51.9% (N=54) and 16.4% (N=17), respectively, and failure occurred in 31.7% (N=33). There was a significant reduction in IOP (mmHg) from preoperatively (23.4±0.8, N=104) to 12 months (14.7±0.6, N=104) (p<0.0001). Antiglaucoma medications also decreased from preoperatively (3.4±0.1, N=104) to 12 months (0.7±0.1, N=104) (p<0.0001). Multivariate analyses showed an association between higher mean deviation and failure (HR 1.055, 95% CI 1.0075 to 1.11, p=0.0227). Complications were hypotony (19.2%; N=20), choroidal detachments (10.6%; N=11), hyphaema (5.8%; N=6) and bleb leak (5.8%; N=6). Needling and 5-fluorouracil injections were performed in 12.5% (N=13) and 33.7% (N=35), respectively, and 11.5% (N=12) required revision surgery. CONCLUSION: The PreserFlo MicroShunt with MMC 0.4 mg/mL showed an overall success rate of 68.3% at 1 year, and led to significant IOP and medication reduction with a low rate of adverse effects.

Exploring the mutational landscape of genes associated with inherited retinal disease using large genomic datasets: identifying loss of function intolerance and outlying propensities for missense changes.

BACKGROUND: Large databases permit quantitative description of genes in terms of intolerance to loss of function ('haploinsufficiency') and prevalence of missense variants. We explored these parameters in inherited retinal disease (IRD) genes. METHODS: IRD genes (from the 'RetNet' resource) were classified by probability of loss of function intolerance (pLI) using online Genome Aggregation Database (gnomAD) and DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) databases. Genes were identified having pLI ≥0.9 together with one or both of the following: upper bound of CI <0.35 for observed to expected (o/e) ratio of loss of function variants in the gnomAD resource; haploinsufficiency score <10 in the DECIPHER resource. IRD genes in which missense variants appeared under-represented or over-represented (Z score for o/e ratio of <-2.99 or >2.99, respectively) were also identified. The genes were evaluated in the gene ontology Protein Analysis THrough Evolutionary Relationships (PANTHER) resource. RESULTS: Of 280 analysed genes, 39 (13.9%) were predicted loss of function intolerant. A greater proportion of X-linked than autosomal IRD genes fulfilled these criteria, as expected. Most autosomal genes were associated with dominant disease. PANTHER analysis showed >100 fold enrichment of spliceosome tri-snRNP complex assembly. Most encoded proteins were longer than the median length in the UniProt database. Fourteen genes (11 of which were in the 'haploinsufficient' group) showed under-representation of missense variants. Six genes (SAMD11, ALMS1, WFS1, RP1L1, KCNV2, ADAMTS18) showed over-representation of missense variants. CONCLUSION: A minority of IRD-associated genes appear to be 'haploinsufficient'. Over-representation of spliceosome pathways was observed. When interpreting genetic tests, variants found in genes with over-representation of missense variants should be interpreted with caution.

Long-term outcomes in Primary congenital glaucoma, aniridia and anterior segment dysgenesis.

AIM: To determine the long-term outcomes of a cohort of complex patients with primary congenital glaucoma, aniridia and anterior segment dysgenesis. METHODS: Retrospective consecutive series between 1990-2021 in two UK tertiary centres: Guy's and St Thomas' NHS Foundation Trust and King's College Hospital NHS Foundation Trust. We recorded the number and types of surgical and laser treatments along with preoperative and postoperative data, including intraocular pressures (IOP) and anti-glaucoma medications. RESULTS: A total of 41 eyes of 21 patients were included. Primary diagnoses were primary congenital glaucoma in 16 eyes (39.0%), aniridia in 14 eyes (34.2%), and anterior segment dysgenesis in 8 eyes (19.5%). Sixteen eyes (39.0%) had one or more glaucoma surgery or laser procedures for advanced glaucoma, and the long-term follow-up was 12.8 ± 3.6 years. There was a significant decrease in postoperative IOP (mmHg) at 3 months (16.5 ± 1.6; p = 0.0067), 6 months (18.7 ± 2.1; p = 0.0386), 12 months (18.6 ± 1.7; p = 0.0229), 3 years (14.7 ± 1.2; p = 0.0126), 5 years (15.5 ± 1.8; p = 0.0330) and 10 years (15.4 ± 2.3; p = 0.7780), compared to preoperatively (24.1 ± 2.6). Surgical success (complete and qualified) was 62.5%, 50.0%, 43.8%, 46.2%, 45.5% and 28.6% at 3 months, 6 months, 12 months, 3 years, 5 years and 10 years, respectively. There was no significant change in the number of anti-glaucoma drugs postoperatively (p > 0.05). Four eyes (25.0%) had postoperative complications (hyphaema, hypotony) that resolved after conservative management. CONCLUSIONS: Surgical management of these complex eyes with advanced glaucoma is challenging. Overall, the cohort had good surgical outcomes with a significant decrease in IOP by 36.1% after long-term follow-up.

Bilateral macular drusen in acquired partial lipodystrophy with type 2 membranoproliferative glomerulonephritis.

A 35-year-old woman with acquired partial lipodystrophy (PLD) and features of type 2 membranoproliferative glomerulonephritis (MPGN-II), presented with difficulty in her fine detailed vision over the past year. She had right amblyopia from a hypermetropic anisometropia with astigmatism, displaying a best-corrected visual acuity of 0.50 and 0.00 LogMAR, in the right and left eye, respectively. Funduscopy showed bilateral symmetrical drusenoid deposits most prominent in the temporal macula with clusters in the superior and inferior retina, outside the temporal vascular arcades. Multimodal retinal imaging was performed, which confirmed hyperautofluorescent drusen located between the retinal pigment epithelium and Bruch's membrane. Electroretinography showed bilateral mild peripheral macular dysfunction, but normal central macular function on the pattern electroretinogram. Both PLD and macular drusen, are rare as distinct disease entities, but an association does exist and may be linked to MPGN-II.