Enabling use of blood spot cards for accurate high throughput Fragile X screening

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DESCRIPTION (provided by applicant): The long term goal of this project is to develop accurate, rapid, high throughput and cost-effective screening for fragile X syndrome (FXS) and related disorders. FXS is the most common known genetic cause of autism and inherited intellectual disability, and affects roughly 1 in 4,000 males and 1 in 6,000 females. The incidence of fragile X carriers is as high as 1 in 130 in females and 1 in 250 in males, and these individuals are at risk for additional disorders that impact childhood early development, including autism. Newborn screening (NBS) for fragile X is timely due to the disease prevalence, lack of a clear phenotype at birth and corresponding "diagnostic odyssey", current and emerging options for early interventions, and impact of associated syndromes. Access to an inexpensive and effective high throughput screening technology, however, has been a key hurdle. To address this technology gap, Asuragen has demonstrated feasibility in phase I studies for a streamlined and automated system for blood card processing and fragile X gene detection that exploits an optimized PCR reagent set. Phase I studies were highly successful, resulting in a technology that can consistently and accurately detect fragile X expansions. In Phase II commercialization, these capabilities will be extended by automating a novel, multiplexed screening assay, developing and integrating an innovative set of controls that ensure reliable data interpretations, establishing an automated algorithm for identifying positives using a workflow that can accommodate thousands of samples per day, and incorporating a confirmation approach that leverages Asuragen's validated AmplideX" product technology. As a result, Asuragen will expand on previously successful fragile X SBIR proposals that have led to multiple cutting-edge products by leveraging a team and environment that is ideally suited to develop, optimize, manufacture, and commercialize the proposed Phase II product. The specific aims of this proposal are: Aim 1: Develop and integrate a set of controls, standards, reagents and QC metrics in an optimized workflow that enables high throughput fragile X NBS from FMR1 normal and mutant blood spots. Aim 2: Establish a screening system that integrates automated assay methods and software that can enable the automated analysis of up to 4000 blood spot samples per day. Aim 3: Validate the system in a retrospective clinical study that includes at least 10,000 newborn blood spot samples, with confirmatory reflex testing of expanded alleles.