Prenatal Testing for Variants in Genes Associated with Hereditary Cancer Risk: Laboratory Experience and Considerations.

Prenatal molecular genetic testing for familial variants that cause inherited disorders has been performed for decades and is accepted as standard of care. However, the spectrum of genes considered for prenatal testing is expanding because of genetic testing for hereditary cancer risk (HCR) and inclusion of conditions with associated cancer risk in carrier screening panels. A few of these disorders, such as ataxia telangiectasia and Bloom syndrome, include increased cancer risk as part of the phenotype, already meet professional guidelines for prenatal testing, and may be associated with increased cancer risk in heterozygous carriers. In addition, recent studies implicate heterozygosity for variants in lysosomal storage disease genes in HCR etiology. Currently, there is no specific professional guidance regarding prenatal testing for HCR. To determine the prevalence of such testing, we reviewed 1345 consecutive prenatal specimens received in our laboratory for familial variant-specific testing and identified 65 (4.8%) with a known or likely HCR component, plus 210 (15.6%) for lysosomal storage disease. These specimens were classified into five distinct categories for clarity and to enable evaluation. Our experience assessing prenatal specimens for variants associated with HCR, with or without a constitutional phenotype, provides metrics for and contributes to the points to consider in prenatal testing for HCR.

Use of Evidence-Based Interventions to Promote Healthy Weight, Nutrition, and Physical Activity in Community Health Improvement Plans from Large Local Health Departments.

We sought to identify evidence-based healthy weight, nutrition, and physical activity strategies related to obesity prevention in large local health department (LHD) Community Health Improvement Plans (CHIPs). We analyzed the content of the most recent, publicly available plans from 72 accredited LHDs serving a population of at least 500 000 people. We matched CHIP strategies to the County Health Rankings and Roadmaps' What Works for Health (WWFH) database of interventions. We identified 739 strategies across 55 plans, 62.5% of which matched a "WWFH intervention" rated for effectiveness on diet and exercise outcomes. Among the 20 most commonly identified WWFH interventions in CHIPs, 10 had the highest evidence for effectiveness while 4 were rated as likely to decrease health disparities according to WWFH. Future prioritization of strategies by health agencies could focus on strategies with the strongest evidence for promoting healthy weight, nutrition, and physical activity outcomes and reducing health disparities.

Incidental molecular diagnoses and heterozygous risk alleles in a carrier screening cohort.

PURPOSE: Expanded pan-ethnic carrier screening is an effective tool for the management of reproductive risk. However, growth in the number of conditions screened, in combination with increasingly more comprehensive test methodologies, can lead to the detection of genetic findings that may affect the health of the tested individual. The objective of this study was to investigate the frequency of pathogenic genotypes in a presumed healthy carrier screening cohort to facilitate broader discussions regarding disclosure of genetic information from carrier screening. METHODS: A retrospective analysis of 73,755 targeted carrier screens was performed to identify individuals with pathogenic genotypes and heterozygous risk alleles. RESULTS: In this study, we identified 79 individuals (0.11%) with pathogenic genotypes associated with moderate to profound autosomal recessive or X-linked conditions. In addition, 10 cases had chromosome X dosage abnormalities suggestive of a sex chromosome abnormality. Heterozygote risk alleles represented the majority of ancillary findings in this cohort, including 280 female carriers of FMR1 premutation alleles, 15 heterozygous females with pathogenic DMD variants, and 174 heterozygotes with pathogenic variants in genes that may confer increased risk for somatic malignancies in the heterozygous state. CONCLUSION: These data suggest that nearly 1% of individuals undergoing carrier screening will have a finding that may require clinical evaluation or surveillance.

"It's Not the Stereotypical 80s Movie Bullying": A Qualitative Study on the High School Environment, Body Image, and Weight Stigma.

BACKGROUND: Schools are crucial for preventing negative health outcomes in youth and are an ideal setting to address weight stigma and poor body image. The current study sought to examine and describe the nature of weight stigma and body image in adolescents, ascertain aspects of the school environment that affect body image, and identify recommendations for schools. METHODS: We conducted 24 semi-structured interviews with students at 2 high schools in 2020. Qualitative data were analyzed using inductive coding and an immersion/crystallization approach. RESULTS: Students did not report weight discrimination or harmful body image messaging from teachers or administrators. Physical education (PE) class and dress codes were 2 instances where covert weight stigma appeared. The most common forms of peer weight stigma reported were weight-based teasing and self-directed appearance critiques. Students recommended that schools eliminate dress codes, diversify PE activities, address body image issues in school, and be cognizant of teasing within friend groups. CONCLUSIONS: Weight stigma presents itself in unique ways in high school settings. Schools can play a role in reducing experiences of weight stigma and negative body image. Weight-related teasing within friend groups was common and may not be captured in traditional assessments of bullying. More nuanced survey instruments may be needed.

