Ophthalmic Genetics最新文献

Introduction: Enhanced S-cone syndrome (ESCS) is usually from biallelic pathogenic variants in NR2E3 (nuclear receptor subfamily 2 group E member 3). A less common cause is biallelic pathogenic variants in NRL (neural retina leucine zipper). When recordable, the ESCS electroretinogram (ERG) is pathognomonic. The diagnostic ERG features of ESCS do not include an electronegative waveform. The purpose of this study is to characterize ESCS in the United Arab Emirates (UAE).

Methods: Retrospective case series of patients diagnosed with ESCS at the Ocular Genetics Clinic of Cleveland Clinic Abu Dhabi (2016-2023, inclusive) who underwent confirmatory genetic analysis (of NR2E3 and, if negative, of NRL).

Results: Ten children (6 families) were identified. One child was homozygous for NR2E3: c.932G>A; p.Arg311Gln. The other 9 children (5 families) were homozygous for NRL: c.339C>G; p.Try113*. Seven children (4 families) had electroretinograms (ERGs), all of which were consistent with ESCS. Six of these children had an electronegative waveform, and they were all homozygous for the specific NRL variant. The child who did not have an electronegative waveform was homozygous for the NR2E3 variant. A literature review for published recordable ERGs in ESCS revealed additional NRL-related cases with an electronegative waveform but no NR23-related cases with an electronegative waveform.

Conclusions: NRL-related ESCS, related to homozygosity for NRL: c.339C>G; p.Try113*, is recurrent in the UAE and likely represents founder effect. The associated ERG includes an electronegative waveform. This finding may be a way to clinically distinguish NRL-related ESCS from NR2E3-related ESCS.

Background: Retinitis pigmentosa (RP) and many other inherited retinal diseases (IRDs) cause progressive retinal degeneration and eventual blindness, significantly impacting patients' health-related quality of life (HRQoL). Social media (SM) can provide valuable, real-world insights into patient and caregiver perspectives on disease burden and treatments.

Methods: This study analyzed publicly available, English-language SM posts from US-based patients or caregivers between 2013 and 2023 to understand the burden of living with IRDs (including RP) and perceptions of genetic testing and gene therapies.

Results: A thematic analysis of 140 SM posts from 115 contributors showed that symptoms (eg, night blindness, decreased peripheral vision, visual acuity) were discussed by 68 contributors (59.1%). Key aspects of HRQoL impacted included emotional well-being (52.2%), difficulty in daily activities (43.5%), careers (25.2%), relationships (24.3%), and independence (20.9%). Four contributors (3.5%) mentioned the burden on caregivers. Discussions on treatments for IRDs were shared by 41 contributors (35.7%), including thoughts about gene therapy. Genetic testing was discussed by 17 contributors (14.8%), including drivers for testing (eg, fear of passing on the condition to children and eligibility for gene therapies).

Conclusion: SM provided valuable insights into the burden of IRDs and highlighted significant patient interest in restorative treatments and gene therapies.

Introduction: Short stature, optic atrophy, and Pelger-Huët anomaly (SOPH) syndrome is a rare autosomal recessive condition associated with variants in the NBAS gene. First described in 2010, SOPH syndrome is a relatively newly recognized condition and our understanding of the range of its manifestations and the variable expressivity of its features continues to evolve. A total of 110 cases of SOPH syndrome have been published in the literature to date, 93 of which were published in two case series reporting on the Yakut population.

Methods: Case report and review of literature.

Results: We present a case of a 25-year-old female with a prior clinical diagnosis of cone-rod dystrophy, who was found to have incomplete SOPH syndrome associated with a paternally inherited splice site variant and a maternally inherited complete NBAS gene deletion. This is the first report of SOPH syndrome without Pelger-Huët anomaly.

Discussion: Our case expands the phenotypic and genetic spectrum of SOPH syndrome. Similarly to many other syndromic conditions, SOPH can display variable expressivity of disease features. Furthermore, our patient's complete deletion of one copy of the NBAS gene provides a unique opportunity to investigate in isolation the effects of the NBAS splice site variant found on the other allele.

