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Context. HD 209458 b is one of the most studied exoplanets to date. Despite this, atmospheric characterisation studies yielded inconsistent species detections and abundances. Values reported for the C/O ratio range from ≈0.1 to 1.0. Of particular interest is the simultaneous detection of H2O and HCN reported by some studies using high-resolution ground-based observations, which would require the atmospheric C/O ratio to be fine-tuned to a narrow interval around 1. HCN has however not been detected from recent space-based observations. Aims. We aim to provide an independent study of HD 209458 b's atmosphere with high-resolution observations, in order to infer the presence of several species, including H2O and HCN. Methods. We observed four primary transits of HD 209458 b at a high resolution (ℛ ≈ 92000) with CRIRES+ in the near infrared (band H, 1.431243–1.837253 μm). After reducing the data with pycrires, we prepared the data using the SysRem algorithm and performed a cross-correlation (CCF) analysis of the transmission spectra. We also compared the results with those obtained from simulated datasets constructed by combining the Exo-REM self-consistent model with the petitRADTRANS package. Results. Combining the four transits, we detect H2O with a signal-to-noise CCF metric of 8.7σ. This corresponds to a signal emitted at Kp = 151.3−23.4+31.1 km s−1 and blueshifted by −6−2+1 km s−1, consistent with what is expected for HD 209458 b. We do not detect any other species among C2H2, CH4, CO, CO2, H2S, HCN, and NH3. Comparing this with our simulated datasets, this result is consistent with a C/O ratio of 0.1 and an opaque cloud top pressure of 50 Pa, at a 3 times solar metallicity. This would also be consistent with recent JWST observations. However, none of the simulated results obtained with a bulk C/O ratio of 0.8, a value suggested by previous studies using GIANO-B and CRIRES, are consistent with our observations. [ABSTRACT FROM AUTHOR]

The land sector is expected to contribute to strategies aimed at mitigating global temperature increases and this necessitates an improved understanding of human actions on land sector emissions and removals. Current Intergovernmental Panel on Climate Change guidelines for the land sector of national greenhouse gas inventories are based on the assumption that all emissions and removals in managed lands are caused by humans. In Canada, however, natural disturbances in managed forests can result in large and highly variable emissions and subsequent removals that mask the impacts of management activities. Here we describe methods to isolate and quantify the impacts of management on trends in estimated anthropogenic emissions and removals in Canada's managed forest by partitioning fluxes from two land components: fluxes from lands dominated by natural disturbance effects and fluxes from the remaining managed forests. The sum of the flux estimates of the two land components is equal to net emissions and removals in managed forest lands. Separating highly variable natural disturbance fluxes from the remaining fluxes in managed forest lands increases the understanding of how human activities impact flux trends. Comparing these anthropogenic emissions and removals with those from natural disturbances quantifies their relative contributions to global atmospheric C[O.sub.2] concentrations. Key words: carbon, greenhouse gas inventory, anthropogenic, managed forest, climate change mitigation, CBM-CFS3. On s'attend a ce que le secteur terrestre contribue aux strategies visant a attenuer l'augmentation de la temperature a l'echelle du globe, ce qui necessite une meilleure comprehension de l'impact de l'activite humaine sur les emissions et les absorptions associes au secteur terrestre. Les directives actuelles du Groupe d'experts intergouvernemental sur revolution du climat pour le secteur terrestre concernant les inventaires nationaux des gaz a effet de serre s'appuient sur l'hypothese que la totalite des emissions et des absorptions sur les terres amenagees sont d'origine anthropique. Au Canada cependant, les perturbations dans les forets amenagees peuvent entrainer d'importantes et tres variables emissions et captures subsequentes qui masquent les impacts des activites d'amenagement. Nous decrivons dans cet article des methodes pour isoler et quantifier les impacts de l'amenagement sur les tendances des emissions et des absorptions d'origine anthropique estimes dans les forets amenagees du Canada en repartissant les flux associes a deux composantes terrestres: les flux dont la provenance est dominee par les effets des perturbations naturelles et les flux associes au reste des forets amenagees. La somme des flux estimes pour les deux composantes terrestres est egale aux emissions et captures nettes sur les terrains forestiers amenages. La separation des flux excessivement variables associes aux perturbations naturelles du reste des flux sur les terrains forestiers amenages ameliore la comprehension de la facon dont l'activite humaine influence revolution des flux. La comparaison de ces emissions et du piegeage d'origine anthropique a ceux qui sont associes aux perturbations naturelles quantifie leurs contributions relatives aux concentrations globales du C[O.sub.2] atmospherique. [Traduit par la Redaction] Mots-cles: carbone, inventaire des gaz a effet de serre, anthropique, foret amenagee, attenuation des changements climatiques, MBC-SFC3., 1. Introduction The purpose of the annual reporting of national anthropogenic greenhouse gas (GHG) emission and removal estimates to the United Nations Framework Convention on Climate Change (UNFCCC) is to [...]

