Extended optical treatment versus early patching with an intensive patching regimen in children with amblyopia in Europe (EuPatch): a multicentre, randomised controlled trial.

BACKGROUND: Amblyopia, the most common visual impairment of childhood, is a public health concern. An extended period of optical treatment before patching is recommended by the clinical guidelines of several countries. The aim of this study was to compare an intensive patching regimen, with and without extended optical treatment (EOT), in a randomised controlled trial. METHODS: EuPatch was a randomised controlled trial conducted in 30 hospitals in the UK, Greece, Austria, Germany, and Switzerland. Children aged 3-8 years with newly detected, untreated amblyopia (defined as an interocular difference ≥0·30 logarithm of the minimum angle of resolution [logMAR] best corrected visual acuity [BCVA]) due to anisometropia, strabismus, or both were eligible. Participants were randomly assigned (1:1) via a computer-generated sequence to either the EOT group (18 weeks of glasses use before patching) or to the early patching group (3 weeks of glasses use before patching), stratified for type and severity of amblyopia. All participants were initially prescribed an intensive patching regimen (10 h/day, 6 days per week), supplemented with motivational materials. The patching period was up to 24 weeks. Participants, parents or guardians, assessors, and the trial statistician were not masked to treatment allocation. The primary outcome was successful treatment (ie, ≤0·20 logMAR interocular difference in BCVA) after 12 weeks of patching. Two primary analyses were conducted: the main analysis included all participants, including those who dropped out, but excluded those who did not provide outcome data at week 12 and remained on the study; the other analysis imputed this missing data. All eligible and randomly assigned participants were assessed for adverse events. This study is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN51712593) and is no longer recruiting. FINDINGS: Between June 20, 2013, and March 12, 2020, after exclusion of eight participants found ineligible after detailed screening, we randomly assigned 334 participants (170 to the EOT group and 164 to the early patching group), including 188 (56%) boys, 146 (44%) girls, and two (1%) participants whose sex was not recorded. 317 participants (158 in the EOT group and 159 in the early patching group) were analysed for the primary outcome without imputation of missing data (median follow-up time 42 weeks [IQR 42] in the EOT group vs 27 weeks [27] in the early patching group). 24 (14%) of 170 participants in the EOT group and ten (6%) of 164 in the early patching group were excluded or dropped out of the study, mostly due to loss to follow-up and withdrawal of consent; ten (6%) in the EOT group and three (2%) in the early patching group missed the 12 week visit but remained on the study. A higher proportion of participants in the early patching group had successful treatment (107 [67%] of 159) than those in the EOT group (86 [54%] of 158; 13% difference; p=0·019) after 12 weeks of patching. No serious adverse events related to the interventions occurred. INTERPRETATION: The results from this trial indicate that early patching is more effective than EOT for the treatment of most children with amblyopia. Our findings also provide data for the personalisation of amblyopia treatments. FUNDING: Action Medical Research, NIHR Clinical Research Network, and Ulverscroft Foundation.

Eyetracking-enhanced VEP for nystagmus.

Visual evoked potentials (VEPs) are an important prognostic indicator of visual ability in patients with nystagmus. However, VEP testing requires stable fixation, which is impossible with nystagmus. Fixation instability reduces VEP amplitude, and VEP reliability is therefore low in this important patient group. We investigated whether VEP amplitude can be increased using an eye tracker by triggering acquisition only during slow periods of the waveform. Data were collected from 10 individuals with early-onset nystagmus. VEP was obtained under continuous (standard) acquisition, or triggered during periods of low eye velocity, as detected by an eye tracker. VEP amplitude was compared using Bonferroni corrected paired samples t-tests. VEP amplitude is significantly increased when triggered during low eye velocity (95% CI 1.42-6.83 µV, t(15) = 3.25, p = 0.0053). This study provides proof-of-concept that VEP amplitude (and therefore prognostic reliability) can be increased in patients with early onset nystagmus by connecting an eye tracker and triggering acquisition during periods of lower eye velocity.

Human equivalent doses of L-DOPA rescues retinal morphology and visual function in a murine model of albinism.

