Novel causative variants in patients with achromatopsia

ABSTRACT

Purpose: To report five novel genetic variants in seven unrelated consanguineous families with achromatopsia (ACHM).

Methods: Patients were examined with multimodal retinal imaging and full-field electroretinography (ffERG). Genetic testing was conducted using next-generation sequencing (NGS).

Results: Three novel homozygous variants were detected in CNGA3: a missense c.967G > C (p.Ala323Pro) variant was detected in exon 8 (one patient), a splice site variant c.101 + 1G > A in intron 2 (three patients), and a splice site variant c.395 + 1G > T in intron 4(one patient). Another two novel variants were found in PDE6C: a homozygous missense variant c.1899C > A (p.His633Gln) in exon 15 (one patient) and a homozygous splice site variant c.1072-1G > C in intron 7 (one patient). Mutation segregation assessment was possible in 3 of the 7 families. All patients had nonrecordable ffERG 30-Hz flicker responses, reduced single-flash cone responses but preserved rod responses. Patients presented with variable degrees of foveal outer retinal layer loss and variable patterns of foveal hyperautofluorescence.

Conclusions: These novel variants expand the genotypes associated with ACHM and may help in future therapy development for ACHM.     

Clinical characteristics of recessive retinal degeneration due to mutations in the CDHR1 gene and a review of the literature

Background: The clinical phenotype of patients presenting with autosomal recessive CDHR1-related retinopathy has not been well described.

Materials and Methods: This is a retrospective case series of patients presenting to a single institution. Clinical data, including age, visual acuity, dilated fundus exam, fundus photos, fundus autofluorescence (FAF), optical coherence tomography, full-field electroretinograms (ERGs), and results of genetic testing, were collected.

Results: Four patients were identified to have biallelic mutations in the CDHR1 gene. All four patients were found to have at least one c.783G>A (p.Pro261 = ) mutation. A novel splice site mutation, c.152-2A>G, was identified in two patients. Patients became symptomatic between the fourth and sixth decades of life. Three patients presented initially with nyctalopia and peripheral visual field constriction, and one patient presented with simultaneous onset of photophobia and nyctalopia. The fundus appearance was characterized by macular atrophy with or without peripheral retinal pigment epithelium changes and arteriolar attenuation. FAF showed a hyperautofluorescent ring surrounding a central area of speckled hypoautofluorescence. Full-field electroretinography was available on three patients and showed decreased cone-and-rod responses.

Conclusions: CDHR1-related retinal dystrophy should be considered in adult patients with a retinal dystrophy who present with symptoms of cone-and-rod dysfunction and macular atrophy on ophthalmoscopic examination.     

Genetic screening of Russian Usher syndrome patients toward selection for gene therapy

ABSTRACT

Background: Usher syndrome (USH) is heterogeneous in nature and requires genetic test for diagnosis and management. Mutations in USH associated genes are reported in some populations except Russians. Here, we first time represented the mutation spectrum of a Russian USH cohort.

Methods: Twenty-eight patients with USH were selected from 3214 patients from Deaf-Blind Support Foundation “Con-nection” during 2014–2016 following the observational study NCT03319524. Complete ophthalmologic, ENT, and vestibular medical tests were done for clinical characterization. NGS, MLPA, and Sanger sequencing were considered for genetic analysis.

Results: Around 53.57% and 39.28% patients had USH1 and USH2, respectively; 17.85% cases (n = 5/28) had no known mutation. Eleven (73.33%) subjects showed variations in USH1 associated genes MYO7A (72.72%), CDH23 (9.09%), PCDH15 (9.09%), and USH1C (9.09%). Eleven mutations are detected in MYO7A where 54.54% are novel. MYO7A: p.Q18* was most frequent (27.27%) mutation and is associated with early manifestation and most severe clinical picture. Two novel mutations (p.E1301* and c.158-?_318+?del) are detected in PCDH15 gene. Around 90.90% patients suspected to be USH2 are confirmed by genetic testing. Eleven mutations detected in the USH2A gene, where 27.27% were novel. Most common USH2A mutation is p.W3955* (50%) followed by p.E767fs, p.R1653*, and c.8682-9A> G (20% each).

