The growth and maintenance of a highly qualified genetic counselor workforce necessitates the cultivation of competent leaders of accredited genetic counseling graduate programs. This study aimed to identify essential competencies for Genetic Counseling Program Directors (GCPDs) using a modified Delphi approach. The study was facilitated by the Program Leadership Development Subcommittee of the Association of Genetic Counseling Program Directors (now the Genetic Counselor Educators Association) and included experienced program directors and associate directors from accredited programs in North America. The process began with a literature review identifying key leadership competencies in medical education, allied health, and other fields resulting in an initial list of 127 potential competencies across nine domains. Graduate program leaders participated in an initial survey, rating the importance of each competency. Subsequent rounds of ranking and feedback enabled prioritization, refinement, and consolidation of critical competencies. The process achieved consensus among the subcommittee on 34 foundational competencies, classified into four domains: Leadership, Relationships, Operations, and Education, with Leadership positioned at the core due to its integral role. A key addition that had not been identified in the literature review or survey responses was a competency related to applying the principles of equity, diversity, inclusion, and justice throughout the program, bringing the final number of competencies to 35. This framework of competencies provides a scaffolding for designing targeted professional development and educational opportunities, which will, in turn, help create a robust and effective GCPD leadership pipeline and inform the evaluation of GCPDs.

This study analyzed whether differences in cancer reporting exist between different ethno-racial groups in pedigrees from a prenatal genetic counseling setting. Data were collected from 446 charts at University of California, Irvine from January 1, 2015 to August 31, 2020. A total of 795 pedigrees meeting inclusion criteria were analyzed from four ethno-racial groups: White, Hispanic/Latinx, Asian, and African American/Black. The total number of first- and second-degree relatives affected with cancer was analyzed using contingency tables, nonparametric tests, and Poisson regression. Cancer reporting in first- and second-degree relatives was highest among the White group and lower in the Latinx, Asian, and Black groups. Ethno-racial group, presence or absence of the prospective father, and medical interpreter use were significant factors in predicting the number of relatives reported to have cancer in a Poisson regression model. Controlling for the total number of relatives in the pedigree, cancer reporting rates for the Latinx, Black, and Asian groups were 36.3%, 50.2%, and 65.5%, respectively, of that in the White pedigrees. Cancer reporting rates observed in Asian pedigrees (in comparison to White pedigrees) were similar to the rates reported by the Centers for Disease Control and Prevention, but reporting in the Latinx and Black pedigrees was less than would be expected based on population incidence. This suggests that cancer histories in some people of color (POC) may be truncated. Healthcare professionals should recognize that certain patient populations may have limited knowledge of their family cancer history, or that such information may not be disclosed due to nuances of cultural differences or possible provider bias. In order to provide appropriate risk assessment, interventions addressing structural barriers should be undertaken in prenatal clinics to reduce existing health disparities and improve health outcomes in POC, since this may be the only opportunity to obtain a comprehensive family health history.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year overall survival rate of 10%. In November 2018, NCCN recommended that all patients with PDAC receive genetic counseling (GC) and germline testing regardless of family history. We hypothesized that patients with PDAC were more likely to be referred for testing after this change to the guidelines, regardless of presumed predictive factors, and that compliance would be further improved following the implementation of a hereditary cancer clinic (HCC). Methods: We conducted a single-institution retrospective analysis of patients diagnosed with PDAC from June 2017 through December 2021 at University of California, Irvine. We compared rates of genetics referral among patients in different diagnostic eras: the 18-month period before the NCCN Guideline change (pre-NCCN era: June 2017 through November 2018), 14 months following the change (post-NCCN era: December 2018 through January 2020), and 18 months after the creation of an HCC (HCC era: June 2020 through December 2021). Family and personal cancer history, genetics referral patterns, and results of GC were recorded. Data were compared using chi-square, Fisher exact, and multivariate analyses. Results: A total of 335 patients were treated for PDAC (123 pre-NCCN, 109 post-NCCN, and 103 HCC) at University of California, Irvine. Demographics across groups were comparable. Prior to the guideline changes, 30% were referred to GC compared with 54.7% in the postNCCN era. After the implementation of the HCC, 77.4% were referred to GC (P<.0001). The odds ratio (OR) for referral to GC among patients with a positive family history of cancer progressively decreased following the change (pre-NCCN era: OR, 11.90 [95% CI, 3.00-80.14]; postNCCN era: OR, 3.39 [95% CI, 1.13-10.76]; HCC era: OR, 3.11 [95% CI, 0.95-10.16]). Conclusions: The 2018 updates to the NCCN Guidelines for PDAC recommending germline testing for all patients with PDAC significantly increased GC referral rates at our academic medical center. Implementation of an HCC further boosted compliance with guidelines.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year overall survival rate of 10%. In November 2018, NCCN recommended that all patients with PDAC receive genetic counseling (GC) and germline testing regardless of family history. We hypothesized that patients with PDAC were more likely to be referred for testing after this change to the guidelines, regardless of presumed predictive factors, and that compliance would be further improved following the implementation of a hereditary cancer clinic (HCC). Methods: We conducted a single-institution retrospective analysis of patients diagnosed with PDAC from June 2017 through December 2021 at University of California, Irvine. We compared rates of genetics referral among patients in different diagnostic eras: the 18-month period before the NCCN Guideline change (pre-NCCN era: June 2017 through November 2018), 14 months following the change (post-NCCN era: December 2018 through January 2020), and 18 months after the creation of an HCC (HCC era: June 2020 through December 2021). Family and personal cancer history, genetics referral patterns, and results of GC were recorded. Data were compared using chi-square, Fisher exact, and multivariate analyses. Results: A total of 335 patients were treated for PDAC (123 pre-NCCN, 109 post-NCCN, and 103 HCC) at University of California, Irvine. Demographics across groups were comparable. Prior to the guideline changes, 30% were referred to GC compared with 54.7% in the post-NCCN era. After the implementation of the HCC, 77.4% were referred to GC ( P <.0001). The odds ratio (OR) for referral to GC among patients with a positive family history of cancer progressively decreased following the change (pre-NCCN era: OR, 11.90 [95% CI, 3.00–80.14]; post-NCCN era: OR, 3.39 [95% CI, 1.13–10.76]; HCC era: OR, 3.11 [95% CI, 0.95–10.16]). Conclusions: The 2018 updates to the NCCN Guidelines for PDAC recommending germline testing for all patients with PDAC significantly increased GC referral rates at our academic medical center. Implementation of an HCC further boosted compliance with guidelines.