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Quantitative assessment of Canada's boreal forest mitigation potential is not yet possible, though the range of mitigation activities is known, requirements for sound analyses of options are increasingly understood, and there is emerging recognition that biogeophysical effects need greater attention. Use of a systems perspective highlights trade-offs between activities aimed at increasing carbon storage in the ecosystem, increasing carbon storage in harvested wood products (HWPs), or increasing the substitution benefits of using wood in place of fossil fuels or more emissions-intensive products. A systems perspective also suggests that erroneous conclusions about mitigation potential could result if analyses assume that HWP carbon is emitted at harvest, or bioenergy is carbon neutral. The greatest short-run boreal mitigation benefit generally would be achieved by avoiding greenhouse gas emissions; but over the longer run, there could be significant potential in activities that increase carbon removals. Mitigation activities could maximize landscape carbon uptake or maximize landscape carbon density, but not both simultaneously. The difference between the two is the rate at which HWPs are produced to meet society's demands, and mitigation activities could seek to delay or reduce HWP emissions and increase substitution benefits. Use of forest biomass for bioenergy could also contribute though the point in time at which this produces a net mitigation benefit relative to a fossil fuel alternative will be situation-specific. Key knowledge gaps exist in understanding boreal mitigation strategies that are robust to climate change and how mitigation could be integrated with adaptation to climate change. Key words: boreal forest, Canada, carbon, climate change, mitigation. L'evaluation quantitative du potentiel de mitigation des forets boreales canadiennes n'est pas encore possible bien que l'on connaisse l'amplitude des activites de mitigation, que les besoins en analyses solides des options soient de mieux en mieux compris et qu'on observe une reconnaissance emergente que les effets biogeographiques necessitent une plus grande attention. Une approche par systeme souligne les balances entre les activites cherchant a augmenter l'immobilisation du carbone dans l'ecosysteme, a augmenter l'accumulation du carbone dans les produits ligneux recoltes (PLRs), ou a augmenter les benefices de substitution consistant a utiliser le bois plutot que les combustibles fossiles ou des produits a plus fortes emissions. Une approche par systeme suggere egalement que les conclusions erronees quant au potentiel de mitigation pourraient apparaitre si les analyses assument que le carbone PLR est emis a la recolte, ou que la bioenergie est carbone neutre. Le meilleur benefice a court terme de la mitigation boreale serait generalement atteint en evitant les emissions a effet serre, mais sur le long terme il pourrait y avoir un potentiel significatif dans les activites augmentant la suppression du carbone. Les activites de mitigation pourraient maximiser l'absorption du carbone du paysage ou maximiser la densite en carbone du paysage, mais non pas les deux simultanement. La difference entre les deux se trouve dans le taux avec lequel les PLRs sont produits pour rencontrer les besoins de la societe et les activites de mitigation pourraient chercher a retarder ou reduire les emissions des PRL et a augmenter les benefices de la substitution. L'utilisation de la biomasse pour l'energie pourrait aussi contribuer bien que le moment auquel ceci produit un benefice net de mitigation par rapport a l'alternative du combustible fossile sera specifique a une situation. Il existe un manque de connaissances pour comprendre les strategies de mitigation boreales qui soient robustes par rapport au changement climatique et savoir comment on pourrait integrer la mitigation avec l'adaptation au changement climatique. [Traduit par la Redaction] Mots-cles: foret boreale, Canada, carbone, changement climatique, mitigation., 1. Introduction Global emissions of carbon dioxide (C[O.sub.2]) averaged 32.3 [+ or -] 3.2 Gt C[O.sub.2]/year in 2000-2009 as a result of fossil fuel combustion, cement production, and land-use change [...]

Drained organic soils are a significant source of greenhouse gas (GHG) emissions to the atmosphere. Rewetting these soils may reduce GHG emissions and could also create suitable conditions for return of the carbon (C) sink function characteristic of undrained organic soils. In this article we expand on the work relating to rewetted organic soils that was carried out for the 2014 Intergovernmental Panel on Climate Change (IPCC) Wetlands Supplement. We describe the methods and scientific approach used to derive the Tier 1 emission factors (the rate of emission per unit of activity) for the full suite of GHG and waterborne C fluxes associated with rewetting of organic soils. We recorded a total of 352 GHG and waterborne annual flux data points from an extensive literature search and these were disaggregated by flux type (i.e. CO2, CH4, N2O and DOC), climate zone and nutrient status. Our results showed fundamental differences between the GHG dynamics of drained and rewetted organic soils and, based on the 100 year global warming potential of each gas, indicated that rewetting of drained organic soils leads to: net annual removals of CO2 in the majority of organic soil classes; an increase in annual CH4 emissions; a decrease in N2O and DOC losses; and a lowering of net GHG emissions. Data published since the Wetlands Supplement (n = 58) generally support our derivations. Significant data gaps exist, particularly with regard to tropical organic soils, DOC and N2O. We propose that the uncertainty associated with our derivations could be significantly reduced by the development of country specific emission factors that could in turn be disaggregated by factors such as vegetation composition, water table level, time since rewetting and previous land use history. [ABSTRACT FROM AUTHOR]

Copyright of Environmental Reviews is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Canada's forests play an important role in the global carbon (C) cycle because of their large and dynamic C stocks. Detailed monitoring of C exchange between forests and the atmosphere and improved understanding of the processes that affect the net ecosystem exchange of C are needed to improve our understanding of the terrestrial C budget. We estimated the C budget of Canada's 2.3 × 10 km managed forests from 1990 to 2008 using an empirical modelling approach driven by detailed forestry datasets. We estimated that average net primary production (NPP) during this period was 809 ± 5 Tg C yr (352 g C m yr) and net ecosystem production (NEP) was 71 ± 9 Tg C yr (31 g C m yr). Harvesting transferred 45 ± 4 Tg C yr out of the ecosystem and 45 ± 4 Tg C yr within the ecosystem (from living biomass to dead organic matter pools). Fires released 23 ± 16 Tg C yr directly to the atmosphere, and fires, insects and other natural disturbances transferred 52 ± 41 Tg C yr from biomass to dead organic matter pools, from where C will gradually be released through decomposition. Net biome production (NBP) was only 2 ± 20 Tg C yr (1 g C m yr); the low C sequestration ratio (NBP/NPP=0.3%) is attributed to the high average age of Canada's managed forests and the impact of natural disturbances. Although net losses of ecosystem C occurred during several years due to large fires and widespread bark beetle outbreak, Canada's managed forests were a sink for atmospheric CO in all years, with an uptake of 50 ± 18 Tg C yr [net ecosystem exchange (NEE) of CO=−22 g C m yr]. [ABSTRACT FROM AUTHOR]

Information on biomass distribution is needed to estimate GHG emissions and removals from land use changes in Canada's north for UNFCCC reporting. This paper reports aboveground biomass measurements along the Dempster Highway transect in 2004, and around Yellowknife and the Lupin Gold Mine in 2005. The measured aboveground biomass ranges are 10-100 t ha-1 for woodlands, 1-100 t ha-1 for shrub sites, and 0.5-10 t ha-1 for grass/herbs sites. The root mean squared error (RMSE) of measurements is 21%, and the median absolute percentage error (MedAPE) is 14%. The combination of JERS backscatter and Landsat TM4/TM5 gives the best biomass equation for the Dempster Highway transect, with r 2 = 0.72 when using a one-step approach (i.e. using all points) and 0.78 when using a two-step approach (i.e. stratifying data into three classes: grass, shrub, and woodlands). The two-step approach reduces the MedAPE from 53% to 33%. The validation against Yellowknife & Lupin data indicates that the equations have good transferability. The improvement of two-step approach over the one-step approach, however, is not significant for the validation dataset, suggesting that the one-step approach is as good as the two-step approach when applied over areas outside where the equations are developed. The relationships and error analysis of this study, as well as the final estimate of GHG emission/removal over Canada's north have been incorporated into Canada's 2006 UNFCCC report. [ABSTRACT FROM AUTHOR]

