-
The British Journal of Ophthalmology Dec 2022To identify the mutation spectrum and genotype-phenotype correlations of () mutations in a Chinese cohort with congenital ectopia lentis (EL).
AIMS
To identify the mutation spectrum and genotype-phenotype correlations of () mutations in a Chinese cohort with congenital ectopia lentis (EL).
METHODS
Patients clinically suspected of congenital zonulopathy were screened using panel-based next-generation sequencing followed by multiplex ligation-dependent probe amplification. All the probands were subjected to thorough ocular examinations. Molecular and clinical data were integrated in pursuit of genotype-phenotype correlation.
RESULTS
A total of 131 probands of mutations from unrelated families were recruited. Around 65% of the probands were children younger than 9 years old. Overall, 110 distinct mutations were identified, including 39 novel ones. The most at-risk regions were exons 13, 2, 6, 15, 24 and 33 in descending order of mutation frequency. The most prevalent mutation was c.184C>T (seven, 5.34%) in the coding sequence and c.5788+5G>A (three, 2.29%) in introns. Missense mutations were the most frequent type (103, 78.63%); half of which were distributed in the N-terminal regions (53, 51.46%). The majority of missense mutations were detected in one of the calcium-binding epidermal growth factor-like domains (62, 60.19%), and 39 (62.90%) of them were substitutions of conserved cysteine residues. Microspherophakia (MSP) was found in 15 patients (11.45%). Mutations in the middle region (exons 22-42), especially exon 26, had higher risks of combined MSP (OR, 5.51 (95% CI 1.364 to 22.274), p=0.017).
CONCLUSIONS
This study extended the knowledge of the mutation spectrum and provided novel insights into its clinical correlation regarding EL and MSP in the Chinese population.
Topics: Humans; Ectopia Lentis; Fibrillin-1; Fibrillins; Marfan Syndrome; Microfilament Proteins; Phenotype; Mutation; Genotype; China; DNA Mutational Analysis
PubMed: 34281902
DOI: 10.1136/bjophthalmol-2021-319084 -
BMC Medical Genomics Sep 2021Microspherophakia (MSP, OMIM 251,750) is a rare inherited autosomal recessive eye disorder characterized by small spherically shaped lens. Several studies have...
BACKGROUND
Microspherophakia (MSP, OMIM 251,750) is a rare inherited autosomal recessive eye disorder characterized by small spherically shaped lens. Several studies have indicated that the transforming growth factor-beta (TGF-beta) binding proteins(LTBP2) gene mutation is the predominant cause of MSP. In our study, novel compound heterozygous mutations in the LTBP2 gene associated with MSP were reported, which was different from previous reported homozygous mutations.
CASE PRESENTATION
The proband was an 18-year-old male in Western China with bilateral MSP, accompanied by ectopia lentis, secondary glaucoma and blindness in both eyes. In our hospital, he received bilateral lens resection and trabeculectomy combined with peripheral iridotomy. Using next-generation sequencing (NGS)-based gene panel tests, we identified pathogenic mutations in the peripheral blood DNA sample from the proband: c.3614_3618dupCTGGC (exon24, NM_000428) and c.2819G > A (exon18, NM_000428). The presence of the novel compound heterozygous mutations in the LTBP2 gene was linked with the development of MSP. Sanger sequencing confirmed the existence of one of the two variants in each parent respectively.
CONCLUSION
Our results demonstrated a rare case of MSP phenotype associated with novel compound heterozygous mutations in the LTBP2 gene using NGS technology.
Topics: Corneal Diseases; Ectopia Lentis; Glaucoma; Iris
PubMed: 34535142
DOI: 10.1186/s12920-021-01080-0 -
Matrix Biology : Journal of the... Jan 2021Latent-transforming growth factor beta-binding protein 2 (LTBP-2) is a major component of arterial and lung tissue and of the ciliary zonule, the system of extracellular...