Prader–Willi syndrome (PWS) is a complex genetic disorder with three genetic classes. Patients with PWS are characterized by severe hypotonia, developmental delay, behavioral problems, learning disabilities and morbid obesity in early childhood if untreated. Data were collected through Rare Disease Clinical Research Network (RDCRN) from four study centers which evaluated patients with PWS. The Behavior Assessment System for Children 2nd edition (BASC-2) was chosen to provide behavioral assessment. Data from 330 participants ((64% 15q11-q13 deletion (DEL), 36% maternal disomy 15 (UPD)) were separated into three age groups and analyzed, 68% of whom were still actively receiving recombinant human growth hormone (rhGH) treatment. When comparing the BASC results by molecular subtype, parent-reported aggression was higher for the deletion than for the UPD cohort (p = 0.007). Participants who were on rhGH treatment showed lower scores for parent-reported hyperactivity and aggression (p = 0.04, 0.04, respectively), and a trend for anger control (p = 0.06) and teacher-reported attention problems and aggression (p = 0.01, 0.004, respectively). Additional adjusted analyses were undertaken and significant differences were noted in the GH versus non-GH treated groups for only teacher-reported aggression, which increased in the No GH treated patient group (p = 0.03). This study showed documented differences in PWS behavior by molecular class and rhGH treatment. RhGH therapy may be beneficial for certain behaviors in patients with PWS; however, observed differences need more studies for confirmation in the future.

