Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation to clinical practice. Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 cystic fibrosis patients in registries and clinics in North America and Europe. Among these patients, 159 CFTR variants had an allele frequency of ≥0.01%. These variants were evaluated for both clinical severity and functional consequence with 127 (80%) meeting both clinical and functional criteria consistent with disease. Assessment of disease penetrance in 2,188 fathers of cystic fibrosis patients enabled assignment of 12 of the remaining 32 variants as neutral while the other 20 variants remained indeterminate. This study illustrates that sourcing data directly from well-phenotyped subjects can address the gap in our ability to interpret clinically-relevant genomic variation.

BACKGROUND: After newborn screening has been completed, many states retain residual newborn screening dried blood samples for various purposes, including program evaluation, quality assurance, and biomedical research. The extent to which states possess legal authority to retain residual dried blood samples (DBS) and use them for purposes unrelated to newborn screening is unclear. OBJECTIVE: The purpose of this study was to evaluate state laws regarding the retention and use of DBS. METHODS: State statutes and regulations related to newborn screening of all 50 states plus the District of Columbia were accessed online between November 2008 and December 2009 and reviewed by 2 independent reviewers to determine the extent to which the retention and use of DBS were addressed. RESULTS: The retention or use of DBS has not been addressed in 18 states. In 4 states, DBS becomes state property. Eight states require that parents be provided information regarding the retention of DBS. Parents in 5 states may request the destruction of their child's residual sample. Parental consent is required under certain circumstances to release DBS for research in 6 states. One state prohibits DBS from being used for research purposes. CONCLUSIONS: States have wide variability in their policies regarding the retention and use of DBS. Many states have not addressed key issues, and some states that retain DBS may be acting outside the scope of their legal authority. The lack of transparency on the part of states in retaining DBS may undermine public trust in state newborn screening programs and the research enterprise.

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.

WHAT'S KNOWN ON THIS SUBJECT:The retention and use of residual bloodspots is a practice of many state newborn screening programs. This practice has become controversial, and little is known about public attitudes on the retention and research use of newborn residual bloodspots. WHAT THIS STUDY ADDS:This study offers a detailed analysis of public attitudes regarding bloodspot retention and use for biomedical research. The results also offer insights on how education regarding this practice influences support for newborn screening and residual bloodspot use. abstract BACKGROUND AND OBJECTIVES: Many state newborn screening (NBS) programs retain residual NBS bloodspots after the completion of screening. Potential uses for residual specimens include laboratory quality assurance, biomedical research, and, rarely, forensic applications. Our objective was to evaluate public opinion about the policies and practices relevant to the retention and use of residual bloodspots for biomedical research. METHODS:A total of 3855 respondents were recruited using 3 methods: focus groups (n = 157), paper or telephone surveys (n = 1418), and a Knowledge Networks panel (n = 2280). Some participants (n = 1769) viewed a 22-minute movie about the retention and use of residual specimens while other participants were provided only written information about this practice. All participants were surveyed using a 38-item questionnaire. RESULTS:A diverse set of participants was recruited. Respondents were very supportive of NBS in general and accepting of the use of residual bloodspots for important research activities. Respondents were evenly divided on the acceptability of NBS without parental permission, but the majority of respondents supported the use of an "optin" process for parental permission for residual bloodspot retention and use. Viewing the educational movie was associated with greater support for bloodspot retention and use. CONCLUSIONS:Our results show that the general public surveyed here was supportive of NBS and residual sample retention and research use. However, there was a clear preference for an informed permission process for parents regarding these activities. Education about NBS was associated with a higher level of support and may be important to maintain public trust in these important programs.

The storage and use of residual newborn screening dried blood specimens has generated significant controversy in the past 5 years, primarily because of public concerns over the lack of parental knowledge and consent for these activities. State policies addressing the management of these specimens vary widely, and there is currently little guidance to aid new state policy development to address the concerns of program professionals, investigators, and the general public. This article offers guidance for state policy based on multiple sources of data, including public attitudes, professional statements, state experience, and an analysis of the ethical, social, legal, and biomedical issues from a multidisciplinary group of scholars. This guidance will be useful for state programs that seek to develop policies that are informed by a contemporary analysis of the key ethical, legal, and social aspects of this practice. This article represents the work of the authors and does not represent American Academy of Pediatrics policy.

In the originally published version of this article, Table 1 unfortunately included c.542G>A instead of c.542G>T. This mutation was correctly notated as c.

Rationale: The advent of precision treatment for cystic fibrosis using small-molecule therapeutics has created a need to estimate potential clinical improvements attributable to increases in cystic fibrosis transmembrane conductance regulator (CFTR) function.Objectives: To derive CFTR function of a variety of CFTR genotypes and correlate with key clinical features (sweat chloride concentration, pancreatic exocrine status, and lung function) to develop benchmarks for assessing response to CFTR modulators.Methods: CFTR function assigned to 226 unique CFTR genotypes was correlated with the clinical data of 54,671 individuals enrolled in the Clinical and Functional Translation of CFTR (CFTR2) project. Crosssectional FEV 1 % predicted measurements were plotted by age at which measurement was obtained. Shifts in sweat chloride concentration and lung function reported in CFTR modulator trials were compared with function-phenotype correlations to assess potential efficacy of therapies.Measurements and Main Results: CFTR genotype function exhibited a logarithmic relationship with each clinical feature. Modest increases in CFTR function related to differing genotypes were associated with clinically relevant improvements in cross-sectional FEV 1 % predicted over a range of ages (6-82 yr). Therapeutic responses to modulators corresponded closely to predictions from the CFTR2-derived relationship between CFTR genotype function and phenotype.Conclusions: Increasing CFTR function in individuals with severe disease will have a proportionally greater effect on outcomes than similar increases in CFTR function in individuals with mild disease and should reverse a substantial fraction of the disease process. This study provides reference standards for clinical outcomes that may be achieved by increasing CFTR function.

The new rounding system has the potential to reduce waste and improve the quality of patient care while improving caregiver satisfaction and medical student teaching. Adaptive leadership skills will be required to overcome resistance to change. The use of athletic analogies can improve teamwork and facilitate the adoption of a systems approach to the delivery of patient care.