Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study.

PURPOSE: To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). DESIGN: Multicenter, observational study. PARTICIPANTS: A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384). METHODS: Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans. MAIN OUTCOME MEASURES: Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA). RESULTS: The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH. CONCLUSIONS: We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.

Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles.

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.

Discordant phenotypes in twins with infantile nystagmus.

Infantile nystagmus (IN) may result from aetiologies including albinism and FRMD7 mutations. IN has low prevalence, and twins with IN are rare. Whilst discordant presentation has been previously reported for IN, we present for the first time the comprehensive assessment of diagnostically discordant monozygotic twins. From a cohort of over 2000 patients, we identified twins and triplets discordant for nystagmus. Using next-generation sequencing, high-resolution infra-red pupil tracking and optical coherence tomography, we characterised differences in genotype and phenotype. Monozygotic twins (n = 1), dizygotic twins (n = 3) and triplets (n = 1) were included. The monozygotic twins had concordant TYR variants. No causative variants were identified in the triplets. Dizygotic twins had discordant variants in TYR, OCA2 and FRMD7. One unaffected co-twin demonstrated sub-clinical nystagmus. Foveal hypoplasia (FH) was noted in four of five probands. Both co-twins of the monozygotic pair and triplets displayed FH. In three families, at least one parent had FH without nystagmus. FH alone may be insufficient to develop nystagmus. Whilst arrested optokinetic reflex pathway development is implicated in IN, discordant twins raise questions regarding where differences in development have arisen. In unaffected monozygotes therefore, genetic variants may predispose to oculomotor instability, with variable expressivity possibly responsible for the discordance observed.

Current and emerging treatments for albinism.

Albinism is a group of rare inherited disorders arising from impairment of melanin biosynthesis. The reduction of melanin synthesis leads to hypopigmentation of the skin and eyes. A wide range of ophthalmic manifestations arise from albinism, including reduction of visual acuity, nystagmus, strabismus, iris translucency, foveal hypoplasia, fundus hypopigmentation, and abnormal decussation of retinal ganglion cell axons at the optic chiasm. Currently, albinism is incurable, and treatment aims either surgically or pharmacologically to optimize vision and protect the skin; however, novel therapies that aim to directly address the molecular errors of albinism, such as l-dihydroxyphenylalanine and nitisinone, are being developed and have entered human trials though with limited success. Experimental gene-based strategies for editing the genetic errors in albinism have also met early success in animal models. The emergence of these new therapeutic modalities represents a new era in the management of albinism. We focus on the known genetic subtypes, clinical assessment, and existing and emerging therapeutic options for the nonsyndromic forms of albinism.

Recurrent Rare Copy Number Variants Increase Risk for Esotropia.

Purpose: To determine whether rare copy number variants (CNVs) increase risk for comitant esotropia. Methods: CNVs were identified in 1614 Caucasian individuals with comitant esotropia and 3922 Caucasian controls from Illumina SNP genotyping using two Hidden Markov model (HMM) algorithms, PennCNV and QuantiSNP, which call CNVs based on logR ratio and B allele frequency. Deletions and duplications greater than 10 kb were included. Common CNVs were excluded. Association testing was performed with 1 million permutations in PLINK. Significant CNVs were confirmed with digital droplet polymerase chain reaction (ddPCR). Whole genome sequencing was performed to determine insertion location and breakpoints. Results: Esotropia patients have similar rates and proportions of CNVs compared with controls but greater total length and average size of both deletions and duplications. Three recurrent rare duplications significantly (P = 1 × 10-6) increase the risk of esotropia: chromosome 2p11.2 (hg19, 2:87428677-87965359), spanning one long noncoding RNA (lncRNA) and two microRNAs (OR 14.16; 95% confidence interval [CI] 5.4-38.1); chromosome 4p15.2 (hg19, 4:25554332-25577184), spanning one lncRNA (OR 11.1; 95% CI 4.6-25.2); chromosome 10q11.22 (hg19, 10:47049547-47703870) spanning seven protein-coding genes, one lncRNA, and four pseudogenes (OR 8.96; 95% CI 5.4-14.9). Overall, 114 cases (7%) and only 28 controls (0.7%) had one of the three rare duplications. No case nor control had more than one of these three duplications. Conclusions: Rare CNVs are a source of genetic variation that contribute to the genetic risk for comitant esotropia, which is likely polygenic. Future research into the functional consequences of these recurrent duplications may shed light on the pathophysiology of esotropia.

