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Background: The Atonal Homolog 7 (ATOH7) gene has been implicated in association studies with optic nerve head diameter size. Hence, we screened optic nerve hypoplasia (ONH) patient DNA samples from Australia, France, and the United States for sequence variants in theATOH7 gene using Sanger sequencing. Methods: Sanger sequencing of theATOH7 gene was performed on 34 affected individual DNA samples. Sequencing was also carried out in three unaffected family members to confirm segregation of identified single nucleotide variations. Results: Seven sequence variations were identified in ATOH7. No disease-causing sequence changes in the ATOH7 gene was discovered in the ONH patient samples. Conclusions: Mutations within the ATOH7 gene are not implicated in the pathogenesis of optic nerve hypoplasia in our patient cohort. [ABSTRACT FROM AUTHOR]

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

Corneal astigmatism refers to refractive abnormalities and irregularities in the curvature of the cornea, and this interferes with light being accurately focused at a single point in the eye. This ametropic condition is highly prevalent, influences visual acuity, and is a highly heritable trait. There is currently a paucity of research in the genetic etiology of corneal astigmatism. Here we report the results from five genome-wide association studies of corneal astigmatism across three Asian populations, with an initial discovery set of 4,254 Chinese and Malay individuals consisting of 2,249 cases and 2,005 controls. Replication was obtained from three surveys comprising of 2,139 Indians, an additional 929 Chinese children, and an independent 397 Chinese family trios. Variants in PDGFRA on chromosome 4q12 (lead SNP: rs7677751, allelic odds ratio = 1.26 (95% CI: 1.16-1.36), Pmeta = 7.87 x 10-9) were identified to be significantly associated with corneal astigmatism, exhibiting consistent effect sizes across all five cohorts. This highlights the potential role of variants in PDGFRA in the genetic etiology of corneal astigmatism across diverse Asian populations. [ABSTRACT FROM AUTHOR]

Purpose: Neurofibromatosis type 1 (NF1) is the most common neurocutaneous disorder, with an approximate incidence of 1 in 3,500. Optic pathway gliomas (OPGs) develop in 15% of individuals with NF1, commonly in childhood. OPGs are difficult to detect via a clinical inspection in children, often requiring magnetic resonance imaging (MRI). Given the significant visual risks associated with OPGs in NF1, there is a need for improved noninvasive techniques to diagnose OPGs in children; therefore, we studied optical coherence tomography (OCT) as a potential tool to assess optic nerve and retinal nerve fiber layer (RNFL) abnormalities. This prospective study was designed to evaluate OCT detection of RNFL loss from optic atrophy attributable to OPGs in a cohort of pediatric patients with NF1. Methods: With the use of Stratus OCT, directed testing with the Fast Macular Thickness and Fast RNFL Thickness protocol scans were performed on 9 subjects with NF1 and known OPGs, 6 subjects with NF1 without OPGs, and 15 controls. Results: NF1 subjects with OPGs had thinner RNFLs and macula when compared with age-matched controls and to NF1 subjects without OPGs. After applying the equivalence equation, the average RNFL thickness and macular volume in NF1 subjects without OPGs was equivalent to controls. Conclusions: Our study suggests that OCT can be used to detect RNFL thinning secondary to OPGs in NF1 subjects. This objective tool shows promise as a useful adjunct to routine clinical ophthalmologic evaluation in children with NF1.▪ [Copyright &y& Elsevier]

Background: Children with Down syndrome (DS) have an increased prevalence of ocular disorders, including amblyopia, strabismus, and refractive error. Health maintenance guidelines from the Down Syndrome Medical Interest Group recommend ophthalmologic examinations every 1 to 2 years for these children. Photoscreening may be a cost-effective option for subsequent screening evaluations after an initial complete examination, but no study has evaluated the accuracy of photoscreening in children with DS. The purpose of this study is to determine the sensitivity, specificity, and positive and negative predictive values of photoscreening in detecting treatable ocular conditions in children with DS. Methods: Photoscreening and complete ophthalmologic evaluations were performed in 50 consecutive 3- to 10-year-old children with DS. Sensitivity, specificity, and positive and negative predictive values were calculated with the use of ophthalmologic examination findings as the reference standard. Results: Most children were able to complete photoscreening (94% with Medical Technology and Innovations [MTI] and 90% with Visiscreen OSS-C [VR]). Many children had an identified diagnosis on ophthalmologic examination (n = 46, 92%). Of these, approximately one-half (n = 27, 54%) had one or more condition(s) requiring treatment. Both the MTI and VR photoscreening devices had a sensitivity of 93% (95% confidence interval 0.76−0.99) for detecting treatable ocular conditions. The specificities for the MTI and VR photoscreening were 0.35 (0.18-0.57) and 0.55 (0.34-0.74), respectively. Conclusions: Photoscreening is sensitive but less specific at detecting treatable ocular conditions in children with DS. In specific instances, the use of photoscreening in the DS population has the potential to save time and expense related to routine eye examinations, particularly in children with a normal baseline comprehensive examination.▪ [Copyright &y& Elsevier]

