Ophthalmic Genetics最新文献

Purpose: To characterize an undiagnosed patient with retinal dystrophy, ataxia, and neurodevelopmental delay.

Materials and methods: A 13-year-old female patient presenting with nystagmus and defective vision since infancy, underwent ophthalmological, neurological examination, ultra-wide field fundus photography, autofluorescence and electroretinogram. Exome sequencing (ES) was done followed by segregation analysis. Analysis of the glycosylation profiles of plasma glycoprotein markers was performed using immunoblotting.

Results: Visual acuity was counting fingers; her fundus examination and imaging revealed an Early Childhood Onset Retinal Dystrophy (ECORD) phenotype. Ichthyosiform skin lesions were noted, and neurological assessment revealed proximal limb-girdle pattern of weakness, hyperactive reflexes, extensor plantar responses with evidence of cerebellar dysfunction. ES uncovered a homozygous, likely pathogenic missense variant c.509A > G, p.(Tyr170Cys) in SRD5A3 gene. In silico functional analysis prediction tools supported the variant being deleterious. Segregation analysis confirmed carrier status of parents and the brother, while plasma glycoprotein markers for N- and O-glycosylation showed an aberrant glycosylation profile.

Conclusion: We report a variant in the SRD3A5 gene reported for the first time in a case of CDG. We are expanding the neurophenotypic spectrum by reporting proximal limb-girdle pattern of weakness combined with diffusely brisk reflexes and bilateral extensor plantar responses suggestive of corticospinal or neuromuscular axis involvement.

With the availability of high-sensitivity molecular genetic testing, prenatal diagnosis by amniocentesis, early-term delivery of at-risk neonates, and hand-held optical coherence tomography for detection of subclinical tumors, there is an opportunity to optimize eye and vision salvage and minimize the burden of invasive treatments in hereditary retinoblastoma. Providing this standard of care requires consistent practice patterns and collaboration between diagnostic laboratories and tertiary retinoblastoma centers. We describe two cases that highlight the importance of timely and accurate RB1 genetic testing and identification and clinical evaluation of at-risk family members, to optimize outcomes for individuals with hereditary retinoblastoma.

Introduction: KIF11 gene mutations can result in a rare autosomal dominant inheritable disease called microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR/MLCRD). Recently, such mutations were also found to be associated with familial exudative vitreoretinopathy (FEVR).

Methods: Retrospective case report.

Results: A 2-month-old female child came to our clinic for fundus evaluation. On examination, there was microcephaly with dysmorphism of broad and bulbous nose and bilateral pitting edema. Fundus examination revealed bilateral symmetrical chorio-retinal atrophic spots with dysplasia and temporal peripheral avascular retina. Fluorescein angiography revealed peripheral avascular retina without any neovascularisation elsewhere. Whole genome sequencing along with mitochondrial genome sequencing revealed a heterozygous, likely pathogenic, mutation in KIF11 c.2830C > T (pArg944Cys) (Transcript: NM_004523.4) in exon 20 with an inheritance of autosomal dominant confirming the diagnosis of KIF11-related Retinopathy.

Conclusion: Genetic counseling and family screening are paramount for managing this multisystem disorder and advising on recurrence risk. Genetic testing confirmed the KIF11 mutation, providing insights into the management and prognosis.

Background: Kearns Sayre syndrome (KSS) is a rare multisystem mitochondrial disorder. KSS primarily targets energy supply in cells through impaired oxidative metabolism and reduced ATP (Adenosine triphosphate) production. KSS is clinically characterized by a classic triad of chronic progressive external ophthalmoplegia, retinitis pigmentosa and cardiac conduction defect. Additional features may include neurological abnormalities, endocrinopathies, renal disease, growth failure, myopathy and more.

Materials and methods: We present a case of a young male with KSS, retinal dystrophy and multiple systemic abnormalities.

Results: Despite treatment with three intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections, the CNV demonstrated limited response and progressive enlargement, leading to poor final visual outcome.

Conclusion: To our knowledge, CNV has not been previously documented in Kearns -Sayre syndrome. This report underscores the need for ongoing surveillance in patients with rare retinal dystrophies, given the potential for unforeseen complications.

Purpose: To report multimodal imaging findings and natural history of clinical features in two probands with bradyopsia harboring homozygous variants (c.895T>C) in Regulator of G-protein Signaling 9 (RGS9).

Methods: Ophthalmic history, clinical examination, fundus autofluorescence (FAF), optical coherence tomography (OCT), microperimetry, flood-illuminated adaptive optics (AO) imaging, and electroretinogram (ERG) were obtained.

Results: A 37-year-old male and a 67-year-old female from non-consanguineous parents had normal fundus examination, FAF, and OCT. ERGs for the male case between the age of 4 and 38 years showed no progression. Both probands had flat International Society for Clinical Electrophysiology of Vision (ISCEV) Standard full-field ERG light-adapted (LA) responses but dark-adapted (DA) red x-wave and S-cone responses were present. DA 30 Hz flicker was present after 2 but not after 10 seconds. The reduced amplitude and b:a ratio of the DA10 response improved with increasing interstimulus interval. AO and microperimetry demonstrated preservation of foveal cone density and subnormal retinal sensitivity, respectively. Both measures remained stable over 3 years. The c.895T>C variant was classified as pathogenic.

Conclusions: Bradyopsia associated with homozygous RGS9 c.895T>C variants is characterized by normal retinal structure but subnormal macular sensitivity. Extended ERG protocols can be used to confirm delayed phototransduction recovery.

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).