SLC38A8 mutations result in arrested retinal development with loss of cone photoreceptor specialization.

Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this multi-centre study, a custom-targeted next generation sequencing (NGS) gene panel was used to identify SLC38A8 mutations from a cohort of 511 nystagmus patients. We report 16 novel SLC38A8 mutations. The sixth transmembrane domain is most frequently disrupted by missense SLC38A8 mutations. Ninety percent of our cases were initially misdiagnosed as PAX6-related phenotype or ocular albinism prior to NGS. We characterized the retinal development in vivo in patients with SLC38A8 mutations using high-resolution optical coherence tomography. All patients had severe grades of arrested retinal development with lack of a foveal pit and no cone photoreceptor outer segment lengthening. Loss of foveal specialization features such as outer segment lengthening implies reduced foveal cone density, which contributes to reduced visual acuity. Unlike other disorders (such as albinism or PAX6 mutations) which exhibit a spectrum of foveal hypoplasia, SLC38A8 mutations have arrest of retinal development at an earlier stage resulting in a more under-developed retina and severe phenotype.

Congenital monocular elevation deficiency associated with a novel TUBB3 gene variant.

BACKGROUND: The genetic basis of monocular elevation deficiency (MED) is unclear. It has previously been considered to arise due to a supranuclear abnormality. METHODS: Two brothers with MED were referred to Leicester Royal Infirmary, UK from the local opticians. Their father had bilateral ptosis and was unable to elevate both eyes, consistent with the diagnosis of congenital fibrosis of extraocular muscles (CFEOM). Candidate sequencing was performed in all family members. RESULTS: Both affected siblings (aged 7 and 12 years) were unable to elevate the right eye. Their father had bilateral ptosis, left esotropia and bilateral limitation of elevation. Chin up head posture was present in the older sibling and the father. Bell's phenomenon and vertical rotational vestibulo-ocular reflex were absent in the right eye for both children. Mild bilateral facial nerve palsy was present in the older sibling and the father. Both siblings had slight difficulty with tandem gait. MRI revealed hypoplastic oculomotor nerve. Left anterior insular focal cortical dysplasia was seen in the older sibling. Sequencing of TUBB3 revealed a novel heterozygous variant (c.1263G>C, p.E421D) segregating with the phenotype. This residue is in the C-terminal H12 α-helix of ß-tubulin and is one of three putative kinesin binding sites. CONCLUSION: We show that familial MED can arise from a TUBB3 variant and could be considered a limited form of CFEOM. Neurological features such as mild facial palsy and cortical malformations can be present in patients with MED. Thus, in individuals with congenital MED, consideration may be made for TUBB3 mutation screening.

Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus.

Herein we present a consanguineous family with three children affected by foveal hypoplasia with infantile nystagmus, following an autosomal recessive mode of inheritance. The patients showed normal electroretinography responses, no signs of albinism, and no anterior segment or brain abnormalities. Upon whole exome sequencing, we identified a homozygous mutation (c.1861C>T;p.Q621*) in the aryl hydrocarbon receptor (AHR) gene that perfectly co-segregated with the disease in the larger family. AHR is a ligand-activated transcription factor that has been intensively studied in xenobiotic-induced toxicity. Further, it has been shown to play a physiological role under normal cellular conditions, such as in immunity, inflammatory response and neurogenesis. Notably, knockout of the Ahr gene in mouse impairs optic nerve myelin sheath formation and results in oculomotor deficits sharing many features with our patients: the eye movement disorder in Ahr-/- mice appears early in development and presents as conjugate horizontal pendular nystagmus. We therefore propose AHR to be a novel disease gene for a new, recessively inherited disorder in humans, characterized by infantile nystagmus and foveal hypoplasia.