L-DOPA is deficient in the developing albino eye, resulting in abnormalities of retinal development and visual impairment. Ongoing retinal development after birth has also been demonstrated in the developing albino eye offering a potential therapeutic window in humans. To study whether human equivalent doses of L-DOPA/Carbidopa administered during the crucial postnatal period of neuroplasticity can rescue visual function, OCA C57BL/6 J-c2J OCA1 mice were treated with a 28-day course of oral L-DOPA/Carbidopa at 3 different doses from 15 to 43 days postnatal age (PNA) and for 3 different lengths of treatment, to identify optimum dosage and treatment length. Visual electrophysiology, acuity, and retinal morphology were measured at 4, 5, 6, 12 and 16 weeks PNA and compared to untreated C57BL/6 J (WT) and OCA1 mice. Quantification of PEDF, ßIII-tubulin and syntaxin-3 expression was also performed. Our data showed impaired retinal morphology, decreased retinal function and lower visual acuity in untreated OCA1 mice compared to WT mice. These changes were diminished or eliminated when treated with higher doses of L-DOPA/Carbidopa. Our results demonstrate that oral L-DOPA/Carbidopa supplementation at human equivalent doses during the postnatal critical period of retinal neuroplasticity can rescue visual retinal morphology and retinal function, via PEDF upregulation and modulation of retinal synaptogenesis, providing a further step towards developing an effective treatment for albinism patients.

Minimal reporting guideline for research involving eye tracking (2023 edition).

A guideline is proposed that comprises the minimum items to be reported in research studies involving an eye tracker and human or non-human primate participant(s). This guideline was developed over a 3-year period using a consensus-based process via an open invitation to the international eye tracking community. This guideline will be reviewed at maximum intervals of 4 years.

Children's visual acuity tests without professional supervision: a prospective repeated measures study.

BACKGROUND: Home visual acuity tests could ease pressure on ophthalmic services by facilitating remote review of patients. Home tests may have further utility in giving service users frequent updates of vision outcomes during therapy, identifying vision problems in an asymptomatic population, and engaging stakeholders in therapy. METHODS: Children attending outpatient clinics had visual acuity measured 3 times at the same appointment: Once by a registered orthoptist per clinical protocols, once by an orthoptist using a tablet-based visual acuity test (iSight Test Pro, Kay Pictures), and once by an unsupervised parent/carer using the tablet-based test. RESULTS: In total, 42 children were recruited to the study. The mean age was 5.6 years (range 3.3 to 9.3 years). Median and interquartile ranges (IQR) for clinical standard, orthoptic-led and parent/carer-led iSight Test Pro visual acuity measurements were 0.155 (0.18 IQR), 0.180 (0.26 IQR), and 0.300 (0.33 IQR) logMAR respectively. The iSight Test Pro in the hands of parents/carers was significantly different from the standard of care measurements (P = 0.008). In the hands of orthoptists. There was no significant difference between orthoptists using the iSight Test Pro and standard of care (P = 0.289), nor between orthoptist iSight Test Pro and parents/carer iSight Test Pro measurements (P = 0.108). CONCLUSION: This technique of unsupervised visual acuity measures for children is not comparable to clinical measures and is unlikely to be valuable to clinical decision making. Future work should focus on improving the accuracy of the test through better training, equipment/software or supervision/support.

Analysis of Fibroblast Growth Factor 14 (FGF14) structural variants reveals the genetic basis of the early onset nystagmus locus NYS4 and variable ataxia.

Nystagmus (involuntary, rhythmical eye movements) can arise due to sensory eye defects, in association with neurological disorders or as an isolated condition. We identified a family with early onset nystagmus and additional neurological features carrying a partial duplication of FGF14, a gene associated with spinocerebellar ataxia type 27 (SCA27) and episodic ataxia. Detailed eye movement analysis revealed oculomotor anomalies strikingly similar to those reported in a previously described four-generation family with early onset nystagmus and linkage to a region on chromosome 13q31.3-q33.1 (NYS4). Since FGF14 lies within NYS4, we revisited the original pedigree using whole genome sequencing, identifying a 161 kb heterozygous deletion disrupting FGF14 and ITGBL1 in the affected individuals, suggesting an FGF14-related condition. Therefore, our study reveals the genetic variant underlying NYS4, expands the spectrum of pathogenic FGF14 variants, and highlights the importance of screening FGF14 in apparently isolated early onset nystagmus.

