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Genetics in Ophthalmology
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Genetics in Ophthalmology

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (15 February 2021) | Viewed by 51722

Special Issue Editors

Dr. Jean-Michel Rozet

E-Mail Website
Guest Editor
Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Imagine–Institute of Genetic Diseases, Paris Descartes University, 75015 Paris, France
Interests: congenital and childhood-onset inherited retinal dystrophy, including ciliopathies (nonsyndromic and syndromic); primary optic neuropathy; ocular developmental defects; gene discovery; genotype–phenotype associations; genome sequencing; noncoding variant analysis; antisense oligonucleotide-mediated therapy of intronic mutations; ocular genomic medicine
Prof. Dr. Hélene Dollfus

E-Mail Website
Guest Editor
Centre de Référence pour les Affections Génétiques Ophtalmologiques CARGO, CHRU Strasbourg, INSERM 1112, Université de Strasbourg, 67081 Strasbourg, France
Interests: human genetics; syndromic retinal dystrophy; ciliopathies; genome biology; genome sequencing; gene discovery; noncoding variant analysis; genotype–phenotype associations in retinal disease; pharmaceutical and gene therapies; ocular genomic medicine

Special Issue Information

Dear Colleagues,

Heritable ocular diseases are among the most common causes of eyesight loss in childhood and young adults in developed countries. Diagnosing these disorders has long been received as a life sentence to blindness, and disease management was reduced to low vision-aids, prevention of complications, and genetic counseling, often with an uncertain outcome.

In less than three decades, the combination of genome investigation and ophthalmic imaging have revolutionized the field. Hundreds of causal genes and dozens of biological pathways and pathomechanisms have been discovered, novel insights into disease development have been gained, prognostic-valuable genotype–phenotype correlations have been identified, and a wide range of therapeutic developments are emerging in clinical research or even practice.

This Special Issue of Genes aims at highlighting some of these advances and the transformation of the management of monogenic hereditary ocular diseases as well as today’s and tomorrow’s challenges in ocular genomic medicine.

Dr. Jean-Michel Rozet
Prof. Hélene Dollfus
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Hereditary ocular diseases
  • Clinical and molecular diagnosis
  • Ophthalmic genetics
  • Ocular genomic medicine
  • Therapies

Published Papers (15 papers)

