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Recent Advances in Inherited Eye Disease
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Recent Advances in Inherited Eye Disease

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 (31 October 2019) | Viewed by 64143

Special Issue Editors

Dr. Gavin Arno

E-Mail Website
Guest Editor
1. UCL Institute of Ophthalmology, University College London, London WC1E 6BT, UK
2. Moorfields Eye Hospital, London WC1E 6BT, UK
3. GOSH NIHR Biomedical Research Centre, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1E 6BT, UK
4. Laboratory of Visual Physiology/Ophthalmic Genetics, National Institute of Sensory Organs, Tokyo 152-8902, Japan
Interests: genetics and genomics of inherited eye diseases; application of genomic analysis in mMendelian disease; single molecule sequencing in mendelian disease; ophthalmic genetics; inherited retinal diseases; inherited optic neuropathies
Dr. Robert B Hufnagel

E-Mail Website
Guest Editor
National Eye Institute, Bethesda, MD 20892-2510, USA
Interests: genomics; genetics; eye; retina; inherited retinal disease; ocular syndromes; transcriptomics; ophthalmology; foveal hypoplasia; inherited maculopathies
Special Issues, Collections and Topics in MDPI journals
Dr. Jamie Ellingford

E-Mail Website
Guest Editor
Manchester Centre for Genomic Medicine, The University of Manchester, Manchester M13 9PL, UK
Interests: inherited retinal dystrophy; mendelian disorders; genome biology; gene regulation; gene expression; genome sequencing; non-coding variation; structural variation; transcriptomics

Special Issue Information

Dear Colleagues,

Inherited eye diseases (IED) represent a vast spectrum of blinding genetic disorders affecting all cells and tissue types of the globe. The genetic mechanisms that underlie these diseases are extremely complex and diverse, with hundreds of genes and many thousands of disease variants reported to date. Current diagnostic testing is focused on targeted gene panel analysis. and can identify causative variants in up to 60%–80% of cases where a clear clinical indication is present. However, despite the huge advances in knowledge and technology since the discovery of the first disease variant some 30 years ago, patients without a clear indication are often left without a molecular diagnosis, thus restricting their access to effective clinical management, counselling, and emerging therapeutics.  

We are currently experiencing a revolution in genomic science, with the advent of affordable and accessible massively parallel sequencing in the form of exome-targeted and non-targeted genome-wide analysis, in addition to the availability of publicly accessible large cohort data on genomic variation (in particular, gnomAD aggregating variant data from of over 140,000 individuals). This means that we now have the tools to detect variants across a vast majority of the human genome, and can unpick the relevant disease-associated pathogenic variants from the benign.

The application of exome-targeted or genome-wide sequencing for IED patients will lead to many more discoveries, including unexpected genotype–phenotype associations; novel gene associations; variants that disrupt the normal splicing of a transcript; deep intronic, regulatory region, or intergenic variants that alter, upregulate, or abolish a transcript; and simple and complex structural and copy number variants and rearrangements.

This Issue aims to advance the knowledge of the genetic etiology of IED and to inform future genomic studies, functional biologists, clinical diagnostic laboratories, and health care providers, and the wider field of Mendelian disease research. To this end, we invite papers reporting on novel findings in the genetics underlying any aspect of Mendelian IED.

Dr. Gavin Arno
Dr. Robert B Hufnagel
Dr. Jamie Ellingford
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

  • inherited eye disease
  • ophthalmic genetics
  • genomics
  • non-coding mutation
  • structural variant

Published Papers (15 papers)

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Editorial

Jump to: Research, Review, Other

4 pages, 167 KiB  
Editorial
Phenotype and Genotype Correlations in Inherited Retinal Diseases: Population-Guided Variant Interpretation, Variable Expressivity and Incomplete Penetrance
by Jamie M. Ellingford, Robert B. Hufnagel and Gavin Arno
Genes 2020, 11(11), 1274; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11111274 - 29 Oct 2020
Cited by 5 | Viewed by 1590
Abstract
Inherited retinal diseases (IRDs) are a diverse and variable group of rare human disorders [...] Full article
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)

