PURPOSE:Congenital cataracts are a leading cause of childhood blindness, with clinical impact due both to visual impairment and associated systemic disorders. They exhibit clinical and genetic heterogeneity, with pathogenic variants identified in more than 100 genes complicating genotype-phenotype correlation. Accurate molecular diagnosis is essential for prognosis, reproductive counseling, and tailored surveillance and management. Whole genome sequencing (WGS) offers advantages over gene panels by detecting a broader spectrum of variants, including copy number changes, structural rearrangements, cryptic variants, and those in repetitive regions, thereby improving diagnostic yield, especially when interpreted through multidisciplinary team meetings (MDTMs). METHODS:A retrospective review was performed of 119 consecutive patients undergoing genetic testing for congenital cataracts in the North Thames Genomic Laboratory Hub. Genetic analysis was performed using either targeted gene panels in 76 probands (64%) (2016-2021) or WGS in 43 (36%) (2021-2025). Clinical data were extracted to classify cases as syndromic or nonsyndromic and assess diagnostic outcomes, with complex cases discussed at MDTMs. RESULTS:Nonsyndromic (isolated or wider ocular) and syndromic cataracts accounted for 52.1% and 47.8% of cases, respectively, consistent with previous literature describing frequent multisystem involvement. WGS increased diagnostic yield by 10% compared with gene panels, primarily through detection of variants missed by panel-based approaches. Overall molecular diagnosis was 42%, with higher rates achieved in nonsyndromic forms (51.6%). CONCLUSION:WGS appears more effective for establishing a diagnosis in congenital cataracts than gene panels, because of its ability to detect diverse pathogenic variants. This is critical for provision of prognosis, reproductive counseling, and further management, especially given the high rate of associated syndromic conditions. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Cataracts in infants and children are comparatively rare, but they remain an important cause of potentially lifelong visual impairment, largely because of associated deprivation amblyopia. This is particularly seen in children missed by screening programs and thus presenting late for treatment. However, advances in diagnosis, surgical techniques and amblyopia management have improved the prognosis for most children seen with this condition. This comprehensive review focuses on all aspects of the care required to optimize outcomes. It covers modern genetic investigations, performed to precisely determine underlying cataract etiology, and discusses the use of outcome-based evidence to guide the timing of surgical intervention. The paper also outlines the options available to clinicians for post-operative refractive error correction and compares indications, risks and benefits for the use of contact lenses, spectacles and intraocular lenses (IOL). The challenge of choosing the most appropriate dioptric power of IOL to implant into a growing eye is discussed, as is consideration of types of IOLs that can be considered and the surgical techniques needed. Evidence-based approaches to the clinical management of amblyopia, glaucoma and visual axis opacification, the three most common complications seen following pediatric cataract surgery, are reviewed. Two specific conditions associated with pediatric cataract are discussed in detail--persistent fetal vasculature and ocular trauma. Strategies for assessment, management and surgical treatment of these conditions are reviewed.

Abstract Background Inherited vitreoretinopathies arise as a consequence of congenital retinal vascularisation abnormalities. They represent a phenotypically and genetically heterogeneous group of disorders that can have a major impact on vision. Several genes encoding proteins and effectors of the canonical Wnt/β-catenin pathway have been associated and precise diagnosis, although difficult, is essential for proper clinical management including syndrome specific management where appropriate. This work aimed to investigate the molecular basis of disease in a single proband born to consanguineous parents, who presented with microphthalmia, persistent foetal vasculature, posterior lens vacuoles, vitreoretinal dysplasia, microcephaly, hypotelorism and global developmental delay, and was registered severely visually impaired by 5 months of age. Methods Extensive genomic pre-screening, including microarray comparative genomic hybridisation and sequencing of a 114 gene panel associated with cataract and congenital ophthalmic disorders was conducted by an accredited clinical laboratory. Whole exome sequencing (WES) was undertaken on a research basis and in vitro TOPflash transcriptional reporter assay was utilised to assess the impact of the putative causal variant. Results In the proband, WES revealed a novel, likely pathogenic homozygous mutation in the cadherin-associated protein beta-1 gene (CTNNB1), c.884C>G; p.(Ala295Gly), which encodes a co-effector molecule of the Wnt/β-catenin pathway. The proband’s parents were shown to be heterozygous carriers but ophthalmic examination did not detect any abnormalities. Functional assessment of the missense variant demonstrated significant reduction of β-catenin activity. Conclusions This is the first report of a biallelic disease-causing variation in CTNNB1. We conclude that this biallelic, transcriptional inactivating mutation of CTNNB1 causes a severe, syndromic form of microphthalmia, persistent foetal vasculature and vitreoretinal dysplasia that results in serious visual loss in infancy.

