Positive Genetic Test Research Articles

Exploring the Role of Genetic Testing in Decisions to Redirect Care in Critically Ill Infants.

Genetic disorders are a major determinant of morbidity and mortality within neonatal intensive care units (NICUs). Studies have found genetic testing in critically ill infants may lead to changes in clinical decisions such as pursuing end of life care. This study surveyed palliative care providers to explore the influence of genetic testing on decisions to redirect care in critically ill infants. This study was conducted retrospectively on cases who were admitted to the Level IV NICU at Primary Children's Hospital, underwent redirection to end of life care, and whose death date was between 2019-2023. A review of the case's electronic medical record was performed to construct a clinical case summary. The clinical summary and questionnaire were sent to the case's palliative care provider. Fifty-six cases were included in this study and 73% had genetic testing completed. Our results suggest the information from genetic testing played a relatively minor role in the decision to redirect care for cases with negative or uncertain genetic testing and positive genetic testing results, although the influence appeared higher in the latter group. Our results suggest the assumptions of several studies that genetic testing is responsible for changes in clinical management and cost savings, especially in cases of redirection of care may have been overestimated. Our results fill a critical gap in current literature and demonstrate the need for further investigation to clarify the direct role of genetic testing in clinical decisions in the NICU, especially related to redirection of care.

Enhancement of the Mayo Clinic Genotype Predictor Score using Cardiac MRI

Abstract Introduction Hypertrophic cardiomyopathy (HCM) is the most prevalent heritable cardiomyopathy typically transmitted in an autosomal dominant fashion. There is growing importance in identifying genetic test positive patients given its prognostic value. The Mayo HCM Genotype Predictor Score has been extensively validated for assessment of patient’s pre-test probability for genotype positive HCM and helps guide clinical decision-making based on clinical and echocardiographic variables. Herein, we evaluated the role of cardiac magnetic resonance (CMR) to enhance the genotype predictor score. Purpose Evaluate performance of the Mayo Clinic HCM Genotype Predictor Score using CMR variables, and develop an updated, CMR incorporated score. Methods Retrospective analysis was conducted on 175 unrelated HCM patients with at least 1 MRI and a HCM genetic testing seen at the Mayo Clinic between April 2004 and April 2018. Phenotyping information was obtained through review of electronic medical records. The original Mayo HCM Genotype Predictor Score was calculated using both echocardiography and clinical variables. An updated score was created incorporating CMR-specific variables. Diagnostic accuracy of the models was assessed thought Receiver Operating Characteristic (ROC) curves. Results Overall, 108 (62%) were males with a mean age at CMR of 51 ± 18 years. The yield of positive genetic test for the echocardiogram-derived Mayo HCM Genotype Predictor Score ranged from 38% for patients with -1 point to 100% for patients with 4 or 5 points. There was a significant incremental increase in diagnostic yield between score subgroups (p < 0.01) with an AUC of 0.659 (Figure 1A). Similar findings were observed using CMR variables (AUC of 0.697; Figure 1B). Univariate and multivariate analysis identified late gadolinium enhancement (LGE) as a strong predictor of a positive genetic test (OR 3.72; p=0.002), and it was added to the original score to create a new version. The Updated Mayo HCM Genotype Predictor Score predicted a positive genetic test ranging from 25% for patients with -1 point to 100% for patients with 5 or 6 points (p < 0.01). There was a significant increase in diagnostic accuracy when compared to the original score (AUC 0.724 vs 0.679; p=0.03; Figure 1C). Conclusion Using LGE, the updated CMR-based Mayo HCM Genotype Predictor score provides a simple and improved tool to aid in genetic counseling for HCM patients.

