Indo Korean Inherited Retinal Disease Panel Development

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About This Project

Genetic eye disorders are one of the top ten causes of the global ocular health burden. It is increasingly evident that ophthalmic clinical practice by the physician would be deficient if dealt with without genetic knowledge and information. Retinal diseases are one of the leading causes of childhood blindness and inherited retinal disease has a prevalence of 1 in 4000 which is one of the common causes of blindness in children and working adults.

Inherited retinal diseases (IRDs) showing initially the loss of cone photoreceptors, for example, macular degeneration (MD) and Stargardt disease (STGD), manifest with a loss of central vision. Inherited retinal diseases can exhibit autosomal dominant, autosomal recessive or an X- linked pattern of inheritance and demonstrate progressive or stationary and syndromic or nonsyndromic clinical phenotypes.

Recent advances in genomic technologies, particularly next-generation sequencing (NGS) methods, have brought a paradigm shift in discovering eye disease-associated genetic variants from linkage and genome-wide association studies to NGS-based genome /exome studies. Whole Exome Sequencing (WES), primarily very successful in Mendelian disorders, has also offered in identifying causal variants in patients and families with complex diseases.

Our project aims to detect known and novel variants responsible for inherited retinal disorders in 500 patients by whole-exome sequencing with an aim to contribute toward a comprehensive understanding of this heterogeneous group of disorders by developing a genetic analysis and user-friendly consulting software that can be used in hospitals of India and Republic of Korea. Despite substantial progress in sequencing and new disease gene discovery, current strategies can genetically solve only approximately 55–60% of IRD cases. The high number of unsolved cases can be attributed to as-yet-unidentified IRD genes or elusive mutations in the known disease genes. The latter may include silent mutations leading to aberrant splicing, deep intronic mutations, or structural variations (SVs), SVs include large insertions and deletions, also called copy-number variations (CNVs), inversions, translocations, and other complex genomic rearrangements.

Structural variants are increasingly being recognized as the cause of many rare diseases, but these large genomic elements are often undetectable with short-read sequencing tools due to their length and repetitive content. The structural variation affects more base pairs of the human genome than single nucleotide variants and small insertions and deletions combined. With its extraordinarily long reads, SMRT Sequencing detects structural variants with high precision and recall, even at low coverage.

In the present study, we aim to use PacBio’s Sequel II System to detect structural variants for Inherited Retinal disorders which are associated with challenging genomic regions or structural variants including repeat expansions. We believe that long-read SMRT Sequencing will be essential for discovering the causal elements that have proven elusive with previous approaches, and we anticipate that this research will ultimately make it easier for doctors to diagnose structural variants associated with Inherited retinal disorders.

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