Research

Jump to: Editorial, Review, Other

12 pages, 1039 KiB  
Article
Variability in Gene Expression is Associated with Incomplete Penetrance in Inherited Eye Disorders
by David J. Green, Shalaw R. Sallah, Jamie M. Ellingford, Simon C. Lovell and Panagiotis I. Sergouniotis
Genes 2020, 11(2), 179; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11020179 - 09 Feb 2020
Cited by 13 | Viewed by 3820
Abstract
Inherited eye disorders (IED) are a heterogeneous group of Mendelian conditions that are associated with visual impairment. Although these disorders often exhibit incomplete penetrance and variable expressivity, the scale and mechanisms of these phenomena remain largely unknown. Here, we utilize publicly-available genomic and [...] Read more.
Inherited eye disorders (IED) are a heterogeneous group of Mendelian conditions that are associated with visual impairment. Although these disorders often exhibit incomplete penetrance and variable expressivity, the scale and mechanisms of these phenomena remain largely unknown. Here, we utilize publicly-available genomic and transcriptomic datasets to gain insights into variable penetrance in IED. Variants in a curated set of 340 IED-implicated genes were extracted from the Human Gene Mutation Database (HGMD) 2019.1 and cross-checked with the Genome Aggregation Database (gnomAD) 2.1 control-only dataset. Genes for which >1 variants were encountered in both HGMD and gnomAD were considered to be associated with variable penetrance (n = 56). Variability in gene expression levels was then estimated for the subset of these genes that was found to be adequately expressed in two relevant resources: the Genotype-Tissue Expression (GTEx) and Eye Genotype Expression (EyeGEx) datasets. We found that genes suspected to be associated with variable penetrance tended to have significantly more variability in gene expression levels in the general population (p = 0.0000015); this finding was consistent across tissue types. The results of this study point to the possible influence of cis and/or trans-acting elements on the expressivity of variants causing Mendelian disorders. They also highlight the potential utility of quantifying gene expression as part of the investigation of families showing evidence of variable penetrance. Full article
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
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23 pages, 16608 KiB  
Article
Findings from a Genotyping Study of over 1000 People with Inherited Retinal Disorders in Ireland
by Laura Whelan, Adrian Dockery, Niamh Wynne, Julia Zhu, Kirk Stephenson, Giuliana Silvestri, Jacqueline Turner, James J. O’Byrne, Matthew Carrigan, Peter Humphries, David Keegan, Paul F. Kenna and G. Jane Farrar
Genes 2020, 11(1), 105; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11010105 - 16 Jan 2020
Cited by 34 | Viewed by 7180
Abstract
The Irish national registry for inherited retinal degenerations (Target 5000) is a clinical and scientific program to identify individuals in Ireland with inherited retinal disorders and to attempt to ascertain the genetic cause underlying the disease pathology. Potential participants first undergo a clinical [...] Read more.
The Irish national registry for inherited retinal degenerations (Target 5000) is a clinical and scientific program to identify individuals in Ireland with inherited retinal disorders and to attempt to ascertain the genetic cause underlying the disease pathology. Potential participants first undergo a clinical assessment, which includes clinical history and analysis with multimodal retinal imaging, electrophysiology, and visual field testing. If suitable for recruitment, a sample is taken and used for genetic analysis. Genetic analysis is conducted by use of a retinal gene panel target capture sequencing approach. With over 1000 participants from 710 pedigrees now screened, there is a positive candidate variant detection rate of approximately 70% (495/710). Where an autosomal recessive inheritance