Review the important systemic disorders associated with congenital and pediatric cataract. Illustrative case presentations to demonstrate how the use of modern investigative pathways can enhance diagnostic precision and thus enable improved patient care.

We have undertaken targeted genetic testing of children presenting to a specialist children’s hospital with ectopia lentis. We report the presenting clinical features of our case series and the genes identified.

The management of strabismus is a discipline that seems at times more an art form than a science. Although nomograms and tables are helpful, suboptimal outcomes can still occur. In this workshop a panel of experts will discuss surgical strabismus cases that challenged them and helped refine their understanding and management of strabismus.

Childhood cataract affects 2.5–3.5 per 10,000 children in the UK, with a genetic mutation identified in 50–90% of bilateral cases. However, cataracts can also manifest in adolescence and early adulthood in isolation, as part of a complex ocular phenotype or with systemic features making accurate diagnosis more challenging. We investigate our real-world experience through a retrospective review of consecutive bilateral cataract patients (0–25 years) presenting to the ocular genetics service at Moorfields Eye Hospital between 2017 and 2020. Fifty-four patients from 44 unrelated families were identified, with a median age of 13.5 years (range 1 to 68 years) and a median age at diagnosis of 43.9 months IQR (1.7–140.3 months); 40.7% were female and 46.3% were Caucasian. Overall, 37 patients from 27 families (61.4%) were genetically solved (50%) or likely solved (additional 11.4%), with 26 disease-causing variants (8 were novel) in 21 genes; the most common were crystallin genes, in 8 (29.6%) families, with half occurring in the CRYBB2 gene. There was no significant difference in the molecular diagnostic rates between sporadic and familial inheritance (P = 0.287). Associated clinical diagnoses were retinal dystrophies in five (18.5%) and aniridia in three (11.1%) families. Bilateral cataracts were the presenting feature in 27.3% (6/22) of either complex or syndromic cases, and isolated cataract patients were 11.5 years younger (rank-sum Z = 3.668, P = 0.0002). Prompt genetic investigation with comprehensive panel testing can aid with diagnosis and optimise management of cataract patients.

Background Perimetry is important in the management of children with glaucoma, but there is limited evidence-based guidance on its use. We report an expert consensus-based study to update guidance and identify areas requiring further research. Methods Experts were invited to participate in a modified Delphi consensus process. Panel selection was based on clinical experience of managing children with glaucoma and UK-based training to minimise diversity of view due to healthcare setting. Questionnaires were delivered electronically, and analysed to establish ‘agreement’. Divergence of opinions was investigated and resolved where possible through further iterations. Results 7/9 experts invited agreed to participate. Consensus (≥5/7 (71%) in agreement) was achieved for 21/26 (80.8%) items in 2 rounds, generating recommendations to start perimetry from approximately 7 years of age (IQR: 6.75–7.25), and use qualitative methods in conjunction with automated reliability indices to assess test quality. There was a lack of agreement about defining progressive visual field (VF) loss and methods for implementing perimetry longitudinally. Panel members highlighted the importance of informing decisions based upon individual circumstances—from gauging maturity/capability when selecting tests and interpreting outcomes, to accounting for specific clinical features (e.g. poor IOP control and/or suspected progressive VF loss) when making decisions about frequency of testing. Conclusions There is commonality of expert views in relation to implementing perimetry and interpreting test quality in the management of children with glaucoma. However, there remains a lack of agreement about defining progressive VF loss, and utilising perimetry over an individuals’ lifetime, highlighting the need for further research.

