Completed Genetic Testing Research Articles

Social vulnerability and genetic service utilization among unaffected BRIDGE trial patients with inherited cancer susceptibility

BackgroundResearch on social determinants of genetic testing uptake is limited, particularly among unaffected patients with inherited cancer susceptibility.MethodsWe conducted a secondary analysis of the Broadening the Reach, Impact, and Delivery of Genetic Services (BRIDGE) trial at University of Utah Health and NYU Langone Health, involving 2,760 unaffected patients meeting genetic testing criteria for inherited cancer susceptibility and who were initially randomized to either an automated chatbot or an enhanced standard of care (SOC) genetic services delivery model. We used encounters from the electronic health record (EHR) to measure the uptake of genetic counseling and testing, including dichotomous measures of (1) whether participants initiated pre-test cancer genetic services, (2) completed pre-test cancer genetic services, (3) had genetic testing ordered, and (4) completed genetic testing. We merged zip codes from the EHR to construct census tract-weighted social measures of the Social Vulnerability Index. Multilevel models estimated associations between social vulnerability and genetic services utilization. We tested whether intervention condition (i.e., chatbot vs. SOC) moderated the association of social vulnerability with genetic service utilization. Covariates included study arm, study site, age, sex, race/ethnicity, language preference, rural residence, having a recorded primary care provider, and number of algorithm criteria met.ResultsPatients living in areas of medium socioeconomic status (SES) vulnerability had lower odds of initiating pre-test genetic services (adjusted OR [aOR] = 0.81, 95% CI: 0.67, 0.98) compared to patients living in low SES vulnerability areas. Patients in medium household vulnerability areas had a lower likelihood of completing pre-test genetic services (aOR = 0.80, 95% CI: 0.66–0.97) and having genetic testing ordered (aOR = 0.79, 95% CI: 0.63–0.99) relative to patients in low household vulnerability areas. We did not find that social vulnerability associations varied by intervention condition.ConclusionsThese results underscore the importance of investigating social and structural mechanisms as potential pathways to increasing genetic testing uptake among patients with increased inherited risk of cancer. Census information is publicly available but seldom used to assess social determinants of genetic testing uptake among unaffected populations. Existing and future cohort studies can incorporate census data to derive analytic insights for clinical scientists.Trial registrationBRIDGE was registered as NCT03985852 on June 6, 2019 at clinicaltrials.gov.

Genetics of bilateral pediatric cataract in the Israeli and Palestinian populations

PurposeBilateral pediatric cataract (BPC) is one of the most common causes of childhood visual impairment and blindness worldwide. A significant percentage of pediatric cataracts are caused by genetic alterations. We aim to characterize the set of genes and variants that cause BPC in the Israeli and Palestinian populations and to assess genotype-phenotype correlation.MethodsRetrospective study in a multidisciplinary center for visual impairment, located in a tertiary medical center. Medical charts of families who underwent genetic counseling because of BPC in a family member were reviewed. Clinical characteristics and genetic tests results were obtained from medical records of affected subjects.ResultsTwenty-two families (47 patients) underwent genetic counseling and completed genetic testing. Causative variants were identified in 18/22 (81.8%) of the families, including 3 novel variants. Genetic testing used included mainly panel for congenital cataracts and whole exome sequencing. Eleven families performed genetic testing with the intention of future pregnancy planning. Main causative genes identified were crystalline genes followed by transcription factor genes. BCOR gene variants were associated with persistent fetal vasculature (PFV) cataract in two of three families.ConclusionsCombined molecular techniques are useful in identifying variants causing pediatric cataracts and showed a high detection rate in our population. BCOR gene variants might be associated with PFV type of cataracts. The study of pathogenic variants may aid in family planning and prevention of pediatric cataracts in future pregnancies. Additionally, in certain cases, it assists in diagnosing non-suspected syndromic types of pediatric cataracts.

Choroid plexus enlargement in amyotrophic lateral sclerosis patients and its correlation with clinical disability and blood-CSF barrier permeability

BackgroundUsing in vivo neuroimaging techniques, growing evidence has demonstrated that the choroid plexus (CP) volume is enlarged in patients with several neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. However, although animal and postmortem findings suggest that CP abnormalities are likely important pathological mechanisms underlying amyotrophic lateral sclerosis (ALS), the third most common neurodegenerative disease, no available study has been conducted to thoroughly assess CP abnormalities and their clinical relevance in vivo in ALS patients to date. Thus, we aimed to determine whether in vivo CP enlargement may occur in ALS patients. We also aimed to identify the relationships of CP volume with clinical disabilities and blood-CSF barrier (BCSFB) permeability in ALS patients.MethodsIn this retrospective study, based on structural MRI data, CP volume was assessed using a Gaussian mixture model and underwent further manual correction in 155 ALS patients and 105 age- and sex-matched HCs from October 2021 to April 2023. The ALS Functional Rating Scale-Revised (ALSFRS-R) was used to assess clinical disability. The CSF/serum albumin quotient (Qalb) was used to assess BCSFB permeability. Moreover, all the ALS patients completed genetic testing, and according to genetic testing, the ALS patients were further divided into genetic ALS subgroup and sporadic ALS subgroup.ResultsWe found that compared with HCs, ALS patients had a significantly higher CP volume (p < 0.001). Moreover, compared with HCs, CP volume was significantly increased in both ALS patients with and without known genetic mutations after family-wise error correction (p = 0.006 and p < 0.001, respectively), while there were no significant differences between the two ALS groups. Furthermore, the CP volume was significantly correlated with the ALSFRS-r score (r = -0.226; p = 0.005) and the Qalb (r = 0.479; p < 0.001) in ALS patients.ConclusionOur study first demonstrates CP enlargement in vivo in ALS patients, and continues to suggest an important pathogenetic role for CP abnormalities in ALS. Moreover, assessing CP volume is likely a noninvasive and easy-to-implement approach for screening BCSFB dysfunction in ALS patients.