pattern is observed, an additional 9% (64/710) of probands have tested positive for a single candidate variant. Many novel variants have also been detected as part of this endeavor. The target capture approach is an economic and effective means of screening patients with inherited retinal disorders. Despite the advances in sequencing technology and the ever-decreasing associated processing costs, target capture remains an attractive option as the data produced is easily processed, analyzed, and stored compared to more comprehensive methods. However, with decreasing costs of whole genome and whole exome sequencing, the focus will likely move towards these methods for more comprehensive data generation. Full article
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
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12 pages, 832 KiB  
Article
Pathogenicity Reclassification of RPE65 Missense Variants Related to Leber Congenital Amaurosis and Early-Onset Retinal Dystrophy
by Fabiana L. Motta, Renan P. Martin, Fernanda B. O. Porto, Elizabeth S. Wohler, Rosane G. Resende, Caio P. Gomes, João B. Pesquero and Juliana M. F. Sallum
Genes 2020, 11(1), 24; https://doi.org/10.3390/genes11010024 - 24 Dec 2019
Cited by 13 | Viewed by 2885
Abstract
A challenge in molecular diagnosis and genetic counseling is the interpretation of variants of uncertain significance. Proper pathogenicity classification of new variants is important for the conclusion of molecular diagnosis and the medical management of patient treatments. The purpose of this study was [...] Read more.
A challenge in molecular diagnosis and genetic counseling is the interpretation of variants of uncertain significance. Proper pathogenicity classification of new variants is important for the conclusion of molecular diagnosis and the medical management of patient treatments. The purpose of this study was to reclassify two RPE65 missense variants, c.247T>C (p.Phe83Leu) and c.560G>A (p.Gly187Glu), found in Brazilian families. To achieve this aim, we reviewed the sequencing data of a 224-gene retinopathy panel from 556 patients (513 families) with inherited retinal dystrophies. Five patients with p.Phe83Leu and seven with p.Gly187Glu were selected and their families investigated. To comprehend the pathogenicity of these variants, we evaluated them based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) classification guidelines. Initially, these RPE65 variants met only three pathogenic criteria: (i) absence or low frequency in the population, (ii) several missense pathogenic RPE65 variants, and (iii) 15 out of 16 lines of computational evidence supporting them as damaging, which together allowed the variants to be classified as uncertain significance. Two other pieces of evidence were accepted after further analysis of these Brazilian families: (i) p.Phe83Leu and p.Gly187Glu segregate with childhood retinal dystrophy within families, and (ii) their prevalence in Leber congenital amaurosis (LCA)/early-onset retinal dystrophy (EORD) patients can be considered higher than in other inherited retinal dystrophy patients. Therefore, these variants can now be classified as likely pathogenic according to ACMG/AMP classification guidelines. Full article
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
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13 pages, 881 KiB  
Article
Exploring the Genetic Landscape of Retinal Diseases in North-Western Pakistan Reveals a High Degree of Autozygosity and a Prevalent Founder Mutation in ABCA4
by Atta Ur Rehman, Virginie G. Peter, Mathieu Quinodoz, Abdur Rashid, Syed Akhtar Khan, Andrea Superti-Furga and Carlo Rivolta
Genes 2020, 11(1), 12; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11010012 - 21 Dec 2019
Cited by 11 | Viewed by 3145
Abstract
Variants in more than 271 different genes have been linked to hereditary retinal diseases, making comprehensive genomic approaches mandatory for accurate diagnosis. We explored the genetic landscape of retinal disorders in consanguineous families from North-Western Pakistan, harboring a population of approximately 35 million [...] Read more.