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Research

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16 pages, 4422 KiB  
Article
Cone Dystrophy Associated with a Novel Variant in the Terminal Codon of the RPGR-ORF15
by Vlasta Hadalin, Maja Šuštar, Marija Volk, Aleš Maver, Jana Sajovic, Martina Jarc-Vidmar, Borut Peterlin, Marko Hawlina and Ana Fakin
Genes 2021, 12(4), 499; https://doi.org/10.3390/genes12040499 - 29 Mar 2021
Cited by 7 | Viewed by 2502
Abstract
Mutations in RPGRORF15 are associated with rod-cone or cone/cone-rod dystrophy, the latter associated with mutations at the distal end. We describe the phenotype associated with a novel variant in the terminal codon of the RPGRORF15 c.3457T>A (Ter1153Lysext*38), which results in a [...] Read more.
Mutations in RPGRORF15 are associated with rod-cone or cone/cone-rod dystrophy, the latter associated with mutations at the distal end. We describe the phenotype associated with a novel variant in the terminal codon of the RPGRORF15 c.3457T>A (Ter1153Lysext*38), which results in a C-terminal extension. Three male patients from two families were recruited, aged 31, 35, and 38 years. Genetic testing was performed by whole exome sequencing. Filtered variants were analysed according to the population frequency, ClinVar database, the variant’s putative impact, and predicted pathogenicity; and were classified according to the ACMG guidelines. Examination included visual acuity (Snellen), colour vision (Ishihara), visual field, fundus autofluorescence (FAF), optical coherence tomography (OCT), and electrophysiology. All patients were myopic, and had central scotoma and reduced colour vision. Visual acuities on better eyes were counting fingers, 0.3 and 0.05. Electrophysiology showed severely reduced cone-specific responses and macular dysfunction, while the rod-specific response was normal. FAF showed hyperautofluorescent ring centred at the fovea encompassing an area of photoreceptor loss approximately two optic discs in diameter (3462–6342 μm). Follow up after 2–11 years showed enlargement of the diameter (avg. 100 μm/year). The novel c.3457T>A (Ter1153Lysext*38) mutation in the terminal RPGRORF15 codon is associated with cone dystrophy, which corresponds to the previously described phenotypes associated with mutations in the distal end of the RPGRORF15. Minimal progression during follow-up years suggests a relatively stable disease after the initial loss of the central cones. Full article
(This article belongs to the Special Issue Genetics in Ophthalmology)
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13 pages, 4830 KiB  
Article
Genetic Causes of Oculocutaneous Albinism in Pakistani Population
by Zureesha Sajid, Sairah Yousaf, Yar M. Waryah, Tauqeer A. Mughal, Tasleem Kausar, Mohsin Shahzad, Ali R. Rao, Ansar A. Abbasi, Rehan S. Shaikh, Ali M. Waryah, Saima Riazuddin and Zubair M. Ahmed
Genes 2021, 12(4), 492; https://doi.org/10.3390/genes12040492 - 28 Mar 2021
Cited by 5 | Viewed by 4231
Abstract
Melanin pigment helps protect our body from broad wavelength solar radiation and skin cancer. Among other pigmentation disorders in humans, albinism is reported to manifest in both syndromic and nonsyndromic forms as well as with varying inheritance patterns. Oculocutaneous albinism (OCA), an autosomal [...] Read more.
Melanin pigment helps protect our body from broad wavelength solar radiation and skin cancer. Among other pigmentation disorders in humans, albinism is reported to manifest in both syndromic and nonsyndromic forms as well as with varying inheritance patterns. Oculocutaneous albinism (OCA), an autosomal recessive nonsyndromic form of albinism, presents as partial to complete loss of melanin in the skin, hair, and iris. OCA has been known to be caused by pathogenic variants in seven different genes, so far, according to all the currently published population studies. However, the detection rate of alleles causing OCA varies from 50% to 90%. One of the significant challenges of uncovering the pathological variant underlying disease etiology is inter- and intra-familial locus heterogeneity. This problem is especially pertinent in highly inbred populations. As examples of such familial locus heterogeneity, we present nine consanguineous Pakistani families with segregating OCA due to variants in one or two different known albinism-associated genes. All of the identified variants are predicted to be pathogenic, which was corroborated by several in silico algorithms and association with diverse clinical phenotypes. We report an individual affected with OCA carries heterozygous, likely pathogenic variants in TYR and OCA2, raising the question of a possible digenic inheritance. Altogether, our study highlights the significance of exome sequencing for the complete genetic diagnosis of inbred families and provides the ramifications of potential genetic interaction and digenic inheritance of variants in the TYR and OCA2 genes. Full article