EPHA2 is a transmembrane tyrosine kinase receptor that, when disrupted, causes congenital and age-related cataracts. Cat-Map reports 22 pathogenic EPHA2 variants associated with congenital cataracts, variable microcornea, and lenticonus, but no previous association with microphthalmia (small, underdeveloped eye, ≥2 standard deviations below normal axial length). Microphthalmia arises from ocular maldevelopment with >90 monogenic causes, and can include a complex ocular phenotype. In this paper, we report two pathogenic EPHA2 variants in unrelated families presenting with bilateral microphthalmia and congenital cataracts. Whole genome sequencing through the 100,000 Genomes Project and cataract-related targeted gene panel testing identified autosomal dominant heterozygous mutations segregating with the disease: (i) missense c.1751C>T, p.(Pro584Leu) and (ii) splice site c.2826-9G>A. To functionally validate pathogenicity, morpholino knockdown of epha2a/epha2b in zebrafish resulted in significantly reduced eye size ± cataract formation. Misexpression of N-cadherin and retained fibre cell nuclei were observed in the developing lens of the epha2b knockdown morphant fish by 3 days post-fertilisation, which indicated a putative mechanism for microphthalmia pathogenesis through disruption of cadherin-mediated adherens junctions, preventing lens maturation and the critical signals stimulating eye growth. This study demonstrates a novel association of EPHA2 with microphthalmia, suggesting further analysis of pathogenic variants in unsolved microphthalmia cohorts may increase molecular diagnostic rates.

Response to a AAPOS member poll overwhelmingly showed that pediatric ophthalmologists see genetic eye disorder patients at least once a week; however, only 18% of AAPOS members responded to the poll. Many members may not realize they are seeing genetic eye disorders, although they are common in pediatric ophthalmology practice. In the molecular genetic era, early recognition of these genetic disorders in everyday practice is important.

Ian Guy Lloyd was born in Fatfield, County Durham, a village near Sunderland. His father, Alfred Guy Lloyd, was a GP in the area—one of a long line of family doctors. His mother, Honora Patricia, was the daughter of a prominent local businessman who had been a mayor of Durham. Ian was bright and good at sport. At Douai School in Berkshire, he was a key member of the schools very successful first rugby XV. He went on to represent his county in both rugby and tennis. He took up a place to read medicine in Newcastle in 1954—in those days part of Durham University. He enjoyed medical school, played rugby for the Newcastle Medicals first XV, alongside his cousin, Ricky Oliver (a dental student). After qualifying he worked in junior posts at the Royal Victoria Infirmary, Newcastle, and Sunderland General Hospital. He met and fell in love with Kathleen Grange, a student nurse in Newcastle. After marrying her in …

Purpose A key property to consider in all genetic tests is clinical utility, the ability of the test to influence patient management and health outcomes. Here we assess the current clinical utility of genetic testing in diverse pediatric inherited eye disorders (IEDs). Methods Two hundred one unrelated children (0–5 years old) with IEDs were ascertained through the database of the North West Genomic Laboratory Hub, Manchester, UK. The cohort was collected over a 7-year period (2011–2018) and included 74 children with bilateral cataracts, 8 with bilateral ectopia lentis, 28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders. All participants underwent panel-based genetic testing. Results The diagnostic yield of genetic testing for the cohort was 64% (ranging from 39% to 91% depending on the condition). The test result led to altered management (including preventing additional investigations or resulting in the introduction of personalized surveillance measures) in 33% of probands (75% for ectopia lentis, 50% for cataracts, 33% for inherited retinal disorders, 7% for anterior segment dysgenesis, 3% for albinism). Conclusion Genetic testing helped identify an etiological diagnosis in the majority of preschool children with IEDs. This prevented additional unnecessary testing and provided the opportunity for anticipatory guidance in significant subsets of patients.

