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Background Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous set of disorders, for which diagnostic second-generation sequencing (next-generation sequencing, NGS) services have been developed worldwide. Methods We present the molecular findings of 537 individuals referred to a 105-gene diagnostic NGS test for IRDs. We assess the diagnostic yield, the spectrum of clinical referrals, the variant analysis burden and the genetic heterogeneity of IRD. We retrospectively analyse disease-causing variants, including an assessment of variant frequency in Exome Aggregation Consortium (ExAC). Results Individuals were referred from 10 clinically distinct classifications of IRD. Of the 4542 variants clinically analysed, we have reported 402 mutations as a cause or a potential cause of disease in 62 of the 105 genes surveyed. These variants account or likely account for the clinical diagnosis of IRD in 51% of the 537 referred individuals. 144 potentially disease-causing mutations were identified as novel at the time of clinical analysis, and we further demonstrate the segregation of known disease-causing variants among individuals with IRD. We show that clinically analysed variants indicated as rare in dbSNP and the Exome Variant Server remain rare in ExAC, and that genes discovered as a cause of IRD in the post-NGS era are rare causes of IRD in a population of clinically surveyed individuals. Conclusions Our findings illustrate the continued powerful utility of custom-gene panel diagnostic NGS tests for IRD in the clinic, but suggest clear future avenues for increasing diagnostic yields. [ABSTRACT FROM AUTHOR]

Congenital cataract is the commonest worldwide cause of lifelong visual loss in children. Although congenital cataracts have a diverse aetiology, in many children, a cause is not identified; however, autosomal dominant inheritance is commonly seen. Early diagnosis either on the post-natal ward or in the community is important because appropriate intervention can result in good levels of visual function. However, visual outcome is largely dependent on the timing of surgery when dense cataracts are present. Good outcomes have been reported in children undergoing surgery before 6 weeks of age in children with unilateral cataract and before 10 weeks of age in bilateral cases. Placement of an artificial intraocular lens implant after removal of the cataract has become established practice in children over 2 years of age. There remains debate over the safety and predictability of intraocular lens implantation in infants. Despite early surgery and aggressive optical rehabilitation, children may still develop deprivation amblyopia, nystagmus, strabismus, and glaucoma. The diagnosis and management of congenital cataracts has improved substantially over the past 30 years with a concurrent improvement in outcomes for affected children. Many aspects of the pre-, intra-, and postoperative management of these patients continue to be refined, highlighting the need for good quality data and prospective collaborative studies in this field. [ABSTRACT FROM AUTHOR]

To describe our experience of combined trabeculotomy-trabeculectomy in paediatric glaucomas with a special emphasis on the use of 5-fluorouracil and releasable sutures. Retrospective review carried out at Manchester Royal Eye Hospital, UK, a tertiary referral centre. Twenty-nine eyes of 21 consecutive patients with congenital glaucoma undergoing combined trabeculotomy-trabeculectomy augmented with 5-fluorouracil. 5-Fluorouracil augmented combined trabeculotomy-trabeculectomy was carried out with intense postoperative management and suture adjustment of releasable sutures within the first 3 weeks after surgery. Peribleb 5-fluorouracil injections were given repeatedly if there were signs of aggressive bleb scarring. Absolute success was defined as intraocular pressure of 21 mmHg or less, clear cornea and absence of progressive glaucomatous optic disc changes at last follow up, whereas qualified success was defined as these endpoints with anti-glaucoma medication. Absolute success was achieved in 19 out of 29 eyes (65.5%), and a further 4 (13.8%) had qualified success. There was no difference in the surgical outcomes of primary infantile glaucoma and secondary causes of paediatric glaucoma such as anterior segment dysgenesis. Combined trabeculotomy-trabeculectomy had a significantly greater success rate as a secondary procedure rather than as a primary procedure. 5-Fluorouracil-enhanced combined trabeculotomy-trabeculectomy with releasable sutures appears to be an effective procedure for congenital glaucoma refractory to goniotomy. It is less effective as a primary procedure when severe corneal haze prevents goniotomy in newborn congenital glaucoma. Intense postoperative monitoring including active bleb manipulation with needling and 5-fluorouracil injections may increase the success of the procedure. [ABSTRACT FROM AUTHOR]