Purpose: Clinical variability and incomplete penetrance characterize retinal dystrophies associated with PRPH2 gene variants. Here, we utilized adaptive nanopore long-read sequencing (LRS) to solve a genetic diagnosis for dominantly inherited macular dystrophies in two families.

Methods: Patient 1 (P1) and her daughter, Patient 2 (P2) were clinically evaluated using multimodal imaging and electrophysiological testing at Helsinki University Hospital, Finland, and Patient 3 (P3) from a different family, at Loma Linda University, USA. The patients were subjected to retinal dystrophy gene panels and the suspected duplications were characterized with nanopore LRS.

Results: P1 presented with butterfly-shaped pattern dystrophy (BPD) and P2 with vitelliform macular dystrophy. P3 showed BPD in the right eye and late-stage BPD in the left. Gene panels suggested that the patients shared the same heterozygous 482 bp PRPH2 exon 2 duplication. LRS revealed the duplications to be almost 4kb in size with breakpoints (BP) in intronic Alu-elements. In P1 and P2, the 3'BP resides within a novel Alu-element. The duplication has not been reported earlier and is missing from the gnomAD database.

Conclusion: This study presents novel PRPH2 exon 2 duplications associated with macular dystrophies.

Purpose: Non-coding regions are long, and there is little research on their variations contributing to disease. This study analyzed a patient with Usher syndrome Type 1F (USH1F) and discovered two compound heterozygous non-coding variants in the PCDH15 gene.

Methods: The proband underwent ophthalmologic examinations. Whole exome sequencing (WES) was performed. PCDH15 minigene was constructed and validated. Bioinformatics techniques were used to assess the effect of the variant on the encoded proteins.

Results: A 36-year-old male complained of deafness and aphasia at an early age, nyctalopia, and progressive narrowing of visual fields in childhood. Two compound heterozygous variants, c.-183_-29+1del and c.3123-1G>C (NM_033056.4), were identified. In vitro minigene technique showed that the variant c.3123-1G>C caused exon 24 skipping during mRNA splicing. It altered the reading frame of the subsequent translation process, a stop codon appeared earlier, which caused termination of protein translation in the extracellular calcium-binding domain. The tertiary structure and subcellular localization of the protein were predicted to be altered.

Conclusions: Through clinical genetic screening of a family with USH, we identified two variants in the PCDH15 gene. Minigene assay can be used for pathogenicity analysis of variants in long genes such as PCDH15. Our data suggest that PCDH15 c.3123-1G>C is a pathogenic mutation for Usher Syndrome Type 1F (USH1F).

Background and objectives: Congenital cone-rod synaptic disease (CRSD) belongs to a group of genetically and clinically heterogeneous retinal disorders. Pathogenic variants in the CABP4 gene coding for the calcium-binding protein four can lead to this condition. Several disease-causing variants lead to this condition. In support of this, our current study aimed to genetically characterize a consanguineous Lebanese family with two young siblings who show CRSD.

Results: Whole-exome sequencing identified a novel frameshift insertion in both affected siblings; c.363dup, p.(Lys122Glufs *21) in CABP4. The elder sibling carried a secondary homozygous missense variant; c.12575 G > A, p.(Arg4192His) in USH2A that is known to be associated with retinitis pigmentosa. CABP4 variant co-segregated with the phenotype in all the available family members. The ACMG guidelines classified CABP4 and USH2A variants as likely pathogenic and pathogenic, respectively. The secondary USH2A missense variant may lead to a more pronounced phenotype, necessitating an effective follow-up for better patient management.

Conclusion: The current findings highlight the involvement of CABP4 pathogenic variants in CRSD.

Background: Neural retina leucine zipper (NRL) is a crucial transcription factor that plays a key role in the development and differentiation of photoreceptor cells. A variant in this gene can cause a retinal phenotype known as Enhanced S cone Syndrome (ESCS). This study presents three novel autosomal recessive (ar) NRL variants and expands the clinical ophthalmic phenotype of NRL-associated retinopathy to include microphthalmia.

Methods: Investigations included electrodiagnostic testing, best corrected visual acuity (BCVA), optical coherence tomography (OCT), ultra-wide field autofluorescence (UWAF), fundus imaging, and visual fields. PubMed, Cochrane library and ClinVar database were used for literature search.

