Retinal Dystrophies Associated With Peripherin-2: Genetic Spectrum and Novel Clinical Observations in 241 Patients.

Purpose: To describe the clinical, electrophysiological and genetic spectrum of inherited retinal diseases associated with variants in the PRPH2 gene. Methods: A total of 241 patients from 168 families across 15 sites in 9 countries with pathogenic or likely pathogenic variants in PRPH2 were included. Records were reviewed for age at symptom onset, visual acuity, full-field ERG, fundus colour photography, fundus autofluorescence (FAF), and SD-OCT. Images were graded into six phenotypes. Statistical analyses were performed to determine genotype-phenotype correlations. Results: The median age at symptom onset was 40 years (range, 4-78 years). FAF phenotypes included normal (5%), butterfly pattern dystrophy, or vitelliform macular dystrophy (11%), central areolar choroidal dystrophy (28%), pseudo-Stargardt pattern dystrophy (41%), and retinitis pigmentosa (25%). Symptom onset was earlier in retinitis pigmentosa as compared with pseudo-Stargardt pattern dystrophy (34 vs 44 years; P = 0.004). The median visual acuity was 0.18 logMAR (interquartile range, 0-0.54 logMAR) and 0.18 logMAR (interquartile range 0-0.42 logMAR) in the right and left eyes, respectively. ERG showed a significantly reduced amplitude across all components (P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and single-flash b-wave (P < 0.001). Twenty-two variants were novel. The central areolar choroidal dystrophy phenotype was associated with 13 missense variants. The remaining variants showed marked phenotypic variability. Conclusions: We described six distinct FAF phenotypes associated with variants in the PRPH2 gene. One FAF phenotype may have multiple ERG phenotypes, demonstrating a discordance between structure and function. Given the vast spectrum of PRPH2 disease our findings are useful for future clinical trials.

Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.

Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes.

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing-a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

Analysis of the Outer Retinal Bands in ABCA4 and PRPH2-Associated Retinopathy using OCT.

PURPOSE: To evaluate the outer retinal bands using OCT in ABCA4- and PRPH2-associated retinopathy and develop a novel imaging biomarker to differentiate between these 2 genotypes. DESIGN: Multicenter case-control study. PARTICIPANTS: Patients with a clinical and genetic diagnosis of ABCA4- or PRPH2-associated retinopathy and an age-matched control group. METHODS: Macular OCT was used to measure the thickness of the outer retinal bands 2 and 4 by 2 independent examiners at 4 retinal loci. MAIN OUTCOME MEASURES: Outcome measures included the thicknesses of band 2, band 4, and the band 2/band 4 ratio. Linear mixed modeling was used to make comparisons across the 3 groups. Receiver operating characteristic (ROC) analysis determined the optimal cutoff for the band 2/band 4 ratio to distinguish PRPH2- from ABCA4-associated retinopathy. RESULTS: We included 45 patients with ABCA4 variants, 45 patients with PRPH2 variants, and 45 healthy controls. Band 2 was significantly thicker in patients with PRPH2 compared with ABCA4 (21.4 vs. 15.9 µm, P < 0.001) variants, whereas band 4 was thicker in patients with ABCA4 variants than those with PRPH2 variants (27.5 vs. 21.7 µm, P < 0.001). Similarly, the band 2/band 4 ratio was significantly different (1.0 vs. 0.6 for PRPH2 vs. ABCA4, P < 0.001). The area under the ROC curve was 0.87 for either band 2 (> 18.58 µm) or band 4 (< 26.17 µm) alone and 0.99 (95% confidence interval: 0.97-0.99) for the band 2/band 4 ratio with a cutoff threshold of 0.79, providing 100% specificity. CONCLUSIONS: We report an altered outer retinal band profile whereby the band 2/band 4 ratio was able to discriminate between PRPH2- and ABCA4-associated retinopathy. This may have future clinic utility in predicting the genotype and provide further insight into the anatomic correlate of band 2. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Mitochondrial disease in New Zealand: a nationwide prevalence study.

