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1.  Let's Try It: Me for You 
doi:10.1089/gtmb.2013.1546
PMCID: PMC3700458  PMID: 23819845
2.  Disease advocacy organizations catalyze translational research 
Frontiers in Genetics  2013;4:101.
Disease advocacy organizations have long played an important role in the continuum from basic science to therapy development in rare disease research. PXE International has led the field in innovative ways, venturing into specific activities that have traditionally been conducted by scientists. As lay founders, we have engaged in gene discovery, gene patenting, diagnostic test development, epidemiological studies, clinical trials, and therapy research and development. This article will describe the steps that we took, and the ways in which we have scaled these efforts for the larger community.
doi:10.3389/fgene.2013.00101
PMCID: PMC3671180  PMID: 23761807
rare diseases; advocacy; ABCC6; PXE; open access
4.  Community Engagement about Genetic Variation Research 
Population Health Management  2012;15(2):78-89.
Abstract
The aim of this article is to describe the methods and effectiveness of the Public Engagement in Genetic Variation and Haplotype Mapping Issues (PEGV) Project, which engaged a community in policy discussion about genetic variation research. The project implemented a 6-stage community engagement model in New Rochelle, New York. First, researchers recruited community partners. Second, the project team created community oversight. Third, focus groups discussed concerns generated by genetic variation research. Fourth, community dialogue sessions addressed focus group findings and developed policy recommendations. Fifth, a conference was held to present these policy recommendations and to provide a forum for HapMap (haplotype mapping) researchers to dialogue directly with residents. Finally, findings were disseminated via presentations and papers to the participants and to the wider community beyond. The project generated a list of proposed guidelines for genetic variation research that addressed the concerns of New Rochelle residents. Project team members expressed satisfaction with the engagement model overall but expressed concerns about how well community groups were utilized and what segment of the community actually engaged in the project. The PEGV Project represents a model for researchers to engage the general public in policy development about genetic research. There are benefits of such a process beyond the desired genetic research. (Population Health Management 2012;15:78–89)
doi:10.1089/pop.2011.0013
PMCID: PMC3363293  PMID: 21815821
5.  Reporting Actionable Research Results: Shared Secrets Can Save Lives 
Science translational medicine  2012;4(143):143cm8.
In this Commentary, we describe a cryptographic method for returning research results to individuals who participate in clinical studies. Controlled use of this method, which relaxes the typical anonymization guarantee, can ensure that clinically actionable results reach participants while also addressing most privacy concerns.
doi:10.1126/scitranslmed.3003958
PMCID: PMC3501742  PMID: 22814848
6.  Pseudoxanthoma Elasticum: Progress in Diagnostics and Research Towards Treatment Summary of the 2010 PXE International Research Meeting* 
Pseudoxanthoma elasticum (PXE), a prototypic heritable disorder with ectopic mineralization, manifests with characteristic skin findings, ocular involvement and cardiovascular problems. The classic forms of PXE are due to loss-of-function mutations in the ABCC6 gene, which encodes ABCC6, a putative transmembrane efflux transporter expressed primarily in the liver. While considerable progress has recently been made in understanding the molecular genetics and pathomechanisms of PXE, no effective or specific treatment is currently available for this disorder. PXE International, the premiere patient advocacy organization, organized a workshop in November 2010 to assess the current state of diagnostics and research to develop an agenda towards treatment of PXE. This overview summarizes the progress in PXE research, with emphasis on molecular therapies for this, currently intractable, disorder.
doi:10.1002/ajmg.a.34067
PMCID: PMC3121926  PMID: 21671388
Pseudoxanthoma elasticum; Heritable ectopic mineralization disorders; ABC transporters; Antimineralization factors; Molecular therapies for PXE
7.  Acquired Pseudoxanthoma Elasticum Presenting After Liver Transplantation 
Background
Pseudoxanthoma elasticum (PXE) is thought to be a metabolic disorder resulting from mutations in the gene encoding the cellular transporter, ABCC6, which is primarily expressed in liver and kidney. We encountered three patients who developed clinical and histopathological evidence of PXE after liver transplantation, suggesting that PXE could have been acquired from the transplanted organ.
Objective
To delineate the clinical features and screen each patient and samples of donor liver for mutations in the ABCC6 gene.
Methods
Each patient underwent full clinical examination, skin biopsy, and ophthalmological examination, as well as whole genome sequencing using standard techniques. Fixed samples of donor liver tissue were available for mutation analysis in two patients and of donor kidney tissue in one.
Results
All 3 patients had unequivocal clinical and histopathologic evidence of PXE. No patient (or family member available for screening) had evidence of mutations in ABCC6. Neither liver specimen nor the single available kidney specimen showed evidence of mutations in ABCC6.
Limitations
Liver tissue was not available from one patient and DNA was of poor quality in another, resulting in limited screening. Genetic testing does not detect ABCC6 mutations in 10% of patients with confirmed PXE.
Conclusion
Although we were unable to demonstrate ABCC6 mutations in limited screening of fixed donor livers, the absence of any PXE mutations in the affected patients, the timing of onset of PXE, and the known acquisition of other metabolic disorders and coagulopathies from donor liver suggest that PXE was likely acquired via liver transplantation.
doi:10.1016/j.jaad.2010.03.030
PMCID: PMC3078966  PMID: 21397982
8.  Mutation detection in the ABCC6 gene and genotype–phenotype analysis in a large international case series affected by pseudoxanthoma elasticum 
Journal of Medical Genetics  2007;44(10):621-628.