Results: Three patients (P1-3) from 2 different families with novel biallelic NRL variants were reported. P1 had novel homozygous likely-pathogenic NRL variant, p.(Glu86*). Genetic screening of both P2 and P3 identified a second and third novel heterozygous likely pathogenic variants, p.(Leu75Profs *19) and p.(Ser6Alafs *13). Multimodal imaging and functional studies in these patients were consistent with the classical features of ESCS with an additional feature of microphthalmia.

Conclusion: This study expands the genotype and phenotype of NRL-associated retinopathy and compares the ocular phenotype of our cohort with published NRL reports in the literature.

Introduction: Heimler syndrome is a rare autosomal recessive disorder at the mild end of the peroxisomal biogenesis disorders (PBDs), characterized by sensorineural hearing loss, amelogenesis imperfecta, and retinal dystrophy. Nail abnormalities affect a minority.

Case presentation: We present a 67-year-old woman diagnosed with non-syndromic retinitis pigmentosa in her fifties, who was later found to carry compound heterozygous variants in the PEX6 gene. Her medical history included prelingual hearing loss, early tooth decay, and brittle nails that were deemed unrelated for decades. Hearing loss and vision loss remained relatively stable up to last consultation.

Literature review: Our literature review includes 46 published Heimler syndrome cases with confirmed molecular diagnoses. Retinal dystrophy, predominantly of the rod-cone type with pigment clumping, was present in 89% of reported cases, with macular edema noted in 40%. Serum peroxisomal metabolite abnormalities seem to correlate with worse neurodevelopmental outcomes. There are no clear genotype-phenotype correlations, although residual peroxisomal function due to the presence of at least one missense, leaky splice site, or stable truncated allele explains the relatively mild phenotype for PBD.

Discussion: We underscore the importance to include syndromic disorders in the differential diagnosis of retinal dystrophy in older adults.

Background and objectives: The variety of ocular cell types involved in inherited retinal disease (IRD) necessitates the use of gene editing therapeutics which have generalizable components. In our study, we investigate the generalizable characteristics of non-engineered pegRNA design (PE2) for efficient, proof-in-principle gene correction of over 21 genes implicated in IRDs and associated syndromes. We use a single-transgene oligopool approach, comprising approximately 12,000 uniquely barcoded pegRNAs that target a synthetically integrated, 50 bp sequence motif, which faithfully recapitulate the disease context of their various counterpart IRDs. Using this approach, we perform a high throughput, pooled analysis of pegRNA characteristics across non- and ocular cell types to propose a cell-line agnostic set of pegRNA design guidelines.

Results: Briefly, we find that non-engineered pegRNA 3' extensions should mediate substitution-type edits and that the desired edit should be placed within five nucleotides upstream of the nick site induced by the Cas-endonuclease. Further, PBS and RTT lengths of at least 12 and 14 nucleotides, respectively, should be used and each non-engineered pegRNA 3' extension should obviate an initial templating cytosine nucleotide.

Conclusion: We establish a set of recommendations for the generalizable design of the non-engineered pegRNA 3' extension for the correction of several IRDs, enabling overall simplification of design parameters for PE2-based systems.

Background: Jeune syndrome is an autosomal recessive chondrodysplasia characterized by skeletal deformities and extra-skeletal organ involvement. Retinal astrocytic hamartomas (astrocytomas) are benign glial cell 10 15 Q1 tumors that are generally asymptomatic and diagnosed incidentally. The IFT74 gene is responsible for the formation of IFT proteins, which play a major role in ciliogenesis.

Case presentation: In this retrospective clinical laboratory observational study, an 18-year-old male with Jeune syndrome and night vision loss is presented. Fundus examination revealed bilateral optic discs with minimally blurred margins and bilateral retinal pigment epithelium changes in salt-pepper pattern in the peripheral retina. Additionally, a yellowish retinal astrocytoma was observed inferior to the optic disc in the left eye. Genetic analysis of the patient revealed a homozygous deletion in exon 2 of the IFT74 gene.

Conclusions: Our observations on this patient and some relationships between hamartoma and ciliopathies other than eye may potentially suggest a possible association between Jeune syndrome and retinal astrocytoma in the context of IFT74-related ciliopathies.