(This article belongs to the Special Issue Genetics in Ophthalmology)
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21 pages, 5369 KiB  
Article
A Bibliometric and Citation Network Analysis of Myopia Genetics
by Cristina Alvarez-Peregrina, Clara Martinez-Perez, Cesar Villa-Collar and Miguel Ángel Sánchez-Tena
Genes 2021, 12(3), 447; https://doi.org/10.3390/genes12030447 - 21 Mar 2021
Cited by 12 | Viewed by 3126
Abstract
Background: To aim of the study was describe the growth of publications on genetic myopia and understand the current research landscape through the analysis of citation networks, as well as determining the different research areas and the most cited publications. Methods: The Web [...] Read more.
Background: To aim of the study was describe the growth of publications on genetic myopia and understand the current research landscape through the analysis of citation networks, as well as determining the different research areas and the most cited publications. Methods: The Web of Science database was used to perform the publication search, looking for the terms “genetic*” AND “myopia” within the period between 2009 and October 2020. The CitNetExplorer and CiteSpace software were then used to conduct the publication analysis. To obtain the graphics, the VOSviewer software was used. Results: A total of 721 publications were found with 2999 citations generated within the network. The year 2019 was singled out as a “key year”, taking into account the number of publications that emerged in that year and given that in 2019, 200 loci associated with refractive errors and myopia were found, which is considered to be great progress. The most widely cited publication was “Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia”, an article by Verhoeven et al., which was published in 2013. By using the clustering function, we were able to establish three groups that encompassed the different research areas within this field: heritability rate of myopia and its possible association with environmental factors, retinal syndromes associated with myopia and the genetic factors that control and influence axial growth of the eye. Conclusions: The citation network offers a comprehensive and objective analysis of the main papers that address genetic myopia. Full article
(This article belongs to the Special Issue Genetics in Ophthalmology)
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15 pages, 1375 KiB  
Article
Whole Locus Sequencing Identifies a Prevalent Founder Deep Intronic RPGRIP1 Pathologic Variant in the French Leber Congenital Amaurosis Cohort
by Isabelle Perrault, Sylvain Hanein, Xavier Gérard, Nelson Mounguengue, Ryme Bouyakoub, Mohammed Zarhrate, Cécile Fourrage, Fabienne Jabot-Hanin, Béatrice Bocquet, Isabelle Meunier, Xavier Zanlonghi, Josseline Kaplan and Jean-Michel Rozet
Genes 2021, 12(2), 287; https://doi.org/10.3390/genes12020287 - 18 Feb 2021
Cited by 3 | Viewed by 2352
Abstract
Leber congenital amaurosis (LCA) encompasses the earliest and most severe retinal dystrophies and can occur as a non-syndromic or a syndromic disease. Molecular diagnosis in LCA is of particular importance in clinical decision-making and patient care since it can provide ocular and extraocular [...] Read more.
Leber congenital amaurosis (LCA) encompasses the earliest and most severe retinal dystrophies and can occur as a non-syndromic or a syndromic disease. Molecular diagnosis in LCA is of particular importance in clinical decision-making and patient care since it can provide ocular and extraocular prognostics and identify patients eligible to develop gene-specific therapies. Routine high-throughput molecular testing in LCA yields 70%–80% of genetic diagnosis. In this study, we aimed to investigate the non-coding regions of one non-syndromic LCA gene, RPGRIP1, in a series of six families displaying one single disease allele after a gene-panel screening of 722 LCA families which identified 26 biallelic RPGRIP1 families. Using trio-based high-throughput whole locus sequencing (WLS) for second disease alleles, we identified a founder deep intronic mutation (NM_020366.3:c.1468-128T>G) in 3/6 families. We employed Sanger sequencing to search for the pathologic variant in unresolved LCA cases (106/722) and identified three additional families (two homozygous and one compound heterozygous with the NM_020366.3:c.930+77A>G deep intronic change). This makes the c.1468-128T>G the most frequent RPGRIP1 disease allele (8/60, 13%) in our cohort. Studying patient lymphoblasts, we show that the pathologic variant creates a donor splice-site and leads to the insertion of the pseudo-exon in the mRNA, which we were able to hamper using splice-switching antisense oligonucleotides (AONs), paving the way to therapies. Full article