Central corneal thickness (CCT), one of the most highly heritable human traits (h2 typically.0.9), is important for the diagnosis of glaucoma and a potential risk factor for glaucoma susceptibility. We conducted genome-wide association studies in five cohorts from Australia and the United Kingdom (total N = 5058). Three cohorts were based on individually genotyped twin collections, with the remaining two cohorts genotyped on pooled samples from singletons with extreme trait values. The pooled sample findings were validated by individual genotyping the pooled samples together with additional samples also within extreme quantiles. We describe methods for efficient combined analysis of the results from these different study designs. We have identified and replicated quantitative trait loci on chromosomes 13 and 16 for association with CCT. The locus on chromosome 13 (nearest gene FOXO1) had an overall meta-analysis p-value for all the individually genotyped samples of 4.6×10-10. The locus on chromosome 16 was associated with CCT with p = 8.95×10-11. The nearest gene to the associated chromosome 16 SNPs was ZNF469, a locus recently implicated in Brittle Cornea Syndrome (BCS), a very rare disorder characterized by abnormal thin corneas. Our findings suggest that in addition to rare variants in ZNF469 underlying CCT variation in BCS patients, more common variants near this gene may contribute to CCT variation in the general population. [ABSTRACT FROM AUTHOR]

Objective: To report a 3-generation white family clinically diagnosed variably with Wagner, Stickler, and Jansen syndromes and screened for sequence variants in the COL2A1 and CSPG2 genes. Wagner syndrome is an autosomal dominant vitreoretinopathy with a predisposition to retinal detachment and cataracts. It has significant phenotypic overlap with allelic Jansen syndrome and ocular Stickler syndrome type 1. Sticker syndrome type 1maps to chromosome 12q13.11-q13.2, with associated COL2A1 gene mutations. Wagner syndrome maps to chromosome 5q13- q14 and is associated with mutations in CSPG2 encoding versican, a proteoglycan present in human vitreous. Methods: Genomic DNA samples derived from venous blood were collected from all family members. Complete sequencing of COL2A1 was performed on a proband. Primers for polymerase chain reaction and sequencing were designed to cover all exon and intron-exon boundaries. Direct sequencing of CSPG2 was performed on all family member samples. Results: No detectable COL2A1 mutations were noted, making the diagnosis of ocular Stickler syndrome highly unlikely for this family. A unique base pair substitution (c.9265+1G>T) in intron 8 of the CSPG2 gene cosegregating with disease status was identified. This mutation occurred in a highly conserved previously reported splice site witha similar base pair substitution(G>A). Direct sequencingof this splice sitemutationin107unrelated externalcontrols revealed no variants, supporting the rarity of this base pair change and its causation in Wagnersyndrome.Thisn ovel basepair substitution isthoughttocausethe deletion ofexon 8 and formation of a truncated protein product. Conclusion: Mutation screening of CSPG2 in autosomal dominant vitreoretinopathy families is important for accurate diagnosis. Clinical Relevance: This study underscores the importance of obtaining extensive pedigree information and comparative ophthalmologic clinical information, as the phenotypic findings may vary greatly among independent family members. The study also affirms the paradigm shift from diagnosis assignment based on eponyms to that based on gene mutation type. [ABSTRACT FROM AUTHOR]

