Recommendations For Genetic Testing Research Articles

The Impact of Li Fraumeni and Germline Retinoblastoma Mutations on Leiomyosarcoma Initiation, Outcomes and Genetic Testing Recommendations.

Leiomyosarcomas (LMS) are clinically and molecularly heterogeneous, occurring mostly in sporadic but also syndromic settings. The role of pathogenic germline variants (PGV) as LMS drivers and impact on outcome remain uncertain. We perform a comprehensive clinicopathologic and molecular analysis using a tumor-normal DNA next-generation sequencing assay (MSK-IMPACT) of germline-associated LMS compared to sporadic LMS. Among 285 LMS [120 soft tissue LMS (STLMS), 165 uterine (ULMS)] with germline testing, 78 (27%, 43 STLMS, 35 ULMS) cases harbored PGV: 35/78 (45%) of PGV carriers showing biallelic inactivation of the corresponding gene in the tumor (26 STLMS, 9 ULMS). The most frequent germline predispositions were TP53 (Li-Fraumeni syndrome) (17 patients, 16 in STLMS) and RB1 (retinoblastoma) (13 patients, 11 in STLMS). Germline TP53 and somatic RB1 alterations often co-occurred in the tumor, and vice versa. Other biallelically inactivated PGV were enriched in DNA damage repair-related genes: CHEK2, MSH2, MSH6, RAD51D, BRCA2 and FANCA. Monoallelic PGV were mostly in ULMS and associated with co-occurring TP53 and RB1 somatic alterations. STLMS patients with biallelic but not monoallelic PGV were significantly younger than sporadic STLMS patients (median ages 38 vs 52 vs 58 years). No differences in disease-specific or progression-free survival were observed in germline-associated vs sporadic LMS, regardless of biallelic status. While ULMS patients had a relatively low proportion of PGV, a high percentage of STLMS patients with PGV had tumor biallelic status, indicating that PGV drive tumorigenesis in these individuals. These findings have significant implications for genetic testing recommendations.

Genetic testing for inherited arrhythmia syndromes and cardiomyopathies: results of the European Heart Rhythm Association survey.

Indications and clinical impact of genetic testing for cardiac diseases have increased significantly over the past years. The aim of this physician-based European Heart Rhythm Association (EHRA) survey was to assess current clinical practice and access to genetic testing for cardiac diseases across European Society of Cardiology countries and to evaluate adherence to the 2022 EHRA/HRS/APHRS/LAHRS Expert Consensus Statement on genetic testing. An online questionnaire composed of 28 questions was submitted to the EHRA Research Network and European Reference Network GUARD-Heart healthcare partners and promoted via dedicated social media channels. There were 357 respondents from 69 countries, 40% working in a hospital setting with a cardiac genetic service and/or a dedicated clinic focusing on inherited cardiac diseases and 27% with an onsite genetic laboratory. No genetic testing or low annual rate (<10/year) was declared by 39% of respondents. The majority of respondents (78%) declared issues or limitations to genetic testing access in their clinical practice. The main reasons for not providing or limited access to genetic testing were no availability of dedicated unit or genetic laboratory (35%) or reimbursement issues (25%). The most frequently reported indication for genetic testing was diagnostic purpose (55%). Most respondents (92%) declared offering genetic testing preceded by genetic counselling and 42% regular multidisciplinary evaluations for patients with cardiac genetic diseases. The perceived value of genetic testing in the diagnostic, prognostic, and therapeutic assessment was variable (67, 39, and 29%, respectively) and primarily based on the specific inherited disease. The majority of respondents recommended cascade genetic testing for the first-degree family members in case of pathogenic/likely pathogenic variant in the proband. This survey highlights a significant heterogeneity of genetic testing access and provision and issues attributable to the availability of dedicated unit/genetic laboratory and reimbursement. However, adequate adherence to indications in the current recommendations for genetic testing in patients with cardiac diseases was observed.

Advancing Genetic Testing in Kidney Diseases: Report From a National Kidney Foundation Working Group

About 37 million people in the United States have chronic kidney disease, a disease that encompasses diseases of multiple causes. About 10% or more of kidney diseases in adults and about 70% of selected chronic kidney diseases in children are expected to be explained by genetic causes. Despite the advances in genetic testing and an increasing understanding of the genetic bases of certain kidney diseases, genetic testing in nephrology lags behind other medical fields. More understanding of the benefits and logistics of genetic testing is needed to advance the implementation of genetic testing in chronic kidney diseases. Accordingly, the National Kidney Foundation convened a Working Group of experts with diverse expertise in genetics, nephrology, and allied fields to develop recommendations for genetic testing for monogenic disorders and to identify genetic risk factors for oligogenic and polygenic causes of kidney diseases. Algorithms for clinical decision making on genetic testing and a road map for advancing genetic testing in kidney diseases were generated. An important aspect of this initiative was the use of a modified Delphi process to reach group consensus on the recommendations. The recommendations and resources described herein provide support to nephrologists and allied health professionals to advance the use of genetic testing for diagnosis and screening of kidney diseases.