Discovery of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency in Individuals With Common Psychiatric Comorbidities: A Retrospective Case Review.

A retrospective analysis was conducted of a data set collected in an outpatient behavioral health clinic to assess medication metabolism and methylenetetrahydrofolate reductase (MTHFR) and to see if there was a correlation with certain diagnoses and/or gender. The outpatient routine completed genetic testing on their patients and the test results were later collected through a third-party company, which completed the pharmacogenomic test analyzing genetic variations in DNA, medication metabolism, and an MTHFR deficiency. This study reviewed 186 patients seen in an outpatient setting who were tested for an MTHFR deficiency and compared their psychiatric diagnoses and the number of failed medication attempts. Of those 186 patients, 77 had normal MTHFR enzyme function, 85 were found to have a moderate MTHFR deficiency, and 24 had a severe MTHFR deficiency. Those with a severe MTHFR deficiency had a higher number of medication trials as compared to those without the deficiency and there were overall more patients with a moderate MTHFR deficiency in this data set. Currently, MTHFR deficiency is not commonly tested due to lack of insurance coverage and provider knowledge, and due to the cost of the test itself. Thus, the diagnosis can often be missed.

Abstract 6375: Genetic testing station increases access to germline genetic testing

Abstract Despite evidence of clear benefit, genetic testing of pediatric oncology patients for germline variants remains rare due to a variety of factors, including insurance/financial barriers, limited knowledge about genetic testing, and competing interests for time and resources. Limited access to genetic testing, pre-test counseling and multidisciplinary care have been shown to disproportionately affect patients with limited resources. This represents a critical unmet need in pediatric oncology. Genetic testing station (GTS) is a pre-test counseling video tool that reviews what genetic testing is, why it might be indicated, and explains potential results. Similar video tools have been successfully used in other settings to increase rates of genetic testing, but there are no published reports on the effectiveness of a video education intervention to increase genetic testing in pediatric oncology patients. To test the effectiveness of GTS on genetic testing knowledge and feelings about genetic testing compared to in-person counseling, we use 5 previously validated tools pre- and post-intervention. The initial surveys measure genetic testing knowledge, decisional conflict, healthy literacy, evaluation of GTS and demographics. If participants complete genetic testing, we use the MICRA to assess the impact on their cancer risk assessment. Our GTS arm is recruited from UCLA Pediatric Sarcoma patients, and the in-person counseling arm is recruited from the UCLA Cancer Predisposition clinic. We have recruited 28 participants in the GTS arm and seven in the in-person counseling arm, of which 10 are patients over 18 years old, two are patients between 12-17 years old, and 23 are parents. In our GTS arm, there are 20 female and eight male participants. A majority identify as white or Latino. For the in-person counseling arm, there are four male and three female participants who identify as white, Middle Eastern, or Latino. A similar percentage score with high health literacy, 68% in the GTS arm and 71% for the in-person counseling arm. The majority of patients have no decisional conflict pre- or post-intervention for the GTS group, while the in-person counseling arm shows high initial decision conflict that is fully resolved with counseling. There is a statistically significant increase in genetic testing knowledge for five out of 10 questions comparing pre- and post-GTS. For GTS participants who have completed genetic testing and the MICRA, there is overall low distress and uncertainty, but higher scores for parents than adult or minor patients. In conclusion, there has been high interest in germline genetic testing in pediatric oncology patients with all families deciding to pursue genetic testing after viewing GTS. GTS is an effective tool in increasing genetic testing knowledge in participants. Therefore, GTS is a promising approach to increase access to genetic testing, while providing adequate pre-test counseling and no decisional conflict. Citation Format: Camille Hamilton, Mariana Niell Swiller, Franceska Bhansali, Alyssa Hoover, Stephanie Bottomley, Marisa Lewis, Bianca Russell, Julian A. Martinez, Beth Karlan, Noah Federman, Vivian Y. Chang. Genetic testing station increases access to germline genetic testing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6375.

Delivery of hereditary cancer genetics services to patients newly diagnosed with ovarian and endometrial cancers at three gynecologic oncology clinics in the USA, Brazil, and Mexico

ObjectiveThree gynecologic oncology clinics located in the USA, Brazil, and Mexico collaborated to evaluate their delivery of hereditary cancer genetics services. This descriptive retrospective review study aimed to establish baseline...