Conclusion: The Russian USH cohort shows both novel and known USH mutations. Clinically the prevalence of USH2 is low (39.28%) and the frequency of MYO7A mutations responsible for USH1B is very high (63.63%, N = 7/11) compared to other cohorts. These seven patients carrying MYO7A mutations are preliminarily eligible for the UshStat® gene therapy.     

A novel 5-bp deletion in Clarin 1 in a family with Usher syndrome

Background: To identify the genetic defect in a Lebanese family with two sibs diagnosed with Usher Syndrome.

Materials and Methods: Exome capture and sequencing were performed on DNA from one affected member using Agilent in solution bead capture, followed by Illumina sequencing.

Results: This analysis revealed the presence of a novel homozygous 5-bp deletion, in Clarin 1 (CLRN1), a known gene responsible for Usher syndrome type III. The deletion is inherited from both parents and segregates with the disease phenotype in the family. The 5-bp deletion, c.301_305delGTCAT, p.Val101SerfsX27, is predicted to result in a frameshift and protein truncation after 27 amino acids. Sequencing all the coding regions of the CLRN1 gene in the proband did not reveal any other mutation or variant.

Conclusion: Here we describe a novel deletion in CLRN1. Our data support previously reported intra familial variability in the clinical features of Usher syndrome type I and III.     

Ocular Features in Chinese Patients with Blau Syndrome

ABSTRACT

Purpose: To identify pathogenic gene variants in the NOD2 gene and assess the clinical features of a cohort of Chinese patients affected with Blau syndrome.

Methods: Eight patients from seven unrelated families were enrolled. Detailed ophthalmological examinations were performed. Sanger sequencing was used to analyze the NOD2 gene.

Results: The onset age of ocular manifestations varied from 2 to 24 years (median: 5.5 years). Best corrected visual acuity (BCVA) ranged from light perception (LP) to 1.0. One patient presented with recurrent anterior uveitis, six patients had panuveitis and one patient was at the phthisis bulbi stage. One novel disease-associated variant (c.2006A>G, p.His669Arg) and four previously reported disease-causing variants (c.1000C>T, p.Arg334Trp; c.1001G>A, p.Arg334Gln; c.1442G>A, p.Gly481Asp; c.1759C>T, p.Arg587Cys) in the NOD2 gene (NM_022162.1) were identified.

Conclusions: Blau syndrome is a rare autosomal dominant multisystem disease caused by a NOD2 gene defect. Recurrent anterior uveitis and/or panuveitis are the characteristic ocular findings.     

Estrogen receptor gene polymorphisms and their influence on clinical status of Caucasian patients with primary open angle glaucoma

ABSTRACT

Purpose: The aim of this study was to evaluate the frequency of single nucleotide polymorphisms (SNP) of estrogen receptor genes (ESR1: rs12154178, rs1884054 and ESR2: rs1268656, rs7159462) and to assess their possible influence on the clinical phenotype of primary open angle glaucoma (POAG).

Methods: The study included 235 patients with POAG (143 patients with normal-tension glaucoma [NTG] and 92 patients with high-tension glaucoma [HTG]), and 165 healthy controls. DNA was isolated from peripheral blood, and SNP genotyping was performed using the Real-Time Polymerase Chain Reaction method to analyze the frequency of selected polymorphic variants of estrogen receptor genes. The clinical phenotype (best-corrected visual acuity, intraocular pressure [IOP], mean deviation [MD], cup to disc ratio, disc hemorrhages, notches, peripapillary atrophy, cold extremities) of participants were examined for association with the polymorphisms.