BACKGROUND: The complexities of mitochondrial disease make epidemiological studies challenging, yet this information is important in understanding the healthcare burden and addressing service and educational needs. Existing studies are limited to quaternary centres or focus on a single genotype or phenotype and estimate disease prevalence at 12.5 per 100 000. New Zealand's (NZ) size and partially integrated national healthcare system make it amenable to a nationwide prevalence study. AIM: To estimate the prevalence of molecularly confirmed and suspected mitochondrial disease on 31 December 2015 in NZ. METHODS: Cases were identified from subspecialists and laboratory databases and through interrogation of the Ministry of Health National Minimum Dataset with a focus on presentations between 2000 and 2015. Patient records were reviewed, and those with a diagnosis of 'mitochondrial disease' who were alive and residing in NZ on the prevalence date were included. These were divided into molecularly confirmed and clinically suspected cases. Official NZ estimated resident population data were used to calculate prevalence. RESULTS: Seven hundred twenty-three unique national health index numbers were identified. Five hundred five were excluded. The minimum combined prevalence for mitochondrial disease was 4.7 per 100 000 (95% confidence interval (CI): 4.1-5.4). The minimum prevalence for molecularly confirmed and suspected disease was 2.9 (95% CI 2.4-3.4) and 1.8 (95% CI 1.4-2.2) cases per 100 000 respectively. CONCLUSIONS: Within the limitations of this study, comparison to similar prevalence studies performed by specialist referral centres suggests mitochondrial disease is underdiagnosed in NZ. This highlights a need for improved education and referral pathways for mitochondrial disease in NZ.

Genetic testing and gene therapy in retinal diseases: Knowledge and perceptions of optometrists in Australia and New Zealand.

With advances in gene-based therapies for heritable retinal diseases, primary eye care clinicians should be informed on ocular genetics topics. This cross-sectional survey evaluated knowledge, attitudes, and concerns regarding genetic testing and gene therapy for retinal diseases among optometrists in Australia and New Zealand. Survey data included practitioner background, attitudes and practices towards genetic testing for monogenic inherited retinal disease (IRDs) and age-related macular degeneration, and knowledge of ocular genetics and gene therapy. Responses were received from 516 optometrists between 1 April and 31 December 2022. Key perceived barriers to accessing genetic testing were lack of clarity on referral pathways (81%), cost (65%), and lack of treatment options if a genetic cause is identified (50%). Almost all respondents (98%) believed that ophthalmologists should initiate genetic testing for IRDs and fewer understood the role of genetic counsellors and clinical geneticists. This study found that optometrists in Australia and New Zealand have a high level of interest in ocular genetics topics. However, knowledge gaps include referral pathways and awareness of genetic testing and gene therapy outcomes. Addressing perceived barriers to access and promoting sharing of knowledge between interdisciplinary networks can set the foundation for genetic education agendas in primary eye care.

Use of public sector diabetes eye services in New Zealand 2006-2019: Analysis of national routinely collected datasets.