Genome-Wide Association Study Identifies a Susceptibility Locus for Comitant Esotropia and Suggests a Parent-of-Origin Effect.

Purpose: To identify genetic variants conferring susceptibility to esotropia. Esotropia is the most common form of comitant strabismus, has its highest incidence in European ancestry populations, and is believed to be inherited as a complex trait. Methods: White European American discovery cohorts with nonaccommodative (826 cases and 2991 controls) or accommodative (224 cases and 749 controls) esotropia were investigated. White European Australian and United Kingdom cohorts with nonaccommodative (689 cases and 1448 controls) or accommodative (66 cases and 264 controls) esotropia were tested for replication. We performed a genome-wide case-control association study using a mixed linear additive model. Meta-analyses of discovery and replication cohorts were then conducted. Results: A significant association with nonaccommodative esotropia was discovered (odds ratio [OR] = 1.41, P = 2.84 × 10-09) and replicated (OR = 1.23, P = 0.01) at rs2244352 [T] located within intron 1 of the WRB (tryptophan rich basic protein) gene on chromosome 21 (meta-analysis OR = 1.33, P = 9.58 × 10-11). This single nucleotide polymorphism (SNP) is differentially methylated, and there is a statistically significant skew toward paternal inheritance in the discovery cohort. Meta-analysis of the accommodative discovery and replication cohorts identified an association with rs912759 [T] (OR = 0.59, P = 1.89 × 10-08), an intergenic SNP on chromosome 1p31.1. Conclusions: This is the first genome-wide association study (GWAS) to identify significant associations in esotropia and suggests a parent-of-origin effect. Additional cohorts will permit replication and extension of these findings. Future studies of rs2244352 and WRB should provide insight into pathophysiological mechanisms underlying comitant strabismus.

The Effects of Feedback on Adherence to Treatment: A Systematic Review and Meta-analysis of RCTs.

CONTEXT: The aim of this systematic review is to determine whether providing feedback, guided by subjective or objective measures of adherence, improves adherence to treatment. EVIDENCE ACQUISITION: Data sources included MEDLINE, Embase, CINAHL, and PsycINFO, and reference lists of retrieved articles. Only RCTs comparing the effect of feedback on adherence outcome were included. Three independent reviewers extracted data for all potentially eligible studies using an adaptation of the Cochrane Library data extraction sheet. The primary outcome, change in adherence, was obtained by measuring the difference between adherence at baseline visit (prior to feedback) and at the last visit (post-feedback). EVIDENCE SYNTHESIS: Twenty-four studies were included in the systematic review, and 16 found a significant improvement in adherence in the intervention group (change in adherence range, -13% to +22%), whereas adherence worsened in the control group (change in adherence range, -32% to 10.2%). Meta-analysis included six studies, and the pooled effect showed that mean percentage adherence increased by 10.02% (95% CI=3.15%, 16.89%, p=0.004) more between baseline and follow-up in the intervention groups compared with control groups. Meta-regression confirmed that study quality, form of monitoring adherence, delivery of feedback, or study duration did not influence effect size. CONCLUSIONS: Feedback guided by objective or subjective measures of adherence improves adherence and, perhaps more importantly, prevents worsening of adherence over time even when only small absolute improvements in adherence were noted. Increased use of feedback to improve treatment adherence has the potential to reduce avoidable healthcare costs caused by non-adherence.

Association Between Adherence to Glasses Wearing During Amblyopia Treatment and Improvement in Visual Acuity.