A Randomized Trial of Two Remote Health Care Delivery Models on the Uptake of Genetic Testing and Impact on Patient-Reported Psychological Outcomes in Families With Pancreatic Cancer: The Genetic Education, Risk Assessment, and Testing (GENERATE) Study

Background and AimsGenetic testing uptake for cancer susceptibility in family members of cancer patients is suboptimal. Among relatives of pancreatic ductal adenocarcinoma (PDAC) patients, The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated two online genetic education/testing delivery models and their impact on patient-reported psychological outcomes (PRPOs). MethodsEligible participants had ≥1 first-degree relative with PDAC, or ≥1 first-/second-degree relative with PDAC with a known pathogenic germline variant in one of thirteen PDAC predisposition genes. Participants were randomized by family, between 5/8/2019-6/1/2021. Arm 1 participants underwent a remote interactive telemedicine session and online genetic education. Arm 2 participants were offered online genetic education only. All participants were offered germline testing. The primary outcome was genetic testing uptake, compared by permutation tests and mixed-effects logistic regression models. We hypothesized that Arm 1 participants would have a higher genetic testing uptake than Arm 2. Validated surveys were administered to assess patient-reported anxiety, depression, and cancer worry at baseline and 3-months post-intervention. Results424 families were randomized, including 601 participants (n=296 Arm 1; n=305 Arm 2), 90% of whom completed genetic testing (Arm 1 (87%); Arm 2 (93%), p=0.014). Arm 1 participants were significantly less likely to complete genetic testing compared to Arm 2 (adjusted ratio (Arm1/Arm2) 0.90, 95% confidence interval 0.78-0.98). Among participants who completed PRPO questionnaires (Arm 1 (n=194); Arm 2 (n=206)), the intervention did not impact mean anxiety, depression or cancer worry scores. ConclusionsRemote genetic education and testing can be a successful and complementary option for delivering genetics care.

SAT512 Familial Thyroid Cancer With Negative Pre-operative Genetic Screening

Abstract Disclosure: A. Yuen: None. R. Owen: None. S.R. Saul: None. Today it is estimated that the etiology of approximately 90% of thyroid cancer cases are understood, compared to only 25% in the 1990s. However, despite the encouraging progress with oncogenetic screening panels, thyroid cancer-specific testing are not always included. We present a family with 3 generations of thyroid cancer with negative genetic screening ultimately found to have BRAF mutation post-operatively. A 62-year-old woman of Brazilian descent with a medical history of papillary thyroid cancer (PTC) status-post total thyroidectomy presented to clinic. The patient’s PTC was diagnosed 10 years prior when she presented with dysphagia and vocal changes. A thyroid ultrasound revealed a right-sided 2.3 cm solid mass and a fine needle aspiration confirmed PTC. The patient underwent a total thyroidectomy with pathology verifying a PTC with lymphovascular invasion and minimal local extrathyroidal extension as well as a 0.4 cm microcarcinoma in the left lobe. Post-operatively, she received 100 millicurie of radioactive iodine and was started on levothyroxine. Interestingly, the patient reported as strong family history of varying cancers, notably colon, breast, uterine, and thyroid. Her mother was diagnosed at 55-years-old with thyroid cancer that metastasized to her lungs and her daughter was found to have PTC at age 31-years-old. Additionally, the daughter has two teenage sons, both with multiple thyroid nodules who are currently being followed by a pediatric endocrinologist. Given this history, the patient and her daughter both completed genetic testing which was negative for the 42 known mutations associated with an increased risk of cancer, though they both were heterozygous for a mutation of uncertain clinical significance in the MSH2 gene, specifically the c.959C&amp;gt;G (pT320S). Although the standard genetic panel was negative, due to concern for a hereditary mutation, the patient’s thyroidectomy specimen was sent for analysis and confirmed a BRAF mutation. Subsequently, the patient’s daughter also underwent completion thyroidectomy and was found to have the BRAF mutation. This family demonstrated likely hereditary BRAF-associated PTC across 3 generations with children in the fourth generation having known thyroid nodules, generally rare in youth. Although the patient and her daughter were both tested for genetic mutations linked to cancers, neither were positive and it was only after undergoing surgery that they were found to have the BRAF mutation. Although BRAF mutations account for 45% of PTC and are the most commonly associated mutation, they are not commonly included in pre-operative screening or the standard oncogenetic screening panel. Developing a thyroid cancer specific mutation panel to screen family members of patients with thyroid cancer will be an important step in determining these individuals’ best management. Presentation Date: Saturday, June 17, 2023

The association between Helicobacter pylori virulence factor genotypes and gastroduodenal diseases in children