OBJECTIVE: To assess diabetes eye service use in New Zealand among people aged ≥15 years by estimating service attendance, biennial screening rate, and disparities in the use of screening and treatment services. METHODS: We obtained Ministry of Health data from the National Non-Admitted Patient Collection on diabetes eye service events between 1 July 2006 and 31 December 2019 and sociodemographic and mortality data from the Virtual Diabetes Register and linked these using a unique patient identifier (encrypted National Health Index). We 1) summarized attendance at retinal screening and ophthalmology services, 2) calculated biennial and triennial screening rate, 3) summarized treatment with laser and anti-VEGF and used log-binomial regression to examine associations of all of these with age group, ethnicity, and area-level deprivation. RESULTS: In total, 245,844 people aged ≥15 years had at least one diabetes eye service appointment attended or scheduled; half of these (n = 125,821, 51.2%) attended only retinal screening, one-sixth attended only ophthalmology (n = 35,883, 14.6%) and one-third attended both (n = 78,300, 31.8%). The biennial retinal screening rate was 62.1%, with large regional variation (73.9% in Southern District to 29.2% in West Coast). Compared with NZ Europeans, Maori were approximately twice as likely to never receive diabetes eye care or to access ophthalmology when referred from retinal screening, 9% relatively less likely to receive biennial screening and received the fewest anti-VEGF injections when treatment was commenced. Disparities in service access were also present for Pacific Peoples compared to NZ Europeans, younger and older age groups compared to those aged 50-59 years and those living in areas with higher deprivation. CONCLUSIONS: Access to diabetes eye care is suboptimal, with substantial disparity between age groups, ethnicity groups, area level deprivation quintile and across districts. Efforts to improve access to and quality of diabetes eye care services must include strengthening data collection and monitoring.

Genotypic and phenotypic characterisation of RP2- and RPGR-associated X-linked inherited retinal dystrophy, including female manifestations.

BACKGROUND: With the promise of gene replacement therapy, eligible males and females with X-linked inherited retinal dystrophy (XL-IRD) should be identified. METHODS: Retrospective observational cohort study to establish the phenotypic and genotypic spectrum of XL-IRD within New Zealand (NZ). Thirty-two probands, including 9 females, with molecularly proven XL-IRD due to RP2 or RPGR mutations, and 72 family members, of which 43 were affected, were identified from the NZ IRD Database. Comprehensive ophthalmic phenotyping, familial cosegregation, genotyping, and bioinformatics were undertaken. Main outcome measures were: RP2 and RPGR pathogenic variant spectrum, phenotype in males and females (symptoms, age of onset, visual acuity, refraction, electrophysiology, autofluorescence, retinal appearance), and genotype-phenotype correlation. RESULTS: For 32 families, 26 unique pathogenic variants were identified; in RP2 (n = 6, 21.9% of all families), RPGR exons 1-14 (n = 10, 43.75%), and RPGR-ORF15 (n = 10, 34.3%). Three RP2 and 8 RPGR exons 1-14 variants are novel, rare, and cosegregate. Thirty-one percent of carrier females were significantly affected, with 18.5% of families initially classified as autosomal dominant. Of five Polynesian families, 80% had novel disease-causing variants. One Maori family showed keratoconus segregating with an ORF15 variant. CONCLUSIONS: Significant disease was present in 31% of genetically proven female carriers, often leading to an erroneous presumption of the inheritance pattern. Pathogenic variants in 44% of the families were in exon 1-14 of RPGR, more frequent than usually described, which may inform the gene testing algorithm. Proving cosegregation in families for novel variants and identifying affected females and males translates to optimised clinical care and potential for gene therapy.

Harboyan syndrome with biallelic SLC4A11 pathogenic variants misdiagnosed as congenital CMV infection.

Harboyan syndrome is a rare autosomal recessive disorder characterised by congenital hereditary endothelial dystrophy (CHED), with a later onset of sensorineural hearing loss, due to pathogenic variants in the SLC4A11 gene. Congenital cytomegalovirus (CMV) may also manifest with sensorineural hearing loss and visual impairment. We present a case of a 4-year-old girl, diagnosed at birth with a congenital CMV infection, but careful phenotyping and genetic testing permitted a more likely diagnosis of Harboyan syndrome.

The landscape of submicroscopic structural variants at the OPN1LW/OPN1MW gene cluster on Xq28 underlying blue cone monochromacy.

