Mutations of lamin A/C (LMNA) cause a wide range of human disorders, including progeria, lipodystrophy, neuropathies and autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD). EDMD is also caused by X-linked recessive loss-of-function mutations of emerin, another component of the inner nuclear lamina that directly interacts with LMNA. One model for disease pathogenesis of LMNA and emerin mutations is cell-specific perturbations of the mRNA transcriptome in terminally differentiated cells. To test this model, we studied 125 human muscle biopsies from 13 diagnostic groups (125 U133A, 125 U133B microarrays), including EDMD patients with LMNA and emerin mutations. A Visual and Statistical Data Analyzer (VISDA) algorithm was used to statistically model cluster hierarchy, resulting in a tree of phenotypic classifications. Validations of the diagnostic tree included permutations of U133A and U133B arrays, and use of two probe set algorithms (MAS5.0 and MBEI). This showed that the two nuclear envelope defects (EDMD LMNA, EDMD emerin) were highly related disorders and were also related to fascioscapulohumeral muscular dystrophy (FSHD). FSHD has recently been hypothesized to involve abnormal interactions of chromatin with the nuclear envelope. To identify disease-specific transcripts for EDMD, we applied a leave-one-out (LOO) cross-validation approach using LMNA patient muscle as a test data set, with reverse transcription-polymerase chain reaction (RT-PCR) validations in both LMNA and emerin patient muscle. A high proportion of top-ranked and validated transcripts were components of the same transcriptional regulatory pathway involving Rb1 and MyoD during muscle regeneration (CRI-1, CREBBP, Nap1L1, ECREBBP/p300), where each was specifically upregulated in EDMD. Using a muscle regeneration time series (27 time points) we develop a transcriptional model for downstream consequences of LMNA and emerin mutations. We propose that key interactions between the nuclear envelope and Rb and MyoD fail in EDMD at the point of myoblast exit from the cell cycle, leading to poorly coordinated phosphorylation and acetylation steps. Our data is consistent with mutations of nuclear lamina components leading to destabilization of the transcriptome in differentiated cells.

Background/Aims: To predict the potential public health impact of personal genomics, empirical research on public perceptions of these services is needed. In this study, ‘early adopters’ of personal genomics were surveyed to assess their motivations, perceptions and intentions. Methods: Participants were recruited from everyone who registered to attend an enrollment event for the Coriell Personalized Medicine Collaborative, a United States-based (Camden, N.J.) research study of the utility of personalized medicine, between March 31, 2009 and April 1, 2010 (n = 369). Participants completed an Internet-based survey about their motivations, awareness of personalized medicine, perceptions of study risks and benefits, and intentions to share results with health care providers. Results: Respondents were motivated to participate for their own curiosity and to find out their disease risk to improve their health. Fewer than 10% expressed deterministic perspectives about genetic risk, but 32% had misperceptions about the research study or personal genomic testing. Most respondents perceived the study to have health-related benefits. Nearly all (92%) intended to share their results with physicians, primarily to request specific medical recommendations. Conclusion: Early adopters of personal genomics are prospectively enthusiastic about using genomic profiling information to improve their health, in close consultation with their physicians. This suggests that early users (i.e. through direct-to-consumer companies or research) may follow up with the health care system. Further research should address whether intentions to seek care match actual behaviors.

The value of genomic risk assessment depends upon patients making appropriate behavioral changes in response to increased risk leading to disease prevention and early detection. To date, few studies have investigated consumers’ response to personalized genomic disease risk information. To address this gap, we conducted semi-structured interviews with 60 adults participating in the Coriell Personalized Medicine Collaborative. The interviews took place after receiving results providing genomic and other risk information for up to eight common complex diseases. We found that participants were most likely to recall results which conferred an increased risk or those of particular personal interest. Participants understood the multi-factorial nature of common complex disease, and generally did not have negative emotional responses or overly deterministic perceptions of their results. Although most participants expressed a desire to use results to improve their health, a minority had actually taken action (behavior change or shared results with their doctor) at the time of the interview. These results suggest that participants have a reasonable understanding of genomic risk information and that provision of genomic risk information may motivate behavior change in some individuals; however additional work is needed to better understand the lack of change seen in the majority of participants.

