Citations

Abstract Background Among the approximately 8000 Mendelian disorders, >1000 have cutaneous manifestations. In many of these conditions, the underlying mutated genes have been identified by DNA-based techniques which, however, can overlook certain types of mutations, such as exonic-synonymous and deep-intronic sequence variants. Whole-transcriptome sequencing by RNA sequencing (RNA-seq) can identify such mutations and provide information about their consequences. Methods We analyzed the whole transcriptome of 40 families with different types of Mendelian skin disorders with extensive genetic heterogeneity. The RNA-seq data were examined for variant detection and prioritization, pathogenicity confirmation, RNA expression profiling, and genome-wide homozygosity mapping in the case of consanguineous families. Among the families examined, RNA-seq was able to provide information complementary to DNA-based analyses for exonic and intronic sequence variants with aberrant splicing. In addition, we tested the possibility of using RNA-seq as the first-tier strategy for unbiased genome-wide mutation screening without information from DNA analysis. Results We found pathogenic mutations in 35 families (88%) with RNA-seq in combination with other next-generation sequencing methods, and we successfully prioritized variants and found the culprit genes. In addition, as a novel concept, we propose a pipeline that increases the yield of variant calling from RNA-seq by concurrent use of genome and transcriptome references in parallel. Conclusions Our results suggest that “clinical RNA-seq” could serve as a primary approach for mutation detection in inherited diseases, particularly in consanguineous families, provided that tissues and cells expressing the relevant genes are available for analysis.

Abstract Introduction Coronary artery calcification (CAC) is associated with and identifies patients at higher risk of major adverse cardiovascular events (MACE). However, the prevalence, characteristics, and outcomes of cancer patients with CAC on CT before or after chest radiation therapy (RT) are not well addressed. Methods Retrospective cohort study of all breast cancer patients who underwent chest RT at Mayo Clinic Rochester in 2010. All pre-RT CTs were reviewed and the extent of CAC was recorded in addition to history of pre-RT atherosclerotic risk factors (hypertension (HTN), diabetes mellitus (DM), dyslipidemia, and smoking), history of pre-RT cardiovascular disease (CVD), and RT dosage. MACE (sudden cardiac death (SCD), acute coronary syndrome (ACS), and stroke), and CAC progression in follow-up were recorded. CAC extent was quantified before and on 5-year follow-up CT scan in all patients, and a positive change was considered progression. Patients were divided into 2 groups based on the presence of CAC before RT: present (group 1) or absent (group 2). Results Our cohort was comprised of 244 breast cancer patients who received chest RT. A total of 39 patients (16.9%) had evidence of CAC on CT prior to RT. Compared with patients without CAC before RT (n=205), those with CAC before RT were found to be older (71.8±7.7 vs 58.9±11.3, p<0.01), had higher pre-RT history of HTN (84.6% vs 47.8%); p<0.01), DM (20.5% vs 4.4%; p<0.01), dyslipidemia (74.2% vs 40%; p<0.01), CAD (23.1% vs 3.9%; p<0.01), and stroke (7.69% vs 1.45%; p=0.04). Following RT, patients in group 1 were more likely to exhibit ACS (33.3% vs 2.9%; p<0.01), and stroke (22.6% vs 5.2%; p<0.01). Multinomial logistic regression identified pre-RT CAD pre-RT CAC (β=1.01 (0.33–1.69), OR=7.60 (1.93–29.93); p=0.02) pre-RT CAD (β=0.78 (0.06–1.49), OR=4.74 (1.14–19.74); p=0.03) as independent predictors for the development of MACE after RT. Progression in CAC after RT was found in 61.9% of all patients (13/21) who developed MACE. Conclusion MACE in breast cancer patients undergoing RT can be predicted before RT based on the CV risk factor and disease profile. The strongest predictor for MACE, however, is evidence of CAC before RT. These data provide a unique window for the identification and follow-up of breast cancer RT patients who have a risk of MACE. Funding Acknowledgement Type of funding source: None