Genetic testing in early-onset atrial fibrillation.

Atrial fibrillation (AF) is a globally prevalent cardiac arrhythmia with significant genetic underpinnings, as highlighted by recent large-scale genetic studies. A prominent clinical and genetic overlap exists between AF, heritable ventricular cardiomyopathies, and arrhythmia syndromes, underlining the potential of AF as an early indicator of severe ventricular disease in younger individuals. Indeed, several recent studies have demonstrated meaningful yields of rare pathogenic variants among early-onset AF patients (∼4%-11%), most notably for cardiomyopathy genes in which rare variants are considered clinically actionable. Genetic testing thus presents a promising opportunity to identify monogenetic defects linked to AF and inherited cardiac conditions, such as cardiomyopathy, and may contribute to prognosis and management in early-onset AF patients. A first step towards recognizing this monogenic contribution was taken with the Class IIb recommendation for genetic testing in AF patients aged 45 years or younger by the 2023 American College of Cardiology/American Heart Association guidelines for AF. By identifying pathogenic genetic variants known to underlie inherited cardiomyopathies and arrhythmia syndromes, a personalized care pathway can be developed, encompassing more tailored screening, cascade testing, and potentially genotype-informed prognosis and preventive measures. However, this can only be ensured by frameworks that are developed and supported by all stakeholders. Ambiguity in test results such as variants of uncertain significance remain a major challenge and as many as ∼60% of people with early-onset AF might carry such variants. Patient education (including pretest counselling), training of genetic teams, selection of high-confidence genes, and careful reporting are strategies to mitigate this. Further challenges to implementation include financial barriers, insurability issues, workforce limitations, and the need for standardized definitions in a fast-moving field. Moreover, the prevailing genetic evidence largely rests on European descent populations, underscoring the need for diverse research cohorts and international collaboration. Embracing these challenges and the potential of genetic testing may improve AF care. However, further research-mechanistic, translational, and clinical-is urgently needed.

Analysis of the Application of Professional Society Screening Guidelines for Colorectal Polyposis Syndromes at a Single Institution

Several professional society guidelines suggest germline genetic testing for colorectal polyposis syndromes in patients with ≥10 lifetime adenomatous polyps. This study evaluated the factors associated with genetic testing decisions and outcomes when germline testing was recommended per guidelines. Surgical archives revealed 145 patients with a recommendation for germline genetic polyposis testing based on guidelines. Demographic data and medical history were collected to examine their association with testing decisions and results. Germline genetic testing was ordered in 90 out of 145 patients and was ordered in younger patients with more lifetime adenomas. Pathogenic alterations were detected in 12 out of 53 patients who completed testing. Younger ages and higher numbers of lifetime adenomas were not associated with the detection of germline genetic alterations. In fact, patients with a pathogenic germline alteration had higher median ages and fewer lifetime adenomas than those without an alteration. Half of the 12 patients with a pathogenic germline mutation were not White non-Hispanic, although White non-Hispanic patients comprised 75.5% of those tested. This study supports the 10 adenomatous polyp threshold for recommending germline genetic polyposis testing, as an alteration was detected in a sizable proportion (>20%) of patients tested. Although a younger age and a higher number of lifetime adenomas were associated with an increased likelihood of ordered tests, no evidence was found to support these additional factors in testing decisions.

Germline rare variants in HER2-positive breast cancer predisposition: a systematic review and meta-analysis.