342 Background: Pancreatic ductal adenocarcinoma (PDAC) carries a poor prognosis with an overall 5-year survival rate of 10%. Depending on geographic region, 10-20% of cases are hereditary, with mutations in BRCA1 and BRCA2 being the most common. Contrary to popular belief, clinical risk factors such as family history of cancer and young age of onset are not reliable predictors for which patients may carry one of these predisposing mutations. In 2018, the National Comprehensive Cancer Network (NCCN) recommended that all pancreatic cancer patients should receive germline testing, regardless of family history. In a compliance analysis, we hypothesized that patients diagnosed after the NCCN guideline changes were more likely to be referred for genetic testing than those diagnosed beforehand. Methods: We conducted a retrospective chart review to compare trends in genetic testing of PDAC patients diagnosed from 02/17 - 07/18 versus 08/18 - 01/20, pre- and post-changes to NCCN guidelines, respectively.Family and personal cancer history, referral patterns and results of genetic counseling (GC) were recorded. Data were compared using Chi-square, Fisher’s Exact, and multivariate analyses. Results: There were 268 patients treated for PDAC (128 pre-, 140 post-) at a large academic institution. Demographics across both groups were comparable. A total of 175 were seen by our institution’s medical oncologist (84 pre-, 91 post-). Overall, 52 were referred to GC, 32 attended, 12 at our institution. More PDAC patients were referred to GC following the guideline changes (21% vs. 47%, p= 0.0005, Table). Patients with a family history of cancer were more likely to be referred to genetic testing (51% vs. 19%, p = 0.0002). This was the case for both pre- (odds ratio (OR) = 15.217 (95% CI, 2.725, 286.663)) and post- (OR = 3.353, (95% CI 1.263, 9.435)) eras, but the effect was not statistically significant when compared between eras ( p= 0.2034). Of all patients who underwent genetic testing, 27% were found to have a deleterious germline mutation related to hereditary PDAC. Conclusions: Despite a significant increase in referrals of PDAC patients for genetic testing following the guideline changes, adherence remains inconsistent with more than half of patients still not being referred. As a limitation of this study, we were not able to capture if patients were referred for GC outside of our network. Historically, the medical oncologist places the referral. However, as a possible solution to improve guideline adherence, referral for genetic testing could be initiated after initial diagnosis of PDAC by any provider, regardless of their role on the healthcare team.[Table: see text]

Prader-Willi syndrome (PWS) is a complex genetic disorder with three molecular classes but clinical ascertainment is based on distinctive features. The prevalence of dysmorphic features was studied in 355 PWS participants (61% deletion, 36% maternal disomy [UPD], and 3% imprinting defects) from the National Institute of Health PWS Rare Diseases Clinical Research Network. The effect of growth hormone (GH) treatment on growth and dysmorphic features was compared. Among participants, upslanting palpebral fissures were seen in 23%; strabismus in 42%; abnormal dentition in 32%; small hands in 63% and small feet in 70%; hypopigmentation in 30%; striae in 32% and skin picking in 26%. Compared to those with UPD, participants with deletions were found to be heavier (p = 0.002), had smaller head circumference (HC) (p = 0.009), higher incidence of a flat occiput (p = 0.005); low-anterior hairline (p = 0.04); abnormal dentition (p = 0.009); abdominal striae (p = 0.045), nail abnormalities (p = 0.050), and fair-haired (p < 0.001). Participants in both genetic groups receiving GH were taller (p = 0.005), had larger HCs (p = 0.005), and longer hands (p = 0.049). This study suggested that PWS genetic subtypes and GH treatment can influence growth and dysmorphic features that may impact clinical diagnosis of PWS, such as stature, head shape and appearance of the eyes, nose, and genitalia.

This study was designed to observe whether disparities exist between ethnicities in reporting a family history of cancer in a cancer genetic counseling clinic. Four hundred sixty-nine pedigrees collected between 2015 to 2017 from a cancer clinic at the University of California, Irvine, were analyzed. Pedigrees were separated by ethnicity into the following categories: non-Hispanic White, Hispanic, Asian, or Ashkenazi Jewish. The number of first- and second-degree relatives was calculated for each pedigree, and the total number of relatives reported with cancer. The total reported with cancer was divided by total number of relatives to derive a percentage of cancer reporting for each pedigree. The percentages of cancer reporting were analyzed using column proportions, nonparametric tests, and a Poisson regression. Cancer reporting in first- and second-degree relatives was highest among non-Hispanic Whites and Ashkenazi Jewish individuals, with median percentages of 22% and 27%, respectively. The median percentage of cancer reporting in first- and second-degree relatives in both Hispanics and Asians was 10%. Cancer reporting medians were significantly lower in Hispanics and Asians when compared to non-Hispanic Whites and Ashkenazi Jewish individuals (p < .001). Ethnicity was a significant factor for predicting the number of relatives reported to have cancer when analyzed with a Poisson regression. This study concluded that cancer is reported less frequently in families when the proband and their families are Hispanic or Asian. Hispanics and Asians have lower cancer incidence rates; however, incidence rates alone may not explain the reporting disparity observed. Hence, family cancer histories in minority populations may be truncated. Healthcare professionals should be aware of this disparity when assessing cancer risks so appropriate modifications can be made accordingly for recommended cancer screening and/or cancer genetic testing. Further efforts are warranted to disseminate information to minority populations about the value of family health history regarding cancer risk assessment.

