Ophthalmic Genetics最新文献

Purpose: To identify RHO mutations in patients with non-syndromic retinitis pigmentosa (NS-RP).

Methods: A total of 143 probands (46 family history and 97 sporadic cases) with NS-RP were recruited from Southeast China. The coding exons and adjacent intronic regions of RHO were PCR-amplified and sequenced by Sanger sequencing. The candidate variant was evaluated by the guidelines of American College of Medical Genetics and further validated through co-segregation analysis within the family.

Results: Five heterozygous mutations in RHO were detected in 5 out of 143 probands, where the frequency of RHO mutations in our cohort was approximately 3.5% (5/143) and 10.8% (5/46) for probands and families with NS-RP, respectively. Three known disease-causing mutations including c.C1030T (p.Q344X), c.C173G (p.T58R), and c.G266A (p.G89D) were identified in three unrelated families. The other two previously unreported mutations c.557C>A (p.S186X) and c.944delA (p.N315TfsX43) were confirmed in Family RP-087 and Family RP-139, respectively. These mutations co-segregated with available affected individuals in each family were not observed in the unaffected family members or in the 112 unrelated controls.

Conclusions: This report expands the mutational spectrum of RHO gene associated with NS-RP and demonstrates the frequency of RP RHO mutations in Southeast Chinese populations.

Background: We present a case of a child with Floating-Harbor Syndrome (FHS) with bilateral chorioretinal coloboma (CC). To the best of our knowledge, this is the first case report of this association. Floating- Harbor syndrome is an extremely rare autosomal dominant genetic disorder with approximately 100 cases reported. It is characterized by a series of atypical features that include short stature with delayed bone age, low birth weight, skeletal anomalies, delayed speech development, and dysmorphic facial characteristics that typically portray a triangular face, deep-set eyes, long eyelashes, and prominent nose.

Materials and methods: Our patient was examined by a pediatric ophthalmologist for the time at age of 7. Visual acuity, optical coherence tomography (OCT) and Optos imaging were collected on every visit. The patient had whole genome sequencing ordered by a pediatric geneticist to confirm Floating-Harbor syndrome.

Results: We present the patient's OCT and Optos images that illustrate the location of the patient's inferior chorioretinal coloboma in both eyes. The whole genome sequencing report collected revealed a heterozygous de novo pathogenic variant in the SRCAP gene, consistent with a Floating-Harbor syndrome diagnosis in the literature.

Discussion: Both genetic and systemic findings are consistent with the diagnosis of Floating-Harbor syndrome in our patient. Rubenstein-Taybi and Floating-Harbor syndrome share a similarity in molecular and physical manifestations, but because of the prevalence in Rubenstein-Taybi diagnoses, it is a syndromic condition that includes coloboma and frequently associated with each other. Therefore, a retinal exam should become part of the standard protocol for those with FHS, as proper diagnosis, examination and treatment can prevent irreversible retinal damage.

Introduction: Koleen-De Vries syndrome (KDVS) is a rare genetic condition characterized by typical facial features, intellectual disability, cardiac and renal diseases, and ophthalmic manifestations. The syndrome is known to be caused by a microdeletion in the 17q21.31 region, involving multiple genes, including the KANSL1 gene.

Case presentation: We present the case of a 9-year-old boy with no family history of ophthalmic syndromes. The patient exhibited bilateral hypopigmented iris and unilateral choroidal and retinal pigment epithelium (RPE) hypopigmentation.

Discussion: The presence of ophthalmic manifestations, such as bilateral hypopigmented iris and unilateral choroidal and RPE hypopigmentation, in a patient with KDVS adds to the clinical spectrum of this syndrome. Although the exact mechanism underlying these ocular findings is not yet fully understood, the microdeletion in the 17q21.31 region, which includes the KANSL1 gene, is likely to play a role.

Conclusion: This case highlights the importance of considering ophthalmic manifestations in individuals diagnosed with Koleen-De Vries syndrome. Further research is needed to better understand the pathogenesis and clinical implications of these ocular findings.

Introduction: Biotinidase deficiency (BD) is an inherited autosomal recessive metabolic disorder. BD has been associated with optic nerve atrophy, eye infections, and retinopathy. The most prevalent ophthalmic manifestation of BD is optic atrophy, which might be misdiagnosed as multiple sclerosis or neuromyelitis optica, especially in late-onset BD cases.

Methods: In this article, we report a 9-year-old boy with gradual vision loss. Ophthalmologic examination, Brain MRI, and several laboratory tests such as Aquaporin-4 IgG level and biotinidase level were done on the patient.