Isotretinoin (ITR), a teratogen in many species, is associated with increased oxidative stress. Metallothionein (MT) is an important tissue antioxidant whose concentrations are induced by zinc. To study the role of supplemental Zn as an inducer of embryonic MT, we injected pregnant CD-1 mice subcutaneously with saline vehicle, or 20 or 40 mg/kg Zn on gestational day (GD) 6.5. After 48 h, embryonic MT concentrations increased in a dose-related manner (r = 0.64, P < 0.05) with Zn treatment. The possible protective role of Zn pretreatment against ITR teratogenicity was investigated in vivo and in vitro. CD-1 mice were pretreated with saline or Zn (20 and 40 mg/kg) on GD 8.5 and 9.5. ITR was administered to both groups of mice via three intragastric intubations of 100 mg ITR/kg at 4 h intervals on GD 10.5. On GD 18.5, Zn pre-treated mice demonstrated decreased ITR-mediated growth retardation, cleft palates and postpartum mortality. A reduction in embryonic MT concentrations was observed in mice exposed to ITR. Mouse embryos cultured on GD 8.5 with an addition of 15 micromol/L Zn for 48 h had a sixfold greater MT concentration (688 microg/g protein) than controls. The Zn pretreatment of cultured embryos prevented malformations and lessened growth retardation caused by 24 h exposure to 17 micromol/L ITR. These results suggest that Zn-mediated induction of MT in mouse embryos could protect against ITR teratogenicity. [ABSTRACT FROM AUTHOR]

Abstract Background Unbalanced chromosomal translocations may present with a variety of clinical and laboratory findings and provide insight into the functions of genes on the involved chromosomal segments. Case Presentation A 9 year-old boy presented to our clinic with Factor VII deficiency, microcephaly, a seizure disorder, multiple midline abnormalities (agenesis of the corpus callosum, imperforate anus, bilateral optic nerve hypoplasia), developmental delay, hypopigmented macules, short 5th fingers, and sleep apnea due to enlarged tonsils. Cytogenetic and fluorescence in situ hybridization analyses revealed an unbalanced translocation involving the segment distal to 16p13 replacing the segment distal to 13q33 [46, XY, der(13)t(13;16)(q33;p13.3)]. Specific BAC-probes were used to confirm the extent of the 13q deletion. Conclusion This unique unbalanced chromosomal translocation may provide insights into genes important in midline development and underscores the previously-reported phenotype of Factor VII deficiency in 13q deletions.

Quantitative assessment of Canada's boreal forest mitigation potential is not yet possible, though the range of mitigation activities is known, requirements for sound analyses of options are increasingly understood, and there is emerging recognition that biogeophysical effects need greater attention. Use of a systems perspective highlights trade-offs between activities aimed at increasing carbon storage in the ecosystem, increasing carbon storage in harvested wood products (HWPs), or increasing the substitution benefits of using wood in place of fossil fuels or more emissions-intensive products. A systems perspective also suggests that erroneous conclusions about mitigation potential could result if analyses assume that HWP carbon is emitted at harvest, or bioenergy is carbon neutral. The greatest short-run boreal mitigation benefit generally would be achieved by avoiding greenhouse gas emissions; but over the longer run, there could be significant potential in activities that increase carbon removals. Mitigation activities could maximize landscape carbon uptake or maximize landscape carbon density, but not both simultaneously. The difference between the two is the rate at which HWPs are produced to meet society's demands, and mitigation activities could seek to delay or reduce HWP emissions and increase substitution benefits. Use of forest biomass for bioenergy could also contribute though the point in time at which this produces a net mitigation benefit relative to a fossil fuel alternative will be situation-specific. Key knowledge gaps exist in understanding boreal mitigation strategies that are robust to climate change and how mitigation could be integrated with adaptation to climate change. [ABSTRACT FROM AUTHOR]

Colobomatous microphthalmia is a potentially blinding congenital ocular malformation that can present either in isolation or together with other syndromic features. Despite a strong genetic component to disease, many cases lack a molecular diagnosis. We describe a novel autosomal dominant oculo-vertebral-renal (OVR) syndrome in six independent families characterized by colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities. Genome sequencing identified six rare variants in the orphan nuclear receptor gene NR6A1 in these families. We performed in silico, cellular and zebrafish experiments to demonstrate the NR6A1 variants were pathogenic or likely pathogenic for OVR syndrome. Knockdown of either or both zebrafish paralogs of NR6A1 results in abnormal eye and somite development, which was rescued by wild-type but not variant NR6A1 mRNA. Illustrating the power of genomic ascertainment in medicine, our study establishes NR6A1 as a critical factor in eye and vertebral development and a pleiotropic gene responsible for OVR syndrome.

Colobomatous microphthalmia is a potentially blinding congenital ocular malformation that can present either in isolation or together with other syndromic features. Despite a strong genetic component to disease, many cases lack a molecular diagnosis. We describe a novel autosomal dominant oculo-vertebral-renal (OVR) syndrome in six independent families characterized by colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities. Genome sequencing identified six rare variants in the orphan nuclear receptor gene NR6A1 in these families. We performed in silico, cellular and zebrafish experiments to demonstrate the NR6A1 variants were pathogenic or likely pathogenic for OVR syndrome. Knockdown of either or both zebrafish paralogs of NR6A1 results in abnormal eye and somite development, which was rescued by wild-type but not variant NR6A1 mRNA. Illustrating the power of genomic ascertainment in medicine, our study establishes NR6A1 as a critical factor in eye and vertebral development and a pleiotropic gene responsible for OVR syndrome.

Purpose: Hereditary eye diseases (HEDs) are individually rare but affect millions globally. The era of molecular genetics has ushered major advances in the study of these disorders; however, the inclusivity and population diversity of this research is unknown. Questions on the accuracy and applicability of these findings in diverse populations, especially African American patients, came up consistently during counselling sessions. This also raised the possibility of missed opportunities for broader understanding of these rare diseases. We conducted a literature review to measure the representation of African Americans in genomic research surrounding nine HEDs., Methods: A detailed literature search using a predetermined set of search terms for each of nine HED categories was performed across PubMed, Embase, Web of Science, and Scopus focusing on studies published between Jan 1990 and July 2021. Predetermined inclusion criteria were applied to filter the sources., Results: We identified 46 studies clearly reporting HED characterization in African Americans. Analysis of these inclusive studies revealed unique findings demonstrating the known usefulness of including diverse cohorts in genomics research., Conclusions: HED characterization in diverse participants, specifically African Americans, is identified as a knowledge gap area. Genomic research is more applicable to patients when conducted in populations that share their ancestral background. Greater inclusion of African Americans in ophthalmic genetics research is a scientific imperative and a needed step in the pursuit of the best possible patient care for populations of all ancestries., Translational Relevance: This work reveals gaps in genomic research in African Americans with HEDs.

