Ophthalmic Genetics最新文献

Background: Pathogenic variants in KIF11, a kinesin family gene, cause MCLMR and FEVR. In MCLMR, chorioretinal atrophy is present in the majority of cases and can be a helpful diagnostic sign.

Cases: We present the cases of two patients with chorioretinal atrophy and microcephaly who carry novel KIF11 mutations. Both patients have relatively good central vision similar inferior lacunae of retinal atrophy with relative sparing of the foveal center with.

Conclusion: Two cases with classic features of MCLMR have foveal sparing that expands the associated spectrum of ocular findings.

Background: The phenotypic variability of inherited conditions can be due to several factors including environmental, epigenetic, and genetic. One of those genetic factors is the presence of modifying loci which alter the phenotypic expression of a primary disease or phenotype-causing variant. Modifiers are known to affect penetrance, dominance, expressivity, and pleiotropy of disease.

Methods: We review the literature to highlight the impact of modifiers on inherited retinal diseases.

Results: Modifiers have been identified or associated with phenotypic variation in many inherited retinal diseases including retinitis pigmentosa and Stargardt disease. Despite being notoriously difficult to identify, proposed candidate modifiers have been identified using multiple methods including GWAS, family and population studies, and variant calling methods.

Conclusions: Overall, modifiers present themselves as an interesting target for further understanding of underlying disease pathways that could ultimately lead to therapeutic targets.

Purpose: This study sought to analyze the effect of allele mutations and gene functions specific to glaucoma susceptibility among Africans.

Methods: Potentially relevant studies were retrieved from major bibliographic databases (PubMed, Scopus, and Web of Science). Data were extracted and study-specific estimates were meta-analyzed using various models to obtain pooled results.

Results: A total of 11 studies were included in the study. The studies included a total of 3,191 cases with glaucoma and 3,013 controls across all variants. There is no association between the E396E variants of the myocilin (MYOC) gene and an increased likelihood of susceptibility to POAG (OR: 0.91 [95% CI 0.42 to 1.97]). The R141L variant of the Lysyl Oxidase Like 1 (LOXL1) gene is associated with an approximately 3-fold increased likelihood of susceptibility to exfoliative syndrome/exfoliative glaucoma (XFS/XFG) (OR: 2.68 [95% CI 0.04 to 198.94]). There is no association between the G153D variant of the LOXL1 gene and an increased likelihood of susceptibility to XFS/XFG (OR: 0.42 [95% CI 0.02 to 7.65]). The rs59892895*C variant of the Amyloid Beta Precursor Protein Binding Family B Member 2 (APBB2) is associated with a 34% increased likelihood of susceptibility to POAG (OR: 1.34 [95% CI 1.13 to 1.58]).

Conclusion: Although progress has been made in understanding the genetic basis of the pathogenesis of glaucoma, several gene mutations related to glaucoma pathogenesis in Africans are yet to be discovered, especially those associated with the pathogenesis of POAG, the most prevalent glaucoma subtype in Africa.

Purpose: We present the case of a newborn with right anophthalmia, left congenital cystic eye, and two novel variants in the ALDH1A3 gene. This report provides a comprehensive discussion of the clinical presentation, management strategies, and long-term follow-up for this rare condition.

Methods: A thorough ophthalmic examination was performed. Genetic analysis employed next-generation sequencing targeting a panel of 50 genes implicated in microphthalmia, anophthalmia, and coloboma.

Results: A one-day-old female, born to unrelated parents, was referred due to bilateral ocular malformations. Prenatal ultrasound in the third trimester had raised concerns about a congenital ocular developmental anomaly, and fetal magnetic resonance imaging suggested right anophthalmia and left eye aphakia. Postnatal examination revealed an empty right orbital cavity and a bluish lesion bulging from the left lower lid. Orbital imaging confirmed the bilateral absence of ocular structures and identified a cystic lesion in the left orbit. At three months of age, an orbital expander was placed in the right anophthalmic socket. At fifteen months, the left orbital cyst was excised due to rapid growth. Histopathological analysis revealed neuroglial tissue lining the cyst, consistent with a congenital cystic eye. A delay in psychomotor development has been noted, but no other signs of systemic conditions have been identified to date. Genetic testing identified two previously unreported ALDH1A3 variants: c.1036C>A (p.Pro346Thr) and c.981C>G (p.Tyr327*).