Blue cone monochromacy (BCM) is an X-linked retinal disorder characterized by low vision, photoaversion, and poor color discrimination. BCM is due to the lack of long-wavelength-sensitive and middle-wavelength-sensitive cone photoreceptor function and caused by mutations in the OPN1LW/OPN1MW gene cluster on Xq28. Here, we investigated the prevalence and the landscape of submicroscopic structural variants (SVs) at single-base resolution in BCM patients. We found that about one-third (n = 73) of the 213 molecularly confirmed BCM families carry an SV, most commonly deletions restricted to the OPN1LW/OPN1MW gene cluster. The structure and precise breakpoints of the SVs were resolved in all but one of the 73 families. Twenty-two families-all from the United States-showed the same SV, and we confirmed a common ancestry of this mutation. In total, 42 distinct SVs were identified, including 40 previously unreported SVs, thereby quadrupling the number of precisely mapped SVs underlying BCM. Notably, there was no "region of overlap" among these SVs. However, 90% of SVs encompass the upstream locus control region, an essential enhancer element. Its minimal functional extent based on deletion mapping in patients was refined to 358 bp. Breakpoint analyses suggest diverse mechanisms underlying SV formation as well as in one case the gene conversion-based exchange of a 142-bp deletion between opsin genes. Using parsimonious assumptions, we reconstructed the composition and copy number of the OPN1LW/OPN1MW gene cluster prior to the mutation event and found evidence that large gene arrays may be predisposed to the occurrence of SVs at this locus.

Novel disease-causing variants and phenotypic features of X-linked megalocornea.

PURPOSE: The aim of the study was to describe the phenotype and molecular genetic causes of X-linked megalocornea (MGC1). We recruited four British, one New Zealand, one Vietnamese and four Czech families. METHODS: All probands and three female carriers underwent ocular examination and Sanger sequencing of the CHRDL1 gene. Two of the probands also had magnetic resonance imaging (MRI) of the brain. RESULTS: We identified nine pathogenic or likely pathogenic and one variant of uncertain significance in CHRDL1, of which eight are novel. Three probands had ocular findings that have not previously been associated with MGC1, namely pigmentary glaucoma, unilateral posterior corneal vesicles, unilateral keratoconus and unilateral Fuchs heterochromic iridocyclitis. The corneal diameters of the three heterozygous carriers were normal, but two had abnormally thin corneas, and one of these was also diagnosed with unilateral keratoconus. Brain MRI identified arachnoid cysts in both probands, one also had a neuroepithelial cyst, while the second had a midsagittal neurodevelopmental abnormality (cavum septum pellucidum et vergae). CONCLUSION: The study expands the spectrum of pathogenic variants and the ocular and brain abnormalities that have been identified in individuals with MGC1. Reduced corneal thickness may represent a mild phenotypic feature in some heterozygous female carriers of CHRDL1 pathogenic variants.

Intereye Symmetry in Bietti Crystalline Dystrophy.

PURPOSE: To evaluate anatomic and functional intereye symmetry among individuals with Bietti crystalline dystrophy (BCD) using clinical and multimodal imaging methods, with a focus on the number, area, and distribution of the characteristic retinal crystalline deposits. DESIGN: Observational case series with prospective and retrospective data. METHODS: Setting: Multicenter. STUDY POPULATION: Thirteen Australian and New Zealand participants (26 eyes) with confirmed biallelic CYP4V2 mutations and a characteristic BCD fundus appearance. Procedures and main outcome measures: Crystals visible on color fundus photography were manually counted. Crystals were superimposed on aligned multimodal fundus images. Spearman's correlation coefficients (ρ), intraclass correlation coefficients (ICCs), and Bland-Altman plots were used to quantify symmetry between eyes. MAIN OUTCOME MEASURES: Fundus crystal area and count, and absent-autofluorescence (absent-AF) area. RESULTS: Median participant age was 48 years (interquartile range: 40-60 years). Intereye symmetry was high for fundus crystal area (ρ = 1.00, 95% confidence interval [CI]: 1.00-1.00; ICC = 0.97, 95% CI: 0.88-0.99), fundus crystal count (ρ = 0.98, 95% CI: 0.92-1.00; ICC = 0.97, 95% CI: 0.89-0.99), and absent-AF area (ρ = 0.88, 95% CI: 0.53-0.98; ICC = 0.98, 95% CI: 0.90-0.99). Average foveal volume, foveal crystal count and area, average and central foveal thickness, best corrected visual acuity, and average macular and central foveal sensitivity were not highly correlated between eyes. CONCLUSIONS: This study demonstrated strong intereye symmetry measured by fundus crystal area, fundus crystal number, and absent-AF area. This may influence the choice of outcome measures for future therapeutic trials for BCD and provides valuable clinical information for ophthalmologists involved in the care and counseling of patients with BCD.