(This article belongs to the Special Issue Genetics in Ophthalmology)
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9 pages, 1012 KiB  
Article
Identification of Possible Risk Variants of Familial Strabismus Using Exome Sequencing Analysis
by Joon-Yong An, Jae Ho Jung, Leejee Choi, Eric D. Wieben and Brian G. Mohney
Genes 2021, 12(1), 75; https://doi.org/10.3390/genes12010075 - 10 Jan 2021
Cited by 2 | Viewed by 2656
Abstract
Purpose: To investigate candidate genes associated with familial strabismus and propose a theory of their interaction in familial strabismus associated with early neurodevelopment. Methods: Eighteen families, including 53 patients diagnosed with strabismus and 34 unaffected family members, were analyzed. All patients with strabismus [...] Read more.
Purpose: To investigate candidate genes associated with familial strabismus and propose a theory of their interaction in familial strabismus associated with early neurodevelopment. Methods: Eighteen families, including 53 patients diagnosed with strabismus and 34 unaffected family members, were analyzed. All patients with strabismus and available unaffected family members were evaluated using whole exome sequencing. The primary outcome was to identify rare occurring variants among affected individuals and investigate the evidence of their genetic heterogeneity. These results were compared with exome sequencing analysis to build a comprehensive genetic profile of the study families. Results: We observed 60 variants from 58 genes in 53 patients diagnosed with strabismus. We prioritized the most credible risk variants, which showed clear segregation in family members affected by strabismus. As a result, we found risk variants in four genes (FAT3, KCNH2, CELSR1, and TTYH1) in five families, suggesting their role in development of familial strabismus. In other families, there were several rare genetic variants in affected cases, but we did not find clear segregation pattern across family members. Conclusion: Genomic sequencing holds great promise in elucidating the genetic causes of strabismus; further research with larger cohorts or other related approaches are warranted. Full article
(This article belongs to the Special Issue Genetics in Ophthalmology)
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23 pages, 2271 KiB  
Article
Whole Exome Sequencing in Coloboma/Microphthalmia: Identification of Novel and Recurrent Variants in Seven Genes
by Patricia Haug, Samuel Koller, Jordi Maggi, Elena Lang, Silke Feil, Agnès Wlodarczyk, Luzy Bähr, Katharina Steindl, Marianne Rohrbach, Christina Gerth-Kahlert and Wolfgang Berger
Genes 2021, 12(1), 65; https://doi.org/10.3390/genes12010065 - 6 Jan 2021
Cited by 16 | Viewed by 3273
Abstract
Coloboma and microphthalmia (C/M) are related congenital eye malformations, which can cause significant visual impairment. Molecular diagnosis is challenging as the genes associated to date with C/M account for only a small percentage of cases. Overall, the genetic cause remains unknown in up [...] Read more.
Coloboma and microphthalmia (C/M) are related congenital eye malformations, which can cause significant visual impairment. Molecular diagnosis is challenging as the genes associated to date with C/M account for only a small percentage of cases. Overall, the genetic cause remains unknown in up to 80% of patients. High throughput DNA sequencing technologies, including whole-exome sequencing (WES), are therefore a useful and efficient tool for genetic screening and identification of new mutations and novel genes in C/M. In this study, we analyzed the DNA of 19 patients with C/M from 15 unrelated families using singleton WES and data analysis for 307 genes of interest. We identified seven novel and one recurrent potentially disease-causing variants in CRIM1, CHD7, FAT1, PTCH1, PUF60, BRPF1, and TGFB2 in 47% of our families, three of which occurred de novo. The detection rate in patients with ocular and extraocular manifestations (67%) was higher than in patients with an isolated ocular phenotype (46%). Our study highlights the significant genetic heterogeneity in C/M cohorts and emphasizes the diagnostic power of WES for the screening of patients and families with C/M. Full article
(This article belongs to the Special Issue Genetics in Ophthalmology)
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10 pages, 1506 KiB  
Article
Identification of Novel Copy Number Variations of VCAN Gene in Three Chinese Families with Wagner Disease
by Songshan Li, Mengke Li, Limei Sun, Xiujuan Zhao, Ting Zhang, Li Huang, Sijian Huang, Chonglin Chen, Zhirong Wang and Xiaoyan Ding
Genes 2020, 11(9), 992; https://doi.org/10.3390/genes11090992 - 25 Aug 2020
Cited by 4 | Viewed by 2194
Abstract