Results: A similar frequency of the polymorphic variants of the studied genes was observed in patients with NTG, HTG and control group. Initial intraocular pressure was the lowest in NTG patients with GG variant of rs1268656 (p = 0.044). The lowest maximal IOP in HTG patients was observed in CC variant of rs12154178 (p = 0.039). Patients with HTG and CC variant of ESR1 polymorphism rs1884054 had the best visual acuity (p = 0.009), similar tendency was also observed in the NTG group. This polymorphic variant of ESR1 gene in HTG was also related to earlier damage in visual field assessed according to MD values and higher percentage of notches. For rs12154178, homozygotic variant CC was related to earlier glaucoma damage according to MD in HTG patients (p = 0.006). For polymorphism rs12154178, disc hemorrhages were found only for those with the AC variant. Cold extremities were most frequent in NTG patients with TT variant of rs1268656 comparing to other variants (p = 0.021). Notches on optic disc were less frequent in patients with CC variant of rs12154178 of ERS-1 gene (p = 0.022).

Conclusions: The studied polymorphic variants of ESR1 and ESR2 genes may have an influence on the clinical phenotype of patients with POAG.     

Choroidal Changes at the Leakage Site in Acute Central Serous Chorioretinopathy

Purpose: To analyze the choroidal vasculature at leak site and at the center of macula in acute central serous chorioretinopathy (CSCR) and to evaluate their co-relation with eccentricity of leak site.

Methods: This retrospective study involved optical coherence tomography analysis of 27 eyes with acute CSCR. Relationship between macular thickness; large choroidal vessels diameter; baseline subfoveal and leakage point choroidal thickness, and eccentricity of leak point was evaluated.

Results: A larger choroidal vessel caliber/choroidal thickness ratio was found at the leak site than fovea in both active (p = 0.0001) and resolved (p = 0.003) CSCR. Ratio at leakage point decreased after resolution of SRF (p = 0.004). Choroidal thickness at subfovea (p = 0.004), leakage point (p = 0.02); and difference between central and leakage point choroidal thickness (r = 0.6, p = 0.009) were significantly associated with the eccentricity of leakage point.

Conclusion: Subfoveal and leak site choroidal profile could predict the eccentricity of leakage in CSCR.     

Novel homozygous OPA3 mutation in an Afghani family with 3-methylglutaconic aciduria type III and optic atrophy

ABSTRACT

Purpose: To describe and distinguish clinical phenotypes with the overlapping feature of optic atrophy caused by distinct mutations in the same gene, OPA3. We report 3 affected siblings in a consanguineous family harboring a novel OPA3 mutation causing 3-methylglutaconic aciduria type III with optic atrophy.

Methods: Retrospective case series.

Results: Three siblings (2 male, 1 female) among 6 children in a consanguineous Afghani family developed decreased vision from early childhood. Both parents and all extended family members were unaffected. All 3 affected siblings suffered from severe visual impairment ranging from visual acuities of 20/150 to counting fingers. All had spastic lower extremity weakness and ataxia. Two of the three affected siblings also had a history of seizures, and the female sibling had limited cognition with diffuse atrophic changes on brain MRI. Two of the three individuals also had migraine-like headaches. Urine organic acid analysis revealed mildly elevated 3-methylglutaconic acid for the male siblings. Whole exome sequencing and subsequent PCR confirmation revealed a novel variant in OPA3 (intron1, c.142 + 2_142 + 3dupTG), affecting the consensus sequence of the splice site, for which all 3 clinically affected siblings were homozygous.

Discussion: Mutations in OPA3 can cause optic atrophy in a dominant pattern of inheritance associated with cataract or in a recessive pattern associated with spastic paresis and ataxia. The novel recessive mutation and clinical presentations described herein further support how different mutation types affecting OPA3 can produce distinct clinical phenotypes and underscore the critical and susceptible role of mitochondrial health in optic nerve function.     

Targeted next-generation sequencing reveals that a compound heterozygous mutation in phosphodiesterase 6a gene leads to retinitis pigmentosa in a Chinese family

Purpose: Retinitis pigmentosa (RP) is a genetically heterogeneous disease with over 70 causative genes identified to date. However, approximately 40% of RP cases remain genetically unsolved, suggesting that many novel disease-causing mutations are yet to be identified. The purpose of this study is to identify the causative mutations of a Chinese RP family.

Methods: Targeted next-generation sequencing (NGS) for a total of 163 genes which involved in inherited retinal disorders were used to screen the possible causative mutations. Sanger sequencing was used to verify the mutations.