Background
Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, characterised by dystrophic mineralization of connective tissues. It is caused by mutations in the ABCC6 (ATP binding cassette family C member 6) gene, which encodes MRP6 (multidrug resistance‐associated protein 6).
Objective
To investigate the mutation spectrum of ABCC6 and possible genotype–phenotype correlations.
Methods
Mutation data were collected on an international case series of 270 patients with PXE (239 probands, 31 affected family members). A denaturing high‐performance liquid chromatography‐based assay was developed to screen for mutations in all 31 exons, eliminating pseudogene coamplification. In 134 patients with a known phenotype and both mutations identified, genotype–phenotype correlations were assessed.
Results
In total, 316 mutant alleles in ABCC6, including 39 novel mutations, were identified in 239 probands. Mutations were found to cluster in exons 24 and 28, corresponding to the second nucleotide‐binding fold and the last intracellular domain of the protein. Together with the recurrent R1141X and del23–29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype–phenotype analysis failed to reveal a significant correlation between the types of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease.
Conclusions
This study emphasises the principal role of ABCC6 mutations in the pathogenesis of PXE, but the reasons for phenotypic variability remain to be explored.
doi:10.1136/jmg.2007.051094
PMCID: PMC2597973  PMID: 17617515
pseudoxanthoma elasticum; ABC transporters; genotype–phenotype correlations; heritable skin diseases
9.  Call for Action from Genetic Alliance 
doi:10.1089/gtmb.2009.1503
PMCID: PMC2830755  PMID: 19371210
10.  Transparency, Openness, and Genetic Testing 
doi:10.1089/gtmb.2009.1505
PMCID: PMC2840228  PMID: 19663599
12.  From patients to partners: participant-centric initiatives in biomedical research 
Nature reviews. Genetics  2012;13(5):371-376.
Advances in computing technology and bioinformatics mean that medical research is increasingly characterized by large international consortia of researchers that are reliant on large data sets and biobanks. These trends raise a number of challenges for obtaining consent, protecting participant privacy concerns and maintaining public trust. Participant-centred initiatives (PCIs) use social media technologies to address these immediate concerns, but they also provide the basis for long-term interactive partnerships. Here, we give an overview of this rapidly moving field by providing an analysis of the different PCI approaches, as well as the benefits and challenges of implementing PCIs.
doi:10.1038/nrg3218
PMCID: PMC3806497  PMID: 22473380
13.  Managing Incidental Findings and Research Results in Genomic Research Involving Biobanks & Archived Datasets 
Biobanks and archived datasets collecting samples and data have become crucial engines of genetic and genomic research. Unresolved, however, is what responsibilities biobanks should shoulder to manage incidental findings (IFs) and individual research results (IRRs) of potential health, reproductive, or personal importance to individual contributors (using “biobank” here to refer to both collections of samples and collections of data). This paper reports recommendations from a 2-year, NIH-funded project. The authors analyze responsibilities to manage return of IFs and IRRs in a biobank research system (primary research or collection sites, the biobank itself, and secondary research sites). They suggest that biobanks shoulder significant responsibility for seeing that the biobank research system addresses the return question explicitly. When re-identification of individual contributors is possible, the biobank should work to enable the biobank research system to discharge four core responsibilities: to (1) clarify the criteria for evaluating findings and roster of returnable findings, (2) analyze a particular finding in relation to this, (3) re-identify the individual contributor, and (4) recontact the contributor to offer the finding. The authors suggest that findings that are analytically valid, reveal an established and substantial risk of a serious health condition, and that are clinically actionable should generally be offered to consenting contributors. The paper specifies 10 concrete recommendations, addressing new biobanks and biobanks already in existence.
doi:10.1038/gim.2012.23
PMCID: PMC3597341  PMID: 22436882
incidental findings; return of results; biobanks; research ethics; bioethics; genetics; genomics
14.  Conference Proceedings: “Down Syndrome: National Conference on Patient Registries, Research Databases, and Biobanks” 
Molecular genetics and metabolism  2011;104(1-2):13-22.
A December 2010 meeting, “Down Syndrome: National Conference on Patient Registries, Research Databases, and Biobanks,” was jointly sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at the National Institutes of Health (NIH) in Bethesda, MD, and the Global Down Syndrome Foundation (GDSF)/Linda Crnic Institute for Down Syndrome based in Denver, CO. Approximately 70 attendees and organizers from various advocacy groups, federal agencies (Centers for Disease Control and Prevention, and various NIH Institutes, Centers, and Offices), members of industry, clinicians, and researchers from various academic institutions were greeted by Drs. Yvonne Maddox, Deputy Director of NICHD, and Edward McCabe, Executive Director of the Linda Crnic Institute for Down Syndrome. They charged the participants to focus on the separate issues of contact registries, research databases, and biobanks through both podium presentations and breakout session discussions. Among the breakout groups for each of the major sessions, participants were asked to generate responses to questions posed by the organizers concerning these three research resources as they related to Down syndrome and then to report back to the group at large with a summary of their discussions. This report represents a synthesis of the discussions and suggested approaches formulated by the group as a whole.
doi:10.1016/j.ymgme.2011.07.005
PMCID: PMC3171614  PMID: 21835664
Down syndrome; registry; database; biobank; trisomy 21

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