Systematic Review of School Telehealth Evaluations.

School telehealth is an alternative delivery model to increase student health-care access with minimal evaluation to aid decision makers in the adoption or expansion of programs. This systematic review assesses school-based telehealth programs using a dissemination and implementation (D&I) framework to inform practitioners and decision makers of the value of school telehealth. We assessed findings from 20 studies on telehealth published between January 2006 and June 2018 and summarized program evaluation on a range of D&I constructs. The sample population included children in school- or center-based early childhood education under age 22 and included parents, providers, and school personnel across urban and suburban locations. There is some evidence that school telehealth can reduce emergency department visits and improve health status for children with chronic and acute illnesses. Future research should report on barriers and facilitators of implementation of programs, including costs related to application of telehealth services and utilization rates.

Cytogenomic identification and long-read single molecule real-time (SMRT) sequencing of a Bardet-Biedl Syndrome 9 (BBS9) deletion.

Bardet-Biedl syndrome (BBS) is a recessive disorder characterized by heterogeneous clinical manifestations, including truncal obesity, rod-cone dystrophy, renal anomalies, postaxial polydactyly, and variable developmental delays. At least 20 genes have been implicated in BBS, and all are involved in primary cilia function. We report a 1-year-old male child from Guyana with obesity, postaxial polydactyly on his right foot, hypotonia, ophthalmologic abnormalities, and developmental delay, which together indicated a clinical diagnosis of BBS. Clinical chromosomal microarray (CMA) testing and high-throughput BBS gene panel sequencing detected a homozygous 7p14.3 deletion of exons 1-4 of BBS9 that was encompassed by a 17.5 Mb region of homozygosity at chromosome 7p14.2-p21.1. The precise breakpoints of the deletion were delineated to a 72.8 kb region in the proband and carrier parents by third-generation long-read single molecule real-time (SMRT) sequencing (Pacific Biosciences), which suggested non-homologous end joining as a likely mechanism of formation. Long-read SMRT sequencing of the deletion breakpoints also determined that the aberration included the neighboring RP9 gene implicated in retinitis pigmentosa; however, the clinical significance of this was considered uncertain given the paucity of reported cases with unambiguous RP9 mutations. Taken together, our study characterized a BBS9 deletion, and the identification of this shared haplotype in the parents suggests that this pathogenic aberration may be a BBS founder mutation in the Guyanese population. Importantly, this informative case also highlights the utility of long-read SMRT sequencing to map nucleotide breakpoints of clinically relevant structural variants.

Chromosomal Microarray Detection of Constitutional Copy Number Variation Using Saliva DNA.

Chromosomal microarray (CMA) testing to detect copy number aberrations among individuals with multiple congenital anomalies and/or developmental delay is typically performed on peripheral blood DNA. However, the use of saliva DNA may be preferred for some patients, which prompted our validation study using six saliva DNA samples with a range of bacterial content (approximately 3% to 21%) and 20 paired blood and saliva specimens on the Agilent Technologies, Illumina, and Affymetrix CMA platforms. Ten of the 20 paired specimens were previously determined to carry clinically significant copy number aberrations by clinical CMA testing on blood DNA (100 kb to 2.56 Mb; five deletions, eight duplications). Notably, the quality of saliva DNA (DNA Genotek) was equivalent to blood DNA regardless of bacterial content, as was CMA quality and single-nucleotide polymorphism genotyping quality with all CMA platforms. The number of copy number variants and absence of heterozygosity regions detected by CMA were comparable between paired blood and saliva DNA and, more important, all 13 clinically significant copy number aberrations were detected in saliva DNA by all CMA platforms. These data confirm that the quality of saliva DNA is comparable to blood DNA regardless of bacterial content, including important CMA and single-nucleotide polymorphism quality metrics, and that saliva DNA is a reliable alternative for the detection of clinically significant copy number aberrations by clinical CMA testing.

Assessment of a Districtwide Policy on Availability of Competitive Beverages in Boston Public Schools, Massachusetts, 2013.

