Prospective, multi-site study of healthcare utilization after actionable monogenic findings from clinical sequencing.

As large-scale genomic screening becomes increasingly prevalent, understanding the influence of actionable results on healthcare utilization is key to estimating the potential long-term clinical impact. The eMERGE network sequenced individuals for actionable genes in multiple genetic conditions and returned results to individuals, providers, and the electronic health record. Differences in recommended health services (laboratory, imaging, and procedural testing) delivered within 12 months of return were compared among individuals with pathogenic or likely pathogenic (P/LP) findings to matched individuals with negative findings before and after return of results. Of 16,218 adults, 477 unselected individuals were found to have a monogenic risk for arrhythmia (n = 95), breast cancer (n = 96), cardiomyopathy (n = 95), colorectal cancer (n = 105), or familial hypercholesterolemia (n = 86). Individuals with P/LP results more frequently received services after return (43.8%) compared to before return (25.6%) of results and compared to individuals with negative findings (24.9%; p < 0.0001). The annual cost of qualifying healthcare services increased from an average of $162 before return to $343 after return of results among the P/LP group (p < 0.0001); differences in the negative group were non-significant. The mean difference-in-differences was $149 (p < 0.0001), which describes the increased cost within the P/LP group corrected for cost changes in the negative group. When stratified by individual conditions, significant cost differences were observed for arrhythmia, breast cancer, and cardiomyopathy. In conclusion, less than half of individuals received billed health services after monogenic return, which modestly increased healthcare costs for payors in the year following return.

Using Protection Motivation Theory to Predict Intentions for Breast Cancer Risk Management: Intervention Mechanisms from a Randomized Controlled Trial.

The purpose of this study is to evaluate the direct and indirect effects of a web-based, Protection Motivation Theory (PMT)-informed breast cancer education and decision support tool on intentions for risk-reducing medication and breast MRI among high-risk women. Women with ≥ 1.67% 5-year breast cancer risk (N = 995) were randomized to (1) control or (2) the PMT-informed intervention. Six weeks post-intervention, 924 (93% retention) self-reported PMT constructs and behavioral intentions. Bootstrapped mediations evaluated the direct effect of the intervention on behavioral intentions and the mediating role of PMT constructs. There was no direct intervention effect on intentions for risk-reducing medication or MRI (p's ≥ 0.12). There were significant indirect effects on risk-reducing medication intentions via perceived risk, self-efficacy, and response efficacy, and on MRI intentions via perceived risk and response efficacy (p's ≤ 0.04). The PMT-informed intervention effected behavioral intentions via perceived breast cancer risk, self-efficacy, and response efficacy. Future research should extend these findings from intentions to behavior. ClinicalTrials.gov Identifier: NCT03029286 (date of registration: January 24, 2017).

Feasibility, acceptability, and limited efficacy of health system-led familial risk notification: protocol for a mixed-methods evaluation.

BACKGROUND: Genetic testing for pathogenic variants associated with hereditary breast and ovarian cancer risk can improve cancer outcomes through enhanced preventive care in both people with known variants and their biologic relatives. Cascade screening-the process of case-finding in relatives by notifying and inviting them to consider testing-currently relies on the patient to notify their own at-risk relatives. However, many of these relatives never learn they might be at risk. We developed and implemented a new health system-led familial genetic risk notification process where the care team offers to contact at-risk relatives directly. This protocol describes a study to assess the feasibility, acceptability, and limited efficacy of this intervention. METHODS: This feasibility study will use a single-arm, nonrandomized, mixed-methods prospective design. We will enroll two groups of participants: probands and relatives of probands. Eligible probands are currently enrolled Kaiser Permanente Washington (KPWA) members with an upcoming appointment for pre-test genetic counseling for hereditary Lynch syndrome, breast, or ovarian cancer. Eligible relatives, who do not have to be KPWA members, are first-and second-degree relatives of probands. During the appointment with the proband, the genetic counselor will determine whether the proband is appropriate for genetic testing and if so, which relatives might benefit from cascade testing. The genetic counselor then will offer to contact any or all identified relatives directly to discuss genetic risk and testing. The primary outcome of this study is the feasibility of the implemented familial notification process, which we will measure using quantitative and qualitative data on intervention reach, intervention acceptability, and limited efficacy. Analyses will be primarily descriptive and exploratory, with the intent of preparing for a future, larger trial of direct contact interventions. DISCUSSION: Our findings will provide new, foundational evidence for the creation of US-based familial notification systems that directly address logistical and ethical challenges while prioritizing the preferences of patients and families.

Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases.

Importance: Knowledge about the spectrum of diseases associated with hereditary cancer syndromes may improve disease diagnosis and management for patients and help to identify high-risk individuals. Objective: To identify phenotypes associated with hereditary cancer genes through a phenome-wide association study. Design, Setting, and Participants: This phenome-wide association study used health data from participants in 3 cohorts. The Electronic Medical Records and Genomics Sequencing (eMERGEseq) data set recruited predominantly healthy individuals from 10 US medical centers from July 16, 2016, through February 18, 2018, with a mean follow-up through electronic health records (EHRs) of 12.7 (7.4) years. The UK Biobank (UKB) cohort recruited participants from March 15, 2006, through August 1, 2010, with a mean (SD) follow-up of 12.4 (1.0) years. The Hereditary Cancer Registry (HCR) recruited patients undergoing clinical genetic testing at Vanderbilt University Medical Center from May 1, 2012, through December 31, 2019, with a mean (SD) follow-up through EHRs of 8.8 (6.5) years. Exposures: Germline variants in 23 hereditary cancer genes. Pathogenic and likely pathogenic variants for each gene were aggregated for association analyses. Main Outcomes and Measures: Phenotypes in the eMERGEseq and HCR cohorts were derived from the linked EHRs. Phenotypes in UKB were from multiple sources of health-related data. Results: A total of 214 020 participants were identified, including 23 544 in eMERGEseq cohort (mean [SD] age, 47.8 [23.7] years; 12 611 women [53.6%]), 187 234 in the UKB cohort (mean [SD] age, 56.7 [8.1] years; 104 055 [55.6%] women), and 3242 in the HCR cohort (mean [SD] age, 52.5 [15.5] years; 2851 [87.9%] women). All 38 established gene-cancer associations were replicated, and 19 new associations were identified. These included the following 7 associations with neoplasms: CHEK2 with leukemia (odds ratio [OR], 3.81 [95% CI, 2.64-5.48]) and plasma cell neoplasms (OR, 3.12 [95% CI, 1.84-5.28]), ATM with gastric cancer (OR, 4.27 [95% CI, 2.35-7.44]) and pancreatic cancer (OR, 4.44 [95% CI, 2.66-7.40]), MUTYH (biallelic) with kidney cancer (OR, 32.28 [95% CI, 6.40-162.73]), MSH6 with bladder cancer (OR, 5.63 [95% CI, 2.75-11.49]), and APC with benign liver/intrahepatic bile duct tumors (OR, 52.01 [95% CI, 14.29-189.29]). The remaining 12 associations with nonneoplastic diseases included BRCA1/2 with ovarian cysts (OR, 3.15 [95% CI, 2.22-4.46] and 3.12 [95% CI, 2.36-4.12], respectively), MEN1 with acute pancreatitis (OR, 33.45 [95% CI, 9.25-121.02]), APC with gastritis and duodenitis (OR, 4.66 [95% CI, 2.61-8.33]), and PTEN with chronic gastritis (OR, 15.68 [95% CI, 6.01-40.92]). Conclusions and Relevance: The findings of this genetic association study analyzing the EHRs of 3 large cohorts suggest that these new phenotypes associated with hereditary cancer genes may facilitate early detection and better management of cancers. This study highlights the potential benefits of using EHR data in genomic medicine.

Effect of a Randomized Trial of a Web-Based Intervention on Patient-Provider Communication About Breast Density.

