Clinical utility of genetic testing in 201 preschool children with inherited eye disorders.

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.

Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease.

PURPOSE: To assess the clinical usefulness of genetic testing in a pediatric population with inherited retinal disease (IRD). DESIGN: Single-center retrospective case series. PARTICIPANTS: Eighty-five unrelated children with a diagnosis of isolated or syndromic IRD who were referred for clinical genetic testing between January 2014 and July 2016. METHODS: Participants underwent a detailed ophthalmic examination, accompanied by electrodiagnostic testing (EDT) and dysmorphologic assessment where appropriate. Ocular and extraocular features were recorded using Human Phenotype Ontology terms. Subsequently, multigene panel testing (105 or 177 IRD-associated genes) was performed in an accredited diagnostic laboratory, followed by clinical variant interpretation. MAIN OUTCOME MEASURES: Diagnostic yield and clinical usefulness of genetic testing. RESULTS: Overall, 78.8% of patients (n = 67) received a probable molecular diagnosis; 7.5% (n = 5) of these had autosomal dominant disease, 25.4% (n = 17) had X-linked disease, and 67.2% (n = 45) had autosomal recessive disease. In a further 5.9% of patients (n = 5), a single heterozygous ABCA4 variant was identified; all these participants had a spectrum of clinical features consistent with ABCA4 retinopathy. Most participants (84.7%; n = 72) had undergone EDT and 81.9% (n = 59) of these patients received a probable molecular diagnosis. The genes most frequently mutated in the present cohort were CACNA1F and ABCA4, accounting for 14.9% (n = 10) and 11.9% (n = 8) of diagnoses respectively. Notably, in many cases, genetic testing helped to distinguish stationary from progressive IRD subtypes and to establish a precise diagnosis in a timely fashion. CONCLUSIONS: Multigene panel testing pointed to a molecular diagnosis in 84.7% of children with IRD. The diagnostic yield in the study population was significantly higher compared with that in previously reported unselected IRD cohorts. Approaches similar to the one described herein are expected to become a standard component of care in pediatric ophthalmology. We propose the introduction of genetic testing early in the diagnostic pathway in children with clinical and/or electrophysiologic findings, suggestive of IRD.

Tuberculous Orbital Apex Syndrome with Severe Irreversible Visual Loss.

A 16-year-old girl presented with a unilateral red eye, progressive visual loss and diplopia. A detailed clinical assessment with appropriate investigations led to a diagnosis of Orbital Apex Syndrome (OAS) secondary to Tuberculosis (TB). We report this unusual case of TB OAS, which resulted in a poor visual outcome despite appropriate management.

Blepharokeratoconjunctivitis in Cockayne syndrome.

Cockayne syndrome is a multisystemic, autosomal recessive disease resulting from abnormalities of DNA repair. Ocular manifestations are common, particularly congenital cataract and retinal dystrophy. This study describes a previously unreported association of blepharokeratoconjunctivitis (BKC) in Cockayne syndrome. The authors conducted a retrospective case review of patients with Cockayne syndrome between 1997 and 2006. The ocular manifestations were documented. All cases were bilaterally aphakic from congenital cataract surgery. Four cases of BKC with resultant corneal changes were identified. Two other cases of BKC without corneal changes were also noted. There were no cases of corneal ulceration or visually significant scarring. These findings are clinically important because many patients with Cockayne syndrome wear contact lenses for the refractive correction of aphakia with a resultant risk of corneal ulceration.

Presumed early-onset sarcoidosis: a case of devastating ocular inflammation in an infant.

Involvement of the orbit and posterior segment of the eye in early-onset sarcoidosis may necessitate prompt and aggressive immunosuppressive treatment to prevent a poor visual outcome.

Clinical and genetic variability in children with partial albinism.

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.

Novel PEX11B Mutations Extend the Peroxisome Biogenesis Disorder 14B Phenotypic Spectrum and Underscore Congenital Cataract as an Early Feature.

Purpose: Peroxisomes perform complex metabolic and catabolic functions essential for normal growth and development. Mutations in 14 genes cause a spectrum of peroxisomal disease in humans. Most recently, PEX11B was associated with an atypical peroxisome biogenesis disorder (PBD) in a single individual. In this study, we identify further PEX11B cases and delineate associated phenotypes. Methods: Probands from three families underwent next generation sequencing (NGS) for diagnosis of a multisystem developmental disorder. Autozygosity mapping was conducted in one affected sibling pair. ExomeDepth was used to identify copy number variants from NGS data and confirmed by dosage analysis. Biochemical profiling was used to investigate the metabolic signature of the condition. Results: All patients presented with bilateral cataract at birth but the systemic phenotype was variable, including short stature, skeletal abnormalities, and dysmorphism-features not described in the original case. Next generation sequencing identified biallelic loss-of-function mutations in PEX11B as the underlying cause of disease in each case (PEX11B c.235C>T p.(Arg79Ter) homozygous; PEX11B c.136C>T p.(Arg46Ter) homozygous; PEX11B c.595C>T p.(Arg199Ter) heterozygous, PEX11B ex1-3 del heterozygous). Biochemical studies identified very low plasmalogens in one patient, whilst a mildly deranged very long chain fatty acid profile was found in another. Conclusions: Our findings expand the phenotypic spectrum of the condition and underscore congenital cataract as the consistent primary presenting feature. We also find that biochemical measurements of peroxisome function may be disturbed in some cases. Furthermore, diagnosis by NGS is proficient and may circumvent the requirement for an invasive skin biopsy for disease identification from fibroblast cells.

Mucopolysaccharidoses and the eye.