Prognostic role of gene variants in sudden cardiac death risk associated to paediatric hypertrophic cardiomyopathy

Abstract Introduction Genetic testing plays an important role in diagnosis of hypertrophic cardiomyopathy (HCM), being sarcomeric genes commonly involved, particularly MYBPC3. However, arrhythmic risk related to genotype remains unclear in adults and almost unexplored in children. Hence, current sudden cardiac death (SCD) risk calculators do not include genetic information. Purpose To analyse risk of arrhythmic events associated with causal variants in MYBPC3 respecting to other genes in a paediatric cohort with non-syndromic HCM from a cardiomyopathy referral centre. Methods This retrospective study included patients with non-syndromic HCM 0-18 years old between 2009-2022. Demographic, clinical, and genetic data were collected. Genetic variants pathogenicity followed American College of Medical Genetics criteria. A positive genetic test was considered if a likely pathogenic or pathogenic variant in HCM related genes was found. Considered outcomes were SCD or a major arrhythmic cardiac event (MACE) within 5 years follow-up: recovered SCD, appropriate ICD therapy, or sustained ventricular tachycardia. Some SCD-risk estimation models (in 5 years) as HCM Risk-SCD model for patients >=15 y.o and/or 55 kg, ESC Guidelines paediatric algorithm, and HCM Risk-Kids model were applied. Results 77 patients were diagnosed with non-syndromic HCM. A causal variant was found in 45/73 (62%). No significant differences in cardiac phenotype were found related to genes. 10/77 patients (13%) presented a MACE in 5 years follow-up. A positive genetic study was significantly associated with having an event (p=0.011). Most patients with a positive genetic test harboured MYBPC3 variants (21/45, 47%), however only 2 patients who suffered a MACE had a causal variant in MYBPC3. Those with causal variants in genes other than MYBPC3 presented more and earlier events (p=0.022). Risk of having a MACE during follow-up was higher when presenting causal variants in genes other than MYBPC3: Hazard Ratio 18.5 (95% CI 2.31, 148), p=0.006. Applying HCM Risk-SCD calculator, model had better predictive discrimination when variable "causal variant in gene other than MYBPC3" was added in multivariate analysis, with high-risk category >=6% (C-statistic =0.931 vs 0.844) and intermediate-risk category 4-6% (C-statistic =0.845 vs 0.514). Same occurred with ESC Guidelines algorithm, adding that variable to 2 risk factors category (C-statistic =0.881 vs 0.742) or 1 risk factor (C-statistic =0.844 vs 0.635). HCM Risk-Kids also improved its predictive discrimination adding the genetic value to high-risk category >=6% (C-statistic =0.896 vs 0.796) and intermediate-risk (C-statistic =0.821 vs 0.506). Conclusions Genotype may have prognostic value in SCD risk in HCM in children. Our results suggests that causal genetic variants in genes other than MYBPC3 can lead to higher risk of SCD. Genetic information might be considered for future models of arrhythmic risk in children with HCM.

Improving the yield of genetic testing in dilated cardiomyopathy using late gadolinium enhancement

Abstract Background Genetic testing has become an important tool in the work-up of dilated cardiomyopathy (DCM), aiding in family screening and providing information about prognosis and arrhythmic risk. Nonetheless, a significant proportion of patients with DCM present negative genetic test results. The "Madrid Score" was created to evaluate the likelihood of positive genetic tests and increase their yield in DCM patients. Purpose To determine if late gadolinium enhancement (LGE) assessment can improve the Madrid Score accuracy and increase the yield of genetic tests for DCM. Methods A single-centre retrospective study of patients diagnosed with DCM who underwent cardiac magnetic resonance (CMR) and genetic test between January 2017 and October 2023. The CMR imaging included the assessment of LGE. Multivariate logistic regression was performed and the model’s change in performance was evaluated when adding LGE. Results A total of 90 patients with the diagnosis of DCM underwent CMR and genetic test during the study period. Patient’s mean age was 51.0±14.6 years, and 57.1% were male. The genetic test was positive (G+) in 42 (46.7%), and negative (G-) in 48 (53.3%) patients. A variant of uncertain significance was present in 31 (34.4%), and these were included in the G- group. Most of the known independent predictors of a G+ given by the Madrid Score were significant in our cohort: Family history of DCM (OR: 4.82; CI: 1.73-11.60; p < 0.001), absence of hypertension (OR: 0.19; CI: 0.06-0.58; p < 0.001), absence of left bundle branch block (OR: 0.22; CI: 0.05-0.98; p = 0.047), and low electrocardiogram voltage in peripheral leads (OR: 3.13; CI: 0.87-11.26; p = 0.081). When analyzing the effect of LGE in the regression model (R2 = 0.622, p < 0.001), we found that the number of LGE segments (OR: 2.54; CI: 1.10-5.90; p = 0.031), and the presence of LGE in the anterior wall (OR: 3.01; CI: 1.42-12.04; p = 0.041), were associated with a higher rate of positive genetic tests. When comparing both regression models, the incorporation of LGE increased the prediction power of the standard Madrid Score, correctly predicting 82.0% of the tests in our sample, with a probability of a G+ result ranging from 2% when all predictors were absent to 84% when ≥6 predictors, including LGE, were present. Conclusion Our study suggests that LGE assessment may enhance the Madrid Score performance and consequently improve genetic testing decisions in DCM, potentially leading to better use of the limited resources in our health care system.