Objective: To investigate the association between Helicobacter pylori (Hp) virulence factor genotypes and the degree and activity of gastric mucosa pathological changes in pediatric gastroduodenal diseases. Methods: This retrospective cohort study was conducted from May 2020 to October 2020. The frozen strains of Hp, which were cultured with the gastric mucosa of 68 children with gastroscopy confirmed gastroduodenal diseases who visited the children's hospital of Zhejiang University School of Medicine from April 2012 to December 2014, were resuscitated. After extracting DNA from these Hp strains, PCR amplification and agarose gel electrophoresis were performed to determine the detection rate of cytotoxin-associated protein A (cagA),vacuolating cytotoxin A (vacA)(s1a、s1b/s2,m1/m2), outer inflammatory protein A (oipA),blood group antigen binding adhesin (babA),duodenal ulcer promoting protein A (dupA) genes; oipA genes were sequenced to determine the gene status. The patients were divided into different groups according to the findings of gastroscopy and gastric mucosa pathology. The detection rates of various virulence factor genotypes among different groups were compared using χ2 tests or Fisher's exact tests. Results: The 68 Hp strains all completed genetic testing. According to the diagnostic findings of gastroscopy, the 68 cases were divided into 47 cases of superficial gastritis and 21 cases of peptic ulcer. Regarding the pathological changes of gastric mucosa, 8 cases were mild, and 60 cases were moderate and severe according to the degree of inflammation; 61 cases were active and 7 cases inactive according to the activity of inflammation. The overall detection rates of cagA, vacA, vacA s1/m2, functional oipA, babA2, and dupA virulence factor genes were 100% (68/68), 100% (68/68), 94% (64/68), 99% (67/68), 82% (56/68), and 71% (48/68), respectively. In the superficial gastritis group, their detection rates were 100% (47/47), 100% (47/47), 96% (45/47), 98% (46/47), 81% (38/47), and 70% (33/47), respectively; in the peptic ulcer group, their detection rates were 100% (21/21), 100% (21/21), 90% (19/21), 100% (21/21), 86% (18/21), and 71% (15/21), respectively. There was no statistically significant difference between the two groups (all P>0.05). In the mild gastric mucosa inflammation group, the detection rates of the above six genotypes were 8/8, 8/8, 8/8, 7/8, 7/8, and 5/8, respectively; and in the moderate to severe inflammation groups, the detection rates were 100% (60/60), 100% (60/60), 93% (56/60), 100% (60/60), 82% (49/60), and 72% (43/60), respectively, with no statistically significant difference between the two groups (all P>0.05). In the active inflammation group, the detection rate of six genotypes were 100% (61/61), 100% (61/61), 93% (57/61), 98% (60/61), 82% (50/61), and 72% (44/61), respectively; and in the inactive inflammation group, they were 7/7, 7/7, 7/7, 7/7, 6/7, and 4/7, respectively. Again, there was no statistically significant difference between the two groups (all P>0.05). There was no statistically significant difference in the detection rate of combinations of 4 or 5 virulence factor genes among the different groups (all P>0.05). Conclusions: CagA, vacA, vacA s1/m2, functional oipA, babA2, and dupA genes are not associated with superficial gastritis and peptic ulcer in children, or with the degree and activity of gastric mucosa pathological inflammation. Different gene combinations of cagA, vacA, oipA, babA2, and dupA have no significant effects on predicting the clinical outcome of Hp infection in children.

Completion of Genetic Testing and Incidence of Pathogenic Germline Mutation among Patients with Early-Onset Colorectal Cancer: A Single Institution Analysis.

Over the past 20 years, rates of early-onset colorectal cancer (eoCRC), defined as <50 years of age at diagnosis, have increased, with 16-25% associated with a pathogenic germline variant (PGV) resulting in a hereditary cancer syndrome. In the present study, we sought to further characterize PGVs observed in patients with eoCRC. We conducted a retrospective analysis of patients with a history of CRC referred for genetic counseling at Mayo Clinic Rochester between April 2019 and April 2022. Three hundred and three CRC patients were referred to medical genetics, including 124 with a history of eoCRC. Only 84 patients (68%) with eoCRC referred for genetic counseling completed genetic testing, with an average of 48 genes evaluated. PGVs were identified in 27.4% with eoCRC, including 8.3% with Lynch syndrome (LS). Other detected PGVs known to increase the risk of CRC included MUTYH (4.8%), CHEK2 (3.6%), APC, BMPR1A, and TP53 (1.3% each). Among those with aoCRC, 109 patients (61%) completed genetic testing, among which 88% had either a dMMR tumor, personal history of an additional LS malignancy, or family history of LS malignancy, with PGVs detected in 23% of patients. This study reinforces the importance for all patients with CRC, especially those with eoCRC, to undergo germline testing.

Measuring real-world concordance with evidence-based guidelines for genetic testing in patients with breast cancer: A retrospective quality review.