AbstractBackgroundMobilization regimen choice is a significant contributing factor for successful hematopoietic progenitor cell (HPC) collection by leukocytapheresis and reaching the target CD34+ cell dose. How mobilization regimen affects collection efficiency and the quality of products collected using the Spectra Optia apheresis instrument is not fully known.MethodsWe evaluated the impact of granulocyte‐colony stimulating factor (GCSF) and GCSF/plerixafor mobilization regimens on CE and product composition. We studied 373 leukocytapheresis HPC collections for 147 autologous transplants from January 1, 2010 to December 31, 2014. Patients were categorized in two groups; good mobilizers, mobilized with GCSF only (GM) and poor mobilizers, mobilized with GCSF and Plerixafor (PM).ResultsOverall, compared with PM group, total nucleated cell (TNC) yield was significantly lower in GM group (P = <.001). In contrast, median percent mononuclear cell (MNC) collected from GM (86.5%) was significantly higher than products collected from PM group (79.5%; P < .001). Compared with GM group, CD34+ cell CE was about 10% lower in PM group (P < .008). In addition, daily CD34+ cell/Kg yield was significantly higher in GM (2.08 × 10/Kg) compared with PM group (1.64 x 10/Kg, P = .019). Overall, the median number of collections per patient was two for GM and three for PM (P = .004).ConclusionProducts collected from PM group contained higher TNC content relative to GM group but had lower MNC enrichment, CD34+ cell CE and daily CD34+ cell yield per Kg.

Erdheim-Chester disease is a rare non-Langerhans cell histiocytosis with multisystem involvement and insidious symptoms. In this article, we describe an interesting case of Erdheim-Chester disease that was eventually diagnosed 8 years after symptoms initially started.

Background— Whether disclosing genetic risk for coronary heart disease (CHD) to individuals influences information seeking and information sharing is not known. We hypothesized that disclosing genetic risk for CHD to individuals influences information seeking and sharing. Methods and Results— The MI-GENES study (Myocardial Infarction Genes) randomized participants (n=203) aged 45 to 65 years who were at intermediate CHD risk based on conventional risk factors and not on statins to receive their conventional risk score alone or also a genetic risk score based on 28 variants. CHD risk was disclosed by a genetic counselor and then discussed with a physician. Surveys assessing information seeking were completed before and after risk disclosure. Information sharing was assessed post-disclosure. Six-month post-disclosure, genetic risk score participants were more likely than conventional risk score participants to visit a website to learn about CHD (odds ratio [OR], 4.88 [confidence interval (CI), 1.55–19.13]; P =0.01), use the internet for information about how genetic factors affect CHD risk (OR, 2.11 [CI, 1.03–4.47]; P =0.04), access their CHD risk via a patient portal (OR, 2.99 [CI, 1.35–7.04]; P =0.01), and discuss their CHD risk with others (OR, 3.13 [CI, 1.41–7.47]; P =0.01), particularly their siblings (OR, 1.92 [CI, 1.06–3.51]; P =0.03), extended family (OR, 3.8 [CI, 1.37–12.38]; P= 0.01), coworkers (OR, 2.42 [CI, 1.09–5.76]; P =0.03), and primary care provider (PCP; OR, 2.00 [CI, 1.08–3.75]; P =0.03). Conclusions— Disclosure of a genetic risk score for CHD increased information seeking and sharing. Clinical Trial Registration— URL: https://clinicaltrials.gov/ . Unique identifier: NCT01936675.