Purpose: To describe a novel optical coherence tomography (OCT) finding of outer retina microcavitations in RP1 -related retinopathy and other retinal degenerations., Methods: Medical charts and OCT images of 28 patients with either autosomal dominant retinitis pigmentosa or autosomal recessive retinitis pigmentosa RP1 -related retinopathy were reviewed. Outer retina microcavitations were defined as hyporeflective OCT structures of at least 30 µ m in diameter between the ellipsoid zone and retinal pigment epithelium. Comparison was made based on the following metrics: (1) functional measures including best-corrected visual acuity and color discrimination errors on D-15 test; and (2) structural measures, including central subfield, average macular thickness, and preserved transfoveal ellipsoid zone width. Mann-Whitney tests were used for comparisons with significance set at P < 0.05. The specificity of microcavitations for RP1 -related retinopathy was estimated against 26 patients with non- RP1 retinitis pigmentosa., Results: Among 15 included patients, microcavitations were found in at least one eye of all patients with arRP and 7/12 (58%) of patients with adRP. Patients with adRP and microcavitations were older at the time of examination (51 vs. 43 years of age; P = 0.04) and their eyes demonstrated worse best-corrected visual acuity (0.09 vs. 0 logMAR; P = 0.008), reduced central subfield (256 vs. 293 µ m; P = 0.01), average macular thickness (241 vs. 270 µ m; P = 0.02), and shorter transfoveal ellipsoid zone widths (1.67 vs. 4.98 mm; P < 0.0001). The finding of microcavitations showed a specificity of 0.92 for RP1 -related retinopathy., Conclusion: A novel OCT finding of outer retina microcavitations was commonly observed in patients with RP1 -related retinopathy. Eyes with outer retinal OCT microcavitations had worse visual function and more affected central retinal structure.

Purpose: To describe a group of patients with retinitis pigmentosa GTPase regulator (RPGR)-related retinopathy with a tapetal-like retinal sheen and corresponding changes in the reflectivity of the ellipsoid zone on optical coherence tomography (OCT) imaging., Methods: A retrospective case series of 66 patients with a disease-causing variant in RPGR was performed. An expert examiner, masked to patient demographics, clinical evaluations, and specific RPGR variant, analyzed color fundus photographs for the presence of a tapetal-like retinal sheen and assessed OCT images for the presence of an abnormally broad hyper-reflective band in the outer retina. Longitudinal reflectivity profiles were generated and compared with healthy controls., Results: Twelve patients (18.2%) had a retinal sheen on color images that cosegregated with an abnormally broad hyper-reflective ellipsoid zone band on OCT imaging. Three-fourths of these patients were male, had a cone-rod dystrophy, and had pathogenic RPGR variants located toward the 3'-end of ORF15. This group had a different longitudinal reflectivity profile signature compared with controls. After a period of prolonged dark adaptation, the abnormal hyper-reflective band on OCT became less apparent, and the outer retinal layers adopted a more normal appearance., Conclusions: RPGR-related retinopathy should be considered for males presenting with retinal sheen, abnormal ellipsoid zone hyper-reflectivity, and cone or cone-rod dysfunction on ERG, and pursued with molecular testing. Our results have implications for understanding the role of the C-terminal domain encoded by RPGR ORF15 in the phototransduction cascade. Further, the findings may be important to incorporate into both inclusion criteria and outcome measure developments in future RPGR-related cone or cone-rod dystrophy clinical trials.

Background: Variations in the protocadherin gene FAT1 have recently been associated with a syndrome that includes coloboma, facial dysmorphism, renal failure, syndactyly, and other developmental defects., Materials and Methods: Detailed medical and family history, physical examination, and molecular analysis., Results: This non-dysmorphic, intellectually normal 51-year-old woman presented with bilateral colobomata and renal failure of unclear etiology, and asymmetric sensorineural hearing loss. Family history was notable for multiple family members with various forms of cancer. Whole exome sequencing revealed a homozygous frame shift variant in FAT1 , predicted to truncate the FAT1 protein at the furthest position in the protein structure published to date in a patient with coloboma., Conclusions: This case provides further evidence of the pleiotropic effects of FAT1 in optic fissure closure and kidney function. Also, because this variant is in the last exon, it would be anticipated to escape nonsense-mediated decay, opening the possibility that the protein is made and expressed, but not completely functional, as its intracellular domain is truncated.

Purpose: Uveal coloboma is a congenital eye malformation caused by failure of the optic fissure to close in early human development. Despite significant progress in identifying genes whose regulation is important for executing this closure, mutations are detected in a minority of cases using known gene panels, implying additional genetic complexity. We have previously shown knockdown of znf503 (the ortholog of mouse Zfp503) in zebrafish causes coloboma. Here we characterize Zfp503 knockout (KO) mice and evaluate transcriptomic profiling of mutant versus wild-type (WT) retinal pigment epithelium (RPE)/choroid., Methods: Zfp503 KO mice were generated by gene targeting using homologous recombination. Embryos were characterized grossly and histologically. Patterns and level of developmentally relevant proteins/genes were examined with immunostaining/in situ hybridization. The transcriptomic profile of E11.5 KO RPE/choroid was compared to that of WT., Results: Zfp503 is dynamically expressed in developing mouse eyes, and loss of its expression results in uveal coloboma. KO embryos exhibit altered mRNA levels and expression patterns of several key transcription factors involved in eye development, including Otx2, Mitf, Pax6, Pax2, Vax1, and Vax2, resulting in a failure to maintain the presumptive RPE, as evidenced by reduced melanin pigmentation and its differentiation into a neural retina-like lineage. Comparison of RNA sequencing data from WT and KO E11.5 embryos demonstrated reduced expression of melanin-related genes and significant overlap with genes known to be dynamically regulated at the optic fissure., Conclusions: These results demonstrate a critical role of Zfp503 in maintaining RPE fate and optic fissure closure.