The VCAN/versican gene encodes an important component of the extracellular matrix, the chondroitin sulfate proteoglycan 2 (CSPG2/versican). Heterozygous variants targeting exon 8 of VCAN have been shown to cause Wagner disease, a rare autosomal dominant non-syndromic vitreoretinopathy that induces retinal detachment, cataracts and [...] Read more.
The VCAN/versican gene encodes an important component of the extracellular matrix, the chondroitin sulfate proteoglycan 2 (CSPG2/versican). Heterozygous variants targeting exon 8 of VCAN have been shown to cause Wagner disease, a rare autosomal dominant non-syndromic vitreoretinopathy that induces retinal detachment, cataracts and permanent visual loss. In this study, we report on six patients from three unrelated families with Wagner disease in whom we identified three novel copy number variations of VCAN. Quantitative real-time polymerase chain reaction analysis identified deletions, including one exon–intron boundary of exon 8 or both exons 8 and 9, causing the haploinsufficiency of VCAN mRNAs. Full article
(This article belongs to the Special Issue Genetics in Ophthalmology)
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11 pages, 1895 KiB  
Article
Mutation Spectrum and De Novo Mutation Analysis in Stickler Syndrome Patients with High Myopia or Retinal Detachment
by Li Huang, Chonglin Chen, Zhirong Wang, Limei Sun, Songshan Li, Ting Zhang, Xiaoling Luo and Xiaoyan Ding
Genes 2020, 11(8), 882; https://doi.org/10.3390/genes11080882 - 3 Aug 2020
Cited by 9 | Viewed by 3223
Abstract
Stickler syndrome is a connective tissue disorder that affects multiple systems, including the visual system. Seven genes were reported to cause Stickler syndrome in patients with different phenotypes. In this study, we aimed to evaluate the mutation features of the phenotypes of high [...] Read more.
Stickler syndrome is a connective tissue disorder that affects multiple systems, including the visual system. Seven genes were reported to cause Stickler syndrome in patients with different phenotypes. In this study, we aimed to evaluate the mutation features of the phenotypes of high myopia and retinal detachment. Forty-two probands diagnosed with Stickler syndrome were included. Comprehensive ocular examinations were performed. A targeted gene panel test or whole exome sequencing was used to detect the mutations, and Sanger sequencing was conducted for verification and segregation analysis. Among the 42 probands, 32 (76%) presented with high myopia and 29 (69%), with retinal detachment. Pathogenic mutations were detected in 35 (83%) probands: 27 (64%) probands had COL2A1 mutations, and eight (19%) probands had COL11A1 mutations. Truncational mutations in COL2A1 were present in 21 (78%) probands. Missense mutations in COL2A1 were present in six probands, five of which presented with retinal detachment. De novo COL2A1 mutations were detected in 10 (37%) probands, with a mean paternal childbearing age of 29.64 ± 4.97 years old. The mutation features of probands with high myopia or retinal detachment showed that the probands had a high prevalence of COL2A1 mutations, truncational mutations, and de novo mutations. Full article
(This article belongs to the Special Issue Genetics in Ophthalmology)
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7 pages, 453 KiB  
Communication
Preferentially Paternal Origin of De Novo 11p13 Chromosome Deletions Revealed in Patients with Congenital Aniridia and WAGR Syndrome
by Tatyana A. Vasilyeva, Andrey V. Marakhonov, Natella V. Sukhanova, Sergey I. Kutsev and Rena A. Zinchenko
Genes 2020, 11(7), 812; https://doi.org/10.3390/genes11070812 - 17 Jul 2020
Cited by 4 | Viewed by 2536
Abstract
The frequency of pathogenic large chromosome rearrangements detected in patients with different Mendelian diseases is truly diverse and can be remarkably high. Chromosome breaks could arise through different known mechanisms. Congenital PAX6-associated aniridia is a hereditary eye disorder caused by mutations or [...] Read more.
The frequency of pathogenic large chromosome rearrangements detected in patients with different Mendelian diseases is truly diverse and can be remarkably high. Chromosome breaks could arise through different known mechanisms. Congenital PAX6-associated aniridia is a hereditary eye disorder caused by mutations or chromosome rearrangements involving the PAX6 gene. In our recent study, we identified 11p13 chromosome deletions in 30 out of 91 probands with congenital aniridia or WAGR syndrome (characterized by Wilms’ tumor, Aniridia, and Genitourinary abnormalities as well as mental Retardation). The loss of heterozygosity analysis (LOH) was performed in 10 families with de novo chromosome deletion in proband. In 7 out of 8 informative families, the analysis revealed that deletions occurred at the paternal allele. If paternal origin is not random, chromosome breaks could arise either (i) during spermiogenesis, which is possible due to specific male chromatin epigenetic program and its vulnerability to the breakage-causing factors, or (ii) in early zygotes at a time when chromosomes transmitted from different parents still carry epigenetic marks of the origin, which is also possible due to diverse and asymmetric epigenetic reprogramming occurring in male and female pronuclei. Some new data is needed to make a well-considered conclusion on the reasons for preferential paternal origin of 11p13 deletions. Full article