Background— There has been a gradual decline in the prevalence of abnormal stress single-photon emission computed tomography (SPECT) myocardial perfusion imaging studies among patients without history of coronary artery disease (CAD). The trends of SPECT studies among patients with known CAD have not been evaluated previously. Methods and Results— We assessed the Mayo Clinic nuclear cardiology database for all stress SPECT tests performed between January 1991 and December 2012 in patients with history of CAD defined as having previous myocardial infarction, percutaneous coronary intervention, and coronary artery bypass grafting. The study cohort was divided into 5 time periods: 1991 to 1995, 1996 to 2000, 2001 to 2005, 2006 to 2010, and 2011 to 2012. There were 19 373 patients with a history of CAD who underwent SPECT between 1991 and 2012 (mean age, 66.2±10.9 years; 75.4% men). Annual utilization of SPECT in these patients increased from an average of 495 tests per year in 1991 to 1995 to 1425 in 2003 and then decreased to 552 tests in 2012 without evidence for substitution with other stress modalities. Asymptomatic patients initially increased until 2006 and then decreased. Patients with typical angina decreased, whereas patients with dyspnea and atypical angina increased. High-risk SPECT tests significantly decreased, and the percentage of low-risk SPECT tests increased despite decreased SPECT utilization between 2003 and 2012. Almost 80% of all tests performed in 2012 had a low-risk summed stress score compared with 29% in 1991 ( P <0.001). Conclusions— In Mayo Clinic, Rochester, annual SPECT utilization in patients with previous CAD increased between 1992 and 2003, but then decreased after 2003. High-risk SPECT tests declined, whereas low-risk tests increased markedly. Our results suggest that among patients with a history of CAD, SPECT was being increasingly utilized in patients with milder CAD. This trend parallels reduced utilization of other stress modalities, coronary angiography, reduced smoking, and greater utilization of optimal medical therapy for prevention and treatment of CAD.

AbstractLittle is known about individuals’ motivation, perception, and treatment beliefs towards the use of genetic information in risk estimates for coronary heart disease (CHD). In this study, participants at intermediate 10‐year risk of CHD were randomized to receive either their estimated conventional risk score (CRS) alone, or a CRS and a genetic risk score (GRS), by a genetic counselor. Surveys on motivation to participate in and perception of genetic testing for CHD were administered at 3 months and treatment beliefs at 6 months following risk disclosure. Survey responses used Likert scales. Linear and logistic regression were used for analysis. Overall, motivation to participate in genomic clinical trials was favorable and did not differ between the CRS and GRS groups (16.95 ± 0.82 vs. 17.58 ± 0.83, p = 0.091), but participants who initially received their GRS indicated a greater desire to find ways to improve health as a reason for participation (OR: 0.53 (95%CI: 0.29, 0.94), p = 0.028). Perception of genetic testing was also favorable in both groups (15.29 ± 0.39 vs. 15.12 ± 0.40, p = 0.835). Participants who initially received their GRS were more inclined to recommend genetic testing to family and friends (9.95 ± 1.88 vs. 10.52 ± 2.17, p = 0.023). In the MI‐GENES study, motivation to participate in and perception of genetic testing among study participants were overall favorable. Genetic risk disclosure was associated with increased motivation to recommend genetic testing to family and friends.

Whether disclosure of genetic risk for coronary heart disease (CHD) influences shared decision-making (SDM) regarding use of statins to reduce CHD risk is unknown. We randomized 207 patients, age 45–65 years, at intermediate CHD risk, and not on statins, to receive the 10-year risk of CHD based on conventional risk factors alone (n=103) or in combination with a genetic risk score (n=104). A genetic counselor disclosed this information followed by a physician visit for SDM regarding statin therapy. A novel decision aid was used in both encounters to disclose the CHD risk estimates and facilitate SDM regarding statin use. Patients reported their decision quality and physician visit satisfaction using validated surveys. There were no statistically significant differences between the two groups in the SDM score, satisfaction with the clinical encounter, perception of the quality of the discussion or of participation in decision-making and physician visit satisfaction scores. Quantitative analyses of a random subset of 80 video-recorded encounters using the OPTION5 scale also showed no significant difference in SDM between the two groups. Disclosure of CHD genetic risk using an electronic health record-linked decision aid did not adversely affect SDM or patients’ satisfaction with the clinical encounter. Trial registration number NCT01936675; Results.