The genetic landscape of crystallins in congenital cataract

Background: The crystalline lens is mainly composed of a large family of soluble proteins called the crystallins, which are responsible for its development, growth, transparency and refractive index. Disease-causing sequence variants in the crystallins are responsible for nearly 50% of all non-syndromic inherited congenital cataracts, as well as causing cataract associated with other diseases, including myopathies. To date, more than 300 crystallin sequence variants causing cataract have been identified. Methods: Here we aimed to identify the genetic basis of disease in five multi-generation British families and five sporadic cases with autosomal dominant congenital cataract using whole exome sequencing, with identified variants validated using Sanger sequencing. Following bioinformatics analysis, rare or novel variants with a moderate to damaging pathogenicity score, were filtered out and tested for segregation within the families. Results: We have identified 10 different heterozygous crystallin variants. Five recurrent variants were found: family-A, with a missense variant (c.145C>T; p.R49C) in CRYAA associated with nuclear cataract; family-B, with a deletion in CRYBA1 (c.272delGAG; p.G91del) associated with nuclear cataract; and family-C, with a truncating variant in CRYGD (c.470G>A; W157*) causing a lamellar phenotype; individuals I and J had variants in CRYGC (c.13A>C; T5P) and in CRYGD (c.418C>T; R140*) causing unspecified congenital cataract and nuclear cataract, respectively. Five novel disease-causing variants were also identified: family D harboured a variant in CRYGC (c.179delG; R60Qfs*) responsible for a nuclear phenotype; family E, harboured a variant in CRYBB1 (c.656G>A; W219*) associated with lamellar cataract; individual F had a variant in CRYGD (c.392G>A; W131*) associated with nuclear cataract; and individuals G and H had variants in CRYAA (c.454delGCC; A152del) and in CRYBB1 (c.618C>A; Y206*) respectively, associated with unspecified congenital cataract. All novel variants were predicted to be pathogenic and to be moderately or highly damaging. Conclusions: We report five novel variants and five known variants. Some are rare variants that have been reported previously in small ethnic groups but here we extend this to the wider population and record a broader phenotypic spectrum for these variants

Variants in PAX6, PITX3 and HSF4 causing autosomal dominant congenital cataracts.

BackgroundLens development is orchestrated by transcription factors. Disease-causing variants in transcription factors and their developmental target genes are associated with congenital cataracts and other eye anomalies.MethodsUsing whole exome sequencing, we identified disease-causing variants in two large British families and one isolated case with autosomal dominant congenital cataract. Bioinformatics analysis confirmed these disease-causing mutations as rare or novel variants, with a moderate to damaging pathogenicity score, with testing for segregation within the families using direct Sanger sequencing.ResultsFamily A had a missense variant (c.184 G>A; p.V62M) in PAX6 and affected individuals presented with nuclear cataract. Family B had a frameshift variant (c.470-477dup; p.A160R*) in PITX3 that was also associated with nuclear cataract. A recurrent missense variant in HSF4 (c.341 T>C; p.L114P) was associated with congenital cataract in a single isolated case.ConclusionsWe have therefore identified novel variants in PAX6 and PITX3 that cause autosomal dominant congenital cataract

Pathogenic variants in the CYP21A2 gene cause isolated autosomal dominant congenital posterior polar cataracts

Background: Congenital cataracts are the most common cause of visual impairment worldwide. Inherited cataract is a clinically and genetically heterogeneous disease. Here we report disease-causing variants in a novel gene, CYP21A2, causing autosomal dominant posterior polar cataract. Variants in this gene are known to cause autosomal recessive congenital adrenal hyperplasia (CAH). Methods: Using whole-exome sequencing (WES), we have identified disease-causing sequence variants in two families of British and Irish origin, and in two isolated cases of Asian-Indian and British origin. Bioinformatics analysis confirmed these variants as rare with damaging pathogenicity scores. Segregation was tested within the families using direct Sanger sequencing. Results: A nonsense variant NM_000500.9 c.955 C > T; p.Q319* was identified in CYP21A2 in two families with posterior polar cataract and in an isolated case with unspecified congenital cataract phenotype. This is the same variant previously linked to CAH and identified as Q318* in the literature. We have also identified a rare missense variant NM_000500.9 c.770 T > C; p.M257T in an isolated case with unspecified congenital cataract phenotype. Conclusion: This is the first report of separate sequence variants in CYP21A2 associated with congenital cataract. Our findings extend the genetic basis for congenital cataract and add to the phenotypic spectrum of CYP21A2 variants and particularly the CAH associated Q318* variant. CYP21A2 has a significant role in mineralo- and gluco-corticoid biosynthesis. These findings suggest that CYP21A2 may be important for extra-adrenal biosynthesis of aldosterone and cortisol in the eye lens

Variants in PAX6, PITX3 and HSF4 causing autosomal dominant congenital cataracts

Background: Lens development is orchestrated by transcription factors. Disease-causing variants in transcription factors and their developmental target genes are associated with congenital cataracts and other eye anomalies. Methods: Using whole exome sequencing, we identified disease-causing variants in two large British families and one isolated case with autosomal dominant congenital cataract. Bioinformatics analysis confirmed these disease-causing mutations as rare or novel variants, with a moderate to damaging pathogenicity score, with testing for segregation within the families using direct Sanger sequencing. Results: Family A had a missense variant (c.184 G>A; p.V62M) in PAX6 and affected individuals presented with nuclear cataract. Family B had a frameshift variant (c.470–477dup; p.A160R*) in PITX3 that was also associated with nuclear cataract. A recurrent missense variant in HSF4 (c.341 T>C; p.L114P) was associated with congenital cataract in a single isolated case. Conclusions: We have therefore identified novel variants in PAX6 and PITX3 that cause autosomal dominant congenital cataract