Background: To report the clinical findings in two brothers presenting with a pigmentary retinopathy and post-axial polydactyly, who were found to have a mutation in the BBS1 gene, confirming a diagnosis of Bardet-Biedl syndrome (BBS). Materials and Methods: Documentation of the clinical history, electrophysiological investigations, clinical examination and ocular findings of two brothers born to non-consanguineous white parents, with careful delineation of their clinical phenotypes. Screening of the BBS 1 gene on chromosome 11q13 by PCR-amplified exon alterations followed by direct sequencing was carried out to identify pathogenic mutations. Results: Although both probands had polydactyly and the characteristic ocular signs of BBS on both ophthalmological examination and electro-retinography, neither of them had dysmorphic facial features, obesity, hypogonadism, cognitive impairment, or renal anomalies. The first proband did have mild learning difficulties, although this did not restrict him in activities of daily living. Both probands were homozygous positive for the presence of a c.1169T > G (p.Met390Arg) mutation in BBS1. Conclusion: Although neither proband fulfilled the typical criteria for BBS, this diagnosis was confirmed on mutation analysis. These cases serve to highlight the degree of clinical variability observed in BBS which may be under-diagnosed in patients with milder phenotypes. [ABSTRACT FROM AUTHOR]

Molecular characterization of chromosomal rearrangements is a powerful resource in identification of genes associated with monogenic disorders. We describe the molecular characterization of a balanced familial chromosomal translocation, t(16;22)(p13.3;q11.2), segregating with congenital lamellar cataract. This led to the discovery of a cluster of lens-derived expressed sequence tags (ESTs) close to the 16p13.3 breakpoint. This region harbors a locus associated with cataract and microphthalmia. Long-range PCR and 16p13.3 breakpoint sequencing identified genomic sequence in a human genome sequence gap, and allowed identification of a novel four-exon gene, designated TMEM114, which encodes a predicted protein of 223 amino acids. The breakpoint lies in the promoter region of TMEM114 and separates the gene from predicted eye-specific upstream transcription factor binding sites. There is sequence conservation among orthologs down to zebrafish. The protein is predicted to contain four transmembrane domains with homology to the lens intrinsic membrane protein, LIM2 (also known as MP20), in the PMP-22/EMP/MP20 family. TMEM114 mutation screening in 130 congenital cataract patients revealed missense mutations leading to the exchange of highly-conserved amino acids in the first extracellular domain of the protein (p.I35T, p.F106L) in two separate patients and their reportedly healthy sibling and mother, respectively. In the lens, Tmem114 shows expression in the lens epithelial cells extending into the transitional zone where early fiber differentiation occurs. Our findings implicate dysregulation of expression of this novel human gene, TMEM114, in mammalian cataract formation. Hum Mutat 28(10), 968-977, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Coats' disease is characterized by abnormal retinal vascular development (so-called 'retinal telangiectasis') which results in massive intraretinal and subretinal lipid accumulation (exudative retinal detachment). The classical form of Coats' disease is almost invariably isolated, unilateral and seen in males. A female with a unilateral variant of Coats' disease gave birth to a son affected by Norrie disease. Both carried a missense mutation within the NDP gene on chromosome Xp11.2. Subsequently analysis of the retinas of nine enucleated eyes from males with Coats' disease demonstrated in one a somatic mutation in the NDP gene which was not present within non-retinal tissue. We suggest that Coats' telangiectasis is secondary to somatic mutation in the NDP gene which results in a deficiency of norrin (the protein product of the NDP gene) within the developing retina. This supports recent observations that the protein is critical for normal retinal vasculogenesis. [ABSTRACT FROM AUTHOR]

Focuses on the controversies related to the use of intraocular lens (IOL) implantation in infants in Great Britain. Disease diagnosis within the first 18 months of life; Use of aphakic spectacles for optical correction; Difficulties in choosing appropriate IOL for a growing eye; Comparison of eye growth in normal versus pseudophakic eyes.