Purpose: To describe the relationships between foveal structure and visual function in a cohort of individuals with foveal hypoplasia (FH) and to estimate FH grade and visual acuity using a deep learning classifier., Design: Retrospective cohort study and experimental study., Participants: A total of 201 patients with FH were evaluated at the National Eye Institute from 2004 to 2018., Methods: Structural components of foveal OCT scans and corresponding clinical data were analyzed to assess their contributions to visual acuity. To automate FH scoring and visual acuity correlations, we evaluated the following 3 inputs for training a neural network predictor: (1) OCT scans, (2) OCT scans and metadata, and (3) real OCT scans and fake OCT scans created from a generative adversarial network., Main Outcome Measures: The relationships between visual acuity outcomes and determinants, such as foveal morphology, nystagmus, and refractive error., Results: The mean subject age was 24.4 years (range, 1-73 years; standard deviation = 18.25 years) at the time of OCT imaging. The mean best-corrected visual acuity (n = 398 eyes) was equivalent to a logarithm of the minimal angle of resolution (LogMAR) value of 0.75 (Snellen 20/115). Spherical equivalent refractive error (SER) ranged from -20.25 diopters (D) to +13.63 D with a median of +0.50 D. The presence of nystagmus and a high-LogMAR value showed a statistically significant relationship ( P < 0.0001). The participants whose SER values were farther from plano demonstrated higher LogMAR values (n = 382 eyes). The proportion of patients with nystagmus increased with a higher FH grade. Variability in SER with grade 4 (range, -20.25 D to +13.00 D) compared with grade 1 (range, -8.88 D to +8.50 D) was statistically significant ( P < 0.0001). Our neural network predictors reliably estimated the FH grading and visual acuity (correlation to true value > 0.85 and > 0.70, respectively) for a test cohort of 37 individuals (98 OCT scans). Training the predictor on real OCT scans with metadata and fake OCT scans improved the accuracy over the model trained on real OCT scans alone., Conclusions: Nystagmus and foveal anatomy impact visual outcomes in patients with FH, and computational algorithms reliably estimate FH grading and visual acuity.

Background: Uveal colobomata are eye defects that result from failure of the optic fissure of the neuroectoderm-derived optic cup to close between weeks 5-7 of fetal life. Mutations in YAP1 have previously been linked to uveal coloboma. We present the clinical features and genetic basis of a one-year-old male with bilateral uveal colobomata., Materials and Methods: Clinical features were gathered from an age-appropriate evaluation and retrospectively from clinical records. DNA samples were collected from the proband, his uncle (who also had coloboma), both parents, and one sibling. Whole-genome sequencing of the coding regions and intron-exon boundaries confirmed a mutation in the proband. These genetic findings were verified using the Sanger method of DNA sequencing., Results: The proband is a male with congenital bilateral colobomata (iris/retina/nerve), reduced vision, nystagmus with null point, bilateral microcornea, right microphthalmia, possible mild right hemifacial microsomia, a tubular nose, possible spina bifida occulta, and astigmatism. Whole-genome sequencing confirmed a heterozygous YAP1 frameshift mutation NM&#95;001130145.3:c.178dupG p.(Asp60GlyfsTer52) in the proband. This mutation was absent in all other tested family members., Conclusions: We report a de novo mutation in YAP1 that likely results in nonsense-mediated decay. Given the association with YAP1 haploinsufficiency and colobomatous microphthalmia, this novel variant provides a molecular diagnosis for the proband. Further insight into YAP1 mutations may have implications in the prevention/treatment of uveal coloboma and other syndromic disorders.

This is the fourth Active Healthy Kids (AHK) Wales Report Card. The 2021 card produced grades on children and young people's physical activity (PA) using pre-COVID-19 data that were not used in previous versions. Eleven quality indicators of PA were graded through expert consensus and synthesis of the best available evidence. Grades were assigned as follows: Overall PA-F; Organised Sport and PA-C; Active Play-C+; Active Transportation-C-; Sedentary Behaviours-F; Physical Fitness-C-; Family and Peer Influences-D+; School-B-; Community and the Built Environment-C; National Government and Policy-C; and Physical Literacy-C-. All but three grades remained the same or decreased from the 2018 AHK-Wales Report Card (Active Play increased from C- to C+; Active Transportation, D+ to C-; Family and Peers, D to D+). This is concerning for children's health and well-being in Wales, particularly given recent evidence that PA has further decreased during the COVID-19 pandemic. The results from the Report Card should be used to inform the decision making of policy makers, practitioners and educators to improve children and young people's PA levels and opportunities and decrease PA inequalities.

Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Uveal coloboma is a condition defined by missing ocular tissues and is a significant cause of childhood blindness. It occurs from a failure of the optic fissure to close during embryonic development and may lead to missing parts of the iris, ciliary body, retina, choroid, and optic nerve. Because there is no treatment for coloboma, efforts have focused on prevention. While several genetic causes of coloboma have been identified, little definitive research exists regarding the environmental causes of this condition. We review the current literature on environmental factors associated with coloboma in an effort to guide future research and preventative counseling related to this condition., (Copyright © 2021. Published by Elsevier Inc.)

Importance: Sorsby fundus dystrophy is a typically adult-onset maculopathy with high risk for choroidal neovascularization. Sorsby fundus dystrophy, inherited as an autosomal dominant fully penetrant trait, is associated with TIMP3 variants that cause protein aggregation in the extracellular matrix., Objective: To evaluate the phenotype and underlying biochemical mechanism of disease-causing TIMP3 variants altering the N-terminal signal peptide in 2 families who have early-onset diffuse maculopathy without choroidal neovascularization with cosegregation of TIMP3 variants in the signal peptide sequence., Design, Setting, and Participants: This case series of 2 families with early-onset diffuse maculopathy was conducted at the National Eye Institute, National Institutes of Health Clinical Center. Data were collected and analyzed from October 2009 to December 2021., Main Outcomes and Measures: Clinical imaging and molecular genetic testing were performed in 2 families with macular dystrophy. Cosegregation analysis of TIMP3 variants was performed in affected and unaffected family members. Candidate TIMP3 signal peptide variants were assessed for cleavage defects after transfection., Results: Eleven individuals from 2 families with early-onset diffuse maculopathy without choroidal neovascularization harbor TIMP3 variants (L10H or G12R) in the N-terminal signaling peptide were analyzed. Cosegregation with phenotype was confirmed in additional family members. Biochemical analysis confirmed defects in both protein maturation and extracellular deposition., Conclusions and Relevance: This study found that TIMP3 variants altering signal peptide function deviated from classic Sorsby fundus dystrophy both in phenotypic features and underlying mechanism. These results suggest atypical patient presentations are caused by TIMP3 signal peptide defects, associated with impaired cleavage and deposition into the extracellular matrix, implicating a novel macular dystrophy disease.