IMPORTANCE: Occlusion dose monitors have helped establish that better adherence to occlusion is associated with improved visual outcomes in patients undergoing amblyopia treatment. However, the role of adherence to glasses wearing is unknown. OBJECTIVES: To establish the feasibility and reliability of objectively monitoring adherence to glasses wearing using age-based norms, establish the association between adherence to glasses wearing and improvement in visual acuity (VA) after optical treatment and occlusion therapy, and analyze the effect of age, sex, refractive errors, type of amblyopia, and adherence to glasses wearing on improvement in VA. DESIGN, SETTING, AND PARTICIPANTS: A prospective, observational, nonmasked, cohort study was conducted between June 8, 2008, and June 30, 2013, among patients at a pediatric ophthalmology clinic of a tertiary care hospital who were newly diagnosed with anisometropic and/or strabismic amblyopia and had not undergone previous treatment. The study consisted of a glasses phase (18 weeks) and a patching phase (glasses and occlusion for 10 hours per day for 12 weeks). Reliability of the glasses monitors was assessed by comparing diary entries and monitor recordings in adults. INTERVENTIONS: Objective monitoring of glasses wearing and occlusion. MAIN OUTCOMES AND MEASURES: Adherence to glasses wearing (hours per day) and effect on VA. RESULTS: Among 20 children with anisometropia (mean [SD] age, 6.20 [2.16] years; 11 boys and 9 girls) and 20 with strabismic or mixed amblyopia (mean [SD] age, 4.90 [1.36] years; 10 boys and 10 girls), adherence to glasses wearing was successfully monitored in all but 1 patient. Agreement between diaries and monitored times wearing glasses in adults was high (intraclass correlation coefficient, 1.00; 95% CI, 0.999-1.00). Median (SD) adherence to glasses wearing was 70% (25.3%). A moderate correlation was observed between adherence to glasses wearing and percentage improvement in VA during the glasses phase (r = 0.462; P = .003). Multiple regression revealed that age (ß = -0.535; P = .001), type of amblyopia (ß = -0.347; P = .02), and adherence to glasses wearing (ß = 0.287; P = .04) were independently associated with improvement in VA after the glasses phase and explained 42% of the variability (F3,35 = 8.457; P < .001). A strong correlation between glasses wearing and occlusion adherence was observed (r = 0.719; P < .001). CONCLUSIONS AND RELEVANCE: The results suggest that adherence to glasses wearing is less than optimal and highly variable but is important in achieving good VA. This study emphasizes the importance of encouraging children to not only have good adherence to occlusion therapy but also to glasses wearing.

In Vivo Morphology of the Optic Nerve and Retina in Patients With Parkinson's Disease.

PURPOSE: To investigate optic nerve (ON) and macular morphology in patients with Parkinson's disease (PD) using spectral-domain optical coherence tomography (SD-OCT). SUBJECTS: Twenty-five participants with PD (19 males and 6 females; mean age 60.79; SD ± 9.24) and 25 sex-, age-, ethnicity-, and refraction-matched healthy controls. METHODS: A high-resolution SD-OCT device was used to acquire scans in 25 participants with PD (mean age 60.79; ± SD 9.24) and 25 sex-, age-, ethnicity-, and refraction-matched healthy controls. Main outcome measures included optic nerve head parameters (disc/cup diameters/areas, cup/rim volumes, cup depth, cup/disc ratio; peripapillary retinal nerve fiber layer [ppRNFL] thickness), retinal thickness (in inner and outer annuli around the foveal center) and thickness of individual retinal layers. RESULTS: Our study showed significant ppRNFL thinning in PD patients in all quadrants (P < 0.05) associated with a shallower optic cup (P = 0.03) as compared with controls. Foveal remodelling with retinal thinning (nasal and temporal segments in both annuli; and superior segment in outer annulus; P < 0.05), foveal pit widening (P = 0.05), central outer plexiform layer (OPL) thickening (P < 0.001), and nasal RPE thinning (P < 0.001) was also found in PD. The differences were more obvious in hemiretinae related to the predominantly affected cerebral hemisphere. Changes were more pronounced in advanced stages and longer PD duration. CONCLUSIONS: Optic nerve changes in PD are likely to be caused by primary neurodegeneration. Central retinal thinning, pit widening, central OPL thickening, and RPE thinning indicate foveal remodelling. Specific changes of the fovea and thinning of individual retinal layers, correlating with disease severity and duration, indicate that ON and retinal changes have potential to be used as biomarkers for PD.