The mucopolysaccharidoses (MPSs) are a group of disorders caused by inherited defects in lysosomal enzymes resulting in widespread intra- and extra-cellular accumulation of glycosaminoglycans. They have been subdivided according to enzyme defect and systemic manifestations and include MPS IH (Hurler), MPS IS (Scheie), MPS IH/S (Hurler/Sheie), MPS II (Hunter), MPS III (Sanfilippo), MPS IV (Morquio), MPS VI (Maroteaux-Lamy), MPS VII (Sly) and MPS IX (Natowicz). The mucopolysaccharidoses have a spectrum of systemic manifestations, including airway and respiratory compromise, skeletal deformities, intellectual and neurological impairment, cardiac abnormalities, and gastrointestinal problems. Ocular manifestations are common in the mucopolysaccharidoses and may result in significant visual impairment. Corneal opacification of varying severity is frequently seen, as well as retinopathy, optic nerve swelling and atrophy, ocular hypertension, and glaucoma. New treatment modalities for the systemic manifestations of the mucopolysaccharidoses include bone marrow transplant and enzyme replacement therapy, and have resulted in an improved prognosis in many cases. This article reviews the systemic and ocular manifestations of the mucopolysaccharidoses, as well as new treatment options, and discusses the ophthalmic management of mucopolysaccharidosis patients.

Accuracy of Intraocular Pressure Measurement With the Icare Tonometer in Children.

PURPOSE: The aim of this study was to evaluate the difference between intraocular pressure (IOP) measurements in children with the Icare tonomer (IT) and applanation (AT), pneumatic (PT), or digital tonometers (TT). DESIGN: A randomized prospective trial of children younger than age 16 attending the pediatric ophthalmology department of Manchester Royal Eye Hospital was conducted. METHODS: Children had IOP measured twice, once with an IT and again with a TT, PT, or AT during the same clinic appointment. RESULTS: Forty-four children (88 eyes) were included, with a mean [range (R)] age of 57 (2-144) months. Twelve eyes had anterior segment pathology (ASP), defined as aniridia, congenital glaucoma, or Peters anomaly. Regardless of the presence or absence of ASP, total mean difference (MD), R, positive bias (PB), and limits of agreement (LOA) between IT and other instruments were as follows: PT: MD = 3.2, R = 0 to 8, PB = 2.9, LOA = -1.0 to 6.9; TT: MD = 2.6, R = 0 to 6, PB = 0.9, LOA = -1.8 to 3.5; and AT: MD = 1.4, R = -3 to 5, PB = 0.6, LOA = -4.2 to 7.3. In eyes with ASP, IT comparisons with PT were as follows: MD = 3.9, R = 0 to 8, PB = 3.9, LOA = -0.9 to 8.8. CONCLUSIONS: In children with ASP, IOP measured with IT is higher than expected when compared with other tonometers, in some cases by up to 8 mm Hg. We found an overestimation of IOP in children using the IT with a positive bias of 4 mm Hg. We propose that the IT overestimates IOP measurements in children compared with standard tonometers. Further work should be carried out on a much larger cohort to establish a suitable correction factor for such children.

Abrogation of HMX1 function causes rare oculoauricular syndrome associated with congenital cataract, anterior segment dysgenesis, and retinal dystrophy.

PURPOSE: To define the phenotypic manifestation, confirm the genetic basis, and delineate the pathogenic mechanisms underlying an oculoauricular syndrome (OAS). METHODS: Two individuals from a consanguineous family underwent comprehensive clinical phenotyping and electrodiagnostic testing (EDT). Genome-wide microarray analysis and Sanger sequencing of the candidate gene were used to identify the likely causal variant. Protein modelling, Western blotting, and dual luciferase assays were used to assess the pathogenic effect of the variant in vitro. RESULTS: Complex developmental ocular abnormalities of congenital cataract, anterior segment dysgenesis, iris coloboma, early-onset retinal dystrophy, and abnormal external ear cartilage presented in the affected family members. Genetic analyses identified a homozygous c.650A>C; p.(Gln217Pro) missense mutation within the highly conserved homeodomain of the H6 family homeobox 1 (HMX1) gene. Protein modelling predicts that the variant may have a detrimental effect on protein folding and/or stability. In vitro analyses were able to demonstrate that the mutation has no effect on protein expression but adversely alters function. CONCLUSIONS: Oculoauricular syndrome is an autosomal recessive condition that has a profound effect on the development of the external ear, anterior segment, and retina, leading to significant visual loss at an early age. This study has delineated the phenotype and confirmed HMX1 as the gene causative of OAS, enabling the description of only the second family with the condition. HMX1 is a key player in ocular development, possibly in both the pathway responsible for lens and retina development, and via the gene network integral to optic fissure closure.

Duration of form deprivation and visual outcome in infants with bilateral congenital cataracts.

PURPOSE: To determine optimal timing for operating on dense bilateral congenital cataracts and to define latent periods for binocular visual deprivation. METHODS: A retrospective review of the records of children that had undergone bilateral lensectomies at our center. Infants with bilateral, dense, visually significant cataracts who had undergone lensectomy within the first year of life from 1992 to 2000 were identified. Children with other ocular anomalies, neurological and systemic disorders, intraocular lenses, or with fewer than 5 years of follow-up were excluded. RESULTS: A total of 13 children were identified. The mean age at surgery was 8.7 weeks (range, 3-20; SD 5.3). The mean interval between surgeries of the 2 eyes was 3.8 days (range 0-7; SD 3.2). The median final visual acuity at 5 years of age was 6/18 (range, 6/5-6/36). There was a moderate correlation between (log) visual outcome and time to surgery (r = -0.59, p = 0.002, r(2) = 0.35). CONCLUSIONS: Visual acuity after surgery for bilateral congenital cataracts appears to decline exponentially with duration of visual deprivation.