Conclusion: Our study identifies two previously unreported variants in the ALDH1A3 gene, broadening the understanding of its phenotypic spectrum. We report the first association between ALDH1A3 variants and congenital cystic eye.

Introduction: Round atrophic macular scars with a hyperpigmented rim in an otherwise healthy child are characteristic for prior ocular toxoplasmosis infection, the most common etiology of self-resolved retinitis in immunocompetent patients. However, a specific homozygous gene mutation (NM_148960: CLDN19:c.263T>A; p.Val88Glu) can result in a similar phenotype.

Methods: Retrospective case series (2018-2023) of children homozygous for the gene mutation CLDN19:c.263T>A; p.Val88Glu. Five children (3 families) were identified.

Results: All 5 identified affected children had been referred for reduced vision and had bilateral central macular scars. Three children (2 families) were originally diagnosed with presumed prior ocular toxoplasmosis infection. All 5 children have stable ophthalmic finding over 5-6 years of follow-up. Although other CLDN19 mutations are associated with early-onset pediatric renal disease, none from this cohort with this specific CLDN19 variant has evidence for renal disease to date.

Conclusions: CLDN19-related maculopathy can resemble and be mistaken as prior ocular toxoplasmosis infection. Unlike other CLDN19 mutations, the homozygous variant in this cohort has not been associated with renal disease to date. Genetic maculopathy should be considered in children with macular scars presumed to be related to prior ocular toxoplasmosis infection, particularly when the scarring is bilateral or familial.

Background: Pseudoxanthoma elasticum (PXE) is characterized by aberrant calcification of elastic tissues throughout the body causing varying degrees of skin, cardiac, and ocular disease. Although PXE is classically regarded as an autosomal recessive disease, recent reports have demonstrated a haploinsufficiency phenotype, in which carriers of monoallelic ATP-binding cassette transporter (ABCC6) gene mutations demonstrate mild manifestations of PXE. In this case report, we describe a patient with a monoallelic ABCC6 mutation and atypical angioid streaks.

Materials and methods: Case report.

Observations: A 31-year-old male with a history of paroxysmal tachycardia and right ventricular enlargement presented to the Eye Emergency Department complaining of bilateral eye pain with occasional flashes and bitemporal headaches. Family history was notable for unspecified heart disease in his father but no ocular disease. Best-corrected visual acuity was 20/20 in both eyes. Posterior segment examination demonstrated linear hypopigmented lesions radiating from the superior arcades of both eyes. Fundus autofluorescence of the lesions demonstrated speckled hypo- and hyperautofluorescence and fluorescein angiography revealed window defects consistent with atypical angioid streaks. Genetic testing was positive for a heterozygous c.2889C>A (p.Cys963*) mutation in the ABCC6 gene.

Conclusions and importance: The current case demonstrates the potential for PXE carriers to display both systemic and ophthalmic manifestations of the disease. Individuals with known or suspected monoallelic ABCC6 mutations may benefit from genetic counseling and regular examination.

Background: Neurofibromatosis type 1 is an autosomal dominant disorder predisposing to numerous tumors. Sporadic mutations account for half of the cases. They can occur on a mosaic pattern, which might remain undiagnosed, depending on the clinical phenotype.

Materials and methods: We carried out an extended ophthalmological assessment followed by a neurological examination as well as a cardiovascular and an orthopedic examination. The patient's DNA was drawn and next generation sequencing was used on a multigenic panel (NF1, NF2, SPRED1, LZTR1, SMARCB1, SMARCE1). A written informed consent was obtained from the patient.

Results: We report the case of a thirty-year-old male who presented for a routine ocular checkup. An incidental finding of bilateral numerous bright patchy areas was made on near infrared reflectance imaging, alongside retinal microvascular anomalies. Further questioning and examination revealed café-au-lait macules and axillary freckling, but no Lisch nodules. The patient was referred for genetic testing and a somatic mosaic mutation was found on the NF1 gene (c.4084C>T on the exon 30) with a variant allele frequency of 20%.

Conclusions: This report highlights the role of near infrared reflectance imaging in the incidental finding of choroidal alterations, which led to the diagnosis of NF1 mosaicism.