Comparative Natural History of Visual Function From Patients With Biallelic Variants in BBS1 and BBS10.

Purpose: The purpose of this study was to compare the natural history of visual function change in cohorts of patients affected with retinal degeneration due to biallelic variants in Bardet-Biedl syndrome genes: BBS1 and BBS10. Methods: Patients were recruited from nine academic centers from six countries (Belgium, Canada, France, New Zealand, Switzerland, and the United States). Inclusion criteria were: (1) female or male patients with a clinical diagnosis of retinal dystrophy, (2) biallelic disease-causing variants in BBS1 or BBS10, and (3) measures of visual function for at least one visit. Retrospective data collected included genotypes, age, onset of symptoms, and best corrected visual acuity (VA). When possible, data on refractive error, fundus images and autofluorescence (FAF), optical coherence tomography (OCT), Goldmann kinetic perimetry (VF), electroretinography (ERG), and the systemic phenotype were collected. Results: Sixty-seven individuals had variants in BBS1 (n = 38; 20 female patients and 18 male patients); or BBS10 (n = 29; 14 female patients and 15 male patients). Missense variants were the most common type of variants for patients with BBS1, whereas frameshift variants were most common for BBS10. When ERGs were recordable, rod-cone dystrophy (RCD) was observed in 82% (23/28) of patients with BBS1 and 73% (8/11) of patients with BBS10; cone-rod dystrophy (CORD) was seen in 18% of patients with BBS1 only, and cone dystrophy (COD) was only seen in 3 patients with BBS10 (27%). ERGs were nondetectable earlier in patients with BBS10 than in patients with BBS1. Similarly, VA and VF declined more rapidly in patients with BBS10 compared to patients with BBS1. Conclusions: Retinal degeneration appears earlier and is more severe in BBS10 cases as compared to those with BBS1 variants. The course of change of visual function appears to relate to genetic subtypes of BBS.

Clinical and Genetic Study of X-Linked Juvenile Retinoschisis in the Czech Population.

The aim of this study was to identify RS1 pathogenic variants in Czech patients with X-linked retinoschisis (XLRS) and to describe the associated phenotypes, including natural history, in some cases. Twenty-one affected males from 17 families were included. The coding region of RS1 was directly sequenced and segregation of the identified mutations was performed in available family members. In total, 12 disease-causing variants within RS1 were identified; of these c.20del, c.275G>A, c.[375_379del; 386A>T], c.539C>A and c.575_576insT were novel, all predicted to be null alleles. The c.539C>A mutation occurred de novo. Three patients (aged 8, 11 and 19 years) were misdiagnosed as having intermediate uveitis and treated with systemic steroids. Repeat spectral domain optical coherence tomography examinations in four eyes documented the transition from cystoid macular lesions to macular atrophy in the fourth decade of life. Four individuals were treated with topical dorzolamide and in two of them, complete resolution of the cystic macular lesions bilaterally was achieved, while one patient was noncompliant. Rebound phenomenon after discontinuation of dorzolamide for 7 days was documented in one case. Misdiagnosis of XLRS for uveitis is not uncommon; therefore, identification of disease-causing variants is of considerable benefit to the affected individuals.

Impact of TCF4 Repeat Number on Resolution of Corneal Edema after Descemet's Stripping Only in Fuchs Dystrophy: A Pilot Study.

