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Glaucoma, a leading cause of irreversible blindness, is a highly heritable human disease. Previous genome-wide association studies have identified over 100 loci for the most common form, primary open-angle glaucoma. Two key glaucoma-associated traits also show high heritability: intraocular pressure and optic nerve head excavation damage quantified as the vertical cup-to-disc ratio. Here, since much of glaucoma heritability remains unexplained, we conducted a large-scale multitrait genome-wide association study in participants of European ancestry combining primary open-angle glaucoma and its two associated traits (total sample size over 600,000) to substantially improve genetic discovery power (263 loci). We further increased our power by then employing a multiancestry approach, which increased the number of independent risk loci to 312, with the vast majority replicating in a large independent cohort from 23andMe, Inc. (total sample size over 2.8 million; 296 loci replicated at P< 0.05, 240 after Bonferroni correction). Leveraging multiomics datasets, we identified many potential druggable genes, including neuro-protection targets likely to act via the optic nerve, a key advance for glaucoma because all existing drugs only target intraocular pressure. We further used Mendelian randomization and genetic correlation-based approaches to identify novel links to other complex traits, including immune-related diseases such as multiple sclerosis and systemic lupus erythematosus.

Background. Gastroesophageal reflux disease (GERD), often characterized as heartburn, is a highly common presenting complaint to family physicians. This study is the first large, prospective, nationwide family practice outpatient evaluation [...]

To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs).

IMPORTANCE To date, relatively few genes responsible for a fraction of heritability have been identified by means of large genetic association studies of refractive error. OBJECTIVE To explore the genetic mechanisms that lead to refractive error in the general population. DESIGN, SETTING, AND PARTICIPANTS Genome-wide association studies were carried out in 2 British population-based independent cohorts (N = 5928 participants) to identify genes moderately associated with refractive error. MAIN OUTCOMES AND MEASURES Enrichment analyses were used to identify sets of genes overrepresented in both cohorts. Enriched groups of genes were compared between both participating cohorts as a further measure against random noise. RESULTS Groups of genes enriched at highly significant statistical levels were remarkably consistent in both cohorts. In particular, these results indicated that plasma membrane (P = 7.64 × 10−30), cell-cell adhesion (P = 2.42 × 10−18), synaptic transmission (P = 2.70 × 10−14), calcium ion binding (P = 3.55 × 10−15), and cation channel activity (P = 2.77 × 10−14) were significantly overrepresented in relation to refractive error. CONCLUSIONS AND RELEVANCE These findings provide evidence that development of refractive error in the general population is related to the intensity of photosignal transduced from the retina, which may have implications for future interventions to minimize this disorder. Pathways connected to the procession of the nerve impulse are major mechanisms involved in the development of refractive error in populations of European origin.

Myopia, or nearsightedness, is the most common human eye disorder in the world and is a significant global public health concern. Along with cataract, macular degeneration, infectious disease, and vitamin A deficiency, myopia is one of the most important causes of visual impairment worldwide. Severe or high-grade myopia is a leading cause of blindness because of its associated ocular comorbidities of retinal detachment, macular choroidal degeneration, premature cataract, and glaucoma. Ample epidemiologic and molecular genetic studies support heritability of the nonsyndromic forms of this condition.

Myopia, or nearsightedness, is the most common human eye disorder in the world, and is a significant global public health concern. Along with cataract, macular degeneration, infectious disease, and vitamin A deficiency, myopia is one of the most important causes of visual impairment worldwide. Severe or high-grade myopia is a leading cause of blindness because of its associated ocular morbidities of retinal detachment, macular choroidal degeneration, premature cataract, and glaucoma. Ample evidence documents the heritability of the non-syndromic forms of this condition, especially for high-grade myopia, commonly referred to as myopic spherical refractive power of 5 to 6 diopters or higher. Multiple high-grade myopia genetic loci have been identified, and confirmatory studies identifying high-grade and moderate myopia loci have also occurred. In general, myopia susceptibility genes are unknown with few association studies performed, and without confirmation in other research laboratories or testing of separate patient cohorts.