Visual impairment is a leading cause of morbidity and poor quality of life in our community. Unravelling the mechanisms underpinning important blinding diseases could allow preventative or curative steps to be implemented. Twin siblings provide a unique opportunity in biology to discover genes associated with numerous eye diseases and ocular biometry. Twins are particularly useful for quantitative trait analysis through genome-wide association and linkage studies. Although many studies involving twins rely on twin registries, we present our approach to the Twins Eye Study in Tasmania to provide insight into possible recruitment strategies, expected participation rates and potential examination strategies that can be considered by other researchers for similar studies. Five separate avenues for cohort recruitment were adopted: (1) piggy-backing existing studies where twins had been recruited, (2) utilizing the national twin registry, (3) word-of-mouth and local media publicity, (4) directly approaching schools, and finally (5) collaborating with other research groups studying twins. [ABSTRACT FROM AUTHOR]

Refractive errors (myopia, hyperopia, and astigmatism) are complex heterogeneous disorders of the human eye and are ideal for genetic investigation. Moderate to severe refractive errors can predispose individuals to poor visual development, various types of glaucoma, misshapen corneal surfaces, premature cataracts, and loss of retinal integrity, which can lead to detachment. Knowledge of genetic mechanisms involved in refractive error susceptibility may allow treatment to prevent progression or to further examine geneenvironment interactions. Early genetic predisposition detection for developing severe refractive errors may be useful for efficient and cost-effective screening program design. This review explores the genetic mechanisms associated with nonsyndromic refractive error development known to date. [ABSTRACT FROM AUTHOR]

Background/Purpose: Apert syndrome, a disorder of craniosynostosis, syndactyly, and other craniofacial malformations, is caused by point mutations (Ser252Trp or Pro253Arg) in the fibroblast growth factor receptor 2 gene. This study’s goal was to determine ophthalmic phenotype/genotype correlations in patients with either mutation. Methods: A retrospective chart review of demographic and ophthalmologic data was performed for 18 children carrying either the S252W (11) or the P253R (7) mutation. Fisher exact tests were performed to determine significance of variable phenotypes between the two mutation groups. Results: In the P253R group, 85% had strabismus (14% required surgery), 71% had ptosis, 43% had amblyopia, 14% had nasolacrimal duct obstruction, 14% had myopia, 14% had hyperopia, and 14% had astigmatism. In the S252W group, 91% had strabismus (64% required surgery), 73% had ptosis, 73% had amblyopia, 100% had nasolacrimal duct obstruction, 36% had myopia, 9% had hyperopia, and 82% had astigmatism. Overall, S252W and P253R groups showed significantly different numbers of patients with strabismus requiring surgery (p = 0.039), superior rectus muscle underaction (p = 0.024), nasolacrimal duct obstruction (p = 0.0002), and astigmatism (p = 0.005). Conclusions: Compared with patients with the P253R mutation, Apert syndrome patients with the S252W mutation may have more severe ocular phenotypes with a higher likelihood of developing strabismus, especially vertical deviation. They also are more likely to develop astigmatic refractive errors and tearing secondary to nasolacrimal system anomalies. [Copyright &y& Elsevier]

Background/purpose: Despite the similar clinical phenotype of the Saethre-Chotzen and Muenke craniosynostoses, the 2 syndromes are now genotypically distinct. Patients with Saethre-Chotzen and Muenke syndromes carry mutations in the TWIST and fibroblast growth factor receptor (FGFR) 3 genes, respectively. We sought to assess possible ocular phenotypic differences in patients with mutations of either gene previously grouped according to phenotype only. Methods: A retrospective chart review was performed for 21 children with known mutations of the TWIST (n=10) or the FGFR3 (n=11) genes. Data gathered included patient sex, age, family craniofacial history, craniofacial and ophthalmic surgeries, type of strabismus, ptosis, cycloplegic refraction, visual acuity, the presence of amblyopia, nasolacrimal duct obstruction (NLDO), nystagmus, hypertelorism, epicanthal fold anomalies, and any ocular structural abnormalities. Results: In the TWIST group, ptosis was present in 90%, amblyopia in 70%, horizontal strabismus in 70%, vertical strabismus in 60%, NLDO in 60%, astigmatism in 50%, inferior oblique overaction (IOOA) in 40%, hyperopia in 40%, myopia in 30%, nystagmus in 30%, and optic nerve findings in 30%. In the FGFR3 group, ptosis was present in 36%, amblyopia in 18%, horizontal strabismus in 55%, vertical strabismus in 36%, NLDO in 0%, astigmatism in 9%, IOOA in 45%, hyperopia in 27%, myopia in 18%, nystagmus in 18%, and optic nerve findings in 27%. Conclusions: Patients with TWIST gene mutations may have more ophthalmic abnormalities, including more strabismus, ptosis, NLDO, astigmatism, vertical deviations, and amblyopia compared with patients with FGFR3 gene mutations. [Copyright &y& Elsevier]