Latent-transforming growth factor beta-binding protein 2 (LTBP-2) is a major component of arterial and lung tissue and of the ciliary zonule, the system of extracellular fibers that centers and suspends the lens in the eye. LTBP-2 has been implicated previously in the development of extracellular microfibrils, although its exact role remains unclear. Here, we analyzed the three-dimensional structure of the ciliary zonule in wild type mice and used a knockout model to test the contribution of LTBP-2 to zonule structure and mechanical properties. In wild types, zonular fibers had diameters of 0.5-1.0 micrometers, with an outer layer of fibrillin-1-rich microfibrils and a core of fibrillin-2-rich microfibrils. LTBP-2 was present in both layers. The absence of LTBP-2 did not affect the number of fibers, their diameters, nor their coaxial organization. However, by two months of age, LTBP-2-depleted fibers began to rupture, and by six months, a fully penetrant ectopia lentis phenotype was present, as confirmed by in vivo imaging. To determine whether the seemingly normal fibers of young mice were compromised mechanically, we compared zonule stress/strain relationships of wild type and LTBP-2-deficient mice and developed a quasi-linear viscoelastic engineering model to analyze the resulting data. In the absence of LTBP-2, the ultimate tensile strength of the zonule was reduced by about 50%, and the viscoelastic behavior of the fibers was altered significantly. We developed a harmonic oscillator model to calculate the forces generated during saccadic eye movement. Model simulations suggested that mutant fibers are prone to failure during rapid rotation of the eyeball. Together, these data indicate that LTBP-2 is necessary for the strength and longevity of zonular fibers, but not necessarily for their formation.
Topics: Animals; Cilia; Ectopia Lentis; Eye; Fibroblasts; Humans; Latent TGF-beta Binding Proteins; Longevity; Mice; Mice, Knockout; Microfibrils; Ocular Physiological Phenomena; Saccades; Tensile Strength; Viscoelastic Substances
PubMed: 33039488
DOI: 10.1016/j.matbio.2020.10.002 -
Beyoglu Eye Journal 2023We present the long-term results of the implantation of a capsular tension ring (CTR) and Ahmed capsular tension segments (CTS) together for the management of...
We present the long-term results of the implantation of a capsular tension ring (CTR) and Ahmed capsular tension segments (CTS) together for the management of mikrospherophakia in a 35-year-old female patient. The patient had uncontrolled secondary angle-closure glaucoma, despite previous laser peripheral iridotomy, and visual impairment due to lenticular myopia. Clear lens extraction was performed under general anesthesia. The capsular bag was stabilized with a classical CTR and two Ahmed CTSs sutured to the sclera. A single-piece hydrophobic acrylic intraocular lens (32.0 D for the right and 30.0 D for the left eye) was implanted in the capsular bag. The anterior chamber depth was stable, and intraocular pressure (IOP) was 10-12 mmHg in both eyes in the early post-operative period. The bag complex gradually moved forward, IOP gradually increased, and the left eye underwent trabeculectomy surgery in the 4 year of follow-up.
PubMed: 37521882
DOI: 10.14744/bej.2023.57625 -
American Journal of Ophthalmology Case... Dec 2022To report a case of congenital ciliary body cysts causing microspherophakia, ectopia lentis, and secondary angle closure glaucoma in an infant.
PURPOSE
To report a case of congenital ciliary body cysts causing microspherophakia, ectopia lentis, and secondary angle closure glaucoma in an infant.
OBSERVATIONS
A 16-month-old male was found to have bilateral ciliary body cysts associated with zonular laxity or absence causing microspherophakia and ectopia lentis as demonstrated on multimodal imaging. Additionally, the patient had secondary angle closure glaucoma which was likely multi-factorial related to both lens abnormalities and anterior displacement of the iris from the cysts themselves. The patient underwent lensectomy and cyst removal which resulted in intraocular pressure stabilization and visual rehabilitation.
CONCLUSIONS AND IMPORTANCE
Congenital ciliary body cysts are a rare cause of lens abnormalities and secondary angle closure glaucoma in children. Information regarding genetic underpinnings or systemic associations is limited.
PubMed: 36275188
DOI: 10.1016/j.ajoc.2022.101723 -
BMC Medical Genetics May 2018Microspherophakia is a rare autosomal recessive eye disorder characterized by small spherical lens. It may present as an isolated finding or in association with other...
BACKGROUND
Microspherophakia is a rare autosomal recessive eye disorder characterized by small spherical lens. It may present as an isolated finding or in association with other ocular and/or systemic disorders. This clinical and genetic heterogeneity requires the study of large genes (ADAMTSL4, FBN1, LTBP2, ADAMTSL-10 and ADAMTSL17). The purpose of the present study is to identify the genetic cause of this pathology in a consanguineous Spanish family.
METHODS
A clinical exome sequencing experiment was executed by the TruSight One® Sequencing Panel (TSO) from Illumina©. Sanger sequencing was used to validate the NGS results.
RESULTS
Only the insertion of an adenine in exon 36 of the LTBP2 gene (c.5439_5440insA) was associated with pathogenicity. This new mutation was validated by Sanger sequencing and segregation analysis was also performed. Haplotype analyses using the polymorphic markers D14S1025, D14S43 and D14S999 close to the LTBP2 gene indicated identity by descent in this family.
