Latina immigrants' breast and colon cancer causal attributions: genetics is key.

Latinos in the US suffer health disparities including stage of disease at time of breast or colon cancer diagnosis. Understanding Latinas' causal attributions of breast and colon cancer may provide insight into some of the individual level determinants of cancer disparities in this population. Cultural consensus analysis (CCA) is one way to study causal beliefs. The objective of this study was to describe Latina immigrants' causal attributions of breast and colon cancer. We conducted Spanish-language interviews with 22 Latina immigrants using a qualitative exploratory design comprised of freelisting, ranking, and open-ended questions. Participants freelisted causes and risk factors for breast and colon cancer then ranked risk factors according to their perceived role in the development of each cancer. CCA was conducted on rank orders to identify whether a cultural consensus model was present. Participants answered semi-structured, open-ended questions regarding the risk factors and rankings. Interviews were transcribed and subjected to thematic analysis. CCA showed no consensus around rank of causes for either cancer, and residual agreement analysis suggested the presence of two subcultural groups. "Genetics" and "hereditary factors" ranked first and second on average across participants for both cancers. Based on interview data, participants were less aware of colon cancer than breast cancer. Participants' endorsement of heredity as a cause of breast and colon cancer was similar to beliefs reported in studies of primarily non-Latina populations.

Feasibility of the Genetic Information Assistant Chatbot to Provide Genetic Education and Study Genetic Test Adoption Among Pancreatic Cancer Patients at Johns Hopkins Hospital.

Genetic testing is a valuable tool to guide care of pancreatic cancer patients, yet personal and family uncertainty about the benefits of genetic testing (i.e., decisional conflict) may lead to low adoption. Enabling patients to learn more about genetic testing before their scheduled appointments may help to address this decisional conflict problem. We completed a feasibility assessment of a chatbot to provide genetic education (GEd) with 60 pancreatic cancer patients and using the chatbot to deliver surveys to assess: (a) opinions about the GEd, and (b) decisional conflict about genetic testing. Findings demonstrate intervention and study feasibility with about 80% of participants engaging with the GEd chatbot, 71% of which completed at least one survey. Overall, participants appear to have favorable opinions of the chatbot-delivered education and thought it was helpful to decide about genetic testing. Furthermore, patients who chose to get genetic testing spent more time interacting with the chatbot. Findings will be used to improve chatbot design and to facilitate a well-powered future trial.

The 2019 medical genetics workforce: A focus on laboratory geneticists.

PURPOSE: The aim of this report is to inform the genetics and genomics field about the results of a 2019 workforce survey of US laboratory geneticists. METHODS: The American Board of Medical Genetics and Genomics distributed an electronic survey to board-certified/eligible diplomates in 2019. Analysis of the responses was performed by the American College of Medical Genetics and Genomics. RESULTS: A total of 422 individuals identified as laboratory geneticists. The respondents represent the range of possible certifications. Nearly one-third were Clinical Cytogenetics and Genomics diplomates, another third were Molecular Genetics and Genomics diplomates, and the others were Clinical Biochemical Genetics diplomates or held a combination of certificates. The majority of laboratory geneticists are PhDs. The others were physicians or other degree combinations. Most laboratory geneticists work in academic medical centers or commercial laboratories. Most respondents identified as females and White. The median age was 53 years. A third of the respondents have been in the profession for 21+ years and plan to reduce hours or retire in the next 5 years. CONCLUSION: The genetics field needs to foster the next generation of laboratory geneticists to meet the increasing complexity and demand for genetic testing.

Vascular aneurysms in Ehlers-Danlos syndrome subtypes: A systematic review.

Aneurysmal lesions are commonly seen in Ehlers-Danlos Syndrome (EDS). To better identify the regional and vessel-specific spectrum of aneurysms in different subtypes of EDS, we performed a systematic review. We searched Medline for relevant studies from 1963 to April 2022. Studies providing a report of any EDS subtype by genetic diagnosis, histologic analysis, or clinical criteria were included. A total of 448 patients from 220 studies were included. 720 vessel-specific aneurysms were reported: 386 in the abdominopelvic area, 165 in the intracranial region, 98 in the thorax, 2 in the extremities, and 6 in the venous system. In 27 out of the 65 patients with ruptured aneurysms, the ruptured aneurysm was the initial presentation. Multiple aneurysms were present in 163 out of 249 patients who had been systematically evaluated for other locations of aneurysms. The head and neck and abdominopelvic regions are two potential foci for aneurysm formation in patients with EDS. The aneurysm development in EDS is not confined to arteries; the venous system and cardiac septa may also be affected. Many patients develop multiple aneurysms, either at the time of the initial presentation or throughout their lifetime and aneurysm formation or rupture may be the first presentation of EDS.