Participation rate and yield of indirect cascade genetic screening for familial hypercholesterolemia using a web-based communication platform (CATCH): a randomized multicenter implementation trial

Abstract Introduction Cascade genetic screening for familial hypercholesterolemia (FH) is poorly performed when direct contact with relatives by health professionals is not allowed. We aimed to compare the effectiveness of implementing a web-based communication platform in a large-scale cascade genetic screening program for FH, while maintaining the confidentiality of indirect family contacts. Methods The CATCH study is a prospective randomized open-label multicenter implementation trial that promotes family cascade genetic screening in Swiss adults older than 16 years with a newly diagnosed pathogenic variant for FH. Each family was randomly assigned to a multigenerational indirect cascade genetic screening (1:1) either via the possibility to use of a web-based platform designed to send pre-prepared text messages or emails, and allowing to connect to a specialized clinical center, or a cascade genetic screening via the local recommended procedure. The primary outcome was the 6-month participation rate of relatives, defined as the number of genetic tests performed within 6 months after referral, over the number of eligible relatives for screening, i.e. living first-degree relatives aged 5 years or older. The secondary outcome was the 6-month yield of positive genetic tests, defined as the number of positive tests over the number of eligible relatives. Both outcome estimates were obtained after accounting for family clusters. Results Between 11/20 and 12/23, we enrolled 221 adults with a phenotype of FH for genetic testing, with 87 of them having confirmed genetic FH, corresponding to a total of 401 eligible relatives for cascade screening, with 102 relatives eventually undergoing genetic testing. Among the 87 index cases with genetic FH, 44 were randomly assigned to the web-based platform screening, and 43 were assigned to the local procedure screening. The 6-month participation rate of relatives was 71 of the 218 eligible relatives (29% [95% CI 21–38]) for the web-based platform screening, and 31 of the 183 eligible relatives (14% [95% CI 8–23]) for the local procedure screening (odds ratio (OR) 2.46 [95% CI 1.22–4.98]), p=0.012) (Figure). Similarly, the yield of detection of positive relatives was higher for the web-based platform screening, (16% [95% CI 11–23]) compared to the local procedure screening (7% [95% CI 4–13]), with OR of 2.43 [95% CI 1.11–5.30], p=0.026. Among the 55 positive relatives identified with genetic FH within 6-months, 13.0% were younger than 18 years, 25.5% were current smokers, and 56.0% were not using any lipid-lowering drugs. Conclusions The effectiveness of cascade genetic screening for FH was approximately doubled by integrating a web-based platform that facilitates family communication and access to specialized clinical centers. Modern communication technology is well suited to be integrated in large-scale indirect genetic screening programs to increase the early identification of patients at high cardiovascular risk.

Exome sequencing for nonimmune hydrops fetalis and clinical utility of data reanalysis.