Background: Breast density increases breast cancer risk and decreases mammographic detection. We evaluated a personalized web-based intervention designed to improve breast cancer risk communication between women and their providers. Materials and Methods: This was a secondary outcome analysis of an online randomized trial. Women aged 40-69 years were randomized, February 2017-May 2018, to a control (n = 503) versus intervention website (n = 492). The intervention website included information about breast density, personalized breast cancer risk, chemoprevention, and magnetic resonance imaging. Participants self-reported communication about density with providers (yes/no) at 6 weeks and 12 months. We used logistic regression with generalized estimating equations to evaluate the association of study arm with density communication. In secondary analyses, we tested if the intervention was associated with indicators of patient activation (breast cancer worry, perceived risk, or health care use). Results: Women (mean age 62 years) in the intervention versus control arm were 2.39 times (95% confidence interval [CI] = 1.37-4.18) more likely to report density communication at 6 weeks; this effect persisted at 12 months (odds ratio [OR] = 1.71, 95% CI = 1.25-2.35). At 6 weeks, this effect was only significant among women who reported (OR = 3.23, 95% CI = 1.24-8.40) versus did not report any previous density discussions (OR = 1.64, 95% CI = 0.83-3.26). A quarter of women in each arm never had a density conversation at any time during the study. Conclusions: Despite providing personalized density and risk information, the intervention did not promote density discussions between women and their providers who had not had them previously. This intervention is unlikely to be used clinically to motivate density conversations in women who have not had them before. Clinical trial registration number NCT03029286.

Penetrance of Breast Cancer Susceptibility Genes From the eMERGE III Network.

Background: Unbiased estimates of penetrance are challenging but critically important to make informed choices about strategies for risk management through increased surveillance and risk-reducing interventions. Methods: We studied the penetrance and clinical outcomes of 7 breast cancer susceptibility genes (BRCA1, BRCA2, TP53, CHEK2, ATM, PALB2, and PTEN) in almost 13 458 participants unselected for personal or family history of breast cancer. We identified 242 female participants with pathogenic or likely pathogenic variants in 1 of the 7 genes for penetrance analyses, and 147 women did not previously know their genetic results. Results: Out of the 147 women, 32 women were diagnosed with breast cancer at an average age of 52.8 years. Estimated penetrance by age 60 years ranged from 17.8% to 43.8%, depending on the gene. In clinical-impact analysis, 42.3% (95% confidence interval = 31.3% to 53.3%) of women had taken actions related to their genetic results, and 2 new breast cancer cases were identified within the first 12 months after genetic results disclosure. Conclusions: Our study provides population-based penetrance estimates for the understudied genes CHEK2, ATM, and PALB2 and highlights the importance of using unselected populations for penetrance studies. It also demonstrates the potential clinical impact of genetic testing to improve health care through early diagnosis and preventative screening.

Patient and Family Preferences on Health System-Led Direct Contact for Cascade Screening.

Health benefits to relatives of people at known genetic risk for hereditary cancer syndromes is key to realizing the promise of precision medicine. We conducted a qualitative study to design a patient- and family-centered program for direct contact of relatives to recommend cascade genetic testing. We conducted two rounds of data collection using focus groups followed by individual interviews with patients with HBOC or Lynch syndrome and a separate sample of people with a family history of hereditary cancers. Results indicate that U.S.-based health system-led direct contact of relatives is acceptable to patients and families, should take a programmatic approach, include consent of relatives before proband testing, complement to existing patient-mediated disclosure, and allow for relative control of information. Our findings suggest a set of requirements for U.S.-based direct contact programs that could ultimately benefit more relatives than current approaches.

Feasibility and Assessment of a Cascade Traceback Screening Program (FACTS): Protocol for a Multisite Study to Implement and Assess an Ovarian Cancer Traceback Cascade Testing Program.