CONCLUSION
We describe the first case of a microspherophakia phenotype associated with a novel homozygous mutation in the LTBP2 gene in a consanguineous Caucasian family by means of NGS technology.
Topics: Adult; Consanguinity; Corneal Diseases; Ectopia Lentis; Exons; Female; Genetic Association Studies; Genetic Predisposition to Disease; Glaucoma; High-Throughput Nucleotide Sequencing; Humans; Iris; Latent TGF-beta Binding Proteins; Male; Mutagenesis, Insertional; Mutation; Pedigree; Point Mutation; Sequence Analysis, DNA; Spain; White People
PubMed: 29751740
DOI: 10.1186/s12881-018-0590-0 -
Frontiers in Genetics 2022Geleophysic dysplasia and Weill-Marchesani syndrome from the acromelic dysplasias group of genetic skeletal disorders share remarkable clinical and genetic overlap....
Geleophysic dysplasia and Weill-Marchesani syndrome from the acromelic dysplasias group of genetic skeletal disorders share remarkable clinical and genetic overlap. Ophthalmological, physical, radiological examinations were conducted with a female patient in her early 30 s. Whole exome sequencing followed by Sanger sequencing validation was performed to identify the genetic cause. The patient, born to consanguineous Chinese parents, presented with microspherophakia, lens subluxation, high myopia, short statue, small hands and feet, stiff joints, and thickened skin. A diagnosis of Weill-Marchesani syndrome was initially made for her. However, genetic testing reveals that the patient is homozygous for the c.1966G>A (p.Gly656Ser) variant in , and that the patient's healthy mother and daughter are heterozygous for the variant. As mutations in are known to cause autosomal recessive geleophysic dysplasia, the patient is re-diagnosed with geleophysic dysplasia in terms of her genotype and phenotype. The present study describes the clinical phenotype of the homozygous p. Gly656Ser variant, which increases our understanding of the genotype-phenotype correlation in acromelic dysplasias.
PubMed: 36246610
DOI: 10.3389/fgene.2022.1014188 -
Trauma Case Reports Dec 2023We report a case of traumatic bleb leak following trabeculectomy and dislocated intraocular lens treated with combined minimally invasive conjunctival surgery (MICS) and...
PURPOSE
We report a case of traumatic bleb leak following trabeculectomy and dislocated intraocular lens treated with combined minimally invasive conjunctival surgery (MICS) and lens repositioning.
OBSERVATIONS
A 36-year-old woman with a history of phacomorphic glaucoma secondary to microspherophakia and status post trabeculectomy underwent combined MICS and lens repositioning for a late-onset bleb leak and dislocated intraocular lens following minor trauma. The patient's vision rapidly improved postoperatively with prompt resolution of hypotony.
CONCLUSION/IMPORTANCE
MICS is an effective treatment for traumatic bleb leak following trabeculectomy that can be a particularly useful approach for patients undergoing concurrent ophthalmic surgery.
PubMed: 37810536
DOI: 10.1016/j.tcr.2023.100936 -
The National Medical Journal of India 2019
Topics: Child; Corneal Diseases; Ectopia Lentis; Female; Glaucoma; Humans; Iris; Lens, Crystalline
PubMed: 32769256
DOI: 10.4103/0970-258X.291302 -
JPMA. the Journal of the Pakistan... Mar 2020Latent transforming growth factor beta binding protein 2 (LTBP2) plays a critical role in the development of connective tissue structure and function. Mutations in gene...
Latent transforming growth factor beta binding protein 2 (LTBP2) plays a critical role in the development of connective tissue structure and function. Mutations in gene encoding LTBP2 are known to cause syndromic and a non-syndromic microspherophakia. Here, we present a 'first' report of genetic linkage of microspherophakia (MSP) to LTBP2 locus in a large consanguineous Pakistani family with four affected individuals in three loops. Using polymorphic microsatellite markers, haplotypes and linkage analysis, the diseased phenotype in MSP001 family was mapped to the LTBP2 gene. A maximum two point Logarithm of the odds (LOD) score of 4.16 was obtained with marker D14S284 at θ =0. Mutational analysis of exon 36 of LTBP2 using Sanger's sequencing did not reveal any previously reported mutations. Further analysis of the remaining exons are required to identify the causative variant.
Topics: Adolescent; Chromosome Mapping; Chromosomes, Human, Pair 14; Consanguinity; Corneal Diseases; Ectopia Lentis; Female; Glaucoma; Humans; Iris; Latent TGF-beta Binding Proteins; Lens Subluxation; Male; Medical History Taking; Mutation; Myopia; Pakistan; Pedigree; Young Adult
PubMed: 32207437
DOI: 10.5455/JPMA.302440