Nonimmune hydrops fetalis (NIHF) presents as life-threatening fluid collections in multiple fetal compartments and may be led by numerous etiologies. To establish the diagnostic yield of exome sequencing for single-gene disorders in unexplained NIHF and to evaluate the clinical utility of data reanalysis. A series of 53 unexplained cases of NIHF were enrolled, including 39 cases met a strict definition of NIHF, and 14 cases with increased nuchal translucency (NT) and/or cystic hygroma in combination with other fluid collections. Trio ES from fetal samples and parental blood was performed, and clinical reports were returned by geneticists and genetic counselors. Multidisciplinary team forums were conducted for accurate diagnoses and improved patient management. The clinical follow-up assessments were conducted, and the reanalysis was performed for cases with a non-positive result. Diagnostic variants were identified in 22.6% (12/53) of the cases, and variants of potential clinical significance were detected in an additional 13.2% (7/53) of the cases. Of them, 3 possible diagnoses (3/41, 7.3%) were obtained during reanalysis. Notably, half of the diagnosed cases were from the group exhibiting only skin edema and increased nuchal translucency and/or cystic hygroma. The diagnostic rate in this group was 42.8% (6/14), while in the classically defined NIHF group, the rate was 15.4% (6/39). The pregnancy termination and live birth rates of the cases with positive genetic testing results were found to be statistically significantly different from those with negative results (91.7% vs 53.6% and 8.3% vs 36.6%, P < 0.05 for both). ES provides high incremental diagnostic yield for NIHF after standard-of-care testing, and reevaluating non-diagnostic exomes in light of updated knowledge can maximize diagnostic yield. Identifying the etiology of NIHF facilitates prenatal diagnosis, improves the management of NIHF cases, and predicts recurrence risk in future pregnancies.

Clinical Characteristics and Outcomes inPatients With Atrial Fibrillation and Pathogenic TTN Variants.

TTN encodes a sarcomeric protein called titin. Pathogenic rare variants in TTN are the most common finding in patients with atrial fibrillation (AF) and positive genetic testing. This study sought to define the characteristics and outcomes in patients with AF and pathogenic TTN variants compared with genotype-negative patients with AF. Patients who presented initially with AF were enrolled in an AF registry. Retrospectively they underwent research sequencing for cardiomyopathy and arrhythmia genes. TTN(+) AF cases were defined as participants with pathogenic or likely pathogenic (P/LP) rare variants located in exons with high cardiac expression. They were matched 1:2 with control subjects with no P/LP variants. Phenotyping used retrospective manual chart review. Among 2794 participants; 57 (2.0%) TTN(+) AF cases were identified and matched with 114 control subjects. Low QRS complex voltage was present more often in TTN(+) AF cases (18% vs 5%; P< 0.01), with no difference in PR, QRS interval, or QTc. More TTN(+) AF cases had persistent AF at enrollment (44% vs 30%; P = 0.028) and had undergone multiple cardioversions (61% vs. 37%; P< 0.01). By end of follow-up (median 8.3 years; Q1, Q3: 4.5, 13.7 years), 11% of TTN(+) AF cases developed sustained ventricular tachycardia/ventricular fibrillation, 44% left ventricular (LV) systolic dysfunction (LV ejection fraction<50%), and 47% met a combined endpoint of sustained ventricular tachycardia/ventricular fibrillation or LV systolic dysfunction. TTN(+) AF patients undergo more cardioversions and have more persistent forms of AF. Approximately 50% develop LV systolic dysfunction and/or malignant ventricular arrhythmias. These results highlightthe need for diagnostic evaluation and management in TTN(+) patients beyond the usual care for AF.

Clinical features and postoperative outcomes in elderly patients undergoing septal myectomy for hypertrophic cardiomyopathy

BackgroundSurgical septal reduction is sometimes avoided in older adults due to anticipated high operative risk. ObjectiveTo compare the clinical and echocardiographic characteristics of young and older patients undergoing septal myectomy for oHCM and assess differences in early and late postoperative outcomes. Methods2663 patients with oHCM underwent transaortic septal myectomy between 2000 and 2021 and were categorized by age: 18-64, 65-74, and ≥75 years. ResultsMedian age at the time of surgery increased over the study interval. Female sex (p<0.001), hypertension p<0.001), and diabetes (p=0.004) were more prevalent in older patients, but extent of functional limitation (NYHA) was similar (p=0.092). Elderly patients had thinner septal and posterior walls (p<0.001, p=0.006) and less prominent asymmetry (p<0.001). They are less likely to have positive genetic testing. Hospital mortality was 0.2%, 0.5%, and 1.3% in patients <65, 65-74, and ≥75 (p=0.06), and five-year survival rates were 97%, 93%, and 91%. Septal-to-posterior wall thickness ratio significantly correlated with increased mortality in patients >65, but not in patients <65 (p=0.92). Most of the patients reported improved quality of life following myectomy. ConclusionClinical characteristics of oHCM in older patients differ from those in younger ones. More symmetric but less extensive ventricular hypertrophy and less positive genetic testing suggests that HCM has distinct clinical and morphological variants in the elderly. Septal myectomy is safe in older patients, but the presence of LV wall asymmetry portends a poorer prognosis.