e22542 Background: Genetic testing plays an important role in the detection and management of breast cancer. Patients with high-risk mutations may undergo more frequent screening and possible risk reduction with medical and surgical management. Genetic testing also guides treatment decisions, including the recent approval of adjuvant olaparib for patients with high-risk BRCA1/2-mutated early-stage breast cancer. The most recent NCCN guidelines expand the age recommendation for genetic testing for patients with a personal history of breast cancer from age ≤ 45 years to ≤ 50 years though in clinical practice, it is likely patients age 46-50 were undergoing genetic testing prior to this recommendation. The goal of this quality review was to assess real-world concordance with genetic testing as per NCCN guidelines and evaluate practice patterns of genetic testing in patients age 46-50 at two large academic centers with a diverse patient population. Methods: We conducted a retrospective quality review of patients age ≤ 50 years diagnosed with early-stage breast cancer at two academic centers from 2019 to 2021. Imaging, pathology, and genetic testing were abstracted from medical records. Baseline characteristics included age, gender, race, ethnicity, stage at diagnosis, receptor status, and genetic testing data. We used descriptive statistics to describe the population and genetic testing results. Results: There were a total of 376 patients with an average age of 44 years. Of these patients, 374 (99%) were female, 158 (42%) white, 76 (20%) African American, 60 (16%) Asian, and 77 (20%) identified as Hispanic. There were 255 patients (68%) diagnosed with stage I cancer, 82 (22%) with stage II, and 39 (10%) with stage III. There were 261 patients (69%) with hormone-receptor positive, HER2-negative cancer and 45 patients (12%) with triple-negative breast cancer (TNBC). Of the 230 patients age ≤ 45, 225 (98%) completed genetic testing. Of the patients who did not undergo genetic testing, 2 were offered and declined. Genetic mutations were found in 25 patients including 13 patients with BRCA1 and 4 patients with BRCA2. Of the 146 patients age 46-50, 134 (92%) completed genetic testing. Excluding patients with TNBC as genetic testing is recommended at any age for patients with TNBC, 115 patients (91%) underwent genetic testing. Mutations were identified in 8 patients including 3 patients with BRCA1 and 2 patients with BRCA2. Conclusions: Genetic testing is a key component of the pre-treatment diagnostic evaluation for patients with breast cancer given implications for management. Our study demonstrated nearly all patients age ≤ 45 with early-stage breast cancer underwent genetic testing, reflecting concordance with evidence-based guidelines. Furthermore, most patients age 46-50 at our institution had undergone genetic testing prior to the expanded NCCN guidelines.

Digital cancer genetic risk assessment in a gynecologic oncology clinic.

10612 Background: Population-based screening for hereditary cancer syndromes and referral of those who screen positive for genetic testing is a cost effective, evidence-based national health priority. However, under-recognition of hereditary cancer syndromes remains a critical concern, with fewer than 20% of individuals with Hereditary Breast and Ovarian Cancer Syndrome and Lynch Syndrome identified. Here, we evaluate the Ambry Genetics Comprehensive, Assessment, Risk, and Education (CARE) Program, a risk-stratification tool to assess eligibility for National Comprehensive Cancer Network (NCCN) genetic testing criteria and lifetime risk for breast cancer based on the Tyrer-Cuzick (version 8.0) risk algorithm. Methods: Between November 2022 and February 2023, new patients in a gynecologic oncology clinic were prompted by text message to complete CARE prior to their appointment. Those using CARE then completed a System Usability Scale (SUS), a validated 10-item questionnaire for the assessment of perceived usability. Results: Sixty patients presented for a new patient gynecologic oncology appointment and were prompted to complete CARE. The median patient age was 55 years (interquartile range, 40-68). The patients self-identified as Non-Hispanic White (44, 73%), Non-Hispanic Black (5, 8%), Asian (5, 8%), Hispanic (3, 5%), other (2, 3%), and unknown (1, 2%). All identified as female. Forty-three patients (72%) completed CARE. Among CARE users, 11 (26%) were identified as meeting criteria for genetic testing; of these, 9 (82%) proceeded with point-of-care same day genetic testing. Nine (21%) patients were eligible for enhanced breast cancer screening based on an estimated lifetime breast cancer risk of 20% or greater; of these, 100% were referred for high-risk breast screening. There were no patient demographics associated with completion of CARE. Forty-one patients (72%) completed the SUS survey; the median SUS score was 80 (interquartile range, 60-92.5), which corresponded to 85-89th percentile and a letter grade of A-. Conclusions: Implementation of a digital tool for cancer genetic risk assessment identified a quarter of patients to be eligible for genetic testing, among whom 82% completed same-day genetic testing. Additionally, the tool was reviewed favorably by patient users. Large randomized controlled trials of health information technology tools are needed to move closer to the goal of population-based hereditary cancer risk assessment.

Internet-Based Germline Genetic Testing for Men With Metastatic Prostate Cancer.

Germline mutations in DNA repair genes are present in approximately 10% of men with metastatic prostate cancer (mPC), and guidelines recommend genetic germline testing. Notable barriers exist, including access to genetic counseling, insurance coverage, and out-of-pocket costs. The GENTleMEN study was designed to determine the feasibility of an Internet-based, patient-driven germline genetic testing approach for men with mPC. In this prospective cohort study, men with mPC provided informed consent via an Internet-based platform and completed a questionnaire including demographics and family cancer history. Supporting medical data were also collected. Genetic testing was performed using the Color Genomics 30-gene targeted panel of cancer predisposition genes on a mailed saliva sample. Men whose test results identified a germline pathogenic or likely pathogenic variant received results by phone or telehealth genetic counseling; other participants received results by email with an option for phone-based or telehealth genetic counseling. As of August 18, 2021, 816 eligible men were consented, of whom 68% (551) completed genetic testing, and 8.7% (48 of 551) were found to carry a pathogenic or likely pathogenic variant in a germline DNA repair gene: CHEK2 (17), BRCA2 (15), ATM (6), NBN1 (3), BRCA1 (2), PALB2 (2), PMS2 (2), and MSH6 (1). Participants were more likely to complete the testing process if they were non-Hispanic White, married, highly educated, or from a higher-income bracket. Here, we show the feasibility of delivering germline (inherited) genetic testing by a voluntary, patient-driven, Internet-based platform to men with mPC. Preliminary results show rates of germline DNA repair mutations, consistent with other cohorts. Although feasible for some, reduced steps for participation, more dedicated diverse outreach and participant support, and identification and addressing of additional barriers is needed to ensure equitable access and optimization.