The retinal dystrophy phenotype associated with CDHR1 retinopathy is clinically heterogenous. In this study, we describe the clinical and molecular findings of a retinal dystrophy cohort (10 patients) attributed to autosomal recessive CDHR1 and report novel variants in populations not previously identified with CDHR1 -related retinopathy. Seven patients had evaluations covering at least a three-year period. The mean age of individuals at first symptoms was 36 ± 8.5 years (range 5-45 years). Visual acuity at the last visit ranged from 20/20 to 20/2000 (mean LogMAR 0.8 or 20/125). Three clinical subgroups were identified: rod-cone dystrophy (RCD), cone-rod dystrophy (CRD), and maculopathy. Extinguished scotopic electroretinography responses were noted in the RCD patients. Macular involvement was noted in all patients and documented on color fundus photography, fundus autofluorescence, and optical coherence tomography. Notable asymmetry of the degree of macular atrophy was present in two patients. The possible association between CDHR1 variants and clinical findings was predicted using molecular modeling.

Ursu Lake is located in the Middle Miocene salt deposit of Central Romania. It is stratified, and the water column has three distinct water masses: an upper freshwater-to-moderately saline stratum (0-3 m), an intermediate stratum exhibiting a steep halocline (3-3.5 m), and a lower hypersaline stratum (4 m and below) that is euxinic (i.e. anoxic and sulphidic). Recent studies have characterized the lake's microbial taxonomy and given rise to intriguing ecological questions. Here, we explore whether the communities are dynamic or stable in relation to taxonomic composition, geochemistry, biophysics, and ecophysiological functions during the annual cycle. We found: (i) seasonally fluctuating, light-dependent communities in the upper layer (≥0.987-0.990 water-activity), a stable but phylogenetically diverse population of heterotrophs in the hypersaline stratum (water activities down to 0.762) and a persistent plate of green sulphur bacteria that connects these two (0.958-0.956 water activity) at 3-3.5 to 4 m; (ii) communities that might be involved in carbon- and sulphur-cycling between and within the lake's three main water masses; (iii) uncultured lineages including Acetothermia (OP1), Cloacimonetes (WWE1), Marinimicrobia (SAR406), Omnitrophicaeota (OP3), Parcubacteria (OD1) and other Candidate Phyla Radiation bacteria, and SR1 in the hypersaline stratum (likely involved in the anaerobic steps of carbon- and sulphur-cycling); and (iv) that species richness and habitat stability are associated with high redox-potentials. Ursu Lake has a unique and complex ecology, at the same time exhibiting dynamic fluctuations and stability, and can be used as a modern analogue for ancient euxinic water bodies and comparator system for other stratified hypersaline systems., (© 2019 The Authors. Environmental Microbiology published by Society for Applied Microbiology and John Wiley & Sons Ltd.)

Purpose : To describe a family with presumed SOX2 gonadosomatic mosaicism diagnosed upon ophthalmic examination of the proband's mother. Methods : The family underwent comprehensive ophthalmic and physical examination. Variant detection was performed using trio exome analysis on peripheral leukocyte DNA from blood and saliva samples. Variant segregation analysis was performed using a custom panel NGS sequencing. An identified variant in the SOX2 gene was confirmed in the proband by Sanger sequencing. Results : We report an individual with bilateral microphthalmia, developmental delay, hearing loss, and dysmorphic features. Her mother was found to have asymptomatic forme fruste uveal coloboma affecting her anterior segment. Her father, aunt, and sisters were unaffected. Trio exome sequence analysis showed an apparent de novo heterozygous deletion in the proband, NM&#95;003106.3:c.70&#95;89del, NP&#95;003097.1:p.(Asn24Argfs*65), classified as pathogenic. Testing of the other family members' peripheral blood and saliva was negative for this variant. The iris transillumination abnormalities in the proband's mother supports a gonadosomatic mosaicism scenario. Conclusions : The results from this family underscore the importance of performing detailed evaluations of the parents of apparently sporadically affected individuals with heritable ophthalmic disorders. The identification of mildly affected individuals could substantially alter recurrence risks.

Water activity is an important characteristic for describing unusual waters and is a determinant of habitability for microorganisms. However, few empirical studies of water activity have been done for natural waters exhibiting an extreme chemistry. Here, we investigate water activity for acid brines from Western Australia and Chile with pH as low as 1.4, salinities as high as 32% total dissolved solids, and complex chemical compositions. These acid brines host diverse communities of extremophilic microorganisms, including archaea, bacteria, algae, and fungi, according to metagenomic analyses. For the most extreme brine, its water activity (0.714) was considerably lower than that of saturated (pure) NaCl brine. This study provides a thermodynamic insight into life within end-member natural waters that lie at, or possibly beyond, the very edge of habitable space on Earth.

Background: Kearns-Sayre Syndrome (KSS) is characterized by pigmentary retinopathy, external ophthalmoplegia and heart block. We report on a now 24-year-old male with clinical retinoschisis and molecularly confirmed KSS., Materials and Methods: Physical and complete ophthalmic examination, molecular diagnosis., Results: Over nine years of follow-up, the subject manifested progressive signs and symptoms of KSS, including external ophthalmoplegia/strabismus, ptosis, pigmentary retinopathy, corneal edema, Type I diabetes mellitus, gut dysmotility, sensorineural deafness and heart block. At age 21 he was incidentally found to have retinoschisis on optical coherence tomography that remained stable over three years follow-up. Sequencing of the RS1 gene revealed no pathogenic variants, effectively ruling out co-existing X-linked retinoschisis., Conclusions: These findings suggest retinoschisis may be a rare manifestation of KSS. A trial of a carbonic anhydrase inhibitor was frustrated by coexisting corneal edema associated with the condition.