The 12th International Myopia Conference held in Queensland, Australia on July 8–11, 2008 included 11 separate symposia, each with 3–5 presentations. Here, in a single paper, the authors of those Symposia describe the scientific advances noted at the conference and include the full abstracts of the individual myopia papers presented in each symposium. The symposia included molecular studies in humans and animals; twin studies; prevalence, progression and risk factors; outdoor activity and near work; lens compensation and emmetropization; therapies for myopia based on optical strategies; accommodation and ocular aberrations as causative links; eye shape and peripheral refraction relation to myopia; sclera and its role in regulating myopia; signalling cascades in developing myopia; and animal models in understanding myopia.

The SOX2anophthalmia syndrome is emerging as a clinically recognizable disorder that has been identified in 10–15 of individuals with bilateral anophthalmia. Extraocular anomalies are common. The majority of SOX2mutations identified appear to arise de novo in probands ascertained through the presence of anophthalmia or microphthalmia. In this report, we describe two sisters with bilateral anophthalmiamicrophthalmia, brain anomalies and a novel heterozygous SOX2gene singlebase pair nucleotide deletion, c.551delC, which predicts p.Pro184ArgfsX19. The hypothetical protein product is predicted to lead to haploinsufficient SOX2function. Mosaicism for this mutation in the SOX2gene was also identified in their clinically unaffected mother in peripheral blood DNA. Thus it cannot be assumed that all SOX2mutations in individuals with anophthalmiamicrophthalmia are de novo. Testing of parents is indicated when a SOX2mutation is identified in a proband. © 2008 WileyLiss, Inc.

We have identified six children in three families with subtelomeric deletions of 6p25 and a recognizable phenotype consisting of ptosis, posterior embryotoxon, optic nerve abnormalities, mild glaucoma, Dandy–Walker malformation, hydrocephalus, atrial septal defect, patent ductus arteriosus, and mild mental retardation. There is considerable clinical overlap between these children and individuals with the Ritscher–Schinzel (or cranio–cerebello–cardiac (3C)) syndrome (OMIM #220210). Clinical features of 3C syndrome include craniofacial anomalies (macrocephaly, prominent forehead and occiput, foramina parietalia, hypertelorism, down‐slanting palpebral fissures, ocular colobomas, depressed nasal bridge, narrow or cleft palate, and low‐set ears), cerebellar malformations (variable manifestations of a Dandy–Walker malformation with moderate mental retardation), and cardiac defects (primarily septal defects). Since the original report, over 25 patients with 3C syndrome have been reported. Recessive inheritance has been postulated based on recurrence in siblings born to unaffected parents and parental consanguinity in two familial cases [Ritscher et al. (1987); Am J Med Genet 26:481–491; Marles et al. (1995); Am J Med Genet 56:343–350; Orstavik et al. (1998); Am J Med Genet 75:300–303]. Molecular and cytogenetic mapping of the 6p deletions in these three families with subtelomeric deletions of chromosome 6p have defined a 1.3 Mb minimally deleted critical region. To determine if 6p deletions are common in 3C syndrome, we analyzed seven unrelated individuals with 3C syndrome for deletions of this region. Three forkhead genes (FOXF1 and FOXQ1 from within the critical region, and FOXC1 proximal to this region) were evaluated as potential candidate disease genes for this disorder. No deletions or disease‐causing mutations were identified. © 2005 Wiley‐Liss, Inc.

Genetic diseases of the eye and involving the eye continue as a leading cause of blindness in children and adults.