The Development of a Nystagmus-Specific Quality-of-Life Questionnaire.

PURPOSE: To develop a nystagmus-specific quality-of-life (QOL) questionnaire derived from patient concerns based on eudaimonic aspects of well-being. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 206 participants with nystagmus for factor analysis phase and an additional 42 participants with nystagmus for construct validity phase. METHODS: Questionnaire items were written on the basis of the 6 domains of everyday living affected by nystagmus that were elicited by previous semistructured interviews conducted with 21 people with nystagmus. After consultation with 8 nystagmus experts, 37 items were administered to 206 people with nystagmus. Factor analysis was used to identify latent factors among the items and identify items to propose new nystagmus QOL scales. Cronbach's alpha was used to assess the internal reliability of the new scales. To assess for discriminate and concurrent validity between the new nystagmus scales and an existing vision-related QOL tool, the Visual Function Questionnaire-25 (VFQ-25) was administered to 42 additional participants. MAIN OUTCOME MEASURES: Questionnaire response scores on nystagmus-specific QOL items. RESULTS: The factor analysis revealed the retention of 29 items to form a measure comprising 2 distinct subscales reflecting "personal and social" and "physical and environmental" functioning as relating to nystagmus-specific QOL. The Cronbach's alpha coefficients for the "personal and social" functioning scale and "physical and environmental" functioning were 0.95 and 0.93, respectively. Tests for validity of the measure, consistent with a priori predictions, when compared with the VFQ-25, revealed the "physical and environmental" subscale showed concurrent validity (0.88), whereas the "personal and social" subscale was demonstrated to have discriminative validity (0.81). CONCLUSIONS: We have developed a 29-item, nystagmus-specific QOL questionnaire (NYS-29) based on eudaimonic aspects of well-being with subscales that address not only physical functioning but also psycho-social issues. The NYS-29 is grounded in the perspectives and concerns of those who have nystagmus and can be used to determine the impact of nystagmus on daily living in terms of both physical and psychosocial aspects.

The challenges of amblyopia treatment.

The treatment of amblyopia, particularly anisometropic (difference in refractive correction) and/or strabismic (turn of one eye) amblyopia has long been a challenge for many clinicians. Achieving optimum outcomes, where the amblyopic eye reaches a visual acuity similar to the fellow eye, is often impossible in many patients. Part of this challenge has resulted from a previous lack of scientific evidence for amblyopia treatment that was highlight by a systematic review by Snowdon et al. in 1998. Since this review, a number of publications have revealed new findings in the treatment of amblyopia. This includes the finding that less intensive occlusion treatments can be successful in treating amblyopia. A relationship between adherence to treatment and visual acuity has also been established and has been shown to be influenced by the use of intervention material. In addition, there is growing evidence of that a period of glasses wearing only can significantly improve visual acuity alone without any other modes of treatment. This review article reports findings since the Snowdon's report.

Risk factors and genetics in common comitant strabismus: a systematic review of the literature.