Approximately 10% of breast cancer (BC) cases result from hereditary causes. Genetic testing has been widely implemented in BC care to determine hereditary cancer syndromes and personalized medicine. Thus, identification of individuals carrying germline pathogenic variants could be useful to provide appropriate prophylactic or screening measures for each BC subtype, however, there are few formal recommendations for genetic testing in this sense so far. In this study, we assessed rare germline variants in a specific group of genes in order to determine the association with human epidermal growth factor 2 enriched (HER2+) BC phenotype through a systematic review and meta-analysis comparing subtypes overexpressing HER2 with other clinically recognized subtypes of BC. This review was registered with PROSPERO (ID: CRD42023447571). We conducted an online literature search in PubMed (MEDLINE), Scopus, and EMBASE databases. We included original studies that investigated germline variants in HER2+ BC patients and selected the studies that reported only rare and/or pathogenic germline variants. We assessed the risk of bias and quality of the studies using the Joanna Briggs Institute Critical Appraisal checklists and the Modified Newcastle-Ottawa Scale for Genetic Studies, respectively. Considering hormone receptor and HER2 expression status, we compared gene-based risks initially in HR-HER2-, HR+HER2-, HR+HER2+, and HR-HER2+ groups, conducting separate meta-analyses using the random effects model for each comparison, and within them for each gene. Of the total 36 studies describing germline variants, 11 studies provided information on the prevalence of variants in the different clinically relevant BC subtypes and allowed comparisons. Germline variants within eight genes showed significant differences when meta-analyzed between the BC groups: BRCA1, BRCA2, TP53, ATM, CHEK2, PALB2, RAD51C, and BARD1. Notably, TP53, ATM, and CHEK2 germline variants were identified as predisposing factors for HER2+ subtypes, whereas BRCA1, BRCA2, PALB2, RAD51C, and BARD1 germline variants were associated with a predisposition to low HER2 expression. Main concerns about bias and quality assessment were the lack of confounding factors control; and comparability or outcome assessment, respectively. Our findings underscore the connection between germline variants and differential expression of the HER2 protein and BC subtypes. https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023447571.

Prenatal diagnosis of hydranencephaly: a clinical case

Hydranencephaly is a rare abnormality of the central nervous system (CNS) of the fetus, in which the cerebral hemispheres are absent and replaced with cerebrospinal fluid, while the structures of the posterior fossa, thalami and falx cerebri remains normal. The ischemic, hemorrhagic complications, infection of the fetus, the toxic effects of carbon monoxide, butane and genetic abnormalities are potential causes of a hydranencephaly development. The article presents the modern data on the possible causes of the hydranencephaly development, and clinical case of prenatal ultrasound diagnosis of hydranencephaly at 28–29 weeks of gestation, highlighting a specific ultrasound signs of this pathology. The management strategy and genetic testing recommendations are described. The difficulties of differential diagnosis and the key signs of similar disorders are discussed, as well as recommendation for future pregnancy planning.

Pathways for provider initiated genetic testing to bridge the gap in germline genetic testing for metastatic breast cancer.

e23239 Background: Genetic testing for BRCA 1/2 in breast cancer patients have important implications on systemic therapy options, particularly for qualification of PARP inhibitor therapy. NCCN guidelines currently recommend genetic testing for all patients with metastatic or recurrent breast cancer, triple negative breast cancer, as well as high-risk HER2-negative breast cancer. Despite these recommendations, germline genetic testing in these populations remain suboptimal in part due to limited access to genetic counselors. Introducing pathways to identify patients who qualify for genetic testing through nurse navigator screening and increasing provider ordered testing can help bridge the gap to expedite genetic testing. Methods: A retrospective review of metastatic breast cancer patients who were seen at MD Anderson Cancer Center (MDA) between 01/01/2021 and 12/31/2021 was performed to determine a baseline rate at which this population met with genetic counselors. A new protocol was established to aid nurse navigators in identifying patients establishing care at MDA who qualify for testing and guide providers on ordering genetic testing at initial appointment. Nurse navigators and providers underwent a formal training session on protocol with guidelines on patient qualification. Additionally, a best practice advisory (BPA) was implemented into the electronic medical record to alert providers to patients who should be tested. Results: At baseline, 29.6% of patients with metastatic breast cancer had met with genetic counselors at our institution in 2021. Based on this finding, the provider initiated genetic testing process was implemented, where providers order genetic testing at the initial appointment. Initial uptake of this process was low with less than 10 tests ordered in the first three months of intervention. Therefore, a nurse navigator pathway was implemented as well as a BPA within our electronic medical records to alert providers on patients who qualify for testing. This BPA flags patients with stage IV breast cancer that have not seen genetic counselors at our institution and guides providers to either order genetic testing, place a referral for genetic counseling, or dismiss the BPA due to specified reasons. Conclusions: It is imperative that patients with metastatic breast cancer have access to genetic testing at diagnosis to determine optimal therapy. With the expansion of genetic testing recommendations, moving toward a provider driven testing model may expedite and increase access to genetic testing. By implementing additional screening through our nurse navigators and BPA advisories, we hope to increase provider driven testing at our institution. Additionally, we aim to expand these interventions to other subgroups of breast cancer who would qualify for adjuvant PARP therapy in the next phase of intervention.

Clinical phenotypes of adults with monogenic and syndromic genetic obesity.