Whole Exome Sequencing Reveals Novel and Recurrent Disease-Causing Variants in Lens Specific Gap Junctional Protein Encoding Genes Causing Congenital Cataract

Pediatric cataract is clinically and genetically heterogeneous, and is the most common cause of childhood blindness worldwide. In this study, we aimed to identify disease-causing variants in three large British families and one isolated case with autosomal dominant congenital cataract, using whole exome sequencing. We identified four different heterozygous variants, three in the large families and one in the isolated case. Family A, with a novel missense variant (c.178G>C, p.Gly60Arg) in GJA8 with lamellar cataract; family B, with a recurrent variant in GJA8 (c.262C>T, p.Pro88Ser) associated with nuclear cataract; and family C, with a novel variant in GJA3 (c.771dupC, p.Ser258GlnfsTer68) causing a lamellar phenotype. Individual D had a novel variant in GJA3 (c.82G>T, p.Val28Leu) associated with congenital cataract. Each sequence variant was found to cosegregate with disease. Here, we report three novel and one recurrent disease-causing sequence variant in the gap junctional protein encoding genes causing autosomal dominant congenital cataract. Our study further extends the mutation spectrum of these genes and further facilitates clinical diagnosis. A recurrent p.P88S variant in GJA8 causing isolated nuclear cataract provides evidence of further phenotypic heterogeneity associated with this variant

Simulation-based Bayesian inference for epidemic models

A powerful and flexible method for fitting dynamic models to missing and censored data is to use the Bayesian paradigm via data-augmented Markov chain Monte Carlo (DA-MCMC). This samples from the joint posterior for the parameters and missing data, but requires high memory overheads for large-scale systems. In addition, designing efficient proposal distributions for the missing data is typically challenging. Pseudo-marginal methods instead integrate across the missing data using a Monte Carlo estimate for the likelihood, generated from multiple independent simulations from the model. These techniques can avoid the high memory requirements of DA-MCMC, and under certain conditions produce the exact marginal posterior distribution for parameters. A novel method is presented for implementing importance sampling for dynamic epidemic models, by conditioning the simulations on sets of validity criteria (based on the model structure) as well as the observed data. The flexibility of these techniques is illustrated using both removal time and final size data from an outbreak of smallpox. It is shown that these approaches can circumvent the need for reversible-jump MCMC, and can allow inference in situations where DA-MCMC is impossible due to computationally infeasible likelihoods. © 2013 Elsevier B.V. All rights reserved.Trevelyan J. McKinley, Joshua V. Ross, Rob Deardon, Alex R. Coo

Prophylaxis of postoperative endophthalmitis following cataract surgery: Results of the ESCRS multicenter study and identification of risk factors

Purpose: To identify risk factors and describe the effects of antibiotic prophylaxis on the incidence of postoperative endophthalmitis after cataract surgery based on analysis of the findings of the European Society of Cataract & Refractive Surgeons (ESCRS) multicenter study. Setting: Twenty-four ophthalmology units in Austria, Belgium, Germany, Italy, Poland, Portugal, Spain, Turkey, and the United Kingdom. Methods: A prospective randomized partially masked multicenter cataract surgery study recruited 16 603 patients. The study was based on a 2 × 2 factorial design, with intracameral cefuroxime and topical perioperative levofloxacin factors resulting in 4 treatment groups. The comparison of case and non-case data was performed using multivariable logistic regression analyses. Odds ratios (ORs) associated with treatment effects and other risk factors were estimated. Results: Twenty-nine patients presented with endophthalmitis, of whom 20 were classified as having proven infective endophthalmitis. The absence of an intracameral cefuroxime prophylactic regimen at 1 mg in 0.1 mL normal saline was associated with a 4.92-fold increase (95% confidence interval [CI], 1.87-12.9) in the risk for total postoperative endophthalmitis. In addition, the use of clear corneal incisions (CCIs) compared to scleral tunnels was associated with a 5.88-fold increase (95% CI, 1.34-25.9) in risk and the use of silicone intraocular lens (IOL) optic material compared to acrylic with a 3.13-fold increase (95% CI, 1.47-6.67). The presence of surgical complications increased the risk for total endophthalmitis 4.95-fold (95% CI, 1.68-14.6), and more experienced surgeons were more likely to be associated with endophthalmitis cases. When considering only proven infective endophthalmitis cases, the absence of cefuroxime and the use of silicone IOL optic material were significantly associated with an increased risk, and there was evidence that men were more predisposed to infection (OR, 2.70; 95% CI, 1.07-6.8). Conclusions: Use of intracameral cefuroxime at the end of surgery reduced the occurrence of postoperative endophthalmitis. Additional risk factors associated with endophthalmitis after cataract surgery included CCIs and the use of silicone IOLs. © 2007 ASCRS and ESCRS