Prader-Willi syndrome (PWS) affects 1/15,000-1/30,000 live births and is characterized by lack of expression of paternally inherited genes on 15q11.2-15q13 caused by paternal deletions, maternal uniparental disomy (UPD), or imprinting defects. Affected individuals have distinct physical features, and growth hormone (GH) deficiency occurs in some individuals with PWS. The aim of this study is to test the hypotheses that (a) individuals with deletions and UPD have different physical and dysmorphic features, (b) individuals treated with GH have different physical and dysmorphic features than those not treated, and (c) GH treatment effects are different for individuals with UPD in comparison to those with deletions. Study participants included 30 individuals with deletions or UPD, who did or did not have GH treatment. Participants' molecular abnormalities were determined by molecular and cytogenetic analysis. Clinical data were obtained by a single dysmorphologist. Individuals with deletions were found to be heavier (p = .001), taller (p = .031), with smaller head circumferences (p = .042) and were more likely to have fair skin and hair than their family members (p = .031, .049, respectively) compared to UPD patients. Females with deletions more commonly had hypoplastic labia minora (p = .009) and clitoris (.030) in comparison to those with UPD. Individuals who received GH in both deletion and UPD groups were taller (p = .004), had larger hands (p = .011) and feet (p = .006) and a trend for a larger head circumference (p = .103). Interestingly, the GH-treated group also had a lower rate of strabismus (esotropia [p = .017] and exotropia [p = .039]). This study showed statistically significant correlations between phenotype and molecular subtypes and also between phenotype and GH treatment.

American Journal of Medical Genetics Part AVolume 182, Issue 1 p. 1-5 ISSUE INFORMATIONFree Access Table of Contents, Volume 182A, Number 1, January 2020 First published: 11 December 2019 https://doi.org/10.1002/ajmg.a.61218AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume182, Issue1January 2020Pages 1-5 RelatedInformation

Definitive molecular diagnoses in disorders apparently due to genetic or genomic defects are still lacking in a significant number of investigated cases, despite use of studies designed to discover defects in the protein coding regions of the genome. Increasingly studies are being designed to search for defects in the non-protein coding genome, and for alterations in gene expression. Here we review new insights into genomic elements involved in control of gene expression, including methods to analyze chromatin that is accessible for transcription factor binding, enhancers, chromatin looping, transcription, RNA binding proteins, and alternative splicing. We review new studies on levels of genome organization, including the occurrence of transcriptional domains and their boundary elements. Information is presented on specific malformation syndromes that arise due to structural genomic changes that impact the non-protein coding genome and sometimes impact specific transcriptional domains. We also review convergence of genome-wide association with studies of gene expression, discoveries related to expression quantitative trait loci and splicing quantitative trait loci and the relevance of these to specific complex common diseases. Aspects of epigenetic mechanisms and clinical applications of analyses of methylation signatures are also discussed.

In the era of personalized and genomic medicine, awareness of patients with rare diseases is increasing as new approaches to diagnosis and treatment are developed. This study examined perceived barriers experienced by families with rare diseases and explored possible differences between participants in Malaysia and California, USA. The study involved N=108 participants recruited in genetics clinic appointments at the University of Malaya Medical Center and three sites in Southern California. Participants completed a survey involving multiple choice and Likert scale items pertaining to perceived barriers to access genetics-related healthcare. Results from this study provide evidence of similar perceived barriers, despite differences in the two populations. Participants selected the expansion of healthcare provider knowledge of rare diseases to be the most beneficial approach to overcome perceived barriers. In both locations, it was also noted that travel distance to clinic was not perceived as a large stress factor. Taking these observations together, a healthcare model with a central location of providers well-versed in medical genetics may be considered if further data support our findings. The data from this study support a need for improving healthcare provider knowledge of genetics. Future studies exploring how these perceived stress factors are impacting families as well as different methods of educating providers are suggested by findings from the study, as well as studies querying the opinions of those who are unable to access genetics services.