Considering limited evidence on diagnostics of genetic obesity in adults, we evaluated phenotypes of adults with genetic obesity. Additionally, we assessed the applicability of Endocrine Society (ES) recommendations for genetic testing in pediatric obesity. We compared clinical features, including age of onset of obesity and appetite, between adults with non-syndromic monogenic obesity (MO), adults with syndromic obesity (SO), and adults with common obesity (CO) as control patients. A total of 79 adults with genetic obesity (32 with MO, 47 with SO) were compared with 186 control patientswith CO. Median BMI was similar among the groups: 41.2, 39.5, and 38.7 kg/m2 for patients with MO, SO, and CO, respectively. Median age of onset of obesity was 3 (IQR: 1-6) years in patients with MO, 9 (IQR: 4-13) years in patients with SO, and 21 (IQR: 13-33) years in patients with CO (p < 0.001). Patients with genetic obesity more often reported increased appetite: 65.6%, 68.1%, and 33.9% in patients with MO, SO, and CO, respectively (p < 0.001). Intellectual deficit and autism spectrum disorder were more prevalent in patients with SO (53.2% and 21.3%) compared with those with MO (3.1% and 6.3%) and CO (both 0.0%). The ES recommendations were fulfilled in 56.3%, 29.8%, and 2.7% of patients with MO, SO, and CO, respectively (p < 0.001). We found distinct phenotypes in adult genetic obesity. Additionally, we demonstrated low sensitivity for detecting genetic obesity in adults using pediatric ES recommendations, necessitating specific genetic testing recommendations in adult obesity care.

Assessment of gene–disease associations and recommendations for genetic testing for somatic variants in vascular anomalies by VASCERN-VASCA

BackgroundVascular anomalies caused by somatic (postzygotic) variants are clinically and genetically heterogeneous diseases with overlapping or distinct entities. The genetic knowledge in this field is rapidly growing, and genetic testing is now part of the diagnostic workup alongside the clinical, radiological and histopathological data. Nonetheless, access to genetic testing is still limited, and there is significant heterogeneity across the approaches used by the diagnostic laboratories, with direct consequences on test sensitivity and accuracy. The clinical utility of genetic testing is expected to increase progressively with improved theragnostics, which will be based on information about the efficacy and safety of the emerging drugs and future molecules. The aim of this study was to make recommendations for optimising and guiding the diagnostic genetic testing for somatic variants in patients with vascular malformations.ResultsPhysicians and lab specialists from 11 multidisciplinary European centres for vascular anomalies reviewed the genes identified to date as being involved in non-hereditary vascular malformations, evaluated gene–disease associations, and made recommendations about the technical aspects for identification of low-level mosaicism and variant interpretation. A core list of 24 genes were selected based on the current practices in the participating laboratories, the ISSVA classification and the literature. In total 45 gene–phenotype associations were evaluated: 16 were considered definitive, 16 strong, 3 moderate, 7 limited and 3 with no evidence.ConclusionsThis work provides a detailed evidence-based view of the gene–disease associations in the field of vascular malformations caused by somatic variants. Knowing both the gene–phenotype relationships and the strength of the associations greatly help laboratories in data interpretation and eventually in the clinical diagnosis. This study reflects the state of knowledge as of mid-2023 and will be regularly updated on the VASCERN-VASCA website (VASCERN-VASCA, https://vascern.eu/groupe/vascular-anomalies/).

Kidney Measurement and Glomerular Filtration Rate Evolution in Children with Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by renal tubular cystic dilatations. The cysts can develop anywhere along the nephron, and over time the cystic dilatation leads to kidney enlargement. On the other hand, the cysts begin to reduce the number of functional nephrons as a consequence of cystic expansion that further contributes to the decline in renal function over the years. The pressure exerted by the dilated cysts leads to compensatory mechanisms that further contribute to the decline in renal function. These structural changes are responsible of glomerular hyperfiltration states, albuminuria, proteinuria, and hematuria. However, the presentation of ADPKD varies in children, from a completely asymptomatic child with incidental ultrasound detection of cysts to a rapidly progressive disease. There have been reports of early onset ADPKD in children younger than 2 years that showed a more rapid decline in renal function. ADPKD is caused by a mutation in PKD1 and PKD2 genes. Today, the PKD1 gene mutation seems to account for up to 85% of the cases worldwide, and it is associated with worse renal outcomes. Individuals with PKD2 gene mutation seem to present a milder form of the disease, with a more delayed onset of end-stage kidney disease. The cardinal sign of ADPKD is the presence of renal cysts during renal ultrasound. The current guidelines provide clinicians the recommendations for genetic testing in children with a positive family history. Given that the vast majority of children with ADPKD present with normal or supra-normal kidney function, we explored the glomerular filtration rates dynamics and the renal ultrasound-adjusted percentiles. In total, 14 out of 16 patients had kidney percentiles over 90%. The gene mutations were equally distributed among our cohort. In addition, we compared the modified Schwartz formula to the quadratic equation after adjusting the serum creatinine measurements. It seems that even though children with ADPKD have enlarged kidneys, the renal function is more likely normal or near normal when the quadratic estimation of glomerular filtration rate is used (qGFR tended to be lower, 111.95 ± 12.43 mL/min/1.73 m2 when compared to Schwartz eGFR 126.28 ± 33.07 mL/min/1.73 m2, p = 0.14). Also, when the quadratic equation was employed, not even a single patient reached the glomerular hyperfiltration threshold. The quadratic formula showed that glomerular filtration rates are linear or slightly decreasing after 1 year of follow-up (quadratic ΔeGFR = -0.32 ± 5.78 mL/min/1.73 m2), as opposed to the Schwartz formula that can falsely classify children in a hyperfiltration state (ΔeGFR = 7.51 ± 19.46 mL/min/1.73 m2), p = 0.019.