Bridging the language gap - A call for the wider use of Human phenotype ontology by non-geneticist clinicians when requesting genomic tests.

Advances in genomic technology including the development of next-generation sequencing (NGS) have enabled the identification of thousands of variations at a time, allowing the discovery of novel genetic diseases. Given the volume of data generated by these investigations, attention is drawn towards reporting relevant clinical features by clinicians to guide the diagnosis and management of their patients. The Human Phenotype Ontology (HPO) developed in 2008, revolutionized the semantic vocabulary of phenotypic descriptions in genomic medicine allowing researchers, laboratories and clinical geneticists to better understand each other. In this era of personalized medicine where genetic tests are becoming more accessible, non-geneticist clinicians are expected to be more involved than ever in the process of ordering genetic tests and interpreting genetic reports. It is therefore essential that they understand and adequately apply HPO nomenclature to integrate the patient care chain and seize the opportunity offered by this tailored language. The current article highlights the importance of using HPO vocabularies in clinical practice and advocates for its wider use by non-geneticist clinicians. Correct use of HPO will reduce misunderstandings between healthcare professionals and ultimately improve the healthcare system.

Aetiologies of acquired pediatric sixth nerve palsies in a U.K. based population.

Due to the low incidence of sixth cranial nerve palsies in children, there has been limited evidence published on this subject, especially from a population based within the UK. The incidence of etiologies has been found to vary significantly within the literature, especially with regard to neoplasms. The main aim of this study is to present the etiologies of newly diagnosed pediatric sixth nerve palsies in a UK-based population. We also take into consideration if the palsies were isolated or associated with other neurological signs or symptoms. Retrospective data collection was carried out on the medical records of 50 pediatric patients with a new-onset sixth nerve palsy. They all presented to a large tertiary referral hospital in the South of the UK between 1 January 2007 and 31 December 2017. Data collected for each patient included age, gender, ethnicity, unilateral versus bilateral, other signs and symptoms, etiology, where the patient first presented, and whether the palsy was the first presenting feature. Thirty-three (66%) patients had a new-onset sixth nerve palsy in conjunction with other neurological signs or symptoms and were considered non-isolated. Seventeen cases (34%) were found to be isolated. Etiologies included high intracranial pressure (18%), neoplasm (14%), surgery for neoplasm (14%), viral (14%), infection (12%), trauma (8%), idiopathic (6%), benign space-occupying lesion (4%), congenital (2%), inflammation (2%), Alexander's disease (2%), Kawasaki syndrome (2%), and diabetes (2%). Our study found non-isolated sixth nerve palsies to be the most common presentation. These patients had a high number of potentially sinister etiologies, the most common being high intracranial pressure followed by post-surgery for neoplasm and neoplasm. Isolated sixth nerve palsies were more commonly due to viral or idiopathic etiology; however, two cases of benign space-occupying lesion and one of neoplasm were identified.

Evidence that the Ser192Tyr/Arg402Gln in cis Tyrosinase gene haplotype is a disease-causing allele in oculocutaneous albinism type 1B (OCA1B).

Oculocutaneous albinism type 1 (OCA1) is caused by pathogenic variants in the TYR (tyrosinase) gene which encodes the critical and rate-limiting enzyme in melanin synthesis. It is the most common OCA subtype found in Caucasians, accounting for ~50% of cases worldwide. The apparent 'missing heritability' in OCA is well described, with ~25-30% of clinically diagnosed individuals lacking two clearly pathogenic variants. Here we undertook empowered genetic studies in an extensive multigenerational Amish family, alongside a review of previously published literature, a retrospective analysis of in-house datasets, and tyrosinase activity studies. Together this provides irrefutable evidence of the pathogenicity of two common TYR variants, p.(Ser192Tyr) and p.(Arg402Gln) when inherited in cis alongside a pathogenic TYR variant in trans. We also show that homozygosity for the p.(Ser192Tyr)/p.(Arg402Gln) TYR haplotype results in a very mild, but fully penetrant, albinism phenotype. Together these data underscore the importance of including the TYR p.(Ser192Tyr)/p.(Arg402Gln) in cis haplotype as a pathogenic allele causative of OCA, which would likely increase molecular diagnoses in this missing heritability albinism cohort by 25-50%.