Ovarian cancer (OVCA) patients may carry genes conferring cancer risk to biological family; however, fewer than one-quarter of patients receive genetic testing. "Traceback" cascade testing -outreach to potential probands and relatives-is a possible solution. This paper outlines a funded study (U01 CA240747-01A1) seeking to determine a Traceback program's feasibility, acceptability, effectiveness, and costs. This is a multisite prospective observational feasibility study across three integrated health systems. Informed by the Conceptual Model for Implementation Research, we will outline, implement, and evaluate the outcomes of an OVCA Traceback program. We will use standard legal research methodology to review genetic privacy statutes; engage key stakeholders in qualitative interviews to design communication strategies; employ descriptive statistics and regression analyses to evaluate the site differences in genetic testing and the OVCA Traceback testing; and assess program outcomes at the proband, family member, provider, system, and population levels. This study aims to determine a Traceback program's feasibility and acceptability in a real-world context. It will account for the myriad factors affecting implementation, including legal issues, organizational- and individual-level barriers and facilitators, communication issues, and program costs. Project results will inform how health care providers and systems can develop effective, practical, and sustainable Traceback programs.

Genetic Heterogeneity and Core Clinical Features of NOG-Related-Symphalangism Spectrum Disorder.

OBJECTIVES: To better distinguish NOG-related-symphalangism spectrum disorder (NOG-SSD) from chromosomal 17q22 microdeletion syndromes and to inform surgical considerations in stapes surgery for patients with NOG-SSD. BACKGROUND: Mutations in NOG cause a variety of skeletal syndromes that often include conductive hearing loss. Several microdeletions of chromosome 17q22 lead to severe syndromes with clinical characteristics that overlap NOG-SSD. Isolated deletion of NOG has not been described, and therefore the contribution of NOG deletion in these syndromes is unknown. METHODS: Two families with autosomal dominant NOG-SSD exhibited stapes ankylosis, facial dysmorphisms, and skeletal and joint anomalies. In each family, NOG was evaluated by genomic sequencing and candidate mutations confirmed as damaging by in vitro assays. Temporal bone histology of a patient with NOG-SSD was compared with temporal bones of 40 patients diagnosed with otosclerosis. RESULTS: Family 1 harbors a 555 kb chromosomal deletion encompassing only NOG and ANKFN1. Family 2 harbors a missense mutation in NOG leading to absence of noggin protein. The incus-footplate distance of the temporal bone was significantly longer in a patient with NOG-SSD than in patients with otosclerosis. CONCLUSION: The chromosomal microdeletion of family 1 led to a phenotype comparable to that due to a NOG point mutation and much milder than the phenotypes due to other chromosome 17q22 microdeletions. Severe clinical findings in other microdeletion cases are likely due to deletion of genes other than NOG. Based on temporal bone findings, we recommend that surgeons obtain longer stapes prostheses before stapes surgery in individuals with NOG-SSD stapes ankylosis.

Effect of Personalized Breast Cancer Risk Tool on Chemoprevention and Breast Imaging: ENGAGED-2 Trial.

Background: Limited evidence exists about how to communicate breast density-informed breast cancer risk to women at elevated risk to motivate cancer prevention. Methods: We conducted a randomized controlled trial evaluating a web-based intervention incorporating personalized breast cancer risk, information on chemoprevention, and values clarification on chemoprevention uptake vs active control. Eligible women aged 40-69 years with normal mammograms and elevated 5-year breast cancer risk were recruited from Kaiser Permanente Washington from February 2017 to May 2018. Chemoprevention uptake was measured as any prescription for raloxifene or tamoxifen within 12 months from baseline in electronic health record pharmacy data. Secondary outcomes included breast magnetic resonance imaging (MRI), mammography use, self-reported distress, and communication with providers. We calculated unadjusted odds ratios (ORs) using logistic regression models and mean differences using analysis of covariance models with 95% confidence intervals (CIs) with generalized estimating equations. Results: We randomly assigned 995 women to the intervention arm (n = 492) or control arm (n = 503). The intervention (vs control) had no effect on chemoprevention uptake (OR = 1.04, 95% CI = 0.07 to 16.62). The intervention increased breast MRI use (OR = 5.65, 95% CI = 1.61 to 19.74) while maintaining annual mammography (OR = 0.98, 95% CI = 0.75 to 1.28). Women in the intervention (vs control) arm had 5.67-times higher odds of having discussed chemoprevention or breast MRI with provider by 6 weeks (OR = 5.67, 95% CI = 2.47 to 13.03) and 2.36-times higher odds by 12 months (OR = 2.36, 95% CI = 1.65 to 3.37). No measurable differences in distress were detected. Conclusions: A web-based, patient-level intervention activated women at elevated 5-year breast cancer risk to engage in clinical discussions about chemoprevention, but uptake remained low.