Results: As results, we identified two heterozygous mutations: a splicing site mutation c.1407 + 1G>C and a nonsense mutation c. 1957C>T (p.R653X) in phosphodiesterase 6A (PDE6A) gene in the RP patient. These two mutations are inherited from his father and mother, respectively. Furthermore, these mutations are unique in our in-house database and are rare in human genome databases, implicating that these two mutations are pathological.

Conclusion: By using targeted NGS method, we identified a compound heterozygous mutation in PDE6A gene that is associated with RP in a Chinese family.     

Modification of the PROM1 disease phenotype by a mutation in ABCA4

ABSTRACT

Background: The extensive phenotypic heterogeneity of monogenic diseases can be largely traced to intragenic variation; however, recent advances in clinical detection and gene sequencing have uncovered the emerging role of non-allelic variation (i.e. genetic trans-modifiers) in shaping disease phenotypes. Identifying these associations are not only of significant diagnostic value, but also provides scientific insight into the expanded molecular etiology of rare diseases. This reports describes the discordant clinical manifestation of a family segregating mutations in ABCA4 and PROM1.

Methods: Three patients across a two generation family underwent multimodal imaging and functional testing of the retina including color photography, fundus autofluorescence (AF), spectral domain-optical coherence tomography (SD-OCT) and full-field electroretinography (ffERG). Genetic characterization was carried out by direct Sanger and whole exome sequencing.

Results: Clinical examination revealed similar retinal degenerative phenotypes in the proband and her mother. Despite being younger, the proband’s phenotype was more advanced and exhibited additional features related to Stargardt disease not found in the mother. Whole exome sequencing identified a pathogenic missense variant in PROM1, c.400C > T, p.(Arg134Cys), as the underlying cause of retinal disease in both the proband and mother. Sequencing of the ABCA4 locus uncovered a single disease-causing variant, c.5714 + 5G > A in the daughter segregating from the father who, surprisingly, also exhibited very subtle disease changes associated with STGD1 despite being a heterozygous carrier.

Conclusions: Harboring an additional heterozygous ABCA4 mutation increases severity and confers STGD1-like features in patients with PROM1 disease which provides supporting evidence for their shared pathophysiology and potential treatment prospects.     

Identification and characterization of the VAX2 p.Leu139Arg variant: possible involvement of VAX2 in cone dystrophy

Objective: This study was undertaken with the objective to investigate the potential involvement of VAX2 in retinal degeneration.

Methods: A cohort of macular and cone dystrophy patients (n = 70) was screened for variant identification. Polymerase chain reaction (PCR) products were purified using ExoSAP-IT. Direct sequencing of PCR products was performed using BigDye 3.1 on the ABI 3730 DNA Analyzer and analyzed using DNASTAR software tool. Search for known variant was performed using the following platforms: 1000 Genomes Project, Ensembl, UCSC, ExAc, and dbSNP. The VAX2 mutants were generated using the GeneArt® Site-Directed Mutagenesis kit. In vitro analysis was performed in hTERTRPE-1 (RPE-1) cell line. Cells were photographed using a Zeiss AXIOVERT S100 microscope. Images were analyzed using Photoshop CS4 software.

Results: Here, we report the identification of a heterozygous non-synonymous variant (c.416T>G; p.Leu139Arg) in one cone dystrophy proband. Functional characterization of this variant in vitro revealed an aberrant phenotype seen as protein mislocalization to cytoplasm/nucleus and aggregates undergoing degradation or forming aggresomes. The cellular phenotype suggests protein loss-of-function. Analysis of the VAX2 p.Leu139Met, a variant present in the normal population, showed a phenotype similar to the wild-type, further supporting the hypothesis for the Leucine 139 to Arginine change to be damaging.

Conclusions: This study raises the interesting possibility for evaluating VAX2 as a candidate gene for cone dystrophy.     

A recurrent splice-site mutation in EPHA2 causing congenital posterior nuclear cataract

Intoduction: Inherited cataract, opacification of the lens, is the most common worldwide cause of blindness in children. We aimed to identify the genetic cause of autosomal dominant (AD) posterior nuclear cataract in a four generation British family.