A severe case of Bosch-Boonstra-Schaaf optic atrophy syndrome with a novel description of coloboma and septo-optic dysplasia, owing to a start codon variant in the NR2F1 gene.

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare congenital syndrome characterized by a range of phenotypes including optic atrophy and intellectual disability among other features. Pathogenic variants in the NR2F1 (nuclear receptor subfamily 2 group F member 1) gene have been linked to this condition. A recent report has shown that pathogenic variants in the start codon lead to decreased expression of the NR2F1 protein and a relatively mild phenotype, similar to that seen in whole gene deletions, and due to the lack of the dominant negative effect. Here we describe a severe case of BBSOAS with an initiation codon missense variant. The developmental delay, seizures, optic atrophy are in keeping with features observed in this condition, however this is the first report to describe colobomas and septo-optic dysplasia as associated features potentially extending the phenotype linked to BBSOAS. In addition, this is the first description of a severe phenotype linked to a de novo missense variant in the start codon of the NR2F1 gene.

Cerebral visual impairment-related vision problems in primary school children: a cross-sectional survey.

AIM: To estimate how many children in mainstream primary schools have cerebral visual impairment (CVI)-related vision problems and to investigate whether some indicators might be useful as red flags, if they were associated with increased risk for these problems. METHOD: We conducted a survey of primary school children aged 5 to 11 years, using whether they were getting extra educational help and/or teacher- and parent-reported behaviour questionnaires to identify children at risk for CVI. These and a random 5% sample were assessed for CVI-related vision problems. We compared the usefulness of potential red flags using likelihood ratios. RESULTS: We received questionnaires on 2298 mainstream-educated children and examined 248 children (152 [61%] males, 96 females [39%]; mean age 8y 1mo, SD 20mo, range 5y 6mo-11y 8mo). We identified 78 out of 248 children (31.5% of those examined, 3.4% of the total sample), who had at least one CVI-related vision problem. The majority (88%) were identified by one or more red flag but none were strongly predictive. Fewer than one in five children with any CVI-related vision problem had reduced visual acuity. INTERPRETATION: Children with CVI-related vision problems were more prevalent than has been appreciated. Assessment of at-risk children may be useful so that opportunities to improve outcomes for children with CVI-related vision problems are not missed.

Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly.

BACKGROUND: Coat protein complex 1 (COPI) is integral in the sorting and retrograde trafficking of proteins and lipids from the Golgi apparatus to the endoplasmic reticulum (ER). In recent years, coat proteins have been implicated in human diseases known collectively as "coatopathies". METHODS: Whole exome or genome sequencing of two families with a neuro-developmental syndrome, variable microcephaly and cataracts revealed biallelic variants in COPB1, which encodes the beta-subunit of COPI (ß-COP). To investigate Family 1's splice donor site variant, we undertook patient blood RNA studies and CRISPR/Cas9 modelling of this variant in a homologous region of the Xenopus tropicalis genome. To investigate Family 2's missense variant, we studied cellular phenotypes of human retinal epithelium and embryonic kidney cell lines transfected with a COPB1 expression vector into which we had introduced Family 2's mutation. RESULTS: We present a new recessive coatopathy typified by severe developmental delay and cataracts and variable microcephaly. A homozygous splice donor site variant in Family 1 results in two aberrant transcripts, one of which causes skipping of exon 8 in COPB1 pre-mRNA, and a 36 amino acid in-frame deletion, resulting in the loss of a motif at a small interaction interface between ß-COP and ß'-COP. Xenopus tropicalis animals with a homologous mutation, introduced by CRISPR/Cas9 genome editing, recapitulate features of the human syndrome including microcephaly and cataracts. In vitro modelling of the COPB1 c.1651T>G p.Phe551Val variant in Family 2 identifies defective Golgi to ER recycling of this mutant ß-COP, with the mutant protein being retarded in the Golgi. CONCLUSIONS: This adds to the growing body of evidence that COPI subunits are essential in brain development and human health and underlines the utility of exome and genome sequencing coupled with Xenopus tropicalis CRISPR/Cas modelling for the identification and characterisation of novel rare disease genes.

