Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes

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Abstract

Retinal dystrophy (RD) is a heterogeneous group of hereditary diseases caused by loss of photoreceptor function and contributes significantly to the etiology of blindness globally but especially in the industrialized world. The extreme locus and allelic heterogeneity of these disorders poses a major diagnostic challenge and often impedes the ability to provide a molecular diagnosis that can inform counseling and gene-specific treatment strategies. In a large cohort of nearly 150 RD families, we used genomic approaches in the form of autozygome-guided mutation analysis and exome sequencing to identify the likely causative genetic lesion in the majority of cases. Additionally, our study revealed six novel candidate disease genes ( C21orf2, EMC1, KIAA1549, GPR125, ACBD5, and DTHD1), two of which ( ACBD5 and DTHD1) were observed in the context of syndromic forms of RD that are described for the first time.

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Retinitis pigmentosa.

Dyonne Hartong, Eliot L. Berson, Thaddeus Dryja (2006)

Hereditary degenerations of the human retina are genetically heterogeneous, with well over 100 genes implicated so far. This Seminar focuses on the subset of diseases called retinitis pigmentosa, in which patients typically lose night vision in adolescence, side vision in young adulthood, and central vision in later life because of progressive loss of rod and cone photoreceptor cells. Measures of retinal function, such as the electroretinogram, show that photoreceptor function is diminished generally many years before symptomic night blindness, visual-field scotomas, or decreased visual acuity arise. More than 45 genes for retinitis pigmentosa have been identified. These genes account for only about 60% of all patients; the remainder have defects in as yet unidentified genes. Findings of controlled trials indicate that nutritional interventions, including vitamin A palmitate and omega-3-rich fish, slow progression of disease in many patients. Imminent treatments for retinitis pigmentosa are greatly anticipated, especially for genetically defined subsets of patients, because of newly identified genes, growing knowledge of affected biochemical pathways, and development of animal models.

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The molecular basis of human retinal and vitreoretinal diseases.

Wolfgang Berger, Barbara Kloeckener-Gruissem, John Neidhardt (2010)

During the last two to three decades, a large body of work has revealed the molecular basis of many human disorders, including retinal and vitreoretinal degenerations and dysfunctions. Although belonging to the group of orphan diseases, they affect probably more than two million people worldwide. Most excitingly, treatment of a particular form of congenital retinal degeneration is now possible. A major advantage for treatment is the unique structure and accessibility of the eye and its different components, including the vitreous and retina. Knowledge of the many different eye diseases affecting retinal structure and function (night and colour blindness, retinitis pigmentosa, cone and cone rod dystrophies, photoreceptor dysfunctions, as well as vitreoretinal traits) is critical for future therapeutic development. We have attempted to present a comprehensive picture of these disorders, including biological, clinical, genetic and molecular information. The structural organization of the review leads the reader through non-syndromic and syndromic forms of (i) rod dominated diseases, (ii) cone dominated diseases, (iii) generalized retinal degenerations and (iv) vitreoretinal disorders, caused by mutations in more than 165 genes. Clinical variability and genetic heterogeneity have an important impact on genetic testing and counselling of affected families. As phenotypes do not always correlate with the respective genotypes, it is of utmost importance that clinicians, geneticists, counsellors, diagnostic laboratories and basic researchers understand the relationships between phenotypic manifestations and specific genes, as well as mutations and pathophysiologic mechanisms. We discuss future perspectives. Copyright 2010 Elsevier Ltd. All rights reserved.

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Safety and efficacy of gene transfer for Leber's congenital amaurosis.

Xing Ma, Arkady Lyubarsky, Francesca Simonelli … (2008)

Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477 [ClinicalTrials.gov]). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA. Copyright 2008 Massachusetts Medical Society.

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Author and article information

Journal

Journal ID (nlm-ta): Genome Res

Journal ID (iso-abbrev): Genome Res

Journal ID (publisher-id): GENOME

Title: Genome Research

Publisher: Cold Spring Harbor Laboratory Press

ISSN (Print): 1088-9051

ISSN (Electronic): 1549-5469

Publication date (Print): February 2013

Volume: 23

Issue: 2

Pages: 236-247

Affiliations

[1 ]Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia;

[2 ]UCL Institute of Ophthalmology, Department of Genetics, London EC1V 9EL, United Kingdom;

[3 ]Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 11573, Saudi Arabia;

[4 ]Department of Ophthalmology, College of Medicine, Imam Muhammed Bin Saud Islamic University, Riyadh 13317, Saudi Arabia;

[5 ]Department of Pediatrics, King Khaled Eye Specialist Hospital, Riyadh 11462, Saudi Arabia;

[6 ]Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia;

[7 ]Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia;

[8 ]Department of Ophthalmology, King Faisal Specialist Hospital and Research Center, Jeddah 21499, Saudi Arabia;

[9 ]Department of Ophthalmology, College of Medicine, King Abdulaziz University, Jeddah 21352, Saudi Arabia;

[10 ]Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11573, Saudi Arabia;

[11 ]Department of Retina, King Khaled Eye Specialist Hospital, Riyadh 11462, Saudi Arabia;

[12 ]Department of Ophthalmology, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia;

[13 ]Department of Ophthalmology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia;

[14 ]Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh 11573, Saudi Arabia

Author notes

[15]

These authors contributed equally to this work.

[16 ]Corresponding author E-mail falkuraya@ 123456kfshrc.edu.sa

Article

Medline ID: 9518021

DOI: 10.1101/gr.144105.112

PMC ID: 3561865

PubMed ID: 23105016

SO-VID: fc2a3f6d-6e52-4fd7-a85a-ff4de0c6e395

License:

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/.

History

Date received : 3 June 2012

Date accepted : 4 October 2012

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Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes

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Most cited references 63

Retinitis pigmentosa.

The molecular basis of human retinal and vitreoretinal diseases.

Safety and efficacy of gene transfer for Leber's congenital amaurosis.

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Cited by 114

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