Objective: To evaluate individuals with Cornelia de Lange syndrome previously screened for mutations in the NIPBL gene for genotype-phenotype correlations with regard to severity of ophthalmologic findings. Methods: Fifty-four patientswith Cornelia de Lange syndrome (26 mutation positive and 28 mutation negative) with varying extent and severity of ophthalmologic findings participated in the study. We conducted a retrospective analysis of ophthalmologic data obtained through survey responses and medical records. The severity of nasolacrimal duct obstruction, myopia, ptosis, and strabismus was classified. The severity of eye findings was compared relative to the presence vs the absence of mutations in the coding region of NIPBL and relative to mutations predicted to result in a truncated protein (nonsense and frameshift mutations) vs missense mutations. Fisher exact test was used to determine the significance of these correlations. Results: A trend toward increased ptosis severity was found among individuals with truncating (nonsense and frameshift) mutations compared with individuals with missense mutations (P=.07). Conclusion: NIPBL may be directly involved in ptosis pathogenesis. Clinical Relevance: Elucidating the pathogenetic mechanisms of ophthalmologic morbidities in patients with de Lange syndrome may lead to more effective treatment. [ABSTRACT FROM AUTHOR]

Introduction: We sought to define the prevalence and natural history of ocular hypertension and glaucoma for at least a 10-year period after pediatric cataract surgery. Methods: We conducted a prospective observational study of patients who received pediatric cataract surgery. Inclusion criteria included 2 directed ophthalmologic examinations performed at a minimum of 5 and 10 years after surgery. Results: A total of 63 patients (22 with bilateral cataracts and 41 with unilateral cataracts) were examined at a median of 15.1 year (range, 10.3-21.3 years) after surgery. A majority of the subjects had glaucoma or ocular hypertension (ie, 59%; 37/63). Nineteen percent (12/63) had glaucoma (5/22 with bilateral cataracts and 7/41 with unilateral cataracts). Approximately half (7/12) had developed glaucoma during the first 5-year observational period and the remainder (5/12) developed it during the following observational period. Forty percent (25/63) of the patients had ocular hypertension in at least one aphakic eye (9/23 with bilateral cataracts and 16/40 with unilateral cataracts). The rate of progression from ocular hypertension to glaucoma over a mean observational period of 7.2 years (range, 6.2-8.1 years) was 23% (5/22). Discussion: Patients who receive surgery for pediatric cataracts are at very high risk of developing ocular hypertension and glaucoma. Patients can develop late-onset glaucoma and ocular hypertension more than 10 years after surgery. Years of ocular hypertension may precede the diagnosis of late-onset glaucoma. [Copyright &y& Elsevier]

Background Ankyloblepharon, ectodermal defects, and cleft lip and palate (AEC) syndrome is a rare autosomal dominant disorder caused by mutations in the sterile α motif region of TP63, a homologue of the tumor suppressor TP53. Recent structure-function studies have identified complexities in the genotype-phenotype correlation of the p63 syndromes. Observations We report 2 sporadic cases of AEC syndrome in infants. Both patients demonstrated skin erosions with prominent scalp involvement. Histologic studies demonstrated mild basal layer vacuolization and rare dyskeratotic keratinocytes, with evidence of both acantholysis and cytolysis at the blister edge. Immunohistochemistry using anti-p63 monoclonal antibody demonstrated basal epidermal nuclear staining in both healthy control and patient tissue samples. Ultrastructural studies showed focal disruption of anchoring fibrils near the blister edge of one patient and normal desmosomes, hemidesmosomes, and basement membrane zone in the nonblistered skin of the other patient. The DNA analysis of each patient revealed 2 novel missense mutations in the TP63 gene that resulted in L514S and R555P amino acid substitutions within the sterile α motif region of the p63 protein. Conclusions We report 2 novel TP63 mutations resulting in AEC syndrome. The R555P mutation is the most carboxy-terminal of all the reported AEC missense mutations of p63. The presence of skin fragility, manifested as erosive skin lesions in body areas in addition to the scalp, is postulated to be an important diagnostic feature of AEC syndrome. [ABSTRACT FROM AUTHOR]