Methods: Whole genome sequence (WGS) was performed on two affected and one unaffected individual of the family and further validated by direct sequencing. Haplotype analysis was performed via genotying.

Results: A splice-site mutation c.2826-9G>A in the gene EPHA2, encoding EPH receptor A2 was identified and found to co-segregate with disease.

Conclusions: We have identified a recurrent splice-site mutation c.2826-9G>A in EPHA2 causing isolated posterior nuclear cataract, providing evidence of further phenotypic heterogeneity associated with this variant.     

Case report of four siblings in southeast Turkey with a novel RAB3GAP2 splice site mutation: Warburg micro syndrome or Martsolf syndrome?

Background: Warburg micro syndrome is a very rare autosomal recessive disorder characterized by a mutation in the RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20 genes. Warburg Micro syndrome 2 and Martsolf syndrome are clinically overlapping conditions characterized by variable clinical signs counting postnatal growth retardation, cataract, intellectual deficiency, contractures, and central nervous system abnormalities due to RAB3GAP2 gene mutations. The RAB3GAP2 gene encodes a member of the Rab3 protein family, which is involved in regulated exocytosis of neurotransmitters and hormones.

Case presentation: We describe four siblings from healthy consanguineous Turkish parents with developmental delay, congenital cataract, and speech delay. In this study, we performed whole exom sequencing (WES) in a index patient. WES analyses in proposita showed a homozygous c.1998 + 1 G > A mutation in RAB3GAP2 gene. After the Sanger confirmation, the same mutation was detected in the other three siblings.

Conclusion: The four siblings had a novel splice site mutation in RAB3GAP2. This report compares the symptoms and features of the our patients with clinical summary of Warburg Micro syndrome 2 and Martsolf syndrome. Further reports will make possible knowing of the genetic and clinical backgrounds of this orphan diseases.

Abbreviation: MRI: Magnetic resonance imaging     

The role of apolipoprotein E (rs7412 and rs429358) in age-related macular degeneration

Background: Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in the developed countries. The main pathological change in AMD is the formation of drusen containing 40% of lipids, dominated by esterified cholesterol (EC) and phosphatidylcholine (PC), and protein. Haplotype ε4 of apolipoprotein E

(ApoE) acts as a ligand for the low-density lipoprotein receptor and is involved in the maintenance and repair of neuronal cell membranes.

Purpose: This study aimed to evaluate the association of AMD with ApoE gene polymorphism variants (rs7412 and rs429358).

Methodology: A total of 2133 subjects were enrolled in our research. The study group comprised patients with early AMD (n = 413) and exudative AMD (n = 307), and the control group enrolled randomly selected persons (n = 1413). The genotyping of ApoE (rs7412 and rs429358) was performed using the real-time polymerase chain reaction (PCR) method.

Results: Statistical analysis revealed that ApoE 4/2 genotype was less frequently observed in in older patients with exudative AMD compared to older healthy controls (0.4% vs. 4.0%, p = 0.003).

Conclusion: Our data demonstrated that ApoE 4/2 genotype was less frequently observed in old patients (65 years and more) with exudative AMD compared to old healthy controls. It leads to hypothesis on the protective effect of ApoE 4/2 to develop AMD in the elderly.     

Retinal cadherins and the retinal cadherinopathies: Current concepts and future directions