IMPORTANCE: Understanding the development of common strabismus is important in locating "at-risk" populations and implementing optimal treatment. This systematic review will bring together reported genetic and environmental risk factors for common strabismus to reveal relationships between risk factors and guide future research. OBJECTIVE: To identify known environmental and genetic risk factors for comitant strabismus reported in the literature. DATA SOURCES: A systematic literature search was performed in Medline, Embase, BioSciences Information Service Previews, Web of Science, and the OMIM database during a 2-week period in July 2011 (including all available years) using the following key words: gene, genetic environmental factor, inheritance, risk factor, esotropia, exotropia, strabismus, squint, convergent strabismus, and divergent strabismus. STUDY SELECTION: No language restrictions were placed on the search. Exclusion criteria consisted of associated syndromes, strabismus not the primary outcome, poor study design or quality, and logarithm of the odds score less than 3. DATA EXTRACTION AND SYNTHESIS: A study quality and extraction tool was used. Analysis was performed descriptively because of the variant characteristics of the study designs. MAIN OUTCOMES AND MEASURES: Risk factor, twin, pedigree, and genetic studies. RESULTS: Forty-one articles fulfilled the inclusion criteria set out by the study, which highlighted 4 subcategories: risk factor, twin, pedigree, and genetic studies. Significant risk factors for strabismus reported by the studies included low birth weight, cicatricial retinopathy of prematurity, prematurity, smoking throughout pregnancy, anisometropia, hyperopia, and inheritance. Inheritance was further supported by twin and pedigree studies, which revealed the complexity of the inheritance pattern. At present the STBMS1 locus is the only gene location that has been supported; however, others have been reported. CONCLUSIONS AND RELEVANCE: Certain subgroups within the population are at higher risk of developing comitant strabismus and should be identified and monitored to allow for earlier detection. It is evident that a strong hereditary link is present particularly in intermittent and accommodative forms; however, further research is required to identify possible links between subtypes of strabismus. Further genetic research could also help to locate additional causative genes to aid the understanding of strabismus development.

Diagnostic potential of iris cross-sectional imaging in albinism using optical coherence tomography.

PURPOSE: To characterize in vivo anatomic abnormalities of the iris in albinism compared with healthy controls using anterior segment optical coherence tomography (AS-OCT) and to explore the diagnostic potential of this technique for albinism. We also investigated the relationship between iris abnormalities and other phenotypical features of albinism. DESIGN: Prospective cross-sectional study. PARTICIPANTS: A total of 55 individuals with albinism and 45 healthy controls. METHODS: We acquired 4.37×4.37-mm volumetric scans (743 A-scans, 50 B-scans) of the nasal and temporal iris in both eyes using AS-OCT (3-µm axial resolution). Iris layers were segmented and thicknesses were measured using ImageJ software. Iris transillumination grading was graded using Summers and colleagues' classification. Retinal OCT, eye movement recordings, best-corrected visual acuity (BCVA), visual evoked potential (VEP), and grading of skin and hair pigmentation were used to quantify other phenotypical features associated with albinism. MAIN OUTCOME MEASURES: Iris AS-OCT measurements included (1) total iris thickness, (2) stroma/anterior border (SAB) layer thickness, and (3) posterior epithelial layer (PEL) thickness. Correlation with other phenotypical measurements, including (1) iris transillumination grading, (2) retinal layer measurements at the fovea, (3) nystagmus intensity, (4) BCVA, (5) VEP asymmetry, (6) skin pigmentation, and (7) hair pigmentation (of head hair, lashes, and brows). RESULTS: The mean iris thickness was 10.7% thicker in controls (379.3 ± 44.0 µm) compared with the albinism group (342.5 ± 52.6 µm; P>0.001), SAB layers were 5.8% thicker in controls (315.1 ± 43.8 µm) compared with the albinism group (297.7 ± 50.0 µm; P=0.044), and PEL was 44.0% thicker in controls (64.1 ± 11.7 µm) compared with the albinism group (44.5 ± 13.9 µm; P<0.0001). The most ciliary quartile of the PEL yielded a sensitivity of 85% and specificity of 78% for detecting albinism. Phenotypic features of albinism, such as skin and hair pigmentation, BCVA, and nystagmus intensity, were significantly correlated to AS-OCT iris thickness measurements. CONCLUSIONS: We have characterized in vivo abnormalities of the iris associated with albinism for the first time and show that PEL thickness is particularly affected. We demonstrate that PEL thickness has diagnostic potential for detecting iris abnormalities in albinism. Anterior segment OCT iris measurements are significantly correlated to BCVA and nystagmus intensity in contrast to iris transillumination grading measurements that were not. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.