Parental Experiences with Newborn Screening and Gene Replacement Therapy for Spinal Muscular Atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) is a genetic neurodegenerative disorder with onset predominantly in infants and children. In recent years, newborn screening and three treatments, including gene replacement therapy (Onasemnogene abeparvovec-xioi), have become available in the United States, aiding in the diagnosis and treatment of children with SMA. OBJECTIVE: To evaluate parents' experiences with newborn screening and gene replacement therapy and to explore best practices for positive newborn screen disclosure and counseling of families. METHODS: We conducted semi-structured interviews (n = 32) and online surveys (n = 79) of parents whose children were diagnosed with SMA (on newborn screening or symptomatically) and treated with gene replacement therapy. RESULTS: Gene replacement therapy was most parents' first treatment choice, although concerns regarding long term efficacy (65%) and safety (51%) were common. Information provided during the newborn screening disclosure was quite variable. Only 34% of parents reported the information provided was sufficient and expressed need for more information about treatment. Although many parents experienced denial of the diagnosis at initial disclosure, 94% were in favor of inclusion of SMA on newborn screening. Parents were almost universally anxious following diagnosis and over half remained anxious at the time of study participation with uncertainty of the future being a key concern. Many parents had difficulty processing information provided during their first clinic appointment due to its complexity and their emotional state at the time. CONCLUSIONS: Utilizing this data, we provide a recommendation for the information provided in newborn screening disclosure, propose adjustments to education and counseling during the first clinic visit, and bring awareness of parents' mental health difficulties.

Genetic Testing to Guide Risk-Stratified Screens for Breast Cancer.

Breast cancer screening modalities and guidelines continue to evolve and are increasingly based on risk factors, including genetic risk and a personal or family history of cancer. Here, we review genetic testing of high-penetrance hereditary breast and ovarian cancer genes, including BRCA1 and BRCA2, for the purpose of identifying high-risk individuals who would benefit from earlier screening and more sensitive methods such as magnetic resonance imaging. We also consider risk-based screening in the general population, including whether every woman should be genetically tested for high-risk genes and the potential use of polygenic risk scores. In addition to enabling early detection, the results of genetic screens of breast cancer susceptibility genes can be utilized to guide decision-making about when to elect prophylactic surgeries that reduce cancer risk and the choice of therapeutic options. Variants of uncertain significance, especially missense variants, are being identified during panel testing for hereditary breast and ovarian cancer. A finding of a variant of uncertain significance does not provide a basis for increased cancer surveillance or prophylactic procedures. Given that variant classification is often challenging, we also consider the role of multifactorial statistical analyses by large consortia and functional tests for this purpose.