Variants in more than 271 different genes have been linked to hereditary retinal diseases, making comprehensive genomic approaches mandatory for accurate diagnosis. We explored the genetic landscape of retinal disorders in consanguineous families from North-Western Pakistan, harboring a population of approximately 35 million inhabitants that remains relatively isolated and highly inbred (~50% consanguinity). We leveraged on the high degree of consanguinity by applying genome-wide high-density single-nucleotide polymorphism (SNP) genotyping followed by targeted Sanger sequencing of candidate gene(s) lying inside autozygous intervals. In addition, we performed whole-exome sequencing (WES) on at least one proband per family. We identified 7 known and 4 novel variants in a total of 10 genes (ABCA4, BBS2, CNGA1, CNGA3, CNGB3, MKKS, NMNAT1, PDE6B, RPE65, and TULP1) previously known to cause inherited retinal diseases. In spite of all families being consanguineous, compound heterozygosity was detected in one family. All homozygous pathogenic variants resided in autozygous intervals ≥2.0 Mb in size. Putative founder variants were observed in the ABCA4 (NM_000350.2:c.214G>A; p.Gly72Arg; ten families) and NMNAT1 genes (NM_022787.3:c.25G>A; p.Val9Met; two families). We conclude that geographic isolation and sociocultural tradition of intrafamilial mating in North-Western Pakistan favor both the clinical manifestation of rare “generic” variants and the prevalence of founder mutations. Full article
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
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12 pages, 3682 KiB  
Article
Clinical and Haplotypic Variability of Slovenian USH2A Patients Homozygous for the c. 11864G>A Nonsense Mutation
by Andrej Zupan, Ana Fakin, Saba Battelino, Martina Jarc-Vidmar, Marko Hawlina, Crystel Bonnet, Christine Petit and Damjan Glavač
Genes 2019, 10(12), 1015; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10121015 - 05 Dec 2019
Cited by 12 | Viewed by 2820
Abstract
Purpose: to determine a detailed clinical and haplotypic variability of the Slovenian USH2A patients with homozygous c.11864G>A (p.Trp3955Ter) nonsense mutation and to develop sensitive, accurate and rapid screening test. Methods: Ten unrelated homozygous patients with detailed ophthalmological exam were included in our study. [...] Read more.
Purpose: to determine a detailed clinical and haplotypic variability of the Slovenian USH2A patients with homozygous c.11864G>A (p.Trp3955Ter) nonsense mutation and to develop sensitive, accurate and rapid screening test. Methods: Ten unrelated homozygous patients with detailed ophthalmological exam were included in our study. The High-Resolution Melting (HRM) method was developed for fast and reliable detection of the c.11864G>A mutation. Results: The c.11864G>A mutation represents the vast majority of pathogenic alleles in Slovenian USH2A-Usher syndrome population (84%). The median age of onset of nyctalopia was 16 years and all patients younger than 40 years had hyperautofluorescent rings on fundus autofluorescence imaging. The Kaplan Meier survival analysis showed a decline of central vision after the age of 40, with 50% patients reaching visual acuity (VA) ≤ 0.05 at the average age of 66 years visual field diameter less than 20° at the average age of 59 years. There was a relatively large phenotypic variability in the retinal and audiological phenotype. Analysis of the p.Trp3955Ter-homozygous patients revealed four different haplotypes, with the frequency of the most common haplotype ~65%. Disease severity did not correlate with the haplotype. Conclusions: According to the natural history of homozygous p.Trp3955Ter patients any therapy aimed to slow disease progression in these patients would be best started before the age of 40. Phenotypic variability suggests the presence of cis and/or trans factors outside the USH2A gene that are able to affect disease severity. High frequency of p.Trp3955Ter mutation in Slovenian USH2A gene pool appears to be initiated from different unrelated founders because of migrations from neighboring populations. The mutation on haplotype 2 seems to be the major founder allele. Full article