Cost-effectiveness of genetic testing of endocrine tumor patients using a comprehensive hereditary cancer gene panel.

Heterogenous clinical manifestations, overlapping phenotypes and complex genetic backgrounds are common in patients with endocrine tumors. There are no comprehensive recommendations for genetic testing and counselling of these patients compared to other hereditary cancer syndromes. The application of multigene panel testing is common in clinical genetic laboratories, but their performance for patients with endocrine tumors has not been assessed. As a national reference center, we prospectively tested the diagnostic utility and cost-efficiency of a multigene panel covering 113 genes representing genetic susceptibility for solid tumors. 1279 patients (including 96 cases with endocrine tumors) were evaluated between October 2021 and December 2022 who were suspected to have hereditary tumor syndromes. The analytical performance of the hereditary cancer panel was suitable for diagnostic testing. Clinical diagnosis was confirmed in 24% (23/96); incidental findings in genes not associated with the patient's phenotype were identified in 5% (5/96). A further 7% of pathogenic/likely pathogenic variants were detected in genes with potential genetic susceptibility roles but currently no clear clinical consequence. Cost-benefit analysis showed that the application of a more comprehensive gene panel in a diagnostic laboratory yielded a shorter turnaround time and provided additional genetic results with the same cost and workload. Using comprehensive multigene panel results in faster turnaround time and cost-efficiently identifies genetic alterations in hereditary endocrine tumor syndromes. Incidentally identified variants in patients with poor prognoses may serve as a potential therapeutic target in tumors where therapeutic possibilities are limited.

Current understanding of the genetics of thoracic aortic disease

Thoracic aortic dissection is a feared, highly lethal condition most commonly developing from aneurysmal dilation of the thoracic aorta. Elective prophylactic replacement of thoracic aortic aneurysms dramatically mitigates this risk. However, diagnosis of a thoracic aortic aneurysm can be challenging. Thoracic aortic disease - horacic aortic aneurysm and dissection (TAAD) - can be sporadic or heritable. Patients with syndromic heritable TAAD present with classic phenotype and clinical features correlating to their disease. In contrast, patients with non-syndromic heritable disease are harder to diagnose due to their lack of defining uniform phenotypes. Recent advances in genomics have begun to elucidate the genetic underpinnings of non-syndromic TAAD (ns-TAAD) for better understanding this complex disease and improve diagnosis and management. Herein, we review the foundation of knowledge in ns-TAAD heritability and key research studies identifying gene mutations in vascular smooth muscle cells, the extracellular matrix, and TGF-beta signaling present in ns-TAAD. We summarize the current guidelines for the diagnosis, screening, and surgical management of ns-TAAD including recommendations for genetic testing of high-risk individuals. Finally, we highlight areas of future research that will continue to advance our understanding of the complex genetic and epigenetic factors in TAAD.