Agreement between parent-proxy and child self-report in pediatric hypermobile Ehlers-Danlos syndrome.

Hypermobile Ehlers-Danlos syndrome (hEDS) is a common disorder in children and adolescents that negatively impacts health-related quality of life (HRQOL). It can include chronic pain, fatigue, autonomic dysfunction, and mood problems. The objective of this study was to examine levels of agreement between children and parents in the setting of hEDS and HRQOL. Individuals with hEDS, ages 10-20 years, and their parents were recruited to complete a series of surveys. Instruments included pediatric quality of life generic and multidimensional fatigue scales, Functional Disability Index, Pain-Frequency-Severity-Duration scale, Brief Illness Perception Questionnaire, and Herth Hope Index. Agreement on each measure was evaluated using statistical calculations. Thirty-six parent-child dyads completed the surveys. There were no significant differences between the means of parent and child scores. There was moderate to strong agreement on all survey scores. However, the proportion of dyads with disagreement was relatively high for each individual score. Eighteen dyads disagreed on at least half of the surveys. Body mass index centile and child perception of cognitive fatigue most strongly predicted disagreement in total HRQOL score. Proxy-reporters for children and adolescents with hEDS may agree with their child on average. However, due to significant frequency of clinically important disagreement, information from both children and their parents should be sought whenever possible.

Monochorionic twins with 15q26.3 duplication presenting with selective intrauterine growth restriction and discordant cardiac anomalies: A case report.

BACKGROUND: Duplication of the distal end of chromosome 15q has been previously implicated in a characteristic overgrowth syndrome. Additionally, many patients have other congenital malformations, including cardiac, renal, genital, and musculoskeletal anomalies. However, some patients may present with intrauterine growth restriction and short stature. Different breakpoints within 15q, as well as different environmental factors, may underlie these varied presentations. CASE PRESENTATION: We discuss monochorionic-diamniotic twins with a ~345 kb maternally inherited duplication in 15q26.3. The twins presented with discordant pathology-one twin with a single umbilical artery, selective intrauterine growth restriction, and multiple cardiac defects including aortic coarctation, aortic valve stenosis, and ventricular septal defect, whereas the other twin was unaffected. To our knowledge, this case represents the smallest reported duplication of distal 15q. CONCLUSION: The discordant phenotype seen in the twins is likely due to a complex interplay between genetic and environmental causes. The affected infant presented prenatally with growth restriction and a single umbilical artery rather than overgrowth, potentially due to a unique breakpoint within 15q. This, in turn, may have produced hemodynamic perturbations between the twins, leading to discordant cardiac disease. Our report thus highlights the importance of genetic and nongenetic mechanisms underlying discordant anomalies in monochorionic twins.

Case report of bilateral ovarian fibromas associated with de novo germline variants in PTCH1 and SMARCA4.

BACKGROUND: Ovarian sex cord-stromal tumors (OSCTs) are rare ovarian tumors that can develop from sex cord, stromal cells, or both. OSCTs can be benign or malignant. Bilateral and/or unilateral ovarian fibromas, a type of OSCT of the stromal cells, have been reported in individuals diagnosed with nevoid basal cell carcinoma syndrome (NBCCS). Calcified ovarian fibromas have been reported in 15-25% of individuals diagnosed with NBCCS while 75% of those cases occur bilaterally. The average age at diagnosis of OSCT/ovarian fibromas in patients with NBCSS is in the second to third decade compared with age 50 in the general population. Ovarian tumors are rare in pediatric populations. METHODS: The patient is a 5-year-old female diagnosed with bilateral ovarian fibromas at age 4. Multigene panel for the patient and subsequent targeted molecular evaluation of parents were completed. Histological evaluations on the surgically resected ovaries were performed for microscopic characterization of fibromas. RESULTS: Germline testing identified de novo heterozygous novel likely pathogenic variants in PTCH1 gene, exon 12 deletion, and an SMARCA4 splicing variant c.2002-1G > A. Microscopic examination of bilateral tumors was consistent with an ovarian fibroma. CONCLUSIONS: To our knowledge, this is the first report of bilateral benign ovarian fibroma in a child with a diagnosis of nevoid basal cell carcinoma syndrome (NBCCS) with a potential predisposition to Rhabdoid Tumor Predisposition Syndrome (RTPS).

Considerations in Methods and Timing for Delivery of Genetic Counseling Information to Pediatric Oncology Patients and Families.