Real world rates of genetic referrals and germline testing in patients with prostate adenocarcinoma at an academic cancer center in southern New Jersey.

114 Background: Prostate adenocarcinoma is the second leading cause of cancer-related death in men in the United States. A major risk factor is family history, with prostate cancer in a first-degree relative effectively doubling a patient’s risk. However, relying on family history alone fails to identify many patients with clinically relevant cancer-related germline mutations, which can have important prognostic and therapeutic implications for patients and their families. In 2018, the NCCN recommended expanding the germline testing to include all men with high risk, very high risk, regional or metastatic prostate cancer. We sought to identify the rate of genetic testing within this patient population at the MD Anderson Cancer Center at Cooper University Hospital. Methods: The institution database was queried to identify patients with the ICD-10 diagnosis of prostate adenocarcinoma between 01-2019 and 12-2020; the inclusion criteria were age 18 years or older, biopsy-proven prostate adenocarcinoma, and qualification to receive germline genetic testing per NCCN guidelines. A total of 201 patients were screened and 97 cases were analyzed. Results: Of the 97 patients who qualified for genetic testing, 53 were referred to genetics (54.6%). 27 of the 53 patients who met with our genetics team underwent testing (50.9%). Of the 27 patients tested, nine patients (33.3%) were found to have clinically relevant cancer-related germline mutations with therapeutic implications for the patient and/or screening recommendations for the patient and their family members. Conclusions: Overall, the proportion of patients who qualified for and completed genetic testing was low at 27.8%. Of those who completed testing, the rate of detection of a significant germline mutation was high at 33.3%, indicating that a significant proportion of those untested may carry a genetic mutation of clinical importance. Based on these results, we developed an electronic Best Practice Alert that notifies providers if a patient qualifies for a genetic risk evaluation based on his prostate cancer risk. We implemented this system, with reported high utilization demonstrating feasibility of this tool. Preliminary data shows improved rates of referral among prostate cancer patients.

Identification of individuals at high-risk for pancreatic cancer using a digital patient-input tool combining family cancer history screening and new-onset diabetes

Capturing family history might be a valuable tool for identification of individuals at increased risk of pancreatic cancer, which would allow enrollment into pancreatic surveillance programs. In addition, weight loss and concurrent new-onset diabetes may be utilized as an early marker for pancreatic cancer. This study evaluates the yield of combining family history and the Enriching New-Onset Diabetes for Pancreatic Cancer (ENDPAC) model to identify individuals who could benefit from pancreatic surveillance. A novel questionnaire and digital input tool was created that combined questions on family cancer history and criteria of the ENDPAC model. Individuals meeting ENDPAC criteria were enrolled directly in the high-risk pancreatic clinic. Individuals who met the criteria for a significant family history of cancer were offered referral to a genetic counselor. The questionnaire was completed by 453 patients. Of those, 25.8% (117/453) had significant familial risk factors. Eighteen individuals (15.4%) completed genetic testing previously, of whom five had a pathogenic variant. Thirty-four (29.9%) out of 117 individuals with a strong family history – flagged by the questionnaire – underwent genetic testing. Four (11.8%) of these patients harbored a pathogenic variant. Additionally, through cascade family testing, two siblings were found to carry pathogenic variants. Four (0.9%) of the 453 patients matched ENDPAC criteria. Two were diagnosed with pancreatic cancer and the others were enrolled in the surveillance program. In conclusion, identification of high-risk individuals for pancreatic cancer can be achieved by combining family history screening and the ENDPAC model to facilitate referral to genetic counseling and high-risk clinics.

A retrospective cohort study of genetic referral and diagnosis of Lynch syndrome in patients with cutaneous sebaceous lesions.

Immunohistochemistry (IHC) of cutaneous sebaceous lesions (SL) can be used to screen patients for Lynch syndrome (LS). There is little data on rates of genetic referral and outcomes of genetic testing for patients with SL. This single-center retrospective study characterizes 400 + patients with SL, including IHC results, genetics referrals, and outcomes of genetic testing. Retrospective chart reviews were performed for patients with a pathology-confirmed diagnosis of SL at the University of Michigan between January 2009 and December 2019. 447 patients with 473 SL were identified. Excluding 20 patients with known LS, IHC was conducted in 173 (41%) patients. 92/173 (53%) patients had abnormal results. 69 of these 92 (75%) patients were referred to genetics. 32 additional patients were referred with normal IHC (n = 22) or without IHC (n = 10). Of 101 patients referred, 65 (64%) were seen and 47 (47%) completed genetic testing. 7/47 (15%) had pathogenic variants associated with LS, six with concordant abnormal IHC and one without IHC. Cancer genetics referral of patients with SL, particularly for lesions with abnormal IHC, yields a significant rate of LS diagnosis. Providers should consider genetics referral for patients with SL.