The FamilyTalk randomized controlled trial: patient-reported outcomes in clinical genetic sequencing for colorectal cancer.

As genetics gains favor in clinical oncology, it is important to address patient concerns around confidentiality, privacy, and security of genetic information that might otherwise limit its utilization. We designed a randomized controlled trial to assess the social impact of an online educational tool (FamilyTalk) to increase family communication about colorectal cancer (CRC) risk and screening. Of 208 randomized participants, 149 (71.6%) returned six-month surveys. Overall, there was no difference in CRC screening between the study arms. Privacy and confidentiality concerns about medical and genetic information, reactions to genetic test results, and lifestyle changes did not differ between arms. Participants with pathogenic or likely pathogenic (P/LP) and variant of uncertain significance (VUS) results were more likely than those with negative results to report that the results accurately predicted their disease risks (OR 5.37, p = 0.02 and OR 3.13, p = 0.02, respectively). This trial demonstrated no evidence that FamilyTalk impacted patient-reported outcomes. Low power, due to the limited number of participants with P/LP results in the overall sample, as well as the short follow-up period, could have contributed to the null findings.

What improves the likelihood of people receiving genetic test results communicating to their families about genetic risk?

OBJECTIVE: We currently rely on probands to communicate genetic testing results and health risks within a family to stimulate preventive behaviors, such as cascade testing. Rates of guidelines-based cascade testing are low, possibly due to low frequency or non-urgent communication of risk among family members. Understanding what is being communicated and why may help improve interventions that increase communication and rates of cascade testing. METHODS: Participants (n = 189) who were to receive both positive and negative colorectal cancer (CRC) sequencing results completed surveys on family communication, family functioning, impact of cancer in the family, and future communication of risk and were participants in eMERGE3. Questions were taken from existing surveys and administered electronically using email and a web driven tool. RESULTS: Common family member targets of CRC risk communication, before results were received, were mothers and fathers, then sisters and grandchildren and finally, children and brothers. A communication impact score of 0.66 (sd = 0.83) indicated low-to-moderate communication impact. Age and education were significantly associated with frequency of familial communication, but not on the cancer-related impact of familial communication. CONCLUSIONS: There is infrequent communication about cancer risk from probands to family members. PRACTICE IMPLICATIONS: These results demonstrate an opportunity to help families improve communication.

Relationship between genetic knowledge and familial communication of CRC risk and intent to communicate CRCP genetic information: insights from FamilyTalk eMERGE III.

Successful translation of genetic information into patient-centered care and improved outcomes depends, at least in part, on patients' genetic knowledge. Although genetic knowledge is believed to be an important facilitator of familial communication of genetic risk information, empirical evidence of this association is lacking. We examined whether genetic knowledge was related to frequency of current familial communication about colorectal cancer and polyp (CRCP) risk, and future intention to share CRCP-related genomic test results with family members in a clinical sample of patients. We recruited 189 patients eligible for clinical CRCP sequencing to the eMERGE III FamilyTalk randomized controlled trial and surveyed them about genetic knowledge and familial communication at baseline. Participants were primarily Caucasian, 47% male, average age of 68 years, mostly well educated, and with high-income levels. Genetic knowledge was positively associated with future-intended familial communication of genetic information (odds ratio = 1.11, 95% confidence interval: 1.02-1.23), but not associated with current communication of CRC risk (ß = 0.01, p = .58). Greater current communication of CRC risk was associated with better family functioning (ß = 0.04, p = 8.2e-5). Participants' genetic knowledge in this study was minimally associated with their intended familial communication of genetic information. Although participants have good intentions of communication, family-level factors may hinder actual follow through of these intentions. Continued focus on improving proband's genetic knowledge coupled with interventions to overcome family-level barriers to communication may be needed to improve familial communication rates.