PURPOSE: To investigate whether Fuchs endothelial corneal dystrophy (FECD) genotype, specifically transcription factor 4 (TCF4) CTG triplet repeat "load" predicts time to clearance following Descemet's Stripping Only (DSO). METHODS: This prospective, interventional trial was conducted on consecutive FECD patients undergoing DSO. Genetic analysis using patients' saliva was performed to assess the extent of CTG expansion using short tandem repeat analysis, corroborated gel electrophoresis and Sanger sequencing. Polymerase chain reaction and bidirectional Sanger sequencing was undertaken. Partial least square regression and logistic regression modelling was used to evaluate the predictive power of TCF4 repeats on corneal clearance. RESULTS: Of 11 eyes of 11 patients, 8 showed complete corneal clearance. For these 8 patients, mean TCF4 allele repeat was 24.8 (SD: 23.7, range: 11-63) and 63.4 (SD: 30.3; range: 11-97), respectively. In total, 9/11 (81.8%) had expanded CTG repeats (>40) in one allele. In cases with an allele repeat ≥80, there was a significantly increased risk of corneal non-clearance (odds ratio 18.2, p = 0.009). CONCLUSION: Whilst it was not possible to predict time to corneal clearance based on CTG repeats, there is a significant correlation between allele repeats and achievement of corneal clearance.

Megalocornea, anterior megalophthalmos, keratoglobus and associated anterior segment disorders: A review.

Megalocornea and anterior megalophthalmos (megalocornea spectrum) disorders are typically defined by corneal diameter > 12.5 mm in the absence of elevated intraocular pressure. Clinical features overlap with keratoglobus but are distinct from buphthalmos and severe (globus) keratoconus. Megalocornea spectrum disorders and keratoglobus are primarily congenital disorders, often with syndromic associations; both can present with large and thin corneas, creating difficulty in diagnosis, however, only keratoglobus is typically progressive. Molecular genetics provide significant insight into underlying aetiologies. Nonetheless, careful clinical assessment remains intrinsic to diagnosis. Surgical management can be challenging due to the enlarged ciliary ring and weakened zonules in megalocornea spectrum disorders and the extreme corneal thinning of keratoglobus. In this review, the established literature on measurement of corneal diameter, diagnosis of megalocornea, anterior megalophthalmos and keratoglobus, differentiation from severe keratoconus, recent molecular genetics research and key surgical modalities in the management of these rare disorders are outlined and discussed.

Childhood and Early Onset Glaucoma Classification and Genetic Profile in a Large Australasian Disease Registry.

PURPOSE: To report the relative frequencies of childhood and early onset glaucoma subtypes and their genetic findings in a large single cohort. DESIGN: Retrospective clinical and molecular study. PARTICIPANTS: All individuals with childhood glaucoma (diagnosed 0 to <18 years) and early onset glaucoma (diagnosed 18 to <40 years) referred to a national disease registry. METHODS: We retrospectively reviewed the referrals of all individuals with glaucoma diagnosed at <40 years of age recruited to the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). Subtypes of glaucoma were determined using the Childhood Glaucoma Research Network (CGRN) classification system. DNA extracted from blood or saliva samples underwent sequencing of genes associated with glaucoma. MAIN OUTCOME MEASURES: The phenotype and genotype distribution of glaucoma diagnosed at <40 years of age. RESULTS: A total of 290 individuals (533 eyes) with childhood glaucoma and 370 individuals (686 eyes) with early onset glaucoma were referred to the ANZRAG. Primary glaucoma was the most prevalent condition in both cohorts. In the childhood cohort, 57.6% of individuals (167/290, 303 eyes) had primary congenital glaucoma (PCG), and 19.3% (56/290, 109 eyes) had juvenile open-angle glaucoma. Juvenile open-angle glaucoma constituted 73.2% of the early onset glaucoma cohort (271/370, 513 eyes). Genetic testing in probands resulted in a diagnostic yield of 24.7% (125/506) and a reclassification of glaucoma subtype in 10.4% of probands (13/125). The highest molecular diagnostic rate was achieved in probands with glaucoma associated with nonacquired ocular anomalies (56.5%). Biallelic variants in CYP1B1 (n = 29, 23.2%) and heterozygous variants in MYOC (n = 24, 19.2%) and FOXC1 (n = 21, 16.8%) were most commonly reported among probands with a molecular diagnosis. Biallelic CYP1B1 variants were reported in twice as many female individuals as male individuals with PCG (66.7% vs. 33.3%, P = 0.02). CONCLUSIONS: We report on the largest cohort of individuals with childhood and early onset glaucoma from Australasia using the CGRN classification. Primary glaucoma was most prevalent. Genetic diagnoses ascertained in 24.7% of probands supported clinical diagnoses and genetic counseling. International collaborative efforts are required to identify further genes because the majority of individuals still lack a clear molecular diagnosis.