Prevalence of Undiagnosed Acute Hepatic Porphyria in Cyclic Vomiting Syndrome and Overlap in Clinical Symptoms.

Acute hepatic porphyria (AHP) presents with nausea and vomiting and can mimic cyclic vomiting syndrome (CVS). The prevalence of AHP in CVS and overlap in clinical symptomatology is not known. We thus sought to determine the prevalence of pathogenic variants for AHP and characterize symptom overlap between CVS and AHP. We conducted a cross-sectional study of 234 CVS patients using Rome criteria. Patients were eligible for AHP genetic testing if they had recurrent episodes of severe, diffuse abdominal pain with ≥ 2 of the following-peripheral nervous system (muscle weakness/aching, numbness, tingling), central nervous system (confusion, anxiety, seizures, hallucinations), autonomic nervous system (hyponatremia, tachycardia, hypertension, constipation) symptoms, red/brownish urine, or blistering skin lesions on sun-exposed areas. A family history of AHP or elevated urinary porphobilinogen (PBG)/aminolaevulinic acid (ALA) were also criteria for genetic testing and was performed using a 4-gene panel. Mean age was 38.7 ± 14.5years, 180 (76.9%) were female and 200 (85.5%) were Caucasian. During a CVS attack, 173 (92%) reported abdominal pain, 166 (87.2%) had peripheral nervous system, 164 (86.8%) had central nervous system and 173 (92) % had autonomic symptoms. Ninety-one eligible patients completed genetic testing. None were positive for AHP but two had variants of uncertain significance (VUS) in the HMBS gene. There is a high prevalence of non-gastrointestinal symptoms in CVS, like AHP, which is important for clinicians to recognize. AHP was not detected in this study and larger studies are warranted to ascertain its prevalence.

Abstract 13143: Genetic Testing Referral Patterns Among Women With Peripartum Cardiomyopathy

Introduction: The genetic architecture of peripartum cardiomyopathy (PPCM) and dilated cardiomyopathy (DCM) overlap, and 15% of patients with PPCM have a disease-causing variant in a DCM-associated gene. Despite the impact of genetics on cascade screening and risk stratification, there are no recommendations for genetic testing in PPCM. We aimed to quantify the percentage of individuals with PPCM referred for genetic testing and to identify factors that may impact the likelihood of referral for genetic testing. Methods : We conducted a retrospective cohort study of 205 patients diagnosed with PPCM from 1986-2018 within the University of Pennsylvania Health System who had outpatient follow-up. We determined the referral rate for genetic testing and examined differences in referral based on race, timing of PPCM diagnosis, hypertensive disorders of pregnancy (HDP), NYHA class at diagnosis, LVEF at diagnosis, family history, recurrent PPCM, and referral to a heart failure specialist. We compared continuous variables using the Student t test and categorical variables using Pearson’s chi-square test. Results : Of 205 patients with PPCM, 23 (11%) were referred for genetic testing. Women referred for genetic testing were more likely to have HDP (61% vs. 37%, p=0.03), LVEF &lt;30% at diagnosis (65% vs. 42%, p=0.04), recurrent PPCM (17% vs. 5%, p=0.04), a first-degree family member with heart failure or cardiomyopathy (70% vs. 17%, p&lt;0.001), and any documented family history at the first cardiology visit (78% vs. 54%, p=0.03). Of those referred, 17 (74%) underwent genetic counseling, and 12 (52%) completed genetic testing. Two patients (17%) had a pathogenic or likely pathogenic variant in TTN and were recommended for cascade screening, and 9 (75%) had variants of unknown significance which were predominately missense variants. Conclusions : A minority of women with PPCM are referred for genetic testing. Referral is largely driven by family history, which may lead to under-diagnosis of pathogenic mutations. Increasing referral rates may improve the detection of pathogenic mutations which may impact the care provided to affected women and their families.

OR18-3 Case Series of 16 Patients With 17β-Hydroxysteroid Dehydrogenase Type 3 Deficiency at Five Children's Hospitals in the United States