Comparison of the handheld RETeval ERG system with a routine ERG system in healthy adults and in paediatric patients.

BACKGROUND: Electroretinograms (ERG) are necessary for the evaluation of retinal function, however testing children is challenging and only performed at a few specialised centres. The handheld RETeval ERG instrument could prove a valuable tool for clinicians in assessing retinal function. This study evaluates this device using an ISCEV approved modified paediatric protocol and compares it to standard methods using a photic stimulator. SUBJECTS AND METHOD: Cone and rod ERGs were recorded using a standard photic stimulator (Grass) and the RETeval device. Both methods involve using skin electrodes, without mydriasis and under dark and light conditions. Two groups of participants were recruited: 44 healthy adult subjects (mean age = 39 years) and 37 paediatric patients (mean = 5 years). Three of the paediatric patients were not sufficiently compliant to undertake the RETeval recording. RESULTS: Adult ERG reference range data are presented for the RETeval and compared to the standard system. There is lack of absolute agreement in the measurements between the two devices, highlighting the need for device-specific reference data. In the paediatric group there is a high level of diagnostic agreement between both systems (Cohen's Kappa k = 0.80). The relative sensitivity and specificity of the RETeval was 1.0 and 0.91. Qualitative patient and user feedback is discussed. CONCLUSIONS: ERGs are similar between the two methodologies. This study demonstrates that the RETeval device is a useful tool for assessing retinal function in children. Importantly, it is quick, relatively easy to use and can potentially reduce the burden and costs of paediatric electrodiagnostic assessments.

Novel therapeutics in nystagmus: what has the genetics taught us so far?

Nystagmus is a disorder characterised by uncontrolled, repetitive, to-and-fro movement of the eyes. It can occur as a seemingly isolated disorder but is most commonly the first, or most obvious, feature in a host of ophthalmic and systemic disorders. The number of underlying causes is vast, and recent improvements in the provision of genetic testing have shown that many conditions can include nystagmus as a feature, but that phenotypes overlap significantly. Therefore, an increase in the understanding of the genetic causes of nystagmus has shown that successful novel therapeutics for 'nystagmus' can target either specific underlying disorders and mechanisms (aiming to treat the underlying condition as a whole), or a final common pathway (aiming to treat the nystagmus directly). Plain language summary: Novel treatments for a disorder of eye movement (nystagmus): what has the genetics taught us so far? Nystagmus is a disorder of eye movement characterised by uncontrolled, to-and-fro movements. It can occur as an isolated disorder, in conditions affecting other parts of the eye, in conditions affecting multiple other parts of the body or secondary to neurological diseases (brain diseases). In recent years, advances in genetic testing methods and increase in genetic testing in healthcare systems have provided a greater understanding of the underlying causes of nystagmus. They have highlighted the bewildering number of genetic causes that can result in what looks like a very similar eye movement disorder.In recent years, new classes of drugs have been developed for some of the causes of nystagmus, and some new drugs have been developed for other conditions which have the potential to work in certain types of nystagmus. For these reasons, genetics has taught us that identifying new possible treatments for nystagmus can either be dependent on identifying the underlying genetic cause and aiming to treat that, or aiming to treat the nystagmus per se by targeting a final common pathway. A toolkit based on specific treatments for specific conditions is more to have meaningful impact on 'nystagmus' than pursuing a panacea based on a 'one size fits all' approach.

Disorders of vision in neonatal hypoxic-ischaemic encephalopathy: a systematic review.