Peripheral pigmented lesions in ABCA4-associated retinopathy.

Purpose: To investigate the prevalence and characteristics of peripheral pigmented retinal lesions and the associated clinical and genetic findings in patients with pathogenic variants in the ABCA4 gene.Methods: Records at a single tertiary hospital were retrospectively reviewed to identify the presence of peripheral pigmented retinal lesions on wide-field retinal imaging in patients with ABCA4-associated disease, compared with an RDS/PRPH2 cohort, and an age-matched control group. Data on patient demographics, genetic variants, severity of disease, and phenotype were collected and assessed.Results: Of 91 patients with at least one pathogenic variant in the ABCA4 gene and fundal changes consistent with ABCA4 retinal dystrophy, 15 (16.5%) had peripheral pigmented retinal lesions in 20 eyes, and were bilateral in 6 patients. These flat, subretinal lesions were located in the mid- or far periphery, not involving the macula, and had well-defined borders. Most affected eyes had a solitary lesion (n = 18) with lesions more commonly present in the temporal half of the retina. Twenty-one unique genetic variants in ABCA4 were associated with these lesions. In 26 subjects (52 eyes) with RDS/PRPH-2-associated IRD, and in 30 age-matched controls (60 eyes), only one control eye had a pigmented lesion consistent with congenital hypertrophy of the retinal pigment epithelium and there were no peripheral pigmented lesions.Conclusions: Almost one-fifth of patients with ABCA4-associated retinopathy have peripheral pigmented retinal lesions. The presence of these lesions is associated with more severe disease with an earlier onset than in patients without the lesions, and is an aid to diagnosis.

Heterozygous COL9A3 variants cause severe peripheral vitreoretinal degeneration and retinal detachment.

The COL9A3 gene encodes one of the three alpha chains of Type IX collagen, with heterozygous variants reported to cause multiple epiphyseal dysplasia, and suggested as contributory in some cases of sensorineural hearing loss. Patients with homozygous variants have midface hypoplasia, myopia, sensorineural hearing loss, epiphyseal changes and carry a diagnosis of Stickler syndrome. Variants in COL9A3 have not previously been reported to cause vitreoretinal degeneration and/or retinal detachments. This report describes two families with autosomal dominant inheritance and predominant features of peripheral vitreoretinal lattice degeneration and retinal detachment. Genomic sequencing revealed a heterozygous splice variant in COL9A3 [NG_016353.1(NM_001853.4):c.1107 + 1G>C, NC_000020.10(NM_001853.4):c.1107 + 1G>C, LRG1253t1] in Family 1, and a heterozygous missense variant [NG_016353.1(NM_001853.4):c.388G>A p.(Gly130Ser)] in Family 2, each segregating with disease. cDNA studies of the splice variant demonstrated an in-frame deletion in the COL2 domain, and the missense variant occurred in the COL3 domain, both indicating the critical role of Type IX collagen in the vitreous base of the eye.