We describe a white female infant with neurocutaneous melanosis (NCM) and encephalocraniocutaneous lipomatosis (ECCL). Multiple, giant and small congenital melanocytic nevi (CMN) were observed on the head, neck and trunk and involved 70% of body surface area. Histologic examination of several CMN revealed atypical nodular proliferations of dermal nevomelanocytes. In a small (<1 cm) truncal CMN, single and dyscohesive intraepidermal nests of atypical nevomelanocytes simulating a superficial spreading melanoma, were observed. The placenta was grossly normal and histologically demonstrated multiple banal appearing nevomelanocytes within the stroma of its villi. At the 17-month follow-up no evidence of primary or metastatic melanoma was present. This previously undescribed association of NCM, ECCL and placental nevomelanocytes provides strong support for the hypothesized causal role of anomalous neural crest morphogenesis and migration in the development of all three disorders. The genetic mechanism underlying these complex birth defects has been hypothesized to result from the action of lethal autosomal dominant genes surviving by mosaicism. (J Am Acad Dermatol 2002;47:S196-200.)

Purpose:This report is a summary of the data of the IOLAB, Inc pediatric intraocular lens (IOL) implantation investigation. The goal of this study was to evaluate the safety and efficacy of IOL implantation for the treatment of pediatric aphakia, pending approval by the Food and Drug Administration. Methods:From May 1981 to July 1994, a total of 1260 pediatric eyes received 171 styles of IOLs implanted by 361 US investigators. Preoperative, operative, and postoperative status reports over the first year were required for each eye entered into the study. Annual visit reports were requested thereafter to determine the long-term effects. The study was terminated in November 1995. All IOLs were obtained from IOLAB, Inc (now Chiron Vision Corp). Results:Reporting compliance was 98.3% for the preoperative and operative reports, 45.1% at 1 year, and 13.8% at 3 years. The subjects' ages ranged from younger than 1 year to 17 years. Nine subjects (0.7%) were younger than 1 year, with the largest group of 533 subjects (42.3%) aged between 6 and 12 years at the time of surgery. Cataract types were congenital (45.6%), traumatic (37.1%), secondary (11%), senile (0.95%), and unrecorded (5.4%). The IOL was implanted primarily in 74.8% of cases and secondarily in 21.4% of cases. There was no record in 3.8% of the cases. IOL types included anterior chamber (4.1%), iridocapsular (0.71%), posterior chamber (93.6%), and unrecorded (1.59%). There were 130 adverse reactions that required secondary surgical intervention. The most frequently performed surgical procedures included lens removal without replacement, vitrectomy, lens repositioning, and lens replacement. More than half (52%) of all eyes had a visual acuity of 20/200 or worse before surgery; amblyopia was reported in 21.1% of all participants at baseline. Postoperative visual acuity data were available on 563 eyes at 1 year after surgery. Overall, 52.8% of all eyes attained a visual acuity of 20/40 or better by the 1-year visit, and only 15.5% had visual acuity worse than 20/200. In general, the older patient, traumatic cataract, and secondary cataract categories were overrepresented in the better visual acuity outcome group. Conclusion:The IOLAB, Inc pediatric IOL study is the first multiple- practitioner, national study designed to evaluate the safety and efficacy of IOL implantation in children. The study results are compromised by the almost 50% loss of follow-up at the 1-year evaluation. Other variables that most likely influenced outcome results were the methods of cataract extraction, medical management, and IOL design, all of which evolved dramatically over the time course of the study. Despite these issues, pediatric IOL implantation seems to be a reasonable treatment modality for aphakia, on the basis of the available 1-year follow-up data of the remaining 45.1% of eyes in the study. (J AAPOS 1999;3:295-302)

Purpose:While elevated Intraocular pressure (IOP) is associated with myopia in adults, its potential influence on the growth of eyes in juveniles without glaucoma is controversial. To address this issue, a possible relation between IOP and refraction in children was sought.

Purpose:Spasmus nutans is a condition that includes asymmetric nystagmus and occurs during the amblyogenic period. Because specific alterations in early visual experience are known to be associated with changes in visual development, relations between spasmus nutans and abnormal visual sequelae were examined.