AAPOS Genetic Eye Disease Committee workshop: does this patient have a genetic eye disease? (1) Clinicians will develop a systematic approach to identify patients with genetic eye disorders. In a rapidly changing field, this case-based workshop will provide up-to-date algorithms to confidently provide the best care for patients with genetic eye disorders. [Extracted from the article]

To better understand AAPOS member pediatric ophthalmologists' knowledge and needs regarding genetic eye disorders, the AAPOS Genetic Eye Disease Task Force developed a 16-question survey that was circulated to national and international AAPOS members. Responses to questions on practice patterns, baseline knowledge, and educational interests regarding patients with suspected ophthalmic genetic disorders were collected. A majority of respondents (93%) evaluate patients with suspected genetic disorders. Knowledge gaps were present in heritability of certain conditions, genetic testing strategies, and referral to clinical trials. Most respondents expressed interest in further education in these areas. A model for care is proposed as a first step in the education process. [ABSTRACT FROM AUTHOR]

The article discusses an observational study of patients diagnosed with X linked retinoschisis (XLRS), who underwent MP-1 macular microperimetry and a series of Fourier domain optical coherence tomography (OCT) through the anatomical fovea. The patients' best-corrected visual acuity (BCVA), central retinal sensitivity, macular thickness and preferred retinal locus were measured. The study showed the relevance of microperimetry using MP-1 in patients with XLRS.

Abstract: We wished to study how the severity and duration of early onset visual deprivation affects eye alignment and ocular stability. Thirty-three patients (aged 1 week to 12.8 years) with infantile cataracts (16 bilateral, 17 unilateral) were examined for periods up to 61 months. Twenty-three patients were considered to have cataracts, which were a major obstacle to vision (major form deprivation), 9 of whom underwent surgery within 8 weeks of birth (mean and SD=5.2±2.3 weeks) and 10 after 8 weeks (mean and SD=33.9±29.7 months). Eye alignment and fixation stability was measured using infrared recording systems and video. Visual acuity was assessed using forced-choice preferential looking techniques in the neonates and infants and with optotypes in the children. Fifteen of the 23 (65%) patients who experienced major form deprivation exhibited a nystagmus, of which 11 (73%) were manifest latent nystagmus (MLN). Nineteen of the 23 (85%) had strabismus. Of the nine patients who underwent early surgery (⩽8 weeks), two displayed a preoperative nystagmus whilst between 10 and 39 months post-operatively 8 (89%) exhibited a nystagmus. Of the group of 10 patients with minor cataracts only 2 (1 late surgery, 1 no surgery) had nystagmus and 2 strabismus. We conclude that following optimal post-operative management of infantile cataracts a sustained nystagmus—typically an MLN—is the most likely ocular motor outcome, even when the period of deprivation is as short as 3 weeks. [Copyright &y& Elsevier]

The article presents a case study of a male infant in 2002 who was diagnosed with non-syndromic infantile-onset retinal dystrophy and whose younger sister in 2006, was also diagnosed the same condition. Whole exome sequencing was used to test the boy's DNA in 2013 and identified a homozygous two-nucleotide delection in the IQCB1 gene. Further investigation of the boy at age twelve proved he has renal impairment and anaemia.

Purpose To assess the utility of integrating genomic data from next-generation sequencing and phenotypic data to enhance the diagnosis of bilateral congenital cataract (CC). Design Evaluation of diagnostic technology. Participants Thirty-six individuals diagnosed with nonsyndromic or syndromic bilateral congenital cataract were selected for investigation through a single ophthalmic genetics clinic. Methods Participants underwent a detailed ophthalmic examination, accompanied by dysmorphology assessment where appropriate. Lenticular, ocular, and systemic phenotypes were recorded. Mutations were detected using a custom-designed target enrichment that permitted parallel analysis of 115 genes associated with CC by high-throughput, next-generation DNA sequencing (NGS). Thirty-six patients and a known positive control were tested. Suspected pathogenic variants were confirmed by bidirectional Sanger sequencing in relevant probands and other affected family members. Main Outcome Measures Molecular genetic results and details of clinical phenotypes were identified. Results Next-generation DNA sequencing technologies are able to determine the precise genetic cause of CC in 75% of individuals, and 85% patients with nonsyndromic CC were found to have likely pathogenic mutations, all of which occurred in highly conserved domains known to be vital for normal protein function. The pick-up rate in patients with syndromic CC also was high, with 63% having potential disease-causing mutations. Conclusions This analysis demonstrates the clinical utility of this test, providing examples where it altered clinical management, directed care pathways, and enabled more accurate genetic counseling. This comprehensive screen will extend access to genetic testing and lead to improved diagnostic and management outcomes through a stratified medicine approach. Establishing more robust genotype–phenotype correlations will advance knowledge of cataract-forming mechanisms. [ABSTRACT FROM AUTHOR]