Genetic testing for pediatric sensorineural hearing loss in the era of gene therapy.

To summarize indications, methods, and diagnostic yields for genetic testing for pediatric hearing loss. Genetic testing has become a cornerstone of clinical care for children with sensorineural hearing loss. Recent studies have shown the efficacy of gene panels and exome sequencing for any child with sensorineural hearing loss. Recent findings have underscored the importance of a diagnosis in clinical care. Clinical trials for gene therapy for hearing loss have begun. Genetic testing has become critical for personalized care for children with hearing loss. Recent studies have shown a 43% overall diagnostic yield for genetic testing for pediatric hearing loss, though the diagnostic yield may range from 10 to 60% depending on clinical features. Syndromic diagnoses comprise 25% of positive genetic tests for pediatric sensorineural hearing loss. While diagnostic yield is lower for children with unilateral or asymmetric sensorineural hearing loss, the likelihood of syndromic hearing loss finding is higher. An early and accurate genetic diagnosis is required for participating in clinical trials for gene therapy for hearing loss.

The Importance of Genetic Testing for Familial Hypercholesterolemia: A Pediatric Pilot Study

Background and Objectives: Familial hypercholesterolemia (FH) is a genetic disease that is massively underdiagnosed worldwide. Affected patients are at high risk of cardiovascular events at young ages. Early intervention in childhood could help prevent heart attacks and cerebral strokes in these patients. Materials and Methods: We conducted an interventional study including 10 patients that previously underwent genetic testing for familial hypercholesterolemia. These patients received lifestyle and diet recommendations that they followed for a year before being reevaluated. Results: Patients with negative genetic testing were able to achieve lower levels in their lipid panel values compared to the patients with positive genetic testing, with lifestyle changes alone. LDL-cholesterol levels decreased by 18.5% in patients without FH while patients genetically confirmed with FH failed to achieve lower LDL-cholesterol levels without medication. Conclusions: Genetic testing for FH is not always part of screening algorithms for FH. Some studies even advise against it. Our study proved the importance of genetic testing for FH when suspecting this disorder and choosing the treatment course for patients.

Risk-reducing surgeries for breast cancer in Brazilian patients undergoing multigene germline panel: impact of results on decision making.

To assess the behavior change of high-risk breast cancer patients regarding the intention to undergo risk-reducing mastectomies (RRM) before and after genetic testing results and to identify the main influencing factors in decision-making. Prospective cohort study conducted between November 2021 and October 2022 with women under follow-up at the high-risk outpatient clinic of the State University of Campinas (UNICAMP). Patients were referred for genetic testing, followed by counseling according to the test result. A total of 373 women were included. In the pre-genetic testing analysis, 54.1% of patients intended to undergo RRMs. After testing, 42.2% opted for the procedure. Behavior change occurred in 26.2%, mainly from "yes" to "no/don't know" (72,6%) (p < 0.001). The genetic test result was positive (LPV or PV) in 29.7% of patients. Among the 90 patients with positive results, 62 (68.9%) agreed to RRM, while 22 (24.4%) remained unwilling to accept RRM, regardless of the positive test. Significant influencing factors for behavior change pre- and post-genetic testing (in favor of surgery) in multivariate analysis were: positive genetic test result (OR 2.94, p < 0.001), personal cancer history (OR 2.7, p = 0.008), and ages between 40 and 49years (OR 2.07, p = 0.008) and ≥ 50years (OR 3.47, p < 0.001). In a Brazilian population at high-risk for breast cancer and users of the public health system, it was observed that most desired RRM, however, when genetic testing and counseling were performed, behavior change was observed, especially when the result was positive.