Abstract B062: Prevalence of pathogenic BRCA1/2 variants among Latinas in the All of Us Cohort

Abstract Latinas in the United States are disproportionately affected by breast cancer, but little is known about genetic risk factors for breast cancer in this population. Genetic variants in BReast CAncer genes 1 and 2 (BRCA1/2) are known to be associated with heritable cancer risk, yet the prevalence of BRCA1/2 pathogenic variants in the Latina population is not well characterized. This study aims to examine the prevalence of pathogenic BRCA1/2 variants among Latinas in the NIH All of Us research program, which includes a large number of individuals representative of the diversity of the United States population. Using data from the All of Us research program, we will analyze the prevalence of these variants among Latinas, in addition to all other racial and ethnic groups. To date, the All of Us cohort contains 245,400 genomes, and of those 41,940 (17%) are from self-identified Hispanic/Latino/or Spanish participants. We will compare the prevalence of pathogenic, or likely pathogenic, variants across self-reported race/ethnicity and continental genetic ancestry categories. Our study will leverage the diversity of All of Us and enable us to compare our data with those from more Eurocentric databases. With these data, we can potentially 1) identify novel variants that could predispose to increased cancer risk; and 2) clarify the previous designations of variants characterized to have undetermined/unknown significance due to the limitations of using a single Eurocentric reference genome. Identifying the actual prevalence of pathogenic BRCA1/2 variants among Latinas is important for improving breast cancer prevention, detection, and treatment in this population. The findings of this study have the potential to inform genetic counseling and testing recommendations for Latina patients at high risk of developing breast cancer, as well as others. This will also enable healthcare providers to better understand the unique genetic factors contributing to breast cancer risk among this population. Ultimately, this knowledge can improve the care of Latina patients and contribute to the broader effort to advance health equity and reduce disparities in breast cancer outcomes among Latinas. Citation Format: Cathy Samayoa, Erick Olivares, Catherine Gavile, Adriana Visbal. Prevalence of pathogenic BRCA1/2 variants among Latinas in the All of Us Cohort [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B062.

PROMISE Registry: A prostate cancer registry of outcomes and germline mutations for improved survival and treatment effectiveness.

Recently approved treatments and updates to genetic testing recommendations for prostate cancer have created a need for correlated analyses of patient outcomes data via germline genetic mutation status. Genetic registries address these gaps by identifying candidates for recently approved targeted treatments, expanding clinical trial data examining specific gene mutations, and understanding effects of targeted treatments in the real-world setting. The PROMISE Registry is a 20-year (5-year recruitment, 15-year follow-up), US-wide, prospective genetic registry for prostate cancer patients. Five thousand patients will be screened through an online at-home germline testing to identify and enroll 500 patients with germline mutations, including: pathogenic or likely pathogenic variants and variants of uncertain significance in genes of interest. Patients will be followed for 15 years and clinical data with real time patient reported outcomes will be collected. Eligible patients will enter long-term follow-up (6-month PRO surveys and medical record retrieval). As a virtual study with patient self-enrollment, the PROMISE Registry may fill gaps in genetics services in underserved areas and for patients within sufficient insurance coverage. The PROMISE Registry opened in May 2021. 2114 patients have enrolled to date across 48 US states and 23 recruiting sites. 202patients have met criteria for long-term follow-up. PROMISE is on target with the study's goal of 5000 patients screened and 500 patients eligible for long-term follow-up by 2026. The PROMISE Registry is a novel, prospective, germline registry that will collect long-term patient outcomes data to address current gaps in understanding resulting from recently FDA-approved treatments and updates to genetic testing recommendations for prostate cancer. Through inclusion of a broad nationwide sample, including underserved patients and those unaffiliated with major academic centers, the PROMISE Registry aims to provide access to germline genetic testing and to collect data to understand disease characteristics and treatment responses across the disease spectrum for prostate cancer with rare germline genetic variants.

Abstract 13979: Titin-Truncating Variants Predispose to Dilated Cardiomyopathy in Patients Genetically Similar to African Reference Populations

Introduction: Heterozygous mutations within the TTN gene can cause the translation of shortened forms of the titin protein known as titin-truncating variants (TTNtvs) leading to dilated cardiomyopathy (DCM) among certain individuals. We previously reported an odds ratio (OR) of 18.7 for DCM among individuals genetically similar to the European reference population (EUR) with high percentage spliced in (hiPSI) TTNtvs, however we were unable to show a similar relationship among individuals genetically similar to the African reference population (AFR). Methods: Penn Medicine Biobank volunteers with whole exome sequencing were screened for TTNtvs with minor allele frequency &lt;0.001 and percent spliced in &gt;0.9. Participants were also screened for a DCM diagnosis defined using International Classification of Diseases, ninth and tenth revision diagnoses codes. Left ventricular ejection fraction (LVEF) values were extracted from structured transthoracic echocardiography reports. Logistic and linear regression were employed to evaluate the association between hiPSI TTNtvs and DCM or LVEF adjusting for age, sex, and first five genetic principal components. Results: Of the 43,731 participants with sequencing data, 11,136 (27.1%) were genetically similar to the AFR reference population, 50.3% were male, and the median age was 57.8 years (IQR: 44.9-69.5 years). One percent (418 individuals) had a hiPSI TTNtv. The age- and sex-adjusted OR of having DCM was similar among AFR and EUR participants carrying hiPSI TTNtvs (AFR OR: 4.37, 95% CI 2.68 to 7.13, P &lt; 0.001; EUR OR: 5.86, 95% CI 4.58 to 7.49, P &lt; 0.001; meta OR: 5.48, 95% CI 4.31 to 6.97, P &lt; 0.001). Among those individuals with echocardiography data available, hiPSI TTNtvs were associated with significantly decreased minimum LVEF independent of genetic reference population similarity (EUR β: -10.08, 95% CI -12.71 to -7.44, P &lt; 0.001; AFR β: -12.83, 95% CI -18.39 to -7.27, P &lt; 0.001; Meta β: -10.58, 95% CI -12.96 to -8.20, P &lt; 0.001). Conclusions: Our analysis demonstrates a strong association between hiPSI TTNtv and both DCM and minimum LVEF in diverse populations suggesting that genetic testing and counseling recommendations should not differ between these populations.