(This article belongs to the Special Issue Genetics in Ophthalmology)
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17 pages, 1120 KiB  
Article
De Novo Assembly-Based Analysis of RPGR Exon ORF15 in an Indigenous African Cohort Overcomes Limitations of a Standard Next-Generation Sequencing (NGS) Data Analysis Pipeline
by Jordi Maggi, Lisa Roberts, Samuel Koller, George Rebello, Wolfgang Berger and Rajkumar Ramesar
Genes 2020, 11(7), 800; https://doi.org/10.3390/genes11070800 - 15 Jul 2020
Cited by 9 | Viewed by 2780
Abstract
RPGR exon ORF15 variants are one of the most frequent causes for inherited retinal disorders (IRDs), in particular retinitis pigmentosa. The low sequence complexity of this mutation hotspot makes it prone to indels and challenging for sequence data analysis. Whole-exome sequencing generally fails [...] Read more.
RPGR exon ORF15 variants are one of the most frequent causes for inherited retinal disorders (IRDs), in particular retinitis pigmentosa. The low sequence complexity of this mutation hotspot makes it prone to indels and challenging for sequence data analysis. Whole-exome sequencing generally fails to provide adequate coverage in this region. Therefore, complementary methods are needed to avoid false positives as well as negative results. In this study, next-generation sequencing (NGS) was used to sequence long-range PCR amplicons for an IRD cohort of African ancestry. By developing a novel secondary analysis pipeline based on de novo assembly, we were able to avoid the miscalling of variants generated by standard NGS analysis tools. We identified pathogenic variants in 11 patients (13% of the cohort), two of which have not been reported previously. We provide a novel and alternative end-to-end secondary analysis pipeline for targeted NGS of ORF15 that is less prone to false positive and negative variant calls. Full article
(This article belongs to the Special Issue Genetics in Ophthalmology)
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11 pages, 1810 KiB  
Article
Whole Exome Sequencing Reveals Novel and Recurrent Disease-Causing Variants in Lens Specific Gap Junctional Protein Encoding Genes Causing Congenital Cataract
by Vanita Berry, Alex Ionides, Nikolas Pontikos, Ismail Moghul, Anthony T. Moore, Roy A. Quinlan and Michel Michaelides
Genes 2020, 11(5), 512; https://doi.org/10.3390/genes11050512 - 6 May 2020
Cited by 5 | Viewed by 2538
Abstract
Pediatric cataract is clinically and genetically heterogeneous and is the most common cause of childhood blindness worldwide. In this study, we aimed to identify disease-causing variants in three large British families and one isolated case with autosomal dominant congenital cataract, using whole exome [...] Read more.
Pediatric cataract is clinically and genetically heterogeneous and is the most common cause of childhood blindness worldwide. In this study, we aimed to identify disease-causing variants in three large British families and one isolated case with autosomal dominant congenital cataract, using whole exome sequencing. We identified four different heterozygous variants, three in the large families and one in the isolated case. Family A, with a novel missense variant (c.178G>C, p.Gly60Arg) in GJA8 with lamellar cataract; family B, with a recurrent variant in GJA8 (c.262C>T, p.Pro88Ser) associated with nuclear cataract; and family C, with a novel variant in GJA3 (c.771dupC, p.Ser258GlnfsTer68) causing a lamellar phenotype. Individual D had a novel variant in GJA3 (c.82G>T, p.Val28Leu) associated with congenital cataract. Each sequence variant was found to co-segregate with disease. Here, we report three novel and one recurrent disease-causing sequence variant in the gap junctional protein encoding genes causing autosomal dominant congenital cataract. Our study further extends the mutation spectrum of these genes and further facilitates clinical diagnosis. A recurrent p.P88S variant in GJA8 causing isolated nuclear cataract provides evidence of further phenotypic heterogeneity associated with this variant. Full article
(This article belongs to the Special Issue Genetics in Ophthalmology)
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Review

