A FBN1 variant manifesting as non-syndromic ectopia lentis with retinal detachment: clinical and genetic characteristics

Stephenson, Kirk; Dockery, Adrian; O’Keefe, Michael; Green, Andrew J.; Farrar, G. Jane; Keegan, David

doi:10.1038/s41433-019-0580-2

“…In our generated mutant lines ( prss56 re11 and fbn1 re12 ), the observed phenotypes showed a close resemblance to the ocular phenotype described in patients with posterior microphthalmia and MFS, respectively, and to previous reported mouse models. 11 , 33 , 35 , 46 The recognized advantages of zebrafish as an animal model in functional genetics, such as rapid eye development, small size, large clutches of fertilized eggs and the potential for higher throughput assays, together with the evidence and the pipeline provided in our study, highlight the potential of zebrafish for modelling ocular diseases.…”

Section: Discussionmentioning

confidence: 79%

Zebrafish: An In Vivo Screening Model to Study Ocular Phenotypes

Quint

¹

,

Tadema

²

,

Crins

³

et al. 2022

Trans. Vis. Sci. Tech.

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Purpose To establish a set of assays that allow the in vivo screening of candidate genes for ocular diseases in zebrafish, with an emphasis on refractive error. Methods Our pipeline includes the most relevant ocular screening measurements to assess (1) ocular biometry using spectral domain optical coherence tomography, (2) refractive status using an eccentric photorefractor, (3) intraocular pressure by tonometry, and (4) optokinetic response to study visual capability in zebrafish. To validate our pipeline and to demonstrate the potential of zebrafish as a valid animal model, we chose two well-characterized genes with an ocular phenotype ( PRSS56 and FBN1 ) and generated two mutant zebrafish lines ( prss56 and fbn1 ). Mutant fish were assessed at 2, 4, and 6 months after fertilization. Results With the proposed phenotyping pipeline, we showed that ocular biometry, refractive status, intraocular pressure, and visual function can be studied in zebrafish. In the prss56 mutant, the pipeline revealed a dramatic decrease in axial length, mainly owing to a decreased vitreous chamber depth, whereas in the fbn1 mutant, ectopia lentis was the most distinctive ocular phenotype observed. Tonometry in both mutant lines showed an increase in intraocular pressure. Conclusions The proposed pipeline was applied successfully in zebrafish and can be used for future genetic screenings of candidate genes. While validating our pipeline, we found a close resemblance between the ocular manifestations in the zebrafish mutants and patients harboring mutations in PRSS56 and FBN1 . Our results support the validity of our pipeline and highlight the potential of zebrafish as an animal model for in vivo screening of candidate genes for ocular diseases.

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“…The overall diagnostic yield of Marfan syndrome/ectopia lentis was 81.63% (40/49), of which the number of cases caused by DNM accounted for 47.51% (19/40). FBN1 was the predominantly gene for Marfan syndrome/ectopia lentis, 11 84.21% ( n = 16) of the variants were missense, 10.53% ( n = 2) were splice and intron, and 5.26% (1/19) were synonymous. Five IED subgroups, albinism ( n = 7), BCD ( n = 18), corneal abnormalities (corneal dystrophy, n = 12), glaucoma ( n = 17), and HM ( n = 25), caused entirely by paternally and maternally inherited mutations, whereas DNM had no apparent role in the etiology of the disease.…”

Section: Resultsmentioning

confidence: 99%

De Novo Mutations Contributes Approximately 7% of Pathogenicity in Inherited Eye Diseases

Li

¹

,

He

²

,

Yang

³

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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Purpose The purpose of this study was to describe genotype-phenotype associations and novel insights into genetic characteristics in a trio-based cohort of inherited eye diseases (IEDs). Methods To determine the etiological role of de novo mutations (DNMs) and genetic profile in IEDs, we retrospectively reviewed a large cohort of proband-parent trios of Chinese origin. The patients underwent a detailed examination and was clinically diagnosed by an ophthalmologist. Panel-based targeted exome sequencing was performed on DNA extracted from blood samples, containing coding regions of 792 IED-causative genes and their flanking exons. All participants underwent genetic testing. Results All proband-parent trios were divided into 22 subgroups, the overall diagnostic yield was 48.67% (605/1243), ranging from 4% to 94.44% for each of the subgroups. A total of 108 IED-causative genes were identified, with the top 24 genes explaining 67% of the 605 genetically solved trios. The genetic etiology of 6.76% (84/1243) of the trio was attributed to disease-causative DNMs, and the top 3 subgroups with the highest incidence of DNM were aniridia ( n = 40%), Marfan syndrome/ectopia lentis ( n = 38.78%), and retinoblastoma ( n = 37.04%). The top 10 genes have a diagnostic yield of DNM greater than 3.5% in their subgroups, including PAX6 (40.00%), FBN1 (38.78%), RB1 (37.04%), CRX (10.34%), CHM (9.09%), WFS1 (8.00%), RP1L1 (5.88%), RS1 (5.26%), PCDH15 (4.00%), and ABCA4 (3.51%). Additionally, the incidence of DNM in offspring showed a trend of correlation with paternal age at reproduction, but not statistically significant with paternal ( P = 0.154) and maternal ( P = 0.959) age at reproduction. Conclusions Trios-based genetic analysis has high accuracy and validity. Our study helps to quantify the burden of the full spectrum IED caused by each gene, offers novel potential for elucidating etiology, and plays a crucial role in genetic counseling and patient management.

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“…EL with other ocular phenotypes such as microspherophakia, retinal detachment, and secondary glaucoma, and systemic phenotypes such as cardiovascular and skeletal abnormalities have been reported to be associated with missense mutations in FBN1. 37,38 Patients with congenital lens heterotopia have also been reported with China-associated mutations in FBN1 , of which the majority are missense mutations (49/65) 39 . Compared with nonsense and frameshift mutations, FBN1 missense mutations have been reported to be associated with a higher prevalence of EL and earlier onset of pulmonary artery dilatation 40 .…”

Section: Discussionmentioning

confidence: 99%