Characteristics Associated with Participation in ENGAGED 2 - A Web-based Breast Cancer Risk Communication and Decision Support Trial.

PURPOSE: We evaluated demographic and clinical characteristics associated with participation in a clinical trial testing the efficacy of an online tool to support breast cancer risk communication and decision support for risk mitigation to determine the generalizability of trial results. METHODS: Eligible women were members of Kaiser Permanente Washington aged 40-69 years with a recent normal screening mammogram, heterogeneously or extremely dense breasts and a calculated risk of > 1.67% based on the Breast Cancer Surveillance Consortium 5-year breast cancer risk model. Trial outcomes were chemoprevention and breast magnetic resonance imaging by 12-months post-baseline. Women were recruited via mail with phone follow-up using plain language materials notifying them of their density status and higher than average breast cancer risk. Multivariable logistic regression calculated independent odds ratios (ORs) for associations between demographic and clinical characteristics with trial participation. RESULTS: Of 2,569 eligible women contacted, 995 (38.7%) participated. Women with some college (OR = 1.99, 95% confidence interval [CI] 1.34-2.96) or college degree (OR = 3.35, 95% CI 2.29-4.90) were more likely to participate than high school-educated women. Race/ethnicity also was associated with participation (African-American OR = 0.50, 95% CI 0.29-0.87; Asian OR = 0.22, 95% CI 0.12-0.41). Multivariate adjusted ORs for family history of breast/ovarian cancer were not associated with trial participation. DISCUSSION: Use of plain language and potential access to a website providing personal breast cancer risk information and education were insufficient in achieving representative participation in a breast cancer prevention trial. Additional methods of targeting and tailoring, potentially facilitated by clinical and community outreach, are needed to facilitate equitable engagement for all women.

Development of FamilyTalk: an Intervention to Support Communication and Educate Families About Colorectal Cancer Risk.

IFamily members of individuals with colorectal cancer (CRC) may be at increased risk of developing the disease. However, the majority of CRC can be prevented through colonoscopy screening and family members may not be aware if they are recommended to pursue earlier screening because of their family history of CRC. As such, tools must be developed to effectively communicate potential changes to the recommended age for colonoscopy screening and other important CRC-related information to family members. We modified and adapted a successful intervention for families with melanoma to be appropriate for families with CRC to increase communication and screening in family members. The multistep process included the following: (1) developing a paper version of the intervention, (2) piloting the paper version among families with CRC, (3) developing the web-based version, and (4) testing the intervention for usability. Qualitative data was collected and analyzed for pilot testing. Usability testing utilized both qualitative and quantitative data. Patients with CRC liked the paper version and had multiple suggestions, including adding a better introduction, sections on genetics and family history, and clearer communication assistance. The web-based tool was well received and improved upon the linear book format with links, better section instructions, and more proactive communication tools for families. These processes produced materials that satisfied individuals from various families with assistance and support for communicating about CRC. Evaluating the effects of the tools in rigorous research projects is the next step.

Trends in BRCA Test Utilization in an Integrated Health System, 2005-2015.