Abstract Objectives The 17β-hydroxysteroid dehydrogenase type 3 (17βHSD3) enzyme, expressed in the testes, converts androstenedione to testosterone. Deficiency of 17βHSD3 causes a 46,XY difference of sex development (DSD). Until recently, just 12 cases of 17βHSD3 deficiency had been reported in the literature in the United States. We report a series of 16 patients diagnosed at five children's hospitals in the United States. Methods We performed a multi-center chart review of patients with 17βHSD3 deficiency diagnosed based on hormone values and/or sequencing and deletion/duplication analysis of the HSD17B3 gene. Results Sixteen patients were identified, ranging in age at diagnosis from birth to 22.3 years (average age 9.5 years). One patient, assigned female at birth, was diagnosed due to a positive family history of the condition. Three patients underwent testing due to discordance between the sex predicted by prenatal cell-free DNA testing and the external genital appearance on prenatal ultrasound or at birth (two were assigned female, one was assigned male). An additional four patients had non-binary (atypical) appearing external genitalia at birth (two assigned female, two assigned male). Two children assigned female at birth were diagnosed after undescended testes were identified during hernia repair in early childhood. Six patients who were assigned female at birth came to medical attention peri-pubertally due to signs of excess/undesired androgen effects and/or primary amenorrhea. Data on gender identity is limited by the current age of many of the patients, but as of most recent follow-up, one patient assigned male and one assigned female are reported to be exploring their gender identities. Four patients had a prior diagnosis of complete or partial androgen insensitivity syndrome and 8 had a prior diagnosis of 46,XY DSD of unknown etiology. Eleven patients had genetic testing confirming pathogenic or likely pathogenic variants in the HSD17B3 gene (two identified on whole exome, one on a DSD-specific multi-gene panel, and the remaining 8 on single gene testing). Of the patients without genetically confirmed 17βHSD3 deficiency, one had a clinical diagnosis due to a genetically-confirmed diagnosis in a sibling. The remaining four declined or have not completed genetic testing, but had hormonal testing consistent with the diagnosis. Conclusions 17βHSD3 deficiency is likely much more common in the US than previously appreciated, and can present at any age with a range of physical findings. Accurate diagnosis is important, as the broad category of 46,XY DSD encompasses a wide spectrum of gonadal malignancy risk, potential for pubertal hormone function and fertility, and gender identity outcomes. We suggest evaluating for this potential diagnosis with genetic and/or hormonal testing in cases of 46,XY DSD with absent uterus. Presentation: Monday, June 13, 2022 11:30 a.m. - 11:45 a.m.

S244 An Appraisal of the Referral, Uptake and Outcomes of Genetic Counseling and Testing in Patients With Young Onset Colorectal Cancer

Introduction: The incidence of young-onset colorectal cancer (YOCRC) defined as CRC in individuals < 50 years of age is rapidly rising. Germline genetic testing is currently recommended for all patients with CRC< 50 years. Germline pathogenic variants (PV) are detected in 16-20% of patients with YOCRC and many are diagnosed with an actionable PV not typically associated with CRC, highlighting a need for genetic counseling and multi-panel gene testing (MGPT) in these patients. We aimed to determine the rate of referral to genetic counseling, and uptake and outcomes of germline testing in YOCRC patients seen at a tertiary referral center. Methods: Patients diagnosed with YOCRC from 2010-2019 were included. Patients with appendiceal cancer, known family history of a hereditary cancer syndrome and inflammatory bowel disease were excluded. Demographic data including age, sex, race and family history of CRC were extracted from the electronic medical record (EMR).Genetic counseling referral was confirmed through an order in the EMR, clinical documentation in office visits with colorectal surgery, oncology or gastroenterology, or a completed visit with the genetic counselor. Data was analyzed using STATA, Chi-square and t-test and descriptive analyses were included. Results: 793 YOCRC patients (457 male and 336 female) were included. 56% (445) were referred for genetic counseling and 88% of referred patients completed genetic testing. 20.5% had a PV detected; 83% were in CRC associated genes and 18% were in other actionable genes (Table). Referral to genetic counseling was higher in younger patients (mean age= 40 years in those referred vs. mean age= 43 years in those not referred, p < 0.05) and those with a family history of CRC (70% of patients with family history of CRC vs. 53% of patients without family history were referred, p< 0.05) There was no significant association between referral rate and sex or race. Conclusion: Even in a large academic center, the rates of referrals for genetic counseling in patients with YOCRC were documented in only about half the patients. 1 in 5 YOCRC patients had a PV detected. If the 348 patients not referred to genetic counseling underwent testing, an additional 71 patients may be detected with a germline PV. Our findings highlight the need to raise awareness of the importance of genetic counseling and testing in YOCRC patients, and suggest that health systems should consider implementing care pathways to mitigate the potential impact of under-referral. Table 1. - Demographics, Referral to and Uptake of Genetic Counseling and Testing and Outcome of Genetic Testing Number of patients with YOCRC 793 Demographics N (%) Mean (SD) Age 41.9 (6.8) Sex Male 457 (57.6) Female 336 (42.4) Race White 684 (86.3) Black 72 (9.1) Other 37 (4.7) Family History of CRC Yes 280 (40.2) No 417 (59.8) Referral for Genetic Counseling 445 (56.1) Attended Genetic Counseling 390 (87.6) Underwent Genetic Testing 376 (96.4) • Pathogenic Variant Detected 77 (20.5) • Variant of Uncertain Significance Detected 88 (23.4) • No Variant Detected 211 (56.1) Genetic Testing Outcomes Genetic Syndrome Pathogenic Variant Number of Patients Total (%) CRC and polyposis genes N=64 (83%) Lynch syndrome N=37 (48%) MLH1 11 37 (48) MSH2 13 MSH6 8 PMS2 5 FAP N= 15 (19.4%) APC 15 15 (19.4) MYH- Associated polyposis N =10 (12.9%) MUTYH (Biallelic) 6 10 (12.9) MUTYH (Monoallelic) 4 Juvenile polyposis syndrome N = 1 (1.2%) SMAD4 1 1 (1.2) MSH3 (monoallelic) 1 1 (1.2) Other genes N=13 (17%) ATM 4 13 (17) BRCA1/2 4 BLM (monoallelic) 1 CHEK2 2 FLCN 1 CDKN2A 1