Development of provider ordered genetic testing pathway and electronic medical record best practice advisory (BPA) to aid in germline genetic testing for patients with metastatic breast cancer.

443 Background: Genetic testing for BRCA 1/2 in breast cancer patients can have important impacts on patients’ systemic therapy options. NCCN recommendations for genetic testing include all patients with metastatic breast cancer or triple negative breast cancer to determine qualification of PARP inhibitor therapy. New guidelines recommend testing high risk, her2-negative breast cancer patients who would qualify for olaparib adjuvant therapy. It is vital that these breast cancer patients be offered genetic testing early in their cancer diagnosis journey so appropriate therapies can be provided. Due to the limited access to genetic counselors, provider ordered testing can help provide genetic testing in an expedited manner. Methods: A retrospective review of metastatic breast cancer patients who were seen at our institution between 01/01/2021 and 12/31/2021 was performed to determine if they met with genetic counselors at our institution. Based on this data, a new protocol was established guiding providers on ordering genetic testing for patients by their primary team. Additionally, a best practice advisory was designed and input into the electronic medical record to alert providers to patients who should be tested. Results: A review of patients with metastatic breast cancer seen at our institution in 2021 showed that only 29.6% of them had met with genetic counselors at our institution. Based on this finding, we created a provider initiated genetic testing process, where providers order genetic testing at the initial appointment to expedite genetic testing results. Due to an initial low uptake of this process (less than 10 tests ordered in the first three months), we also implemented a best practice advisory (BPA) within our electronic medical records (EMR). This BPA flags patients with stage IV breast cancer, that have not seen genetic counselors at our institution, and guides providers to either order genetic testing, place a referral for genetic counseling, or dismiss the BPA due to reasons. Conclusions: With the expansion of genetic testing recommendations for patients with metastatic breast cancer our institution is moving to oncologist ordered testing to increase the access to genetic testing. We hope to expand this best practice alert to other subgroups of breast cancer who would qualify for adjuvant PARP therapy. Additionally, expanding provider-initiated testing to other providers such as breast surgeons, or oncologists in our regional care centers can help increase the overall yield.

Evaluating the acceptability, usability, and feasibility of a clinic-based genetic testing risk assessment intervention in Black women with breast cancer.

436 Background: Black women diagnosed with breast cancer utilize genetic counseling and testing services less often than White women despite these services having the potential to personalize medical management of breast cancer and identify family members for cascade testing. Lower rates of provider recommendations may be a driver of these disparities, as uptake does not appear to differ by race. The objective of this study was to evaluate the acceptability, usability, and feasibility of a clinic-based genetic risk assessment to facilitate provider recommendations for genetic testing in Black women diagnosed with breast cancer. Methods: A clinic-embedded, race-concordant, trained navigator administered a 15-minute screening tool based on National Comprehensive Cancer Network genetic testing criteria to English-speaking, Black women ≥18 and newly diagnosed with breast cancer. A copy of the results were given to the treating surgeon to facilitate consideration of genetic testing for the patient. However, the decision to recommend genetic testing was left to discretion of the surgeon. After enrollment completion, we conducted semi-structured interviews with a subsample of patients and surgeons who participated in the intervention to elicit their perspectives and experiences. We also used medical record data to determine if surgeons recommended genetic testing to participating patients, and if so, whether they completed it. Results: Between January 2022 and April 2023, 37 patients with a median age of 56.9 years (IQR 15.0-37.5) consented to participate. Surgeons recommended genetic testing to 25/37 patients and 5/37 additional patients were referred outside of this intervention (81.1% total). 12/37 patients (including those who were and were not recommended genetic testing) and 4/4 surgeons completed follow-up interviews. For clinician usability and acceptability, surgeons reported little to no negative impact on their clinic flow. While some found the intervention to be a helpful reminder, others shared it made no discernible impact on their practice, as they reported already incorporating a similar system into their clinic flow. For patient usability and acceptability, some patients found questions on the screening tool difficult to answer and expressed feeling overwhelmed at the time it was administered but the navigator was comforting, reassuring, and informative. Patients, surgeons, and the navigator recommended administering the screening tool prior to the initial appointment with the surgeon and ensuring follow up with patients regarding results. Conclusions: Participating patients and surgeons found this intervention to be feasible and acceptable. Usability challenges warrant further exploration into the logistics of the intervention, including timing, delivery, and medium.