Myopia, or nearsightedness, is the most common eye disorder worldwide. “Pathologic” high myopia, or myopia of ≤−6.00 diopters, predisposes individuals to retinal detachment, macular degeneration, cataract, or glaucoma. A locus for autosomal dominant pathologic high myopia has been mapped to 18p11.31. We now report significant linkage of high myopia to a second locus at the 12q21-23 region in a large German/Italian family. The family had no clinical evidence of connective-tissue abnormalities or glaucoma. The average age at diagnosis of myopia was 5.9 years. The average spherical-component refractive error for the affected individuals was −9.47 diopters. Markers flanking or intragenic to the genes for the 18p locus, Stickler syndromes type I and II (12q13.1-q13.3 and 6p21.3), Marfan syndrome (15q21.1), and juvenile glaucoma (chromosome 1q21-q31) showed no linkage to the myopia in this family. The maximum LOD score with two-point linkage analysis in this pedigree was 3.85 at a recombination fraction of .0010, for markers D12S1706 and D12S327. Recombination events identified markers D12S1684 and D12S1605 as flanking markers that define a 30.1-cM interval on chromosome 12q21-23, for the second myopia gene. These results confirm genetic heterogeneity of myopia. The identification of this gene may provide insight into the pathophysiology of myopia and eye development.

Myopia, or nearsightedness, is the most common human eye disorder. A genomewide screen was conducted to map the gene(s) associated with high, early-onset, autosomal dominant myopia. Eight families that each included two or more individuals with ⩾−6.00 diopters (D) myopia, in two or more successive generations, were identified. Myopic individuals had no clinical evidence of connective-tissue abnormalities, and the average age at diagnosis of myopia was 6.8 years. The average spherical component refractive error for the affected individuals was −9.48 D. The families contained 82 individuals; of these, DNA was available for 71 (37 affected). Markers flanking or intragenic to the genes for Stickler syndrome types 1 and 2 (chromosomes 12q13.1-q13.3 and 6p21.3, respectively), Marfan syndrome (chromosome 15q21.1), and juvenile glaucoma (chromosome 1q21-q31) were also analyzed. No evidence of linkage was found for markers for the Stickler syndrome types 1 and 2, the Marfan syndrome, or the juvenile glaucoma loci. After a genomewide search, evidence of significant linkage was found on chromosome 18p. The maximum LOD score was 9.59, with marker D18S481, at a recombination fraction of .0010. Haplotype analysis further refined this myopia locus to a 7.6-cM interval between markers D18S59 and D18S1138 on 18p11.31.

Retinoblastoma is a rare pediatric malignancy (1/20,000) while Hirschsprung disease is a relatively common pediatric disorder (1/5,000). We describe a boy with bilateral retinoblastoma, Hirschsprung disease, multiple minor anomalies, and an interstitial deletion 13q (q13 → q22). This child and a similar previously reported girl with retinoblastoma and Hirschsprung disease may represent a previously unrecognized contiguous gene syndrome. Am. J. Med. Genet. 77:285–288, 1998. © 1998 Wiley-Liss, Inc.

A heartburn-specific quality of life instrument was developed using an approach which involves several steps: generating and selecting items, pretesting, reproducibility testing, and validity testing. These last two steps were performed in a randomized, double blind, placebo-controlled, six-week clinical trial evaluating ranitidine 150 mg twice daily on the clinical, economic, and humanistic outcomes of patients with gastroesophageal reflux disease. Reliability, content validity, and construct validity were assessed. Scales had high values for Cronbach's alpha and item to scale and scale to scale correlations were as predicted. The SF-36® questionnaire was administered to patients in this trial, and results provided further evidence of validity for the heartburn-specific quality of life instrument. The instrument development and validation process used in this trial can serve as a model to researchers who wish to assess quality of life in a clinical trial. The pragmatic approach used produced an instrument that is both reliable and responsive, with characteristics of a valid instrument.

• A female newborn had a cystic, whitish gray mass at the inferotemporal limbus of the left eye. At age 3 weeks, the newborn underwent excision of the tumor, corneal patch grafting, and superior sector optical iridectomy. Histopathologic and electron microscopic examination of the excised tissue revealed a choristoma consisting of cysts lined with respiratory epithelium. To our knowledge, respiratory epithelium in a limbal choristoma has not been previously reported.