Objective Bornholm eye disease (BED) consists of X-linked high myopia, high cylinder, optic nerve hypoplasia, reduced electroretinographic flicker with abnormal photopic responses, and deuteranopia. The disease maps to chromosome Xq28 and is the first designated high-grade myopia locus (MYP1). We studied a second family from Minnesota with a similar X-linked phenotype, also of Danish descent. All affected males had protanopia instead of deuteranopia. Methods X chromosome genotyping, fine-point mapping, and haplotype analysis of the DNA from 22 Minnesota family individuals (8 affected males and 5 carrier females) and 6 members of the original family with BED were performed. Haplotype comparisons and mutation screening of the red-green cone pigment gene array were performed on DNA from both kindreds. Results Significant maximum logarithm of odds scores of 3.38 and 3.11 at θ = 0.0 were obtained with polymorphic microsatellite markers DXS8106 and DXYS154, respectively, in the Minnesota family. Haplotype analysis defined an interval of 34.4 cM at chromosome Xq27.3-Xq28. Affected males had a red-green pigment hybrid gene consistent with protanopia. We genotyped Xq27-28 polymorphic markers of the family with BED, and narrowed the critical interval to 6.8 cM. The haplotypes of the affected individuals were different from those of the Minnesota pedigree. Bornholm eye disease–affected individuals showed the presence of a green-red hybrid gene consistent with deuteranopia. Conclusions Because of the close geographic origin of the 2 families, we expected affected individuals to have the same haplotype in the vicinity of the same mutation. Mapping studies, however, suggested independent mutations of the same gene. The red-green and green-red hybrid genes are common X-linked color vision defects, and thus are unrelated to the high myopia and other eye abnormalities in these 2 families. Clinical Relevance X-linked high myopia with possible cone dysfunction has been mapped to chromosome Xq28 with intervals of 34.4 and 6.8 centimorgan for 2 families of Danish origin. [ABSTRACT FROM AUTHOR]

INTRODUCTION: High myopia (>-6.00 diopters)is a complex common disorder that predisposes individuals to retinal detachment, glaucoma, macular degeneration, and premature cataracts. A recent linkageanalysis of seven families with autosomal dominant high myopia has identifiedone locus (MYP2) for high myopia on chromosome 18p11.31 (Young et al.: AmJ Hum Genet 1998;63:109–119). Haplotype analysis revealed an initialinterval of 7.6 centimorgans (cM). METHODS: Transmission disequilibrium tests (TDT) with both the StatisticalAnalysis for Genetic Epidemiology (SAGE) 3.1 TDTEX and GENEHUNTER 2 (GH2)programs were performed using chromosome 18p marker alleles for this interval. RESULTS: Using SAGE analysis, the following p values were obtained formarkers in marker order in this region: D18S1146 (p = 0.227), D18S481 (p =0.001), D18S63 (p = 0.062), D18S1138 (p = 0.0004), D18S52 (p = 1.79 ×10[sup -6] ), and D18S62 (p = 0.141). GH2 TDT analysis revealedthe following p values for the best allele for the markers: D18S1146 (p =0.083), D18S481 (p = 0.108), D18S63 (p = 0.034), D18S1138 (p = 0.011), D18S52(p = 0.007), and D18S62 (p = 0.479). CONCLUSION: These data suggest that the gene for 18p11.31-linked highmyopia is most proximal to marker D18S52, with a likely interval of 0.8 cMbetween markers D18S63 and D18S52. Due to the contraction of the intervalsize by TDT, these results provide a basis for focused positional cloningand candidate gene analysis at the MYP2 locus. [ABSTRACT FROM AUTHOR]

Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.

Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [P value = 1.3 × 10−23], HBS1L/MYB [8.5 × 10−15], MYO9B [9.0 × 10−12], and CYBA [1.1 × 10−8] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (<7.0 mmol/L) but elevated HbA1c (≥6.5%), 36.1% had HbA1c <6.5% after adjustment for these six variants. Our East Asian GWAS meta-analysis has identified novel variants associated with HbA1c as well as demonstrated that the effects of known variants are largely transferable across ethnic groups. Variants affecting erythrocyte parameters rather than glucose metabolism may be relevant to the use of HbA1c for diagnosing diabetes in these populations.