Genetic testing in a multisite clinical trial network for inherited eye conditions is described in this retrospective review of data collected through eyeGENE®, the National Ophthalmic Disease Genotyping and Phenotyping Network. Participants in eyeGENE were enrolled through a network of clinical providers throughout the United States and Canada. Blood samples and clinical data were collected to establish a phenotype:genotype database, biorepository, and patient registry. Data and samples are available for research use, and participants are provided results of clinical genetic testing. eyeGENE utilized a unique, distributed clinical trial design to enroll 6,403 participants from 5,385 families diagnosed with over 30 different inherited eye conditions. The most common diagnoses given for participants were retinitis pigmentosa (RP), Stargardt disease, and choroideremia. Pathogenic variants were most frequently reported in ABCA4 (37%), USH2A (7%), RPGR (6%), CHM (5%), and PRPH2 (3%). Among the 5,552 participants with genetic testing, at least one pathogenic or likely pathogenic variant was observed in 3,448 participants (62.1%), and variants of uncertain significance in 1,712 participants (30.8%). Ten genes represent 68% of all pathogenic and likely pathogenic variants in eyeGENE. Cross-referencing current gene therapy clinical trials, over a thousand participants may be eligible, based on pathogenic variants in genes targeted by those therapies. This article is the first summary of genetic testing from thousands of participants tested through eyeGENE, including reports from 5,552 individuals. eyeGENE provides a launching point for inherited eye research, connects researchers with potential future study participants, and provides a valuable resource to the vision community., (Published [2020]. This article is a U.S. Government work and is in the public domain in the USA.)

Molecular variant interpretation lacks disease gene-specific cohorts for determining variant enrichment in disease versus healthy populations. To address the molecular etiology of retinal degeneration, specifically the PRPH2-related retinopathies, we reviewed genotype and phenotype information obtained from 187 eyeGENE® participants from 161 families. Clinical details were provided by referring clinicians participating in the eyeGENE® Network. The cohort was sequenced for variants in PRPH2. Variant complementary DNA clusters and cohort frequency were compared to variants in public databases to help us to determine pathogenicity by current American College of Medical Genetics and Genomics/Association for Molecular Pathology interpretation criteria. The most frequent variant was c.828+3A>T, which affected 28 families (17.4%), and 25 of 79 (31.64%) variants were novel. The majority of missense variants clustered in the D2 intracellular loop of the peripherin-2 protein, constituting a hotspot. Disease enrichment was noted for 23 (29.1%) of the variants. Hotspot and disease-enrichment evidence modified variant classification for 16.5% of variants. The missense allele p.Arg172Trp was associated with a younger age of onset. To the best of our knowledge, this is the largest patient cohort review of PRPH2-related retinopathy. Large disease gene-specific cohorts permit gene modeling for hotspot and disease-enrichment analysis, providing novel variant classification evidence, including for novel missense variants., (Published 2020. This article is a U.S. Goverment work and is in the public domain in the USA.)

Uveal coloboma is a potentially blinding congenital ocular malformation caused by the failure of optic fissure closure during the fifth week of human gestation. We performed custom capture high-throughput screening of 38 known coloboma-associated genes in 66 families. Suspected causative novel variants were identified in TFAP2A and CHD7, as well as two previously reported variants of uncertain significance in RARB and BMP7. The variant in RARB, unlike previously reported disease mutations in the ligand-binding domain, was a missense change in the highly conserved DNA-binding domain predicted to affect the protein's DNA-binding ability. In vitro studies revealed lower steady-state protein levels, reduced transcriptional activity, and incomplete nuclear localization of the mutant RARB protein compared with wild-type. Zebrafish studies showed that human RARB messenger RNA partially reduced the ocular phenotype caused by morpholino knockdown of rarga gene, a zebrafish homolog of human RARB. Our study indicates that sequence alterations in known coloboma genes account for a small percentage of coloboma cases and that mutations in the RARB DNA-binding domain could result in human disease., (© 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.)

Purpose: To describe the motivations, expectations, and other factors men with X-linked retinoschisis (XLRS) consider when making decisions to participate in an early phase ocular gene therapy clinical trial., Design: Qualitative interview study., Methods: Men with XLRS who were considering participation in a phase I/IIa ocular gene therapy clinical trial at the National Eye Institute were eligible for this study. Trial participants (n = 9) were interviewed prior to receiving the gene transfer and then at 3 and 12 months later. Trial participation decliners (n = 2) were interviewed at an initial visit and 12 months later. Those screened for the trial and found ineligible (n = 2) were interviewed at an initial visit only. Interviews were transcribed, coded, and analyzed thematically., Results: Interview participants described decision making factors as risk-benefit assessments, personal intuition, trust in the study team, and religious faith. Altruism and the potential for therapeutic benefit were the main motives for trial participation, whereas the uncertainty of risks and benefits was the reason 2 men declined participation. Although most participants hoped for direct benefit, no one expected to benefit. Almost all interview participants considered their decision straightforward and were satisfied with their decision when interviewed over time. Meaningful relationships with the study team and perceived secondary benefits to participation contributed to positive trial experiences., Conclusions: Engaging prospective research participants in a discussion about their hopes, expectations, and personal factors provides a more complete understanding of patient decision making and may help support informed choices to participate in clinical trials for XLRS., (Published by Elsevier Inc.)

Fungi of the genus Aspergillus are widespread in the environment. Some Aspergillus species, most commonly Aspergillus fumigatus, may lead to a variety of allergic reactions and life-threatening systemic infections in humans. Invasive aspergillosis occurs primarily in patients with severe immunodeficiency, and has dramatically increased in recent years. There are several factors at play that contribute to aspergillosis, including both fungus and host-related factors such as strain virulence and host pulmonary structure/immune status, respectively. The environmental tenacity of Aspergilllus, its dominance in diverse microbial communities/habitats, and its ability to navigate the ecophysiological and biophysical challenges of host infection are attributable, in large part, to a robust stress-tolerance biology and exceptional capacity to generate cell-available energy. Aspects of its stress metabolism, ecology, interactions with diverse animal hosts, clinical presentations and treatment regimens have been well-studied over the past years. Here, we synthesize these findings in relation to the way in which some Aspergillus species have become successful opportunistic pathogens of human- and other animal hosts. We focus on the biophysical capabilities of Aspergillus pathogens, key aspects of their ecophysiology and the flexibility to undergo a sexual cycle or form cryptic species. Additionally, recent advances in diagnosis of the disease are discussed as well as implications in relation to questions that have yet to be resolved., (© 2016 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.)