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
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12 pages, 675 KiB  
Article
Genetic Spectrum of ABCA4-Associated Retinal Degeneration in Poland
by Anna M. Tracewska, Beata Kocyła-Karczmarewicz, Agnieszka Rafalska, Joanna Murawska, Joanna Jakubaszko-Jablonska, Małgorzata Rydzanicz, Piotr Stawiński, Elżbieta Ciara, Muhammad Imran Khan, Arjen Henkes, Alexander Hoischen, Christian Gilissen, Maartje van de Vorst, Frans P. M. Cremers, Rafał Płoski and Krystyna H. Chrzanowska
Genes 2019, 10(12), 959; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10120959 - 21 Nov 2019
Cited by 17 | Viewed by 3199
Abstract
Mutations in retina-specific ATP-binding cassette transporter 4 (ABCA4) are responsible for over 95% of cases of Stargardt disease (STGD), as well as a minor proportion of retinitis pigmentosa (RP) and cone-rod dystrophy cases (CRD). Since the knowledge of the genetic causes [...] Read more.
Mutations in retina-specific ATP-binding cassette transporter 4 (ABCA4) are responsible for over 95% of cases of Stargardt disease (STGD), as well as a minor proportion of retinitis pigmentosa (RP) and cone-rod dystrophy cases (CRD). Since the knowledge of the genetic causes of inherited retinal diseases (IRDs) in Poland is still scarce, the purpose of this study was to identify pathogenic ABCA4 variants in a subgroup of Polish IRD patients. We recruited 67 families with IRDs as a part of a larger study. The patients were screened with next generation sequencing using a molecular inversion probes (MIPs)-based technique targeting 108 genes involved in the pathogenesis of IRDs. All identified mutations were validated and their familial segregation was tested using Sanger sequencing. In the case of the most frequent complex allele, consisting of two variants in exon 12 and 21, familial segregation was tested using restriction fragment length polymorphism (RFLP). The most prevalent variant, a complex change c.[1622T>C;3113C>T], p.[Leu541Pro;Ala1038Val], was found in this cohort in 54% of all solved ABCA4-associated disorder cases, which is the highest frequency reported thus far. Additionally, we identified nine families displaying a pseudo-dominant mode of inheritance, indicating a high frequency of pathogenic variants within this population. Full article
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
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11 pages, 5313 KiB  
Article
Double Hyperautofluorescent Rings in Patients with USH2A-Retinopathy
by Ana Fakin, Maja Šuštar, Jelka Brecelj, Crystel Bonnet, Christine Petit, Andrej Zupan, Damjan Glavač, Martina Jarc-Vidmar, Saba Battelino and Marko Hawlina
Genes 2019, 10(12), 956; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10120956 - 21 Nov 2019
Cited by 10 | Viewed by 2860
Abstract
USH2A mutation is the most common cause of retinitis pigmentosa, with or without hearing impairment. Patients most commonly exhibit hyperautofluorescent ring on fundus autofluorescence imaging (FAF) and rod-cone dystrophy on electrophysiology. A detailed study of three USH2A patients with a rare pattern of [...] Read more.