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13 pages, 2509 KiB  
Review
Congenital Microcoria: Clinical Features and Molecular Genetics
by Clémentine Angée, Brigitte Nedelec, Elisa Erjavec, Jean-Michel Rozet and Lucas Fares Taie
Genes 2021, 12(5), 624; https://doi.org/10.3390/genes12050624 - 22 Apr 2021
Cited by 6 | Viewed by 6568
Abstract
Iris integrity is required to regulate both the amount of light reaching the retina and intraocular pressure (IOP), with elevated IOP being a major risk factor for glaucoma. Congenital microcoria (MCOR) is an extremely rare, autosomal dominant disease affecting iris development and hindering [...] Read more.
Iris integrity is required to regulate both the amount of light reaching the retina and intraocular pressure (IOP), with elevated IOP being a major risk factor for glaucoma. Congenital microcoria (MCOR) is an extremely rare, autosomal dominant disease affecting iris development and hindering both of these functions. It is characterized by absent or underdeveloped dilator muscle fibers and immaturity of the iridocorneal angle—where the aqueous humor is drained—which play a central role in IOP regulation. The dilator muscle anomaly is manifested in pinhole pupils (<2 mm) and thin transilluminable irises, causing both hemeralopia and photoaversion. Axial myopia and juvenile open-angle glaucoma are very frequent (80% and 30% of all cases, respectively). It has been suggested that the immaturity of the chamber angle contributes to glaucoma, and myopia has been ascribed to photoaversion and elevated IOP. Though possible, these mechanisms are insufficient. The disease has been tied to chromosome 13q32.1 structural variations. In addition to compromising iris development, modification of the 13q32.1 architecture could alter signaling pathways for axial ocular length and IOP regulation. Here, we summarize the clinical, histological, and molecular features of this disease, and we discuss the possible etiology of associated anomalies. Full article
(This article belongs to the Special Issue Genetics in Ophthalmology)
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14 pages, 781 KiB  
Review
The Genetic and Clinical Features of FOXL2-Related Blepharophimosis, Ptosis and Epicanthus Inversus Syndrome
by Cécile Méjécase, Chandni Nigam, Mariya Moosajee and John C. Bladen
Genes 2021, 12(3), 364; https://doi.org/10.3390/genes12030364 - 4 Mar 2021
Cited by 8 | Viewed by 6941
Abstract
Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial disorder caused by heterozygous variants of the forkhead box L2 (FOXL2) gene. It shows autosomal dominant inheritance but can also occur sporadically. Depending on the mutation, two phenotypic subtypes have been [...] Read more.
Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial disorder caused by heterozygous variants of the forkhead box L2 (FOXL2) gene. It shows autosomal dominant inheritance but can also occur sporadically. Depending on the mutation, two phenotypic subtypes have been described, both involving the same craniofacial features: type I, which is associated with premature ovarian failure (POF), and type II, which has no systemic features. The genotype–phenotype correlation is not fully understood, but it has been hypothesised that type I BPES involves more severe loss of function variants spanning the whole gene. Type II BPES has been linked to frameshift mutations that result in elongation of the protein rather than complete loss of function. A mutational hotspot has been identified within the poly-alanine domain, although the exact function of this region is still unknown. However, the BPES subtype cannot be determined genetically, necessitating informed genetic counselling and careful discussion of family planning advice in view of the associated POF particularly as the patient may still be a child. Following puberty, female patients should be referred for ovarian reserve and response assessment. Oculofacial features can be managed with surgical intervention and regular monitoring to prevent amblyopia. Full article
(This article belongs to the Special Issue Genetics in Ophthalmology)
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21 pages, 8696 KiB  
Review
Properties and Therapeutic Implications of an Enigmatic D477G RPE65 Variant Associated with Autosomal Dominant Retinitis Pigmentosa