Introduction: Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA) is a recently described syndromic disease linked to ZMIZ1 genetic variants. We present a novel ZMIZ1 variant associated with a phenotype of NEDDFSA in a pediatric patient presenting with multiple anomalies including bilateral congenital ptosis and blepharophimosis, floppy eyelids, telecanthus, downward palpebral slants, myopia, cryptorchidism, hallux valgus and developmental delay.

Methods: Genetic testing performed on a large panel revealed a likely pathogenic de novo variant in the ZMIZ1 gene (heterozygous, c.881C>T), consistent with a molecular diagnosis of an autosomal dominant ZMIZ1-related condition. This variant was predicted to result in the amino acid substitution p.Thr294Ile. We also conducted a targeted literature review for reported cases of ZMIZ1 variants and associated phenotypes by searching MEDLINE through PubMed and Google Scholar from inception to May 2024. References and abstracts were screened independently by two authors. Review of the literature permitted the analysis of 27 cases of ZMIZ1 variants in patients with syndromic phenotypes.

Results: The most common ophthalmic finding was ptosis (35%). Refractive error was common (myopia in 20%, hyperopia in 12%). Other findings included strabismus (12%) and amblyopia (16%).

Discussion: We describe a novel ZMIZ1 variant associated with NEDDFSA and previously undescribed ocular features. Our literature review summarizes the ophthalmic findings in this seldom encountered disorder, thus providing clear and concise data for clinicians and improving patient care.

Introduction: Familial exudative vitreoretinopathy (FEVR) is a rare inherited disorder characterized by abnormal retinal vascular development. While it typically presents in childhood, distinguishing it from retinoblastoma in young infants can be challenging, especially in cases with asymmetric and advanced manifestations.

Methods: Case report.

Results: A 2-month-old female with microcephaly and intrauterine growth restriction (IUGR) presented with a left eye intraocular mass involving the entire globe and a flat anterior chamber. MRI showed no calcifications or contrast enhancement typical of retinoblastoma. Intravenous fluorescein angiography showed incomplete vascularization in the contralateral eye with compensatory neovascularization. The left eye was enucleated, and histology demonstrated a dysplastic retina with a retrolental membrane and abnormal vascular proliferations, confirming a diagnosis of FEVR. Genetic testing identified a novel pathogenic CTNNB1 p.Gly635* variant, inherited from the mother in whom it was present at 10-20% mosaicism.

Discussion: Variants in CTNNB1 cause of CTNNB1-neurodevelopmental disorder, characterized by microcephaly, IUGR, autism spectrum disorder, intellectual disability, and FEVR in 20-40% of cases. Affected children present at an early age and advanced stages of disease. This case highlights that FEVR can have a highly asymmetric and advanced presentation at an early age and must be distinguished from retinoblastoma in the differential diagnosis of leukocoria.

Purpose: Abetalipoproteinemia (ABL, MIM 200,100) is a rare autosomal recessive disorder caused by nonfunctional microsomal triglyceride transfer protein leading to absence of apolipoprotein B-containing lipoproteins in plasma and a retinitis pigmentosa-like fundus. The MTTP gene is expressed in retinal pigment epithelium (RPE) and ganglion cells of the human retina. Understanding ABL pathophysiology would benefit from new cellular-level clinical imaging of affected retinas.

Methods: We report multimodal retinal imaging in two patients with ABL. Case 1 (67-year-old woman) exhibited a bilateral decline of vision due to choroidal neovascularization (CNV) associated with angioid streaks and calcified Bruch membrane. Optical coherence tomography were consistent with basal laminar deposits and subretinal drusenoid deposits (SDD).

Results: Case 2 (46-year-old woman) exhibited unusual hyperpigmentation at the right fovea with count-fingers vision and a relatively unremarkable left fundus with 20/30 vision. The left eye exhibited the presence of nodular drusen and SDD and the absence of macular xanthophyll pigments.

Conclusion: We propose that mutated MTTP within the retina may contribute to ABL retinopathy in addition to systemic deficiencies of fat-soluble vitamins. This concept is supported by a new mouse model with RPE-specific MTTP deficiency and a retinal degeneration phenotype. The observed range of human pathology, including angioid streaks, underscores the need for continued monitoring in adulthood, especially for CNV, a treatable condition.