The genetics and disease mechanisms of rhegmatogenous retinal detachment.

Rhegmatogenous retinal detachment (RRD) is a sight threatening condition that warrants immediate surgical intervention. To date, 29 genes have been associated with monogenic disorders involving RRD. In addition, RRD can occur as a multifactorial disease through a combined effect of multiple genetic variants and non-genetic risk factors. In this review, we provide a comprehensive overview of the spectrum of hereditary disorders involving RRD. We discuss genotype-phenotype correlations of these monogenic disorders, and describe genetic variants associated with RRD through multifactorial inheritance. Furthermore, we evaluate our current understanding of the molecular disease mechanisms of RRD-associated genetic variants on collagen proteins, proteoglycan versican, and the TGF-β pathway. Finally, we review the role of genetics in patient management and prevention of RRD. We provide recommendations for genetic testing and prophylaxis of at-risk patients, and hypothesize on novel therapeutic approaches beyond surgical intervention.

FRI046 Clinical Phenotyping Of Adults With Genetic Obesity

Abstract Disclosure: M.S. Welling: None. M. Mohseni: None. R.E. Meeusen: None. M.R. Boon: None. C.J. de Groot: None. M.M. van Haelst: None. J.A. Visser: None. E.L. van den Akker: None. E.F. van Rossum: None. Introduction: In rare cases of obesity, genetic defects lead to hyperphagia and severe early-onset obesity. Genetic testing in patients with a suspected genetic obesity phenotype is important, as it can lead to patient-tailored treatment advice. For children, the Endocrine Society (ES) recommends genetic testing in children with early-onset of obesity (&amp;lt;5 years) and hyperphagia. It is unclear whether these recommendations can also be used in adult obesity care. Therefore, we aimed to phenotype adult patients with genetic obesity disorders. In addition, we assessed the suitability of the pediatric ES recommendations in these patients. Methods: We analyzed clinical data of patients with non-syndromic genetic obesity (NSO) and syndromic genetic obesity (SO), who visited our academic obesity center (Erasmus Medical Center, Rotterdam, the Netherlands). A standardized medical questionnaire, including topics concerning e.g. age of onset of obesity, hunger and satiation, was assessed. Anthropometrics, body composition (bio-impedance analysis), and resting energy expenditure (REE, indirect calorimetry) were measured. Differences between the NSO and SO groups were studied. Results: Sixty-six patients, of which n=26 with NSO and n=40 with SO, were included: median BMI and age at intake were 41.2 vs 39.2 kg/m2 and 25.7 vs 24.8 yrs, respectively (ns). The median age of onset of obesity was 2.5 [1-5] yrs in NSO and 9.5 [4-14] yrs in SO (p&amp;lt;0.001). Impaired appetite regulation was present in both groups: increased feelings of hunger in 64.0 vs 51.3% and impaired satiation in 47.1 vs 32.0% in NSO vs SO (ns). Binge eating was reported in 63.2% of SO, compared to 40.0% in NSO (p=0.071). The pediatric ES recommendations were fulfilled in 57.5% of NSO and 27.5% of SO (p=0.014). Compared to NSO, SO had a higher prevalence of intellectual deficit (3.8 vs 55.0%, p&amp;lt;0.001), autism (7.7 vs 26.3%, p=0.061) and retinal problems (0 vs 20.0%, p=0.015). There were no differences in body composition or REE. Conclusion: We report distinct phenotypic features concerning the age of onset of obesity, appetite regulation, and the presence of intellectual deficit, autism and retinal problems in adults with non-syndromic genetic obesity or syndromic genetic obesity. Additionally, this study demonstrates that the Endocrine Society’s recommendations for genetic testing in children with obesity, do not suit well for adults with obesity. Recommendations for genetic testing in adults with obesity are needed. Presentation: Friday, June 16, 2023