Anthropometric measurements as a key diagnostic tool for familial partial lipodystrophy in women

BackgroundFamilial Partial Lipodystrophy (FPLD) is a disease with wide clinical and genetic variation, with seven different subtypes described. Until genetic testing becomes feasible in clinical practice, non-invasive tools are used to evaluate body composition in lipodystrophic patients. This study aimed to analyze the different anthropometric parameters used for screening and diagnosis of FPLD, such as thigh skinfold thickness (TS), Köb index (Köbi), leg fat percentage (LFP), fat mass ratio (FMR) and leg-to-total fat mass ratio in grams (LTR), by dual-energy X-ray absorptiometry, focusing on determining cutoff points for TS and LFP within a Brazilian population.MethodsThirty-seven patients with FPLD and seventy-four healthy controls matched for body mass index, sex and age were studied. Data were collected through medical record review after signing informed consent. All participants had body fat distribution evaluated by skinfolds and DXA measures. Fasting blood samples were collected to evaluate glycemic and lipid profiles. Genetic studies were carried out on all patients. Two groups were categorized based on genetic testing and/or anthropometric characteristics: FPLD+ (positive genetic test) and FPLD1 (negative genetic testing, but positive clinical/anthropometric criteria for FPLD).ResultsEighteen (48.6%) patients were classified as FPLD+, and 19 (51.4%) as FPLD1. Unlike what is described in the literature, the LMNA variant in codon 582 was the most common. Among the main diagnostic parameters of FPLD, a statistical difference was observed between the groups for, Köbi, TS, LFP, FMR, and LTR. A cutoff point of 20 mm for TS in FPLD women was found, which is lower than the value classically described in the literature for the diagnosis of FPLD. Additionally, an LFP < 29.6% appears to be a useful tool to aid in the diagnosis of these women.ConclusionCombining anthropometric measurements to assess body fat distribution can lead to a more accurate diagnosis of FPLD. This study suggests new cutoff points for thigh skinfold and leg fat percentage in women with suspected FPLD in Brazil. Further studies are needed to confirm these findings.

A rare case of early onset lewy body dementia with parkinsonism associated with chronic exposure to copper contaminated drinking water.

There is a well-recognized relationship between a person's body burden of essential trace elements such as copper and their neurological function in which both deficiencies and exposures to excessive concentrations are associated with adverse clinical outcomes. Preclinical studies indicate chronic excess copper exposure is associated with altered motor function, dopaminergic neuronal loss, astrocytosis, and microgliosis. Copper also promotes oligomerization and fibrilization of α-synuclein suggesting it may hasten the course of an α-synucleinopathy. Here we report a rare case of early onset Lewy Body Dementia with Parkinsonism in a 53-year-old Caucasian woman exposed to copper contaminated drinking water for more than 10 years. Her hair and that of her daughter had streaks of blue-green discoloration as did the porcelain sinks in their home. Testing confirmed copper contamination of the drinking water. A neurologist diagnosed her with Lewy Body Dementia with Parkinsonism. Skin biopsy for phosphorylated α was consistent with a diagnosis of an α-synucleinopathy. These findings suggest chronic exposure to excessive copper may act as disease modifying factor in Lewy Body Dementia with Parkinsonism. It has previously been recommended that individuals at risk of Alzheimer's disease (AD) avoid excessive intake of copper. Genetic studies indicate that Lewy Body Dementia shares risk factors and pathways with AD. Based on the observations in this patient we recommend that individuals at risk for an α-synucleinopathy based on a positive family history, genetic testing, and/or positive results on a skin biopsy for phosphorylated α-synuclein avoid exposure to excess copper.

Incorporating Next-Generation Sequencing as a Second-Tier Test for Primary Carnitine Deficiency.

Newborn screening (NBS) for primary carnitine deficiency (PCD) has poor performance. This study aimed to evaluate the feasibility of incorporating next-generation sequencing (NGS) as a second-tier PCD test. Between March and December 2020, 60,070 newborns were screened for inherited metabolic disorders. Newborns with free carnitine (C0) levels below 8.5 μmol/L were selected for second-tier genetic testing. In total, 130 (0.22%) newborns with low C0 levels underwent second-tier genetic testing, 87 (66.92%) had positive genetic testing results, and 30 (23.08%) carried pathogenic variants of the SLC22A5 gene. Six newborns were diagnosed with PCD. The incidence of PCD was approximately 1 in 1:10,012 newborns. The PPV reached 20% after combining with second-tier NGS. Of the eight variants identified in patients with PCD, the three most common variants were c.760C>T (p.Arg254*), c.51C>G (p.Phe17Leu), and c.1400C>G (p.Ser467Cys). The C0 levels of patients with PCD were significantly lower than those of PCD carriers (p = 0.0026) and PCD-negative individuals (p = 0.0005). Our results showed that the PPV reached 20% after combining with second-tier NGS. The MS/MS-based NBS and second-tier NGS combination can effectively reduce the false-positive rate and detect PCD in patients.

