Implementation of a registry and open access genetic testing program for inherited retinal diseases within a non‐profit foundation

Mansfield, Brian C.; Yerxa, Benjamin R.; Branham, Kari

doi:10.1002/ajmg.c.31825

Cited by 16 publications

(28 citation statements)

References 24 publications

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“…Currently, the most efficient approach for genetic diagnosis in monogenic diseases, including IRDs, is next-generation sequencing (NGS). NGS technologies facilitate the screening of the entire genome (whole genome sequencing, WGS); of all protein-coding regions (whole exome sequencing, WES); or of protein-coding regions of pre-determined panels of genes (targeted NGS, T-NGS) [79,80]. Since protein-coding regions comprise only 1-2% of the entire genome while harboring over 85% of variants causing Mendelian disorders, WES is still considered as the method of choice for genetic analysis, in both clinical and research settings.…”

Section: Diagnostic Challengesmentioning

confidence: 99%

Syndromic Inherited Retinal Diseases: Genetic, Clinical and Diagnostic Aspects

Tatour

Ben-Yosef

2020

Diagnostics

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Inherited retinal diseases (IRDs), which are among the most common genetic diseases in humans, define a clinically and genetically heterogeneous group of disorders. Over 80 forms of syndromic IRDs have been described. Approximately 200 genes are associated with these syndromes. The majority of syndromic IRDs are recessively inherited and rare. Many, although not all, syndromic IRDs can be classified into one of two major disease groups: inborn errors of metabolism and ciliopathies. Besides the retina, the systems and organs most commonly involved in syndromic IRDs are the central nervous system, ophthalmic extra-retinal tissues, ear, skeleton, kidney and the cardiovascular system. Due to the high degree of phenotypic variability and phenotypic overlap found in syndromic IRDs, correct diagnosis based on phenotypic features alone may be challenging and sometimes misleading. Therefore, genetic testing has become the benchmark for the diagnosis and management of patients with these conditions, as it complements the clinical findings and facilitates an accurate clinical diagnosis and treatment.

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Section: Diagnostic Challengesmentioning

confidence: 99%

Syndromic Inherited Retinal Diseases: Genetic, Clinical and Diagnostic Aspects

Tatour

Ben-Yosef

2020

Diagnostics

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“…Yet, there remains up to 30% of patients without a complete molecular genetics diagnosis for inherited retinal diseases (IRDs). 1 – 3 The genome still has “dark DNA” that may harbor as-yet-undiscovered causative variants due to difficult-to-sequence or inability to assign causation to noncoding regions with low conservation. 4 Epigenetic effects, digenic or multigenic diseases, the presence or absence of hypomorphic alleles, and gene-environment interactions all further complicate molecular genetics diagnoses.…”

Section: Introductionmentioning

confidence: 99%

Assessing Variant Causality and Severity Using Retinal Pigment Epithelial Cells Derived from Stargardt Disease Patients

Matynia

Wang

Kim

et al. 2022

Trans. Vis. Sci. Tech.

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Purpose Modern molecular genetics has revolutionized gene discovery, genetic diagnoses, and precision medicine yet many patients remain unable to benefit from these advances as disease-causing variants remain elusive for up to half of Mendelian genetic disorders. Patient-derived induced pluripotent stem (iPS) cells and transcriptomics were used to identify the fate of unsolved ABCA4 alleles in patients with Stargardt disease. Methods Multiple independent iPS lines were generated from skin biopsies of three patients with Stargardt disease harboring a single identified pathogenic ABCA4 variant. Derived retinal pigment epithelial cells (dRPE) from a normal control and patient cells were subjected to RNA-Seq on the Novaseq6000 platform, analyzed using DESeq2 with calculation of allele specific imbalance from the pathogenic or a known linked variant. Protein analysis was performed using the automated Simple Western system. Results Nine dRPE samples were generated, with transcriptome analysis on eight. Allele-specific expression indicated normal transcripts expressed from splice variants albeit at low levels, and missense transcripts expressed at near-normal levels. Corresponding protein was not easily detected. Patient phenotype correlation indicated missense variants expressed at high levels have more deleterious outcomes. Transcriptome analysis suggests mitochondrial membrane biodynamics and the unfolded protein response pathway may be relevant in Stargardt disease. Conclusions Patient-specific iPS-derived RPE cells set the stage to assess non-expressing variants in difficult-to-detect genomic regions using easily biopsied tissue. Translational Relevance This “Disease in a Dish” approach is likely to enhance the ability of patients to participate in and benefit from clinical trials while providing insights into perturbations in RPE biology.

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“…Barriers to genetic testing remain a challenge for individuals with IRDs and health care professionals. One significant challenge for the widespread implementation of genetic testing is the varied payment/reimbursement mechanisms across countries [ 42 , 43 ]. In some countries, there is limited coverage of genetic testing costs [ 1 , 42 ].…”

Section: Case Studymentioning

confidence: 99%

Genetic testing and diagnosis of inherited retinal diseases

Lam

Leroy

Black

et al. 2021

Orphanet J Rare Dis

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Inherited retinal diseases (IRDs) are a diverse group of degenerative diseases of the retina that can lead to significant reduction in vision and blindness. Because of the considerable phenotypic overlap among IRDs, genetic testing is a critical step in obtaining a definitive diagnosis for affected individuals and enabling access to emerging gene therapy–based treatments and ongoing clinical studies. While advances in molecular diagnostic technologies have significantly improved the understanding of IRDs and identification of disease-causing variants, training in genetic diagnostics among ophthalmologists is limited. In this review, we will provide ophthalmologists with an overview of genetic testing for IRDs, including the types of available testing, variant interpretation, and genetic counseling. Additionally, we will discuss the clinical applications of genetic testing in the molecular diagnosis of IRDs through case studies.

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Implementation of a registry and open access genetic testing program for inherited retinal diseases within a non‐profit foundation

Cited by 16 publications

References 24 publications

Syndromic Inherited Retinal Diseases: Genetic, Clinical and Diagnostic Aspects

Syndromic Inherited Retinal Diseases: Genetic, Clinical and Diagnostic Aspects

Assessing Variant Causality and Severity Using Retinal Pigment Epithelial Cells Derived from Stargardt Disease Patients

Genetic testing and diagnosis of inherited retinal diseases

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