Cadherins are a superfamily of calcium-dependent intercellular adhesion molecules that are widely expressed in living tissues. Within the retina and retinal pigment epithelium (RPE), cadherins contribute to tissue morphogenesis, neural circuit formation, adherens junctions of the outer blood-retinal barrier, photoreceptor disc morphogenesis, maintenance and survival. Four monogenic disorders involving genes which encode cadherins have been identified as causes of inherited retinal degeneration: the retinal cadherinopathies (CDHR1, CDH23, PCDH15, CDH3). Biallelic variants in CDHR1 result in cone-rod dystrophy, rod-cone dystrophy or late-onset macular dystrophy which may be misclassified as dry age-related macular degeneration. Biallelic variants in CDH23 and PCDH15 underlie Usher Syndrome type 1D and 1F. Hypotrichosis with juvenile macular dystrophy results from biallelic variants in CDH3, which contributes to adherens tight junctions between RPE cells. In this review, we summarise the classification of cadherins, and the role of cadherins in the physiology and morphogenesis of the inner and outer retina. Cadherins expressed in primate photoreceptors (CDHR1, CDH23 and PCDH15) have evolved complex roles in outer segment disc morphogenesis and maintenance involving intracellular heterophilic interactions which are as yet incompletely characterised. We highlight what is currently unknown about the molecular function of these cadherins, and review the pathogenesis, clinical phenotype and molecular genetics of each monogenic retinal cadherinopathy. Genes regulating the expression and post-translational modification of retinal cadherins, or those coding for as yet unidentified interacting partners, are candidates for unsolved cases of retinal degeneration. This group of disorders is potentially treatable; we summarise the likely molecular therapeutic approaches and future directions for each retinal cadherinopathy.     

Retained visual function in a subset of patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD)

ABSTRACT

Introduction: LCHADD causes retinopathy associated with low vision, visual field defects, nyctalopia and myopia. We report a retrospective long-term single-center study of 6 LCHADD patients trying to clarify if early diagnosis has an impact on the course and outcome of chorioretinal degeneration.

Methods: Long-term follow-up of visual acuity and staging of chorioretinal degeneration by fundus photography, optical coherence tomography (OCT) and autofluorescence (AF) in all six patients. Three patients (2 m/1 f; age 8–14.8 years) were diagnosed by newborn screening, a single patient early within the first year of life and treated promptly while the other two (1 m/1 f; age 23–24 years) were diagnosed later after developing symptoms. All carried HADHA variants; five were homozygous for the common p.E510Q variant, in one from the symptomatically diagnosed group p.[E510Q]; [R291*] was detected.

Results: All patients showed retinal alterations, but early diagnosis was associated with a milder phenotype and a longer preservation of visual function. Among symptomatic patients, only one showed mild retinal involvement at the time of diagnosis.

Conclusion: Despite the small number our study suggests that early diagnosis does not prevent retinopathy but might contribute to a milder phenotype with retained good visual acuity over time. OCT and AF are reliable non-invasive diagnostic tools to estimate the progression of early-stage retinal changes in LCHADD patients.     

Phenotypes in Defined Genotypes Including Siblings with Usher Syndrome

Objective: To characterize visual function in defined genotypes including siblings with Usher syndrome.

Methods: Thirteen patients with phenotypically different subtypes of Usher syndrome, including 3 families with affected siblings, were selected. Genetic analysis and ophthalmological examinations including visual fields, full-field electroretinography (ERG), multifocal electroretinography (mf ERG), and optical coherence tomography (OCT) were assessed. The patients’ degree of visual handicap was evaluated by a questionnaire (ADL).

Results: Twelve of thirteen patients were genotyped as Usher 1B, 1D, 1F, 2A, 2C or 3A. In 12 of 13 patients examined with ERG the 30 Hz flickering light response revealed remaining cone function. In 3 of the patients with Usher type 1 mf ERG demonstrated a specific pattern, with a sharp distinction between the area with reduced function and the central area with remaining macular function and normal peak time. OCT demonstrated loss of foveal depression with distortion of the foveal architecture in the macula in all patients. The foveal thickness ranged from 159 to 384?µm and was not correlated to retinal function. Three siblings shared the same mutation for Usher 2C but in contrast to previous reports regarding this genotype, 1 of them diverged in phenotype with substantially normal visual fields, almost normal OCT and mf ERG findings, and only moderately reduced rod and cone function according to ERG.

Conclusions: Evaluation of visual function comprising both the severity of the rod cone degeneration and the function in the macular region confirm phenotypical heterogeneity within siblings and between different genotypes of Usher syndrome.     