by Anna-Sophia Kiang, Paul F. Kenna, Marian M. Humphries, Ema Ozaki, Robert K. Koenekoop, Matthew Campbell, G. Jane Farrar and Pete Humphries
Genes 2020, 11(12), 1420; https://doi.org/10.3390/genes11121420 - 27 Nov 2020
Cited by 9 | Viewed by 2712
Abstract
RPE65 isomerase, expressed in the retinal pigmented epithelium (RPE), is an enzymatic component of the retinoid cycle, converting all-trans retinyl ester into 11-cis retinol, and it is essential for vision, because it replenishes the photon capturing 11-cis retinal. To date, almost 200 loss-of-function [...] Read more.
RPE65 isomerase, expressed in the retinal pigmented epithelium (RPE), is an enzymatic component of the retinoid cycle, converting all-trans retinyl ester into 11-cis retinol, and it is essential for vision, because it replenishes the photon capturing 11-cis retinal. To date, almost 200 loss-of-function mutations have been identified within the RPE65 gene causing inherited retinal dystrophies, most notably Leber congenital amaurosis (LCA) and autosomal recessive retinitis pigmentosa (arRP), which are both severe and early onset disease entities. We previously reported a mutation, D477G, co-segregating with the disease in a late-onset form of autosomal dominant RP (adRP) with choroidal involvement; uniquely, it is the only RPE65 variant to be described with a dominant component. Families or individuals with this variant have been encountered in five countries, and a number of subsequent studies have been reported in which the molecular biological and physiological properties of the variant have been studied in further detail, including observations of possible novel functions in addition to reduced RPE65 enzymatic activity. With regard to the latter, a human phase 1b proof-of-concept study has recently been reported in which aspects of remaining vision were improved for up to one year in four of five patients with advanced disease receiving a single one-week oral dose of 9-cis retinaldehyde, which is the first report showing efficacy and safety of an oral therapy for a dominant form of RP. Here, we review data accrued from published studies investigating molecular mechanisms of this unique variant and include hitherto unpublished material on the clinical spectrum of disease encountered in patients with the D477G variant, which, in many cases bears striking similarities to choroideremia. Full article
(This article belongs to the Special Issue Genetics in Ophthalmology)
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Case Report
MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy
by Sylvie Gerber, Christophe Orssaud, Josseline Kaplan, Catrine Johansson and Jean-Michel Rozet
Genes 2021, 12(4), 521; https://doi.org/10.3390/genes12040521 - 2 Apr 2021
Cited by 22 | Viewed by 2490
Abstract
Pathological variants in the nuclear malonyl-CoA-acyl carrier protein transacylase (MCAT) gene, which encodes a mitochondrial protein involved in fatty-acid biogenesis, have been reported in two siblings from China affected by insidious optic nerve degeneration in childhood, leading to blindness in the [...] Read more.
Pathological variants in the nuclear malonyl-CoA-acyl carrier protein transacylase (MCAT) gene, which encodes a mitochondrial protein involved in fatty-acid biogenesis, have been reported in two siblings from China affected by insidious optic nerve degeneration in childhood, leading to blindness in the first decade of life. After analysing 51 families with negative molecular diagnostic tests, from a cohort of 200 families with hereditary optic neuropathy (HON), we identified two novel MCAT mutations in a female patient who presented with acute, sudden, bilateral, yet asymmetric, central visual loss at the age of 20. This presentation is consistent with a Leber hereditary optic neuropathy (LHON)-like phenotype, whose existence and association with NDUFS2 and DNAJC30 has only recently been described. Our findings reveal a wider phenotypic presentation of MCAT mutations, and a greater genetic heterogeneity of nuclear LHON-like phenotypes. Although MCAT pathological variants are very uncommon, this gene should be investigated in HON patients, irrespective of disease presentation. Full article
(This article belongs to the Special Issue Genetics in Ophthalmology)
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