USH2A mutation is the most common cause of retinitis pigmentosa, with or without hearing impairment. Patients most commonly exhibit hyperautofluorescent ring on fundus autofluorescence imaging (FAF) and rod-cone dystrophy on electrophysiology. A detailed study of three USH2A patients with a rare pattern of double hyperautofluorescent rings was performed. Twenty-four patients with typical single hyperautofluorescent rings were used for comparison of the ages of onset, visual fields, optical coherence tomography, electrophysiology, and audiograms. Double rings delineated the area of pericentral retinal degeneration in all cases. Two patients exhibited rod-cone dystrophy, whereas the third had a cone-rod dystrophy type of dysfunction on electrophysiology. There was minimal progression on follow-up in all three. Patients with double rings had significantly better visual acuity, cone function, and auditory performance than the single ring group. Double rings were associated with combinations of null and missense mutations, none of the latter found in the single ring patients. According to these findings, the double hyperautofluorescent rings indicate a mild subtype of USH2A disease, characterized by pericentral retinal degeneration, mild to moderate hearing loss, and either a rod-cone or cone-rod pattern on electrophysiology, the latter expanding the known clinical spectrum of USH2A-retinopathy. Full article
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
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15 pages, 2568 KiB  
Article
Clinical and Genetic Findings of Autosomal Recessive Bestrophinopathy (ARB)
by Imen Habibi, Yosra Falfoul, Margarita G. Todorova, Stefan Wyrsch, Veronika Vaclavik, Maria Helfenstein, Ahmed Turki, Khaled El Matri, Leila El Matri and Daniel F. Schorderet
Genes 2019, 10(12), 953; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10120953 - 21 Nov 2019
Cited by 14 | Viewed by 2619
Abstract
Mutations in BEST1 cause several phenotypes including autosomal dominant (AD) Best vitelliform macular dystrophy type 2 (BVMD), AD vitreo-retino-choroidopathy (ADVIRC), and retinitis pigmentosa-50 (RP50). A rare subtype of Bestrophinopathy exists with biallelic mutations in BEST1. Its frequency is estimated to be 1/1,000,000 [...] Read more.
Mutations in BEST1 cause several phenotypes including autosomal dominant (AD) Best vitelliform macular dystrophy type 2 (BVMD), AD vitreo-retino-choroidopathy (ADVIRC), and retinitis pigmentosa-50 (RP50). A rare subtype of Bestrophinopathy exists with biallelic mutations in BEST1. Its frequency is estimated to be 1/1,000,000 individuals. Here we report 6 families and searched for a genotype-phenotype correlation. All patients were referred due to reduced best-corrected visual acuity (BCVA), ranging from 0.1/10 to 3/10. They all showed vitelliform lesions located at the macula, sometimes extending into the midperiphery, along the vessels and the optic disc. Onset of the disease varied from the age of 3 to 25 years. Electrooculogram (EOG) revealed reduction in the EOG light rise in all patients. Molecular analysis revealed previously reported mutations p.(E35K);(E35K), p.(L31M);(L31M), p.(R141H);(A195V), p.(R202W);(R202W), and p.(Q220*);(Q220*) in five families. One family showed a novel mutation: p.(E167G);(E167G). All mutations were heterozygous in the parents. In one family, heterozygous children showed various reductions in the EOG light rise and autofluorescent deposits. Autosomal recessive Bestrophinopathy (ARB), although rare, can be recognized by its phenotype and should be validated by molecular analysis. Genotype-phenotype correlations are difficult to establish and will require the analysis of additional cases. Full article
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
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13 pages, 2233 KiB  
Article
Rare Genetic Variants in Jewish Patients Suffering from Age-Related Macular Degeneration
by Nadav Shoshany, Chen Weiner, Margarita Safir, Adi Einan-Lifshitz, Russell Pokroy, Ayala Kol, Shira Modai, Noam Shomron and Eran Pras
Genes 2019, 10(10), 825; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10100825 - 18 Oct 2019
Cited by 7 | Viewed by 3363
Abstract
Purpose: To identify rare genetic variants in early age-related macular degeneration (AMD) utilizing whole-exome sequencing (WES). Methods: Eight non-related early-AMD families of different Jewish ethnicities were ascertained. Initial mutation screening (phase-1) included common complement factor-H (CFH) p.Y402H; and age related maculopathy [...] Read more.