The Pathological Pattern of Breast Cancer in the Najran Region of Saudi Arabia: A Retrospective Study.

Background Breast cancer (BC) is the most widespread cancer on a global scale, and its prevalence is likewise significant in the Kingdom of Saudi Arabia. Nevertheless, the data accessible regarding the epidemiology and histopathological characteristics of BC in clinical practice is restricted and primarily confined to research endeavors. Aim This study aims to investigate the histopathological profile of women diagnosed with BC seeking treatment at King Khalid Hospital in the Najran region of the Kingdom of Saudi Arabia. Methods In this retrospective study, BC biopsies performed on Saudi patients at King Khalid Hospital between January 2018 and December 2022 were examined. All records of breast biopsies from this timeframe were extracted from the hospital's histopathology laboratory computer database after written permission from the head of the laboratory department. For all neoplastic lesions, the World Health Organization's 2012 categorization of breast tumors was applied. Results A total of 61 women with BC were included. Women's age ranged from 30 to 89 years, with a mean age of 49.6 ± 12.3 years. The most reported BC was invasive ductal carcinoma (IDC; 70.5%). Other types reported included invasive papillary carcinoma (8.2%), ductal carcinoma in situ (4.9%), and invasive lobular carcinoma (3.3%). A total of 14 (23%) of the study women had multifocal cancer. Ki-67 was high in 19 cases (31.1%); six (9.8%) had BRCA1 mutations, and six (9.8%) had BRCA2 mutations. Conclusion The current study revealed that BC was frequent among young females, mainly IDC, which was reported on both sides at different sizes and grades. Breast lump was the most commonly presented symptom and had a high representation in women with hormonal receptors, mainly estrogen receptors, but positive genetic testing was infrequent.

Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study.

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

Genetic mutations in Parkinson's disease: screening of a selected population from North-Eastern Italy.

Parkinson's disease (PD) is a progressive neurodegenerative disorder with a multifactorial pathogenesis. Several genetic variants increase the risk of PD and about 5-10% of cases are monogenic. This study aims to define the genetic bases and clinical features of PD in a cohort of patients from Northeastern Italy, a peculiar geographical area previously not included in genetic screenings. Using an NGS multigenic panel, 218 PD patients were tested based on age at onset, family history and development of atypical features. A total of 133 genetic variants were found in 103 patients. Monogenic PD was diagnosed in 43 patients (20% of the cohort); 28 (12.8%) carried mutations in GBA1, 10 in LRRK2 (4.6%) and 5 in PRKN (2.3%). In 17% of patients the genetic defect remained of uncertain interpretation. The selection criterion "age of onset < 55years" was a significant predictor of a positive genetic test (OR 3.8, p 0.0037). GBA1 patients showed more severe symptoms and a higher burden of motor and non-motor complications compared to negative patients (dyskinesias OR 3, sleep disturbances OR 2.8, cognitive deficits OR 3.6; p < 0.05), with greater autonomic dysfunction (COMPASS-31 score 34.1 vs 20.2, p 0.03). Applying simple clinical criteria for genetic testing allows to increase the probability to identify patients with monogenic PD and better allocate resources. This process is critical to widen the understanding of disease mechanisms and to increase the individuation of patients potentially benefitting from future disease-modifying therapies.

"Identity theft" in BRCA1/2: impact of positive genetic test results and risk-reducing interventions.