Becker muscular dystrophy (BMD) is a milder form of X-linked Duchenne muscular dystrophy (DMD). Here, we report a study of 75 patients with immunoblot and/or immunostaining findings of muscle biopsy consistent with BMD (abnormal dystrophin). We utilized multiplex ligation dependent probe amplification (MLPA) on genomic DNA (gDNA) to screen all 79 exons for both deletions and duplications. A total of 19 patients testing negative for MLPA mutations were tested for mRNA splicing abnormalities using cDNA-MLPA on muscle biopsy. Complete cDNA sequencing was done on MLPA-negative patients. We identified disease-causing mutations in 66 (88%) of the patients. Of the mutation-positive patients, 42 (64%) showed deletions of one or more exons, 14 (21%) showed duplications, and 10 (15%) showed various mutations detected by cDNA-MLPA and sequencing studies. We found a high rate of "exceptions" to the reading frame rule in this BMD series (out-of-frame BMD; 17/56 deletions/duplications; 30%). This was partly explained by the high incidence of 5' gene deletions in BMD patients (a region known to be a hotspot for exceptions), and due to complex splicing patterns in which a subset of transcripts showed deletions larger than gDNA (exon-skipping). Comparing our findings in BMD to previously published DMD data, BMD patients have higher proportions of duplications, a different distribution of mutations, and higher exception to the reading frame rule.

Aim Despite predictions of increased clinical applications, little is known about primary care providers’ (PCPs’) readiness to apply genomics to patient care. The aim was to assess PCPs’ current experience with genetic testing, their assessment of the understandability and clinical utility of information in sample direct-to-consumer reports for genomic assessment of disease risk and warfarin dosing and attitudes toward genomic medicine. Materials & methods A web-based survey of PCPs who are members of Knowledge Networks’ Physician Consulting Network was conducted. Results Of the 502 respondents (23.3% response rate), most ordered genetic tests infrequently. When presented with the direct-to-consumer genomic testing reports, most believed the reports were understandable, and would be willing to review results with a patient, and many believed the results would be helpful in patient management. Conclusion Despite limited experience with genetic tests, PCPs are open to helping patients understand genomic information. However, additional physician education is needed.

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HD alleles with a CAG repeat length of 36-38 occur at high frequency in the general population. The infrequent diagnosis of HD at this CAG length is likely due to low penetrance. Another important contributing factor may be reduced ascertainment of HD in those of older age.

Professional societies, the FDA, and many direct‐to‐consumer genetic testing (DTC‐GT) companies have highlighted the value of counseling from a medical professional with genetics expertise in order to enhance the value and minimize the risks associated with DTC‐GT. However, there is limited information available identifying genetic counselors' own views on DTC‐GT, their willingness to counsel consumers based on DTC‐GT results, and their experiences to date seeing DTC‐GT consumers in a clinical setting. We surveyed genetic counselors accessed through mailing lists associated with the National Society of Genetic Counselors (NSGC) and the American Board of Genetic Counseling (ABGC). Response rate was estimated to be 12.2% (n = 482). A majority of all respondents (56.4%, n = 263) described themselves as feeling negatively or very negatively toward DTC‐GT; only 6.9% (n = 32) described themselves as feeling positively or very positively. While 90.9% of respondents (n = 398) believed that DTC‐GT would be improved with the involvement of genetic counselors, only 31.2% agreed or strongly agreed that they are comfortable providing counseling to DTC‐GT consumers (n = 142). Clinical counseling of DTC‐GT consumers is not routine but it is also not uncommon; 40.1% of all respondents (n = 189) have seen at least one consumer in clinic for the sole purpose of reviewing DTC‐GT results. The results of our study suggest that most respondents would be more accepting of DTC‐GT if genetic counseling was a part of the process, but the majority of counselors do not feel comfortable providing this service.