DNA methylation at the 9p21 glaucoma susceptibility locus is associated with normal-tension glaucoma

Purpose: Recent genome-wide association studies reported strong association of genetic variation at the CDKN2B/CDKN2B-AS1 locus on 9p21 with normal-tension glaucoma (NTG) in multiple populations. The mechanism by which this locus causes disease remains to be elucidated. We investigated the association of DNA methylation of CpG islands at this locus with NTG.

Methods: We conducted a retrospective case–control study of 178 NTG cases and 202 unaffected controls from Australia. CDKN2B and CDKN2B-AS1 promoter methylation was measured quantitatively using the MassCleave assay, and assessed for association with the disease, and the genotype of the associated risk variants using IBM SPSS statistics 22.0 CpG sites at which methylation status was associated with NTG were validated using pyrosequencing.

Results: We identified one CpG site (F1:13–14) in the CDKN2B promoter which showed significant association with NTG (p = 0.001). The association was highly significant in female cases (p = 0.006) but not in male cases (p = 0.054). The association was validated using an independent method confirming the likely association of DNA methylation with NTG in females (p = 0.015), but not in males (p = 0.497). In addition, methylation at CpG sites in CDKN2B was also associated with genotype at rs1063192, which is known to confer risk for NTG.

Conclusion: This study reveals an association of methylation status in the CDKN2B promoter with NTG, particularly in females. This suggests that the observed genetic association with the disease at this locus could be in part due to epigenetic mechanisms, and is likely to be independent of the association of nonsynonymous coding variation within the gene.     

Diurnal variations of foveoschisis by optical coherence tomography in patients with RS1 X-linked juvenile retinoschisis

Background: To evaluate diurnal variations in macular schisis cavities in patients with X-linked juvenile retinoschisis (XLRS) with pathogenic variants in the RS1 gene using spectral-domain optical coherence tomography (SD-OCT).

Methods: Three consecutive patients with a clinical diagnosis of XLRS and pathogenic variants in the RS1, treated with carbonic anhydrase inhibitors (CAIs).

Observational procedures: SD-OCT scans of the macula were acquired at 9 a.m., 1 p.m., and 4 p.m. within 24 h.

Results: All patients demonstrated increased measures of central foveal thickness in the morning with gradual decrease through the day (9–43%). Major changes were observed between 9 a.m. and 1 p.m. in the central foveal thickness.

Conclusion: The central foveal thickness varies during daytime hours in patients with XLRS. This finding may explain the inconsistent and heterogeneous responses to treatment with CAIs and necessitate standardization of measurement times in treatment trials for XLRS as well as in the routine ophthalmic evaluation of these patients.     

Macular maldevelopment in ATF6-mediated retinal dysfunction

ABSTRACT

Background: Achromatopsia has been previously associated with mutations in the ATF6 gene. Rod-monochromatism, foveal hypoplasia, and disruption of the subfoveal photoreceptor layer are described as phenotypical features. We report detailed structural and electrophysiological assessment of two patients from two families, one manifesting severe macular maldevelopment and one with foveal hypoplasia.

Materials and methods: The patients underwent a complete ophthalmic examination including electroretinography (ERG), spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, and fundus photography. Genetic testing was performed by next-generation sequencing.

Results: In one patient, fundoscopy and SD-OCT revealed well-demarcated coloboma-like excavated lesions at the central macula of both eyes. Genetic analysis identified a novel homozygous p.Asp140Ter mutation in the ATF6 gene. The second patient had foveal hypoplasia in association with a homozygous ATF6 mutation affecting a splice donor site (c.1187 + 5G>C). In both patients, electrophysiological assessment showed normal rod-specific (DA 0.01) and dark-adapted bright white-flash ERGs (DA 10.0). 30 Hz flicker ERGs were undetectable. There were low-amplitude single-flash photopic ERGs (LA 3.0) with timing and shape suggesting S-cone origin.

Conclusions: The findings, particularly a case with severe macular maldevelopment, may expand on the phenotype previously associated with ATF6-mediated achromatopsia. In addition, the comprehensive electrophysiological assessment suggests that preserved S-cone activity can be detected in this particular molecular sub-type of cone dysfunction.