CYP2C19 genotype‐guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, ...communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes, which are both related to the CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions.
Autozygosity, the proportion of the genome that is homozygous by descent, has been associated with variation in multiple health-related traits impacting evolutionary fitness. Autozygosity (FROH) is ...typically measured from runs of homozygosity (ROHs) that arise when identical-by-descent (IBD) haplotypes are inherited from each parent. Population isolates with a small set of common founders have elevated autozygosity relative to outbred populations.
In this study, we examined whether degree of autozygosity was associated with variation in 96 cardiometabolic traits among 7221 Old Order Amish individuals residing in Lancaster County, PA. We estimated the average length of an ROH segment to be 6350 KB, with each individual having on average 17.2 segments 1.5 KB or larger. Measurements of genome-wide and regional FROH were used as the primary predictors of trait variation in association analysis.
In genome-wide FROH analysis, we did not identify any associations that withstood Bonferroni-correction (p = 0.0005). However, on regional FROH analysis, we identified associations exceeding genome-wide thresholds for two traits: serum bilirubin levels, which were significantly associated with a region on chromosome 2 localized to a region surrounding UGT1A10 (p = 1 × 10- 43), and HbA1c levels, which were significantly associated with a region on chromosome 8 localized near CHRNB3 (p = 8 × 10- 10).
These analyses highlight the potential value of autozygosity mapping in founder populations.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Given the expected rise in genomic sequencing projects within the US Military and the increased availability of genetic testing to the United States as a whole, current and prospective active‐duty ...service members (SMs) may undergo genetic counseling services in the civilian sector for pre‐test and post‐test counseling. The overall goal of this study was to better understand genetic counselors' preparedness to address military‐specific policies and psychosocial needs of patients from this underrepresented population. Members of the National Society of Genetic Counselors were asked to complete a four‐part survey including demographic information, Likert scale questions to separately rate self‐efficacy when working with civilians and SMs, case scenarios with multiple‐choice options and open‐ended responses to assess knowledge of military policy, and open‐ended questions regarding psychosocial scenarios related to military service. Eighty‐eight responses were analyzed using Microsoft Office Excel for the qualitive thematic analysis and SPSS/RStudio for the quantitative data. While over 75% (n = 69/88, SD = 0.48) of surveyed genetic counselors scored 4 of 4 on knowledge of military policy and reported similarly high levels of self‐efficacy when working with SMs (mean = 26.77 out of 30, SD = 4.15) and the general population (mean = 27.99 out of 30, SD = 4.31), the qualitative data suggested an alternative perspective. Up to 57% (n = 50/88) of responses were scored as expressing low confidence concerning knowledge of military policy. One potential explanation for this uncertainty may be due to participants reporting that they never (69.32% (n = 61/88) or are unsure if (12.50% (n = 11/88) they received training related to providing counseling services to SMs. We suggest the establishment of educational initiatives for genetic counselors focusing on how to discuss genetic testing with SMs in relation to their health and safety, well‐being, and potential employment implications.
Most monogenic diabetes is misdiagnosed as either type 1 or type 2 diabetes (T1D/T2D). Few studies have examined the diagnostic challenges from the patients’ perspective. This qualitative study aimed ...to investigate patients’ journeys to obtaining a diagnosis of maturity‐onset diabetes of the young (MODY) by elucidating the range of factors that can act as barriers and facilitators throughout this process. We recruited participants from the Personalized Diabetes Medicine Program (PDMP) at University of Maryland and used respondent‐driven sampling to recruit additional patients. We conducted qualitative phone interviews between October 2016 and June 2017 with nine patients with diagnoses of monogenic diabetes (one HNF4A‐MODY, seven GCK‐MODY, and one HNF1A‐MODY) and one parent of a patient with INS‐MODY. Interview data were audio recorded, transcribed, and analyzed both inductively and deductively using thematic content analysis. All patients were female, with a mean age of 35 (range: 7–67 years). The amount of time these patients were misdiagnosed ranged from a few months to 41 years. We identified barriers and facilitators in three broad themes: (a) patient‐related (nature of MODY symptoms, perceived test utility, individual personality); (b) provider‐related (provider awareness and knowledge, provider communication); and (c) healthcare system‐related (cost of testing, access to knowledgeable providers, patient education, and support resources). The diverse range of barriers and facilitators reiterates the complexity of the MODY diagnostic process. Limited awareness and knowledge of MODY from healthcare professionals and patients themselves account for most diagnostic delays described in this study. Efforts to promote awareness of MODY and expand access to screening and testing may result in quicker diagnosis and ensure the downstream benefits of proper treatment.
Functional epialleles at an endogenous human centromere Maloney, Kristin A; Sullivan, Lori L; Matheny, Justyne E ...