Congenital and childhood cataracts are uncommon but regularly seen in the clinics of most paediatric ophthalmology teams in the UK. They are often associated with profound visual loss and a large proportion have a genetic aetiology, some with significant extra-ocular comorbidities. Optimal diagnosis and treatment typically require close collaboration within multidisciplinary teams. Surgery remains the mainstay of treatment. A variety of surgical techniques, timings of intervention and options for optical correction have been advocated making management seem complex for those seeing affected children infrequently. This paper summarises the proceedings of two recent RCOphth paediatric cataract study days, provides a literature review and describes the current UK ‘state of play’ in the management of paediatric cataracts.

Traboulsi syndrome is an extremely rare ophthalmological disorder characterised by facial dysmorphism, lens dislocation, anterior segment abnormalities and spontaneous filtering blebs. It is caused by pathogenic variants in the ASPH gene. To date, only 13 individuals with Traboulsi syndrome from three families have been reported in the literature. We report the first UK family with Traboulsi syndrome associated with two novel ASPH variants. This condition, which has some phenotypic overlap with both Marfan syndrome and homocystinuria, is most likely under ascertained, and we further delineate the clinical features to aid its recognition.

Background: Pathogenic variants in the BCOR gene have been identified in males with X-linked recessive microphthalmia and in females with X-linked dominant oculofaciocardiodental (OFCD) syndrome. This latter condition has previously been regarded as rare but the increased availability of genetic testing in recent years has led to the identification of a greater number of patients. Methods: We report the clinical and molecular findings in a series of 10 patients with pathogenic BCOR variants from 5 families, all seen in a single institution over a two year period. Results: We emphasize the phenotypic variability in this cohort and the diverse genetic mechanisms involved which included point mutations and deletions of BCOR as well as the occurrence of gonadal and somatic mosaicism. Conclusion: In this report we demonstrate the novel findings of four newly identified variants in BCOR associated with an OFCD phenotype, and suggest that the frequency of this condition in females presenting with congenital cataract, including unilateral cataract, is more common than anticipated. We demonstrate the utility of screening for genetic causes of congenital cataract. Although gonadal mosaicism in OFCD had previously been reported, we demonstrate the presence of somatic mosaicism where BCOR mutations may only be detected in DNA from tissues other than blood such as buccal cells.

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 El is proposed as a first step in the education process.

Individuals who have ocular features of albinism and skin pigmentation in keeping with their familial background present a considerable diagnostic challenge. Timely diagnosis through genomic testing can help avert diagnostic odysseys and facilitates accurate genetic counselling and tailored specialist management. Here, we report the clinical and gene panel testing findings in 12 children with presumed ocular albinism. A definitive molecular diagnosis was made in 8/12 probands (67%) and a possible molecular diagnosis was identified in a further 3/12 probands (25%). TYR was the most commonly mutated gene in this cohort (75% of patients, 9/12). A disease-causing TYR haplotype comprised of two common, functional polymorphisms, TYR c.[575 C > A;1205 G > A] p.[(Ser192Tyr);(Arg402Gln)], was found to be particularly prevalent. One participant had GPR143-associated X-linked ocular albinism and another proband had biallelic variants in SLC38A8, a glutamine transporter gene associated with foveal hypoplasia and optic nerve misrouting without pigmentation defects. Intriguingly, 2/12 individuals had a single, rare, likely pathogenic variant in each of TYR and OCA2 – a significant enrichment compared to a control cohort of 4046 individuals from the 100,000 genomes project pilot dataset. Overall, our findings highlight that panel-based genetic testing is a clinically useful test with a high diagnostic yield in children with partial/ocular albinism.