Integrative Curation of Clinically Relevant Variants in X-Linked Inherited Retinal Disease Genes

Baylor College Of Medicine, Houston TX

Investigators

Abstract

Abstract Inherited retinal diseases (IRD) are a major cause of early-onset blindness, profoundly affecting millions of patients. Given the clinical and genetic heterogeneity of IRD, targeted gene therapy is emerging as the principle effective approach for treating the disease with many clinical trials currently underway. Molecular diagnosis is the required first step allowing patients to access and benefit from these emerging therapies. In 2021, coordinating with the ClinGen Ocular Clinical Domain Working Group committee, we established a new variant curation expert panel (VCEP) that is developing variant curation specifications for definitively assigned disease-gene pairs and curating expert assessment of variants in X-linked IRD genes. Here we propose to scale up our variant curation effort while expanding the scope of our initial application which is addressing the variant curation specifications for seven genes (RPGR, CHM, RS1, RP2, OFD1, NDP, and CACNA1F) to include three additional X-linked IRD genes (NYX, OPN1LW, OPN1MW) and provide ClinGen FDA approved assessment of more variants in each gene by applying our specifications. Collectively, mutations in these genes account for >15% of IRD patients with clinical trials ongoing for three genes. Our committed and engaged distinguished panel of scientists from across the world have diverse expertise: practicing ophthalmologic physicians, clinical diagnostic laboratory directors, and world-leading researchers studying the function of the X-linked IRD genes in the clinical and research domains. These experts bring complementary knowledge and resources to this effort including functional laboratory assays to assess the impact of patient variants, clinical trials for gene-based treatments, and collections of patient samples with sequenced variants and a detailed clinical and family history. Together with dedicated bioinformatics, curatorial, and administrative support, the X-linked IRD Variant Curation Panel will continue to deploy the FDA approved ClinGen infrastructure tools and processes in combination with the supportive resources we propose to collect, organize, and provide to the panel to develop rule specifications for new genes and provide ongoing curation of X-linked IRD gene variants. With our panel and team of coordinated curation volunteers, we will curate and expertly assess the variants in these genes. The products of this effort will be two-fold. First, robust, tested specifications that can be applied to assess new variants in the genes including new specifications specific for the proposed new genes and additional examples for the variety of different X-linked IRD genes that can serve as models for other genes. And second, curated variants in the X-linked IRD genes with three-star FDA registered (expert panel assessed) ratings in the ClinVar database that will improve the assessment of de novo patient variants and enable treatments with gene-based therapies.