Purpose: To identify rare genetic variants in early age-related macular degeneration (AMD) utilizing whole-exome sequencing (WES). Methods: Eight non-related early-AMD families of different Jewish ethnicities were ascertained. Initial mutation screening (phase-1) included common complement factor-H (CFH) p.Y402H; and age related maculopathy susceptibility 2 (ARMS2) p.A69S; and rare variants complement factor-I (CFI) p.V412M; and hemicentin1 (HMCN1) c.4163delC identified previously in our population. Four families, whose initial screening for the aforementioned variants was negative, underwent WES (phase-2). Bioinformatics filtering was based on functionality (from a panel of 234 genes with proven or presumed association to AMD); predicted severity; and frequency (rare variants with minor allele frequency <1%). When applicable, further screening for specific rare variants was carried out on additional cases of similar ethnicities and phenotypes (phase-3). Results: Phase-1 identified three families carrying CFI p.V412M mutation. WES analysis detected probable disease-related variants in three out of the remaining families. These included: a family with a variant in PLEKHA1 gene p.S177N; a family with previously reported variant p.R1210C in CFH gene; and two families with the C3 p.R735W variant. Conclusions: Rare, high-penetrance variants have a profound contribution to early-AMD pathogenesis. Utilization of WES in genetic research of multifactorial diseases as AMD, allows a thorough comprehensive analysis with the identification of previously unreported rare variants. Full article
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
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8 pages, 2652 KiB  
Article
NGS Analysis for Molecular Diagnosis of Retinitis Pigmentosa (RP): Detection of a Novel Variant in PRPH2 Gene
by Claudia Strafella, Valerio Caputo, Giulia Pagliaroli, Nicola Iozzo, Giulia Campoli, Stefania Carboni, Cristina Peconi, Rosaria Maria Galota, Stefania Zampatti, Giulietta Minozzi, Giuseppe Novelli, Emiliano Giardina and Raffaella Cascella
Genes 2019, 10(10), 792; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10100792 - 12 Oct 2019
Cited by 10 | Viewed by 2661
Abstract
This work describes the application of NGS for molecular diagnosis of RP in a family with a history of severe hypovision. In particular, the proband received a clinical diagnosis of RP on the basis of medical, instrumental examinations and his family history. The [...] Read more.
This work describes the application of NGS for molecular diagnosis of RP in a family with a history of severe hypovision. In particular, the proband received a clinical diagnosis of RP on the basis of medical, instrumental examinations and his family history. The proband was subjected to NGS, utilizing a customized panel including 24 genes associated with RP and other retinal dystrophies. The NGS analysis revealed a novel missense variant (c.668T > A, I223N) in PRPH2 gene, which was investigated by segregation and bioinformatic analysis. The variant is located in the D2 loop domain of PRPH2, which is critical for protein activity. Bioinformatic analysis described the c.668T > A as a likely pathogenic variant. Moreover, a 3D model prediction was performed to better characterize the impact of the variant on the protein, reporting a disruption of the α-helical structures. As a result, the variant protein showed a substantially different conformation with respect to the wild-type PRPH2. The identified variant may therefore affect the oligomerization ability of the D2 loop and, ultimately, hamper PRPH2 proper functioning and localization. In conclusion, PRPH2_c.668T > A provided a molecular explanation of RP symptomatology, highlighting the clinical utility of NGS panels to facilitate genotype–phenotype correlations. Full article
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
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Review

