Development and Validation of a Newborn Screening Test for Angelman Syndrome

Quick Overview

Dr. Mei Baker, a professor in the Department of Pediatrics and director of the Newborn Screening Laboratory at the University of Wisconsin School of Medicine and Public Health, presented on the development and validation of a newborn screening test for Angelman Syndrome at the 2022 FAST Science Summit. Dr. Baker emphasized the importance of viewing newborn screening as a system and integrating Angelman Syndrome screening into existing programs. She discussed the process of specimen collection, transportation, and testing, highlighting the use of existing DNA samples from other disorders. Dr. Baker also mentioned the need for education and long-term follow-up for newborns identified with Angelman Syndrome. She presented the assay process, which utilizes real-time PCR and mutant curve analysis to detect methylation status changes associated with Angelman Syndrome. Dr. Baker expressed confidence in the assay’s sensitivity and specificity and discussed ongoing validation efforts. She thanked her colleagues for their contributions to the research.

Introduction

Dr. Mei Baker, a professor in the Department of Pediatrics and the director of the Newborn Screening Laboratory at the University of Wisconsin School of Medicine and Public Health, discusses the development and validation of a new newborn screening test for Angelman Syndrome. With 15 years of experience in routine newborn screening, Dr. Baker has a successful track record in implementing new screening tests for disorders. She was instrumental in implementing newborn screening for SCIDs (Severe Combined Immunodeficiency) in Wisconsin in 2008 and has also developed and implemented the Cystic Fibrosis Newborn Screening.

The Importance of Newborn Screening as a System

Dr. Baker emphasizes that newborn screening is not just about individual tests, but rather a comprehensive system. To integrate newborn screening for Angelman Syndrome into the existing system, it is crucial to identify what has already been done and leverage existing resources. Dr. Baker highlights the need for public education and praises the efforts of organizations like FAST (Foundation for Angelman Syndrome Therapeutics) in raising awareness about Angelman Syndrome.

Specimen Collection and Testing

Dr. Baker explains that the screening test for Angelman Syndrome can be integrated into the existing newborn screening system. Dry blood spots, which are already collected for other disorders, can be used for Angelman Syndrome screening. The samples are transported to the laboratory within 24 hours, and the testing is performed using real-time PCR machines that are already available in every state in the United States. Dr. Baker emphasizes the importance of scalability and robustness in the testing process to ensure that every sample is processed efficiently.

Short-Term and Long-Term Follow-Up

Dr. Baker emphasizes the importance of not only identifying newborns with Angelman Syndrome but also ensuring their follow-up care. This includes confirmatory testing and clinical care. She praises the efforts of organizations like FAST in advocating for long-term follow-up and encourages the establishment of programs for long-term follow-up for Angelman Syndrome identified through newborn screening.

The Assay Process

Dr. Baker explains the assay process for Angelman Syndrome screening. The assay utilizes residual DNA from testing for other disorders, such as SCIDs and SMA (Spinal Muscular Atrophy). The DNA undergoes bisulfate treatment and is then subjected to multiplex PCR. The real-time PCR machine is programmed to perform mutant curve analysis, which allows for the identification of methylation patterns associated with Angelman Syndrome. Dr. Baker acknowledges the limitations of the assay, particularly in detecting mutations in the UBE3A gene, and mentions ongoing efforts to improve the assay’s coverage.

Ethical Considerations and Mosaic Systems

Dr. Baker raises the issue of Mosaic systems, where individuals may have a percentage of cells with Angelman Syndrome characteristics but may not exhibit clinical symptoms. She highlights the importance of assessing the benefits and potential harm of identifying individuals in the Mosaic system through newborn screening. Dr. Baker suggests that further discussion and consideration are needed to determine the ethical implications of including Mosaic systems in newborn screening.

Validation and Future Steps

Dr. Baker discusses the validation process for the Angelman Syndrome screening assay. The laboratory has collaborated with patients diagnosed with Angelman Syndrome and Prader-Willi Syndrome to validate the assay’s accuracy. Dr. Baker expresses confidence in achieving 100% sensitivity and specificity for the methylation status of Angelman Syndrome through the validation process. She concludes by thanking her colleagues and collaborators for their contributions to the development and validation of the screening test.

In summary, Dr. Mei Baker presents the development and validation of a new newborn screening test for Angelman Syndrome. The test utilizes existing resources and infrastructure, making it cost-effective and easily integrated into the current newborn screening system. Dr. Baker emphasizes the importance of comprehensive follow-up care and ethical considerations in implementing newborn screening for Angelman Syndrome.