Results: Bilateral optic atrophy and impaired visual acuity were detected on examination. The patient had a biotin level of 1.25 U/min/ml (normal range 3-9 U/min/ml), favoring the BD.

Conclusion: In this study, we report a 9-year-old boy with vision loss diagnosed with BD. We also reviewed the literature to highlight the ophthalmic manifestations of BD. Ophthalmologists must consider BD in children with unexplained ophthalmologic complaints, especially when other characteristic signs of BD (e.g., developmental delay, seizure) are present. Also, patients with BD should undergo regular annual ophthalmologic examinations to be checked for any signs of eye involvement.

Background: Inherited retinopathies can initially present with high refractive error in the first decade of life, before accompanying signs or symptoms are evident.

Case presentation: A 4-year-old girl with high myopia (S-12.00 C-4.00 × 20 in the right and S-14.50 C-2.75 × 160 in the left eye), moderate visual acuity (0.3 logMAR in the right and 0.4 logMAR in the left eye), and left esotropia, presented with unremarkable past medical history and no family history of high refractive error or low vision. In optical coherence tomography imaging, macular thinning was evident, while morphology was normal. Full-field electroretinogram revealed normal implicit time recordings with reduced amplitudes in scotopic and photopic conditions. Fundus autofluorescence showed a radial pattern in both eyes. During a 5-year follow-up, significant myopia progression ensued (S-17.25 C-3.00 × 20 in the right and S-17.25 C-2.00 × 160 in the left eye), with a corresponding increase in axial length and an unchanged visual acuity. Whole-exome sequencing revealed a heterozygous termination codon variant c.212C>G (p.Ser71Ter) in RPGR, considered to be pathogenic. Segregation analysis precluded the variation in the mother and sister. A random pattern of X-chromosome inactivation was detected in the proband, without X-chromosome inactivation deviation.

Conclusion: This is the second report associating this specific RPGR mutation with high myopia and the first report to identify it in a female proband. This case provides additional evidence on the genotypic-phenotypic correlation between RPGR c.212C>G mutation and high myopia.

Purpose: This study aims to evaluate the ABCA4 variants in patients diagnosed with Stargardt disease.

Methods: This is a retrospective study designed to investigate variants in the ABCA4 in Stargardt disease and the clinical findings of the cases. Sex, age, age of onset of symptoms, best-corrected visual acuity, color fundus photography, optical coherence tomography, and visual field test of the patients were recorded. Genetic analyses were screened, and patients with at least two variants in the ABCA4 were included in this study.

Results: Twenty-seven patients diagnosed with Stargardt disease with the ABCA4 variants were included in this study. Twelve of them (44.4%) were female and fifteen (55.5%) were male. The mean age of the cases was 27.44 years (ranging from 8 to 56 years). Thirty different variants were detected in 54 ABCA4 alleles of 27 patients. The two most common pathogenic variants were c.5882 G>A p.(Gly1961Glu) and c.52C>T p.(Arg18Trp) in this cohort. Two novel variants were identified (c.3855_3856dup, c.1554 + 3_1554 + 4del) and the patient with the c.1554 + 3_1554 + 4del variant additionally had a different ABCA4 variant in trans. The other novel variant was homozygous.

Conclusions: In this study, two novel variants were described in a Turkish cohort with Stargardt disease. The variant c.52C>T p.(Arg18Trp) was the most common disease-causing variant besides the c.5882 G>A p.(Gly1961Glu) which was identified frequently in the previous studies. A larger sample size is necessary for describing different pathogenic variants and understanding the phenotype-genotype correlations.

Background: Neurofibromatosis type 1 (NF1) is a multisystem disorder that primarily affects the skin and peripheral nervous system and is caused by chromosomal abnormalities and mostly truncating variants in the NF1 gene. Ocular complications such as Lisch nodules and optic pathway gliomas (OPGs) can occur in NF1 patients. Herein, we report a novel NF1 variant in an NF1 patient with bilateral optic atrophy.

Methods: Ophthalmological examinations and genetic analyses were performed using targeted next-generation sequencing (NGS).

Results: A 14-year-old girl diagnosed with NF1 visited our hospital with decreased visual acuity (VA). The patient had no family history of NF1 or visual impairment. Brain and orbital magnetic resonance imaging revealed no remarkable findings. Ophthalmoscopy revealed temporal pallor of the optic discs, which was confirmed by optical coherence tomography findings of significant thinning of the circumpapillary retinal nerve fiber layer in both eyes. At 23 years of age, the decimal-corrected VA had deteriorated to 0.2 in the right eye and 0.1 in the left eye. Additionally, the targeted NGS panel revealed a novel heterozygous stop-gain variant (p.Tyr628Ter) in the NF1 gene; however, no pathogenic variants in OPA1 or the mitochondrial DNA were identified.