Individuals harboring breast cancer gene 1/2 (BRCA1/2) pathogenic variants are at increased lifetime risk for developing cancer. Learning one's BRCA1/2 carrier status is a watershed moment that can result in psychological distress, anxiety, and depression, as well as feelings of vulnerability and stigma. However, emotional and coping responses to learning one's BRCA1/2 carrier status and after risk-reducing interventions (i.e., preventative bilateral mastectomy) are variable, and existing literature reveals mixed and sometimes contradictory results. Drawing on the concept of narrative identity from the field of psychology, we sought to examine if "identity theft" (the sudden overtaking of one's narrative agency by an external force) may help explain the heterogeneity of emotional and coping responses following the revelation of BRCA carrier status and the subsequent medical intervention one may receive. This Perspective explores BRCA related identity theft using two case studies. Narrative analysis of qualitative interviews uncover the ways that patients experience the disintegration (theft) of their identity as well as their efforts to build and reintegrate a new BRCA carrier identity. This initial qualitative exploration provides preliminary support for the relevance of narrative identity and identity theft to hereditary cancer. We posit that applying the lens of identity theft may hold promise as a unifying concept, integrating across the variable emotional and coping responses among BRCA carriers. Employing a lens of identity theft may help inform the development of tailored narrative interventions as part of precision healthcare to support active coping and psychosocial wellbeing.

Prevalence of Occult Ovarian Cancer and Metastatic Breast Cancer in Ovarian Ablation Specimens of Patients With Hormone Receptor-Positive Breast Cancer: Implications for Tissue Sampling Strategies, Early Ovarian Cancer Detection and Resource Utilization.

Bilateral oophorectomy is one method of hormone suppression for premenopausal patients with hormone receptor-positive breast cancer. Such specimens could, in theory, harbor occult early ovarian cancer and/or metastatic breast cancer but guidelines for tissue sampling for pathologic examination remain to be addressed. Therefore, we evaluated oophorectomy specimens from 166 patients who underwent ovarian ablation for hormone receptor-positive breast cancer. Results of germline genetic testing were documented by the surgeon in only 31.3% of the pathology specimen requisition forms, whereas that information was available for 81.3% of patients elsewhere in the electronic medical records. All but 5.2% tested negative for a hereditary ovarian cancer gene pathogenic variant before oophorectomy. Complete tissue sampling was performed in 77.1% of the cases and representative sampling in the remainder. No cases of ovarian cancer were observed. Ovarian metastasis of breast cancer was identified in 9.6% of patients, all of whom were already known to have advanced-stage disease. The number of tissue cassettes per ovary required for complete tissue submission was on average three times higher than that for representative tissue sampling (P < 0.01) and ranged up to 20 cassettes per ovary when multiple follicle cysts were present. We propose that guidelines for tissue sampling in this context be defined by a combination of hereditary risk and macroscopic examination; representative sampling is reasonable for macroscopically normal ovaries in hormone receptor-positive breast cancer patients whose germline genetic testing is negative. Positive genetic test results merit complete tissue submission even if macroscopically normal. This strategy balances the goals of early ovarian cancer detection and optimal resource utilization. However, it depends on clear documentation of genetic test results. Our study demonstrates that many opportunities remain to close gaps in the communication of genetic test results by clinicians submitting oophorectomy specimens for pathologic evaluation.

The Importance of Copy Number Variant Analysis in Patients with Monogenic Kidney Disease

IntroductionGenetic testing can reveal monogenic causes of kidney diseases, offering diagnostic, therapeutic, and prognostic benefits. While single nucleotide variants (SNVs) and copy number variants (CNVs) can result in kidney disease, CNV analysis is not always included in genetic testing. MethodsWe investigated the diagnostic value of CNV analysis in 2,432 kidney disease patients genetically tested at the University Medical Centre Utrecht between 2014 and May 2022. We combined previous diagnostic testing results, encompassing SNVs and CNVs, with newly acquired results based on retrospective CNV analysis. The reported yield considers both ACMG classification and whether the genotype actually results in disease. ResultsWe report a diagnostic yield of at least 23% for our complete diagnostic cohort. The total diagnostic yield based solely on CNVs was 2.4%. The overall contribution of CNV analysis, defined as the proportion of positive genetic tests requiring CNV analysis, was 10.5% and varied among different disease subcategories, with the highest impact seen in congenital anomalies of the kidney and urinary tract and chronic kidney disease at a young age. We highlight the efficiency of exome-based CNV calling, which reduces the need for additional diagnostic tests. Furthermore, a complex structural variant, likely a COL4A4 founder variant, was identified. Additional findings unrelated to kidney diseases were reported in a small percentage of cases. ConclusionIn summary, this study demonstrates the substantial diagnostic value of CNV analysis, providing insights into its contribution to the diagnostic yield and advocating for its routine inclusion in genetic testing of kidney disease patients.