Purpose: To investigate the frequency and types of systemic findings in patients with apparently isolated uveal coloboma., Design: Cross-sectional observational study., Methods: setting: Single-center ophthalmic genetics clinic. study population: Ninety-nine patients with uveal coloboma seen at the National Eye Institute. observational procedure: Results of audiology testing, echocardiogram, brain magnetic resonance imaging, renal ultrasound, and total spine radiographs. main outcome measure: Prevalence of abnormal findings on systemic testing., Results: Uveal coloboma affected only the anterior segment in 8 patients, only the posterior segment in 23 patients, and both anterior and posterior segments in 68 patients. Best-corrected visual acuity (BCVA) of eyes with coloboma was ≥20/40 in 45% of eyes; 23% of eyes had BCVA of ≤20/400. The majority of patients (74%) had good vision (>20/60) in at least 1 eye. Ten of the 19 patients (53%) who underwent echocardiography had abnormalities, with ventral septal defects being the most prevalent. Abnormal findings were observed in 5 of 72 patients (7%) who had a renal ultrasound and in 5 of 29 patients (17%) who underwent a brain MRI. Audiology testing revealed abnormalities in 13 of 75 patients (17%), and spine radiographs showed anomalies in 10 of 77 patients (13%). Most findings required no acute intervention., Conclusions: Although some patients with coloboma had evidence of extraocular abnormalities, the majority of findings on routine clinical examination did not require acute intervention, but some warranted follow-up. Results from the systemic evaluation of patients with coloboma should be interpreted with caution and in view of their clinical context., (Published by Elsevier Inc.)

Purpose: To screen samples from patients with presumed autosomal dominant retinitis pigmentosa (adRP) for mutations in 12 disease genes as a contribution to the research and treatment goals of the National Ophthalmic Disease Genotyping and Phenotyping Network (eyeGENE)., Methods: DNA samples were obtained from eyeGENE. A total of 170 probands with an intake diagnosis of adRP were tested through enrollment in eyeGENE. The 10 most common genes causing adRP (IMPDH1, KLHL7, NR2E3, PRPF3/RP18, PRPF31/RP11, PRPF8/RP13, PRPH2/RDS, RHO, RP1, and TOPORS) were chosen for PCR-based dideoxy sequencing, along with the two X-linked RP genes, RPGR and RP2. RHO, PRPH2, PRPF31, RPGR, and RP2 were completely sequenced, while only mutation hotspots in the other genes were analyzed., Results: Disease-causing mutations were identified in 52% of the probands. The frequencies of disease-causing mutations in the 12 genes were consistent with previous studies., Conclusions: The Laboratory for Molecular Diagnosis of Inherited Eye Disease at the University of Texas in Houston has thus far received DNA samples from 170 families with a diagnosis of adRP from the eyeGENE Network. Disease-causing mutations in autosomal genes were identified in 48% (81/170) of these families while mutations in X-linked genes accounted for an additional 4% (7/170). Of the 55 distinct mutations detected, 19 (33%) have not been previously reported. All diagnostic results were returned by eyeGENE to participating patients via their referring clinician. These genotyped samples along with their corresponding phenotypic information are also available to researchers who may request access to them for further study of these ophthalmic disorders. (ClinicalTrials.gov number, NCT00378742.).

Objective: Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and multisystem abnormalities. Many TTD patients have a defect in known DNA repair genes. This report systematically evaluates the ocular manifestations of the largest-to-date cohort of TTD patients and xeroderma pigmentosum (XP)/TTD patients., Design: Case series., Participants: Thirty-two participants, ages 1 to 30 years, referred to the National Eye Institute for examination from 2001 to 2010; 25 had TTD and 7 had XP/TTD., Methods: Complete, age- and developmental stage-appropriate ophthalmic examination., Main Outcome Measures: Visual acuity (VA), best-corrected VA, ocular motility, state of the ocular surface and corneal endothelial cell density, corneal diameter, and lens assessment., Results: Developmental abnormalities included microcornea (44% TTD), microphthalmia (8% TTD, 14% XP/TTD), nystagmus (40% TTD), and infantile cataracts (56% TTD, 86% XP/TTD). Corrective lenses were required by 65% of the participants, and decreased best-corrected VA was present in 28% of TTD patients and 71% of XP/TTD patients. Degenerative changes included dry eye (32% TTD, 57% XP/TTD) and ocular surface disease identified by ocular surface staining with fluorescein (32% TTD) that usually are exhibited by much older patients in the general population. The 2 oldest TTD patients exhibited clinical signs of retinal/macular degeneration. Four XP/TTD patients presented with corneal neovascularization., Conclusions: These TTD and XP/TTD study participants had a wide variety of ocular findings including refractive error, infantile cataracts, microcornea, nystagmus, and dry eye/ocular surface disease. Although many of these can be ascribed to abnormal development--likely owing to abnormalities in basal transcription of critical genes--patients may also have a degenerative course., Financial Disclosure(s): Proprietary or commercial disclosures may be found after the references., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

We report on a patient with trisomy 21, microophthalmia, neonatal diabetes mellitus, hypopituitarism, and a complex structural brain anomaly who was a member of a large bilineal family with eye anomalies. The patient inherited a different mutation in PAX6 from each parent and is the only known living and second reported patient with compound heterozygosity for mutations in PAX6. PAX6 is a transcription factor involved in eye and brain development and has roles in pancreatic and pituitary development. Clinical evaluation of the propositus and his parents demonstrated the effects of mutations of differing severity in multiple individuals.

Objective: To describe clinical molecular testing for hereditary retinal degenerations, highlighting results, interpretation, and patient education., Methods: Mutation analysis of 8 retinal genes was performed by dideoxy sequencing. Pretest and posttest genetic counseling was offered to patients. The laboratory report listed results and provided individualized interpretation., Results: A total of 350 tests were performed. The molecular basis of disease was determined in 133 of 266 diagnostic tests; the disease-causing mutations were not identified in the remaining 133 diagnostic tests. Predictive and carrier tests were requested for 9 and 75 nonsymptomatic patients with known familial mutations, respectively., Conclusions: Molecular testing can confirm a clinical diagnosis, identify carrier status, and confirm or rule out the presence of a familial mutation in nonsymptomatic at-risk relatives. Because causative mutations cannot be identified in all patients with retinal diseases, it is essential that patients are counseled before testing regarding the benefits and limitations of this emerging diagnostic tool., Clinical Relevance: The molecular definition of the genetic basis of disease provides a unique adjunct to the clinical care of patients with hereditary retinal degenerations.