INTRODUCTION: Competitive beverages are drinks sold outside of the federally reimbursable school meals program and include beverages sold in vending machines, a la carte lines, school stores, and snack bars. Competitive beverages include sugar-sweetened beverages, which are associated with overweight and obesity. We described competitive beverage availability 9 years after the introduction in 2004 of district-wide nutrition standards for competitive beverages sold in Boston Public Schools. METHODS: In 2013, we documented types of competitive beverages sold in 115 schools. We collected nutrient data to determine compliance with the standards. We evaluated the extent to which schools met the competitive-beverage standards and calculated the percentage of students who had access to beverages that met or did not meet the standards. RESULTS: Of 115 schools, 89.6% met the competitive beverage nutrition standards; 88.5% of elementary schools and 61.5% of middle schools did not sell competitive beverages. Nutrition standards were met in 79.2% of high schools; 37.5% did not sell any competitive beverages, and 41.7% sold only beverages meeting the standards. Overall, 85.5% of students attended schools meeting the standards. Only 4.0% of students had access to sugar-sweetened beverages. CONCLUSION: A comprehensive, district-wide competitive beverage policy with implementation support can translate into a sustained healthful environment in public schools.

Evaluating the Impact of the Healthy Beverage Executive Order for City Agencies in Boston, Massachusetts, 2011-2013.

INTRODUCTION: Intake of sugar-sweetened beverages (SSBs) is associated with negative health effects. Access to healthy beverages may be promoted by policies such as the Healthy Beverage Executive Order (HBEO) established by former Boston mayor Thomas M. Menino, which directed city departments to eliminate the sale of SSBs on city property. Implementation consisted of "traffic-light signage" and educational materials at point of purchase. This study evaluates the impact of the HBEO on changes in beverage availability. METHODS: Researchers collected data on price, brand, and size of beverages for sale in spring 2011 (899 beverage slots) and for sale in spring 2013, two years after HBEO implementation (836 beverage slots) at access points (n = 31) at city agency locations in Boston. Nutrient data, including calories and sugar content, from manufacturer websites were used to determine HBEO beverage traffic-light classification category. We used paired t tests to examine change in average calories and sugar content of beverages and the proportion of beverages by traffic-light classification at access points before and after HBEO implementation. RESULTS: Average beverage sugar grams and calories at access points decreased (sugar, -13.1 g; calories, -48.6 kcal; p<.001) following the implementation of the HBEO. The average proportion of high-sugar ("red") beverages available per access point declined (-27.8%, p<.001). Beverage prices did not change over time. City agencies were significantly more likely to sell only low-sugar beverages after the HBEO was implemented (OR = 4.88; 95% CI, 1.49-16.0). DISCUSSION: Policies such as the HBEO can promote community-wide changes that make healthier beverage options more accessible on city-owned properties.

Grab a Cup, Fill It Up! An Intervention to Promote the Convenience of Drinking Water and Increase Student Water Consumption During School Lunch.

OBJECTIVES: We evaluated a low-cost strategy for schools to improve the convenience and appeal of drinking water. METHODS: We conducted a group-randomized, controlled trial in 10 Boston, Massachusetts, schools in April through June 2013 to test a cafeteria-based intervention. Signage promoting water and disposable cups were installed near water sources. Mixed linear regression models adjusting for clustering evaluated the intervention impact on average student water consumption over 359 lunch periods. RESULTS: The percentage of students in intervention schools observed drinking water during lunch nearly doubled from baseline to follow-up compared with controls (+ 9.4%; P < .001). The intervention was associated with a 0.58-ounce increase in water intake across all students (P < .001). Without cups, children were observed drinking 2.4 (SE = 0.08) ounces of water from fountains; with cups, 5.2 (SE = 0.2) ounces. The percentage of intervention students observed with sugar-sweetened beverages declined (-3.3%; P < .005). CONCLUSIONS: The current default of providing water through drinking fountains in cafeterias results in low water consumption. This study shows that an inexpensive intervention to improve drinking water's convenience by providing cups can increase student water consumption.

Paroxysmal kinesigenic dyskinesia caused by 16p11.2 microdeletion.

BACKGROUND: Four cases of paroxysmal kinesigenic dyskinesia (PKD) have been reported in individuals with proximal 16p11.2 microdeletions that include PRRT2. CASE REPORT: We describe a fifth patient with PKD, features of Asperger's syndrome, and mild language delays. Sanger sequencing of the PRRT2 gene did not identify any mutations implicated in PKD. However, microarray-based comparative genomic hybridization (aCGH) detected a 533.9-kb deletion on chromosome 16, encompassing over 20 genes and transcripts. DISCUSSION: This case underscores the importance of aCGH testing for individuals with PKD who do not have PRRT2 mutations, particularly when developmental delays, speech problems, intellectual disability, and/or autism spectrum disorder are present.