BACKGROUND: Genetic testing to determine BRCA status has been available for over two decades, but there are few population-based studies of test diffusion. We report 10-year trends in BRCAtesting in an integrated health-care system with long-standing access to genetic services. METHODS: A cohort of women aged 18 years and older was created to ascertain BRCA testing (n = 295 087). Annual testing rates between 2005 and 2015 were calculated in all women with and without incident (ie, newly diagnosed) breast and ovarian cancers and in clinically eligible subgroups by family cancer history, personal cancer history, and age at diagnosis. Secular trends were assessed using Poisson regression. Women tested early (2005-2008), midway (2009-2012), and late (2013-2015) in the study period were compared in cross-sectional analyses. RESULTS: Between 2005 and 2015, annual testing rates increased from 0.6/1000 person-years (pys) (95% confidence interval [CI] = 0.4 to 0.7/1000 pys) to 0.8/1000 pys (95% CI = 0.6 to 1.0/1000 pys) in women without incident breast or ovarian cancers. Rates decreased from 71.5/1000 pys (95% CI = 42.4 to 120.8/1000 pys) to 44.4/1000 pys (95% CI = 35.5 to 55.6/1000 pys) in women with incident diagnoses, despite improvements in provision of timely BRCA testing during this time frame. We found no evidence of secular trends in clinically eligible subgroups including women with family history indicating increased hereditary cancer risk, but no personal cancer history. At the end of the study period, 97.0% (95% CI = 96.6% to 97.3%) of these women remained untested. CONCLUSION: Many eligible women did not receive BRCA testing despite having insurance coverage and access to specialty genetic services, underscoring challenges to primary and secondary hereditary cancer prevention.

Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

PURPOSE: To characterize the molecular genetics of autosomal recessive Noonan syndrome. METHODS: Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction. RESULTS: Twelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings. CONCLUSION: These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.

A web-based personalized risk communication and decision-making tool for women with dense breasts: Design and methods of a randomized controlled trial within an integrated health care system.

BACKGROUND: Mammographic breast density is one of the strongest risk factors for breast cancer after age and family history. Mandatory breast density disclosure policies are increasing nationally without clear guidance on how to communicate density status to women. Coupling density disclosure with personalized risk counseling and decision support through a web-based tool may be an effective way to allow women to make informed, values-consistent risk management decisions without increasing distress. METHODS/DESIGN: This paper describes the design and methods of Engaged, a prospective, randomized controlled trial examining the effect of online personalized risk counseling and decision support on risk management decisions in women with dense breasts and increased breast cancer risk. The trial is embedded in a large integrated health care system in the Pacific Northwest. A total of 1250 female health plan members aged 40-69 with a recent negative screening mammogram who are at increased risk for interval cancer based on their 5-year breast cancer risk and BI-RADS® breast density will be randomly assigned to access either a personalized web-based counseling and decision support tool or standard educational content. Primary outcomes will be assessed using electronic health record data (i.e., chemoprevention and breast MRI utilization) and telephone surveys (i.e., distress) at baseline, six weeks, and twelve months. DISCUSSION: Engaged will provide evidence about whether a web-based personalized risk counseling and decision support tool is an effective method for communicating with women about breast density and risk management. An effective intervention could be disseminated with minimal clinical burden to align with density disclosure mandates. Clinical Trials Registration Number:NCT03029286.

Improving performance of multigene panels for genomic analysis of cancer predisposition.

PURPOSE: Screening multiple genes for inherited cancer predisposition expands opportunities for cancer prevention; however, reports of variants of uncertain significance (VUS) may limit clinical usefulness. We used an expert-driven approach, exploiting all available information, to evaluate multigene panels for inherited cancer predisposition in a clinical series that included multiple cancer types and complex family histories. METHODS: For 1,462 sequential patients referred for testing by BROCA or ColoSeq multigene panels, genomic DNA was sequenced and variants were interpreted by multiple experts using International Agency for Research on Cancer guidelines and incorporating evolutionary conservation, known and predicted variant consequences, and personal and family cancer history. Diagnostic yield was evaluated for various presenting conditions and family-history profiles. RESULTS: Of 1,462 patients, 12% carried damaging mutations in established cancer genes. Diagnostic yield varied by clinical presentation. Actionable results were identified for 13% of breast and colorectal cancer patients and for 4% of cancer-free subjects, based on their family histories of cancer. Incidental findings explaining cancer in neither the patient nor the family were present in 1.7% of subjects. Less than 1% of patients carried VUS in BRCA1 or BRCA2. For all genes combined, initial reports contained VUS for 10.5% of patients, which declined to 7.5% of patients after reclassification based on additional information. CONCLUSIONS: Individualized interpretation of gene panels is a complex medical activity. Interpretation by multiple experts in the context of personal and family histories maximizes actionable results and minimizes reports of VUS.Genet Med 18 10, 974-981.