OBJECTIVE: Neonatal hypoxic-ischaemic encephalopathy (HIE) following perinatal asphyxia in term infants is associated with neonatal mortality and a high risk of neurodevelopmental impairment later in life. Visual disorders are an accepted complication of HIE and the association has been cited in the literature many times. This review aims to study the evidence for this association and assess the quality of the data on which this is based. DESIGN: A systematic literature review was conducted and 922 citations were assessed using standard methods outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. RESULTS: The results demonstrate that the majority of studies have reported on various neurodevelopmental outcomes but rarely specifically vision. Based on limited currently available data, extracted from a number of small studies, an association of neonatal HIE with visual impairments seems to exist but detail is lacking. Notably, in the existing studies, there is a striking lack of consistency in the methods used to diagnose HIE and, similarly, a wide variation in the methods employed to measure visual function. CONCLUSIONS: To explore the observed association further in terms of prognosis and the effects of HIE treatments on visual outcomes, future studies will need to address the issues of standardised diagnostic criteria, severity grading and robust, age-appropriate visual assessment.

Characterization of the Frmd7 Knock-Out Mice Generated by the EUCOMM/COMP Repository as a Model for Idiopathic Infantile Nystagmus (IIN).

In this study, we seek to exclude other pathophysiological mechanisms by which Frmd7 knock-down may cause Idiopathic Infantile Nystagmus (IIN) using the Frmd7.tm1a and Frmd7.tm1b murine models. We used a combination of genetic, histological and visual function techniques to characterize the role of Frmd7 gene in IIN using a novel murine model for the disease. We demonstrate that the Frmd7.tm1b allele represents a more robust model of Frmd7 knock-out at the mRNA level. The expression of Frmd7 was investigated using both antibody staining and X-gal staining confirming previous reports that Frmd7 expression in the retina is restricted to starburst amacrine cells and demonstrating that X-gal staining recapitulates the expression pattern in this model. Thus, it offers a useful tool for further expression studies. We also show that gross retinal morphology and electrophysiology are unchanged in these Frmd7 mutant models when compared with wild-type mice. High-speed eye-tracking recordings of Frmd7 mutant mice confirm a specific horizontal optokinetic reflex defect. In summary, our study confirms the likely role for Frmd7 in the optokinetic reflex in mice mediated by starburst amacrine cells. We show that the Frmd7.tm1b model provides a more robust knock-out than the Frmd7.tm1a model at the mRNA level, although the functional consequence is unchanged. Finally, we establish a robust eye-tracking technique in mice that can be used in a variety of future studies using this model and others. Although our data highlight a deficit in the optiokinetic reflex as a result of the starburst amacrine cells in the retina, this does not rule out the involvement of other cells, in the brain or the retina where Frmd7 is expressed, in the pathophysiology of IIN.

Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction.

PURPOSE: Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions. METHODS: We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGUeye) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants. RESULTS: Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease. CONCLUSION: Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants.

A small gene sequencing panel realises a high diagnostic rate in patients with congenital nystagmus following basic phenotyping.

Nystagmus is a disorder of uncontrolled eye movement and can occur as an isolated trait (idiopathic INS, IINS) or as part of multisystem disorders such as albinism, significant visual disorders or neurological disease. Eighty-one unrelated patients with nystagmus underwent routine ocular phenotyping using commonly available phenotyping methods and were grouped into four sub-cohorts according to the level of phenotyping information gained and their findings. DNA was extracted and sequenced using a broad utility next generation sequencing (NGS) gene panel. A clinical subpanel of genes for nystagmus/albinism was utilised and likely causal variants were prioritised according to methods currently employed by clinical diagnostic laboratories. We determine the likely underlying genetic cause for 43.2% of participants with similar yields regardless of prior phenotyping. This study demonstrates that a diagnostic workflow combining basic ocular phenotyping and a clinically available targeted NGS panel, can provide a high diagnostic yield for patients with infantile nystagmus, enabling access to disease specific management at a young age and reducing the need for multiple costly, often invasive tests. By describing diagnostic yield for groups of patients with incomplete phenotyping data, it also permits the subsequent design of 'real-world' diagnostic workflows and illustrates the changing role of genetic testing in modern diagnostic workflows for heterogeneous ophthalmic disorders.