Many pediatric oncology patients and their families may benefit from genetic counseling and testing; however, identifying the best timing and delivery method for these referrals is sometimes a challenge. The goal of this study was to understand how and when caregivers prefer to receive information about genetic counseling and testing. A total of 56 surveys completed by caregivers at The Johns Hopkins Hospital Pediatric Oncology unit in Baltimore, Maryland were analyzed. A sizeable subset of respondents was interested in receiving information about the availability of genetic counseling from an oncology doctor or nurse, but not a genetic counselor (n=13/55, 24%). Most respondents preferred to be informed about genetic services at diagnosis (n=28/54, 52%) or within 1 to 2 months of diagnosis (n=14/54, 26%). In conclusion, patients and their families may benefit from prompt and early recognition of the risk of cancer predisposition syndromes, preferably within the first 2 months following diagnosis. Oncology professionals are an important source of information, and can introduce the availability of genetic counseling services and motivate families to undergo genetic testing, though alternative communication methods such as brochures may also be useful.

The natural history of OTOF-related auditory neuropathy spectrum disorders: a multicenter study.

Pathogenic variations in the OTOF gene are a common cause of hearing loss. To refine the natural history and genotype-phenotype correlations of OTOF-related auditory neuropathy spectrum disorders (ANSD), audiograms and distortion product otoacoustic emissions (DPOAEs) were collected from a diverse cohort of individuals diagnosed with OTOF-related ANSD by comprehensive genetic testing and also reported in the literature. Comparative analysis was undertaken to define genotype-phenotype relationships using a Monte Carlo algorithm. 67 audiograms and 25 DPOAEs from 49 unique individuals positive for OTOF-related ANSD were collected. 51 unique OTOF pathogenic variants were identified of which 21 were missense and 30 were loss of function (LoF; nonsense, splice-site, copy number variants, and indels). There was a statistically significant difference in low, middle, and high frequency hearing thresholds between missense/missense and LoF/missense genotypes as compared to LoF/LoF genotypes (average hearing threshold for low, middle and high frequencies 70.9, 76.0, and 73.4 dB vs 88.5, 95.6, and 94.7 dB) via Tukey's test with age as a co-variate (P = 0.0180, 0.0327, and 0.0347, respectively). Hearing declined during adolescence with missense/missense and LoF/missense genotypes, with an annual mid-frequency threshold deterioration of 0.87 dB/year and 1.87 dB/year, respectively. 8.5% of frequencies measured via DPOAE were lost per year in individuals with serial tests. Audioprofiling of OTOF-related ANSD suggests significantly worse hearing with LoF/LoF genotypes. The unique pattern of variably progressive OTOF-related autosomal recessive ANSD may be amenable to gene therapy in selected clinical scenarios.

Demographic and socioeconomic trends in DNA banking utilization in the USA.

Demographic and clinical information from de-identified individuals utilizing a single DNA banking service over a 22-year period was assessed using descriptive statistics. The socioeconomic characteristics of the study population were estimated using a zip code-level analysis of US Census data and compared to national US Metrics for 2016. Samples from 4,874 individuals were deposited to a single commercial DNA bank from 1997 to 2019. Samples originated from 31 countries across 6 continents, with the majority of samples originating from the United States (US; 97.37%; n = 4,746). A higher proportion of individuals identifying as females (55.58%; n = 2,709) utilized the service compared to males (41.18%; n = 2,007). The age distribution was bimodal, peaking around 5 years of age and again around 65 years of age. Whole blood was the preferred specimen for submission. Sample deposits peaked in 2015 with 559 annual deposits. Clinical genetic counselors were the most common referral source (41.73%; n = 2,034). Individuals utilizing DNA banking services are estimated to reside in wealthier, more educated and less racially diverse zip codes compared to national metrics. Although direct to consumer DNA banking is being utilized by the general public and clinical genetic counselors in the US, it is not widespread.

The 2019 US medical genetics workforce: a focus on clinical genetics.

PURPOSE: This study characterizes the US clinical genetics workforce to inform workforce planning and public policy development. METHODS: A 32-question survey was electronically distributed to American Board of Medical Genetics and Genomics board-certified/eligible diplomates in 2019. We conducted a descriptive analysis of responses from practicing clinical geneticists. RESULTS: Of the 491 clinical geneticists responding to the survey, a majority were female (59%) and White (79%), worked in academic medical centers (73%), and many engaged in telemedicine (33%). Clinical geneticists reported an average of 13 new and 10 follow-up patient visits per week. The average work week was 50 hours and the majority (58%) worked over half-time in clinical duties. Providers indicated that 39% of new emergency patients wait 3 days or more, and 39% of nonemergency patients wait over 3 months to be seen. Respondents were geographically concentrated in metropolitan areas and many reported unfilled clinical geneticist job vacancies at their institution of more than 3 years. CONCLUSION: With the rapid expansion of genomic medicine in the past decade, there is still a gap between genetics services needed and workforce capacity. A concerted effort is required to increase the number of clinical geneticists and enhance interdisciplinary teamwork to meet increasing patient needs.

Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation.

Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in OTUD5, encoding a K48/K63 linkage-specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with OTUD5 patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis.

Improving Detection of Cancer Predisposition Syndromes in Pediatric Oncology.

Implementation and adherence to consensus statement criteria for referral of pediatric cancer patients for genetic evaluation are critical to identify the 5% to 10% with a genetic cancer predisposition syndrome. The authors implemented a Plan-Do-Study-Act quality improvement initiative aimed at increasing referrals of at-risk patients. Retrospective chart review was followed by educational intervention-with impact assessed over a 9-month prospective chart review. Referral rate improved >2-fold and there was an improvement in documented oncologic history to at least a third-degree relative. The integration of quality improvement can be an effective tool to improve the referral of patients with an elevated risk for a cancer predisposition syndrome.

Where culture meets genetics: Exploring Latina immigrants' lay beliefs of disease inheritance.

As medical genetic services become a standard part of healthcare, it will become increasingly important to understand how individuals interpret and use genetic information. Exploring lay beliefs of disease inheritance that differ along cultural lines is one research strategy. The purpose of this study was to describe conceptualizations of disease inheritance held by members of the Latina immigrant population in the United States. Semi-structured interviews were employed to gather qualitative, exploratory data from 20 Latina immigrant women. All interviews were conducted in Spanish, and thematic analysis was used to analyze interview transcripts. Demographic and acculturation data were also collected and analyzed. The final sample was diverse in age, time lived in the United States, country of birth, and education level. From participant interviews, the authors identified one dominant model of disease inheritance to which most participants ascribed as well as two non-dominant models. The main model was characterized by a focus on the ability to modify an underlying disease risk, especially in the case of hereditary predisposition to common complex disease. Of the non-dominant models, one focused on genetic disease as extraordinary and less modifiable while the other placed less emphasis on the role of genes in health and greater emphasis on non-genetic factors. Across these models, participants expressed their uncertainty about their understanding of genetics. Many of the themes that arose from the interviews, including uncertainty in their own understanding of genetics, were similar to those seen in studies among other populations. Importantly, participants in this study demonstrated a lack of genetic fatalism, which may allay fears that explaining the role of genetics in common health conditions will reduce uptake of positive health behaviors. These findings have practice implications for healthcare providers communicating genetic information to Latina immigrants.

"It's a Little Different for Men"-Sponsorship and Gender in Academic Medicine: a Qualitative Study.

BACKGROUND: Women remain underrepresented in top leadership positions in academic medicine. In business settings, a person with power and influence actively supporting the career advancement of a junior person is referred to as a sponsor and sponsorship programs have been used to diversify leadership. Little is known about how sponsorship functions in academic medicine. OBJECTIVE: To explore perceptions of sponsorship and its relationship to gender and career advancement in academic medicine. DESIGN: Qualitative study using semi-structured, one-on-one interviews with sponsors and protégés. PARTICIPANTS: Twelve sponsors (clinical department chairs) and 11 protégés (participants of a school of medicine executive leadership program [N = 23]) at the Johns Hopkins School of Medicine. KEY RESULTS: All sponsors were men and all were professors, six of the 11 protégés were women, and four of the 23 participants were underrepresented minorities in medicine. We identified three themes: (1) people (how and who): women seek out and receive sponsorship differently; (2) process (faster and further): sponsorship provides an extra boost, especially for women; and (3) politics and culture (playing favorites and paying it forward): sponsorship and fairness. Informants acknowledge that sponsorship provides an extra boost for career advancement especially for women. Sponsors and protégés differ in their perceptions of how sponsorship happens. Informants describe gender differences in how sponsorship is experienced and specifically noted that women were less likely to actively seek out sponsorship and be identified as protégés compared to men. Informants describe a tension between sponsorship and core academic values such as transparency, fairness, and merit. CONCLUSION: Sponsorship is perceived to be critical to high-level advancement and is experienced differently by women. Increased understanding of how sponsorship works in academic medicine may empower individual faculty to utilize this professional relationship for career advancement and provide institutions with a strategy to diversify top leadership positions.

An Integrative Review of Family Health History in Pediatrics.

The aim of this integrative review is to investigate current literature regarding family health history (FHH) taking practices, attitudes, and challenges in the pediatric outpatient setting. FHH is a known clinical tool for providers; however, there are no explicit standards for pediatric FHH collection. The integrative review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. PubMed, Embase, CINAHL, PsycINFO, and Cochrane databases were searched for publications between January 2010 and December 2019, and 8 articles were selected for evaluation. Three themes are explored in this review: FHH collection practices, challenges, and tools. FHH collection practices were found to be inconsistent and the most commonly cited challenge was time. No validated FHH collection tools have been identified for the pediatric population. These findings suggest the need for standardization in FHH collection and further development of tools to improve FHH collection.