Proceedings of the National Academy of Sciences - PNAS,
08/2012, Letnik:
109, Številka:
34
Journal Article
Recenzirano
Odprti dostop
Human centromeres are defined by megabases of homogenous alpha-satellite DNA arrays that are packaged into specialized chromatin marked by the centromeric histone variant, centromeric protein A ...(CENP-A). Although most human chromosomes have a single higher-order repeat (HOR) array of alpha satellites, several chromosomes have more than one HOR array. Homo sapiens chromosome 17 (HSA17) has two juxtaposed HOR arrays, D17Z1 and D17Z1-B. Only D17Z1 has been linked to CENP-A chromatin assembly. Here, we use human artificial chromosome assembly assays to show that both D17Z1 and D17Z1-B can support de novo centromere assembly independently. We extend these in vitro studies and demonstrate, using immunostaining and chromatin analyses, that in human cells the centromere can be assembled at D17Z1 or D17Z1-B. Intriguingly, some humans are functional heterozygotes, meaning that CENP-A is located at a different HOR array on the two HSA17 homologs. The site of CENP-A assembly on HSA17 is stable and is transmitted through meiosis, as evidenced by inheritance of CENP-A location through multigenerational families. Differences in histone modifications are not linked clearly with active and inactive D17Z1 and D17Z1-B arrays; however, we detect a correlation between the presence of variant repeat units of D17Z1 and CENP-A assembly at the opposite array, D17Z1-B. Our studies reveal the presence of centromeric epialleles on an endogenous human chromosome and suggest genomic complexities underlying the mechanisms that determine centromere identity in humans.
DNA polymerase stalling activates the ATR checkpoint kinase, which in turn suppresses fork collapse and breakage. Herein, we describe use of ATR inhibition (ATRi) as a means to identify genomic sites ...of problematic DNA replication in murine and human cells. Over 500 high-resolution ATR-dependent sites were ascertained using two distinct methods: replication protein A (RPA)-chromatin immunoprecipitation (ChIP) and breaks identified by TdT labeling (BrITL). The genomic feature most strongly associated with ATR dependence was repetitive DNA that exhibited high structure-forming potential. Repeats most reliant on ATR for stability included structure-forming microsatellites, inverted retroelement repeats, and quasi-palindromic AT-rich repeats. Notably, these distinct categories of repeats differed in the structures they formed and their ability to stimulate RPA accumulation and breakage, implying that the causes and character of replication fork collapse under ATR inhibition can vary in a DNA-structure-specific manner. Collectively, these studies identify key sources of endogenous replication stress that rely on ATR for stability.
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•>500 ATR-dependent sites were identified in the mouse and human genomes•ATR-inhibitor-driven fork collapse occurs primarily at structure-forming repeats•Repeat structures include non-B form DNA and hairpins (AT-rich and inverted repeats)•Discrete repeat types accumulate RPA differentially upon fork collapse
Shastri et al. have identified new classes of difficult-to-replicate sequences in the mouse and human genomes that are highly dependent on ATR function for stability during DNA replication. Structure-forming short tandem repeats, inverted retroelements, and quasi-palindromic AT-rich repeats characterize the sites for fork collapse caused by ATR inhibition.
Precision medicine relies on accurate and consistent classification of sequence variants. A correct diagnosis of hepatocyte nuclear factor (HNF) 1B maturity-onset diabetes of the young, caused by ...pathogenic variants in the HNF1B gene, is important for optimal disease management and prognosis, and it has implications for genetic counseling and follow-up of at-risk family members. We hypothesized that the functional characterization could provide valuable information to assist the interpretation of pathogenicity of HNF1B variants. Using different in vitro functional assays, variants identified among 313 individuals, suspected to have monogenic diabetes with or without kidney disease, were characterized. The data from the functional assays were subsequently conjugated with obtained clinical, biochemical, and in silico data. Two variants (p.A167P, p.H336Pfs∗22) showed severe loss of function due to impaired transactivation, reduced DNA binding (p.A167P), and mRNA instability (p.A167P). Although both these variant carriers were diagnosed with diabetes, the p.H336Pfs∗22 carrier also had congenital absence of a kidney, which is a characteristic trait for HNF1B maturity-onset diabetes of the young. Functional analysis of the p.A167P variant revealed damaging effects on HNF-1B protein function, which may warrant imaging of the kidneys and/or pancreas. In addition, the current study has generated important data, including evidence supporting the benign functional impact of five variants (p.D82N, p.T88A, p.N394D, p.V458G, and p.T544A), and piloting new approaches that will prove critical for the growth of HNF1B-diabetes diagnosis.
The genetic architecture of diabetes mellitus in general and in pregnancy is complex, owing to the multiple types of diabetes that comprise both complex/polygenic forms and monogenic (largely caused ...by a mutation in a single gene) forms such as maturity-onset diabetes of the young (MODY). Type 1 diabetes (T1D) and type 2 diabetes (T2D) have complex genetic etiologies, with over 40 and 90 genes/loci, respectively, implicated that interact with environmental/lifestyle factors. The genetic etiology of gestational diabetes mellitus has largely been found to overlap that of T2D. Genetic testing for complex forms of diabetes is not currently useful clinically, but genetic testing for monogenic forms, particularly MODY, has important utility for determining treatment, managing risk in family members, and pregnancy management. In particular, diagnosing MODY2, caused by
mutations, indicates that insulin should not be used, including during pregnancy, with the possible exception of an unaffected pregnancy during the third trimester to prevent macrosomia. A relatively simple method for identifying women with MODY2 has been piloted. MODY1, caused by
mutations, can paradoxically cause neonatal hyperinsulinemic hypoglycemia and macrosomia, indicating that detecting these cases is also clinically important. Diagnosing all MODY types provides opportunities for diagnosing other family members.
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