Conclusions: A patient with NF1 without OPGs developed bilateral optic atrophy and carried a novel de novo stop-gain variant of NF1. Although the relationship between NF1 variants and bilateral optic atrophy remains unclear, further investigations are required.

Purpose: Retinitis pigmentosa (RP) associated with biallelic variants in CDHR1 has rarely been reported, and detailed phenotyping data are not available. RP implies relative preservation of foveal cones, when compared to cone-rod dystrophy associated with biallelic null variants in CDHR1. We hypothesize that RP may occur in association with one or more hypomorphic CDHR1 alleles.

Materials and methods: Retrospective report of a 48-year-old patient with CDHR1-associated RP with a hypomorphic missense variant c.562 G>A, p. (Gly188Ser) and a novel, unreported variant affecting a canonical splice acceptor site (c.784-1 G>C). Clinical examination, multimodal retinal imaging, electroretinography, visual field testing, and mesopic microperimetry were undertaken 8 years apart. Scotopic microperimetry was also performed. The DNA sequence context of the variants was examined to identify theoretical CRISPR-Cas9 base-editing strategies.

Results: The patient presented at 35 years with a 12-year history of nyctalopia. His best corrected visual acuity was 20/20. Clinical presentation, multimodal retinal imaging studies, electroretinography, and mesopic microperimetry were typical of a progressive rod-cone dystrophy (i.e. classic RP). There were no scotomas within the central field as would be expected at this age in CDHR1-associated cone-rod dystrophy. Scotopic microperimetry suggested some preservation of macular cone over rod function, although both were severely impaired. A suitable CRISPR adenine base editor was identified that could theoretically correct the missense variant c.562 G>A, p. (Gly188Ser).

Conclusions: CDHR1-associated RP shows a relative preservation of cone function in the presence of a presumed hypomorphic allele and may be considered a hypomorphic disease phenotype. Further work is required to identify modifying factors that determine disease phenotype since macular dystrophy, with relative sparing of rods, may also occur with hypomorphic CDHR1 alleles.

Aim: We describe the ophthalmic manifestations of Neuropathy, ataxia, retinitis pigmentosa (NARP) syndrome in three related patients.

Methods: We examined a mother and her two children, who were carriers of the mt 8993T>G mutation. The mother, patient I, is the first known carrier within the family pedigree. Patients II and III are her children from a non-carrier father. NARP syndrome and the heteroplasmy levels were established prior to the first referral of the patients to the Ophthalmology department.We performed a visual acuity testing, followed by a biomicroscopic and fundus examination, as well as additional multimodal imaging testing: optical coherence tomography (OCT) and fundus autofluorescence (FAF), and functional testing: electroretinogram and visual field.

Results: All patients had the clinical manifestations of NARP syndrome, which were variably expressed symptomatically, on the fundus exams, electroretinogram, and visual fields.

Conclusions: Once genetically established, NARP syndrome, as other mitochondrial disorders, has a very variable progression with different degrees of severity. A multimodal approach involving both neurological and ophthalmological diagnosis of NARP syndrome is necessary in order to establish the course of the disease and the measures to be taken.

Introduction: Molecular confirmation of pathogenic sequence variants in the CHM gene is required prior to enrolment in retinal gene therapy clinical trials for choroideremia. Individuals with mild choroideremia have been reported. The molecular basis of genotype-phenotype associations is of clinical relevance since it may impact on selection for retinal gene therapy.

Methods and materials: Genetic testing and RNA analysis were undertaken in a patient with mild choroideremia to confirm the pathogenicity of a novel intronic variant in CHM and to explore the mechanism underlying the mild clinical phenotype.

Results: A 42-year-old male presented with visual field loss. Fundoscopy and autofluorescence imaging demonstrated mild choroideremia for his age. Genetic analysis revealed a variant at a splice acceptor site in the CHM gene (c.1350-3C > G). RNA analysis demonstrated two out-of-frame transcripts, suggesting pathogenicity, without any detectable wildtype transcripts. One of the two out-of-frame transcripts is present in very low levels in healthy controls.

Discussion: Mild choroideremia may result from +3 or -3 splice site variants in CHM. It is presumed that the resulting mRNA transcripts may be partly functional, thereby preventing the development of the null phenotype. Choroideremia patients with such variants may present challenges for gene therapy since there may be residual transcript activity which could result in long-lasting visual function which is atypical for this disease.