A quantitative genetic approach, which involves correlation of transcriptional networks with the phenotype in a recombinant inbred (RI) population and in selectively bred lines of rats, and determination of coinciding quantitative trait loci for gene expression and the trait of interest, has been applied in the present study. In this analysis, a novel approach was used that combined DNA‐Seq data, data from brain exon array analysis of HXB/BXH RI rat strains and six pairs of rat lines selectively bred for high and low alcohol preference, and RNA‐Seq data (including rat brain transcriptome reconstruction) to quantify transcript expression levels, generate co‐expression modules and identify biological functions that contribute to the predisposition of consuming varying amounts of alcohol. A gene co‐expression module was identified in the RI rat strains that contained both annotated and unannotated transcripts expressed in the brain, and was associated with alcohol consumption in the RI panel. This module was found to be enriched with differentially expressed genes from the selected lines of rats. The candidate genes within the module and differentially expressed genes between high and low drinking selected lines were associated with glia (microglia and astrocytes) and could be categorized as being related to immune function, energy metabolism and calcium homeostasis, as well as glial–neuronal communication. The results of the present study show that there are multiple combinations of genetic factors that can produce the same phenotypic outcome. Although no single gene accounts for predisposition to a particular level of alcohol consumption in every animal model, coordinated differential expression of subsets of genes in the identified pathways produce similar phenotypic outcomes.DatabaseThe datasets supporting the results of the present study are available at http://phenogen.ucdenver.edu

BACKGROUND Two features of alcohol addiction that have been widely studied in animal models are relapse drinking following periods of alcohol abstinence and the escalation of alcohol consumption after chronic continuous or intermittent alcohol exposure. The genetic contribution to these phenotypes has not been systematically investigated. METHODS HXB/BXH recombinant inbred (RI) rat strains were given access to alcohol sequentially as follows: alcohol (10%) as the only fluid for 1 week; alcohol (10%) and water in a 2-bottle choice paradigm for 7 weeks ("pre-alcohol deprivation effect [ADE] alcohol consumption"); 2 weeks of access to water only (alcohol deprivation); and 2 weeks of reaccess to 10% alcohol and water ("post-ADE alcohol consumption"). The periods of deprivation and reaccess to alcohol were repeated 3 times. The ADE was defined as the amount of alcohol consumed in the first 24 hours after deprivation minus the average daily amount of alcohol consumed in the week prior to deprivation. Heritability of the phenotypes was determined by analysis of variance, and quantitative trait loci (QTLs) were identified. RESULTS All strains showed increased alcohol consumption, compared to the predeprivation period, in the first 24 hours after each deprivation (ADE). Broad-sense heritability of the ADEs was low (ADE1, 9.1%; ADE2, 26.2%; ADE3, 16.3%). Alcohol consumption levels were relatively stable over weeks 2 to 7. Post-ADE alcohol consumption levels consistently increased in some strains and were decreased or unchanged in others. Heritability of pre- and post-ADE alcohol consumption was high and increased over time (week 2, 38.5%; week 7, 51.1%; week 11, 56.8%; week 15, 63.3%). QTLs for pre- and post-ADE alcohol consumption were similar, but the strength of the QTL association with the phenotype decreased over time. CONCLUSIONS In the HXB/BXH RI rat strains, genotypic variance does not account for a large proportion of phenotypic variance in the ADE phenotype (low heritability), suggesting a role of environmental factors. In contrast, a large proportion of the variance across the RI strains in pre- and post-ADE alcohol consumption is due to genetically determined variance (high heritability).

Purpose: Craniosynostosis is a common cranial malformation occurring in 1 per 2,000–2,500 births. Isolated defects (nonsyndromic) occur in ~75% of cases and are thought to have multifactorial etiology. It is believed that each suture synostosis is a distinct disease, with varying phenotypes and recurrence rates. Methods: We analyzed family histories of 660 mutation-negative nonsyndromic craniosynostosis patients and symptoms in 189 of these patients. Results: The incidence rate of craniosynostosis was highest for first-degree relatives of probands with metopic craniosynostosis (6.4%), followed by those with complex craniosynostosis (4.9%), sagittal craniosynostosis (3.8%), lambdoid craniosynostosis (3.9%), and coronal craniosynostosis (0.7%). Across all suture types, siblings had a greater craniosynostosis incidence rate than parents (7.5 vs. 2.3%). In phenotype comparisons, patients with complex craniosynostosis had the highest frequency of reported symptoms and those with sagittal craniosynostosis had the lowest. Ear infections, palate abnormalities, and hearing problems were more common in complex craniosynostosis patients. Visual problems were more common in coronal craniosynostosis, and metopic craniosynostosis patients noted increased frequency of chronic cough. Conclusion: Our data suggest that the genetic component of nonsyndromic craniosynostosis appears to be suture specific. The incidence rate of craniosynostosis among first-degree relatives varies by suture and family member. Additionally, the phenotype of each suture synostosis shows both unique and shared features. Genet Med 2014:16(4):302–310.