STRAP regulates c-Jun ubiquitin-mediated proteolysis and cellular proliferation.

STRAP is a ubiquitous WD40 protein that has been implicated in tumorigenesis. Previous studies suggest that STRAP imparts oncogenic characteristics to cells by promoting ERK and pRb phosphorylation. While these findings suggest that STRAP can activate mitogenic signaling pathways, the effects of STRAP on other MAPK pathways have not been investigated. Herein, we report that STRAP regulates the expression of the c-Jun proto-oncogene in mouse embryonic fibroblasts. Loss of STRAP expression results in reduced phospho-c-Jun and total c-Jun but does not significantly reduce the level of two other early response genes, c-Myc and c-Fos. STRAP knockout also decreases expression of the AP-1 target gene, cyclin D1, which is accompanied by a reduction in cell growth. No significant differences in JNK activity or basal c-Jun mRNA levels were observed between wild type and STRAP null fibroblasts. However, proteasomal inhibition markedly increases c-Jun expression in STRAP knockout MEFs and STRAP over-expression decreases the ubiquitylation of c-Jun in 293T cells. Loss of STRAP accelerates c-Jun turnover in fibroblasts and ectopic over-expression of STRAP in STRAP null fibroblasts increases c-Jun expression. Collectively, our findings indicate that STRAP regulates c-Jun stability by decreasing the ubiquitylation and proteosomal degradation of c-Jun.

TGF-beta-dependent and -independent roles of STRAP in cancer.

The serine-threonine kinase receptor-associated protein (STRAP) was initially identified as a putative inhibitor of the canonical TGF-beta signaling pathway. Because the Smad-dependent TGF-beta pathway negatively regulates cellular growth, early functional studies suggested that STRAP behaves as an oncogene. Indeed, a correlation between STRAP overexpression and various cancers has been identified. With the emergence of new studies on the biological function of STRAP, it is becoming clear that STRAP regulates several distinct cellular processes and modulates multiple signaling pathways. While STRAP itself does not possess enzymatic activity, it appears that STRAP influences biological processes through associations with cellular proteins. In this review, we will describe the TGF-beta-dependent and -independent functions of STRAP and provide a context for the significance of STRAP activity in the development of cancer.

Serine threonine receptor-associated protein (STRAP) plays a role in the maintenance of mesenchymal morphology.

The stromal tissue, made of extracellular matrix and mesenchymal cells, is vital for the functional design of all complex tissues. Fibroblasts are key components of stromal tissue and play a crucial role during organ development, wound repair, angiogenesis and fibrosis. We have previously reported the identification of a novel WD-domain protein, STRAP(1) that inhibits transforming growth factor-beta (TGF-beta) signaling and enhances tumorigenicity via TGF-beta-dependent and TGF-beta-independent mechanisms. Here, we report, for the first time, that deletion of STRAP from Mouse Embryonic Fibroblasts (MEFs) results in a loss of mesenchymal morphology. These cells lose their spindle shape and exhibit features of an epithelial morphology. Gene expression profiling has confirmed that deletion of STRAP affects expression of sets of genes important for diverse functions including cell-cell adhesion and cell polarization, and upregulates E-cadherin expression leading to the formation of adherens junctions, subsequent localization of beta-catenin to the cell membrane and downregulation of the mesenchymal markers like LEF1 (lymphoid enhancer-binding factor 1). Upregulation of WT1 (Wilms tumor homolog 1) in STRAP null MEFs plays a role in E-cadherin induction. Finally, stable expression of STRAP in these cells results in a loss of WT1 and E-cadherin expressions, and a reversal from epithelial to the mesenchymal morphology. Thus, these results provide a novel TGF-beta-independent function of STRAP and describe a mechanism for the role of STRAP in the maintenance of mesenchymal morphology.

Correlates of exercise adherence in an African American church community.

This study identified correlates of attendance to a community-based exercise program in an African American church congregation. After medical clearance, 48 participants completed measures of social support, health-related quality of life, depression, exercise self-efficacy, and exercise motivation and then participated in an exercise program for 6 months (attendance rate = 27%). Age, a sense of affiliation as a motivator to exercise, and weekly caloric expenditure derived from yard work were positively associated with program attendance, and full- or part-time employment was negatively associated with attendance. The authors concluded that exercise adherence is a complicated phenomenon that is influenced by a variety of environmental, personal, and social factors. Social factors, in particular, may be important in promoting adherence to an exercise program in African Americans.