Jump to: Editorial, Research, Other

22 pages, 2391 KiB  
Review
The Spectrum of PAX6 Mutations and Genotype-Phenotype Correlations in the Eye
by Dulce Lima Cunha, Gavin Arno, Marta Corton and Mariya Moosajee
Genes 2019, 10(12), 1050; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10121050 - 17 Dec 2019
Cited by 95 | Viewed by 13396
Abstract
The transcription factor PAX6 is essential in ocular development in vertebrates, being considered the master regulator of the eye. During eye development, it is essential for the correct patterning and formation of the multi-layered optic cup and it is involved in the developing [...] Read more.
The transcription factor PAX6 is essential in ocular development in vertebrates, being considered the master regulator of the eye. During eye development, it is essential for the correct patterning and formation of the multi-layered optic cup and it is involved in the developing lens and corneal epithelium. In adulthood, it is mostly expressed in cornea, iris, and lens. PAX6 is a dosage-sensitive gene and it is highly regulated by several elements located upstream, downstream, and within the gene. There are more than 500 different mutations described to affect PAX6 and its regulatory regions, the majority of which lead to PAX6 haploinsufficiency, causing several ocular and systemic abnormalities. Aniridia is an autosomal dominant disorder that is marked by the complete or partial absence of the iris, foveal hypoplasia, and nystagmus, and is caused by heterozygous PAX6 mutations. Other ocular abnormalities have also been associated with PAX6 changes, and genotype-phenotype correlations are emerging. This review will cover recent advancements in PAX6 regulation, particularly the role of several enhancers that are known to regulate PAX6 during eye development and disease. We will also present an updated overview of the mutation spectrum, where an increasing number of mutations in the non-coding regions have been reported. Novel genotype-phenotype correlations will also be discussed. Full article
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
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10 pages, 1132 KiB  
Review
Next-Generation Technologies and Strategies for the Management of Retinoblastoma
by Harini V. Gudiseva, Jesse L. Berry, Ashley Polski, Santa J. Tummina and Joan M. O’Brien
Genes 2019, 10(12), 1032; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10121032 - 11 Dec 2019
Cited by 20 | Viewed by 6237
Abstract
Retinoblastoma (RB) is an inherited retinal disorder (IRD) caused by the mutation in the RB1 gene or, rarely, by alterations in the MYCN gene. In recent years, new treatment advances have increased ocular and visual preservation in the developed world. The management of [...] Read more.
Retinoblastoma (RB) is an inherited retinal disorder (IRD) caused by the mutation in the RB1 gene or, rarely, by alterations in the MYCN gene. In recent years, new treatment advances have increased ocular and visual preservation in the developed world. The management of RB has improved significantly in recent decades, from the use of external beam radiation to recently, more localized treatments. Determining the underlying genetic cause of RB is critical for timely management decisions. The advent of next-generation sequencing technologies have assisted in understanding the molecular pathology of RB. Liquid biopsy of the aqueous humor has also had significant potential implications for tumor management. Currently, patients’ genotypic information, along with RB phenotypic presentation, are considered carefully when making treatment decisions aimed at globe preservation. Advances in molecular testing that improve our understanding of the molecular pathology of RB, together with multiple directed treatment options, are critical for developing precision medicine strategies to treat this disease. Full article
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
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9 pages, 1967 KiB  
Review
The RB1 Story: Characterization and Cloning of the First Tumor Suppressor Gene
by Jesse L. Berry, Ashley Polski, Webster K. Cavenee, Thaddeus P. Dryja, A. Linn Murphree and Brenda L. Gallie
Genes 2019, 10(11), 879; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10110879 - 01 Nov 2019
Cited by 28 | Viewed by 5844
Abstract
The RB1 gene is the first described human tumor suppressor gene and plays an integral role in the development of retinoblastoma, a pediatric malignancy of the eye. Since its discovery, the stepwise characterization and cloning of RB1 have laid the foundation for numerous [...] Read more.
The RB1 gene is the first described human tumor suppressor gene and plays an integral role in the development of retinoblastoma, a pediatric malignancy of the eye. Since its discovery, the stepwise characterization and cloning of RB1 have laid the foundation for numerous advances in the understanding of tumor suppressor genes, retinoblastoma tumorigenesis, and inheritance. Knowledge of RB1 led to a paradigm shift in the field of cancer genetics, including widespread acceptance of the concept of tumor suppressor genes, and has provided crucial diagnostic and prognostic information through genetic testing for patients affected by retinoblastoma. This article reviews the long history of RB1 gene research, characterization, and cloning, and also discusses recent advances in retinoblastoma genetics that have grown out of this foundational work. Full article
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
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1 pages, 159 KiB  
Correction
Correction: Habibi I. et al. “Clinical and Genetic Findings of Autosomal Recessive Bestrophinopathy (ARB)” Genes, 2019, 10, 953
by Imen Habibi, Yosra Falfoul, Margarita G. Todorova, Stefan Wyrsch, Veronika Vaclavik, Maria Helfenstein, Ahmed Turki, Khaled El Matri, Leila El Matri and Daniel F. Schorderet
Genes 2020, 11(5), 503; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11050503 - 03 May 2020
Cited by 1 | Viewed by 1509
Abstract
The authors wish to make a correction to the published version of their paper [...] Full article
(This article belongs to the Special Issue Recent Advances in Inherited Eye Disease)
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