Negative Genetic Test Results Research Articles

#1148 Polycystic kidney disease—beyond PKD1 and PKD2

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is a common form of hereditary kidney disease, with an estimated prevalence of 1 out of 1000 individuals worldwide. Although its key clinical manifestation is progressive formation and growth of renal cysts, extra-renal manifestations such as hypertension, cysts in other organs, cardiac valve disease and cerebral aneurysms reflect that it is a systemic disorder. Classical ADPKD is associated with heterozygous PKD1 and PKD2 pathogenic gene variants. Less common involved genes that may present as atypical cystic disease include GNAB, DNAJB11 and more recently ALG5/9. Genes associated to syndromic ciliopathies such IFT140 and OFD1 have also been related to atypical ADPKD. Literature reports that 10% patients with ADPKD phenotype will have de novo pathogenic variant. Around 7% of families have negative genetic testing despite clinical phenotype. Failure to consider broader genetic panels or exome sequencing if available may lessen diagnostic yield. Method We performed descriptive analysis on patients with no family history cystic disease and negative PKD1/PKD2 gene testing in our hereditary nephropathy clinic. Atypical cystic disease was defined as non-enlarged kidneys despite multiple cysts and asymmetrical kidney cyst affection in terms of size and quantity, determined through imaging studies. Results From January 2019 until December 2023, n = 39 genetic tests were performed in patients with cystic disease phenotype, n = 28 (13%) without family history. Twelve patients (31%) had positive PKD1/PKD2 variants analysed by PCR long range multiplex. Fig. 1 represents the genetic test results in the remaining patients (n = 16) with cystic disease phenotype and no family history. Positive genetic testing was obtained in n = 7 (43%). Ten patients (63%) presented features of atypical cystic disease. These had a median referral age of 48 years (IQR 34-58), n = 3 (30%) male. Three causal genetic variants were identified (1 with variants in IFT140 and 2 in OFD1 gene), the remaining with negative genetic test result. Patients without atypical features had a median age of referral 55 years (IQR 38-58), n = 4 (60%) were male. Variants in GANAB, LRP5 and PKHD1 genes were identified in this subgroup. Extra-renal manifestations were seen in in 70% and 50% of patients with and without atypical cystic disease, respectively. The main extra-renal manifestation encountered was hepatic cysts. One patient with a pathogenic OFD1 variant presented syndactyly. Conclusion In recent years, growing knowledge in the field and identification of genes involved in ciliopathies associated with atypical forms polycystic kidney disease have allowed for genetic diagnosis of non-PKD1/PKD2 forms. The identification of new genes associated with atypical forms of polycystic kidney disease has called attention to a potential overlap between polycystic and tubulointerstitial phenotypes. With growing knowledge in genetics leading to improvement of cystic kidney disease panels and increased experience in exome sequencing, diagnostic yield is likely to increase in the coming years. Genetic basis of disease is important considering possibility of avoiding primary transmission through pre-implantatory genetic diagnosis but also in the management and diagnosis of gene-specific systemic manifestations.

Deep Learning–Augmented ECG Analysis for Screening and Genotype Prediction of Congenital Long QT Syndrome

Congenital long QT syndrome (LQTS) is associated with syncope, ventricular arrhythmias, and sudden death. Half of patients with LQTS have a normal or borderline-normal QT interval despite LQTS often being detected by QT prolongation on resting electrocardiography (ECG). To develop a deep learning-based neural network for identification of LQTS and differentiation of genotypes (LQTS1 and LQTS2) using 12-lead ECG. This diagnostic accuracy study used ECGs from patients with suspected inherited arrhythmia enrolled in the Hearts in Rhythm Organization Registry (HiRO) from August 2012 to December 2021. The internal dataset was derived at 2 sites and an external validation dataset at 4 sites within the HiRO Registry; an additional cross-sectional validation dataset was from the Montreal Heart Institute. The cohort with LQTS included probands and relatives with pathogenic or likely pathogenic variants in KCNQ1 or KCNH2 genes with normal or prolonged corrected QT (QTc) intervals. Convolutional neural network (CNN) discrimination between LQTS1, LQTS2, and negative genetic test results. The main outcomes were area under the curve (AUC), F1 scores, and sensitivity for detecting LQTS and differentiating genotypes using a CNN method compared with QTc-based detection. A total of 4521 ECGs from 990 patients (mean [SD] age, 42 [18] years; 589 [59.5%] female) were analyzed. External validation within the national registry (101 patients) demonstrated the CNN's high diagnostic capacity for LQTS detection (AUC, 0.93; 95% CI, 0.89-0.96) and genotype differentiation (AUC, 0.91; 95% CI, 0.86-0.96). This surpassed expert-measured QTc intervals in detecting LQTS (F1 score, 0.84 [95% CI, 0.78-0.90] vs 0.22 [95% CI, 0.13-0.31]; sensitivity, 0.90 [95% CI, 0.86-0.94] vs 0.36 [95% CI, 0.23-0.47]), including in patients with normal or borderline QTc intervals (F1 score, 0.70 [95% CI, 0.40-1.00]; sensitivity, 0.78 [95% CI, 0.53-0.95]). In further validation in a cross-sectional cohort (406 patients) of high-risk patients and genotype-negative controls, the CNN detected LQTS with an AUC of 0.81 (95% CI, 0.80-0.85), which was better than QTc interval-based detection (AUC, 0.74; 95% CI, 0.69-0.78). The deep learning model improved detection of congenital LQTS from resting ECGs and allowed for differentiation between the 2 most common genetic subtypes. Broader validation over an unselected general population may support application of this model to patients with suspected LQTS.

Unraveling Complexities in Genetically Elusive Long QT Syndrome.

Genetic testing has become standard of care for patients with long QT syndrome (LQTS), providing diagnostic, prognostic, and therapeutic information for both probands and their family members. However, up to a quarter of patients with LQTS do not have identifiable Mendelian pathogenic variants in the currently known LQTS-associated genes. This absence of genetic confirmation, intriguingly, does not lessen the severity of LQTS, with the prognosis in these gene-elusive patients with unequivocal LQTS mirroring genotype-positive patients in the limited data available. Such a conundrum instigates an exploration into the causes of corrected QT interval (QTc) prolongation in these cases, unveiling a broad spectrum of potential scenarios and mechanisms. These include multiple environmental influences on QTc prolongation, exercise-induced repolarization abnormalities, and the profound implications of the constantly evolving nature of genetic testing and variant interpretation. In addition, the rapid advances in genetics have the potential to uncover new causal genes, and polygenic risk factors may aid in the diagnosis of high-risk patients. Navigating this multifaceted landscape requires a systematic approach and expert knowledge, integrating the dynamic nature of genetics and patient-specific influences for accurate diagnosis, management, and counseling of patients. The role of a subspecialized expert cardiogenetic clinic is paramount in evaluation to navigate this complexity. Amid these intricate aspects, this review outlines potential causes of gene-elusive LQTS. It also provides an outline for the evaluation of patients with negative and inconclusive genetic test results and underscores the need for ongoing adaptation and reassessment in our understanding of LQTS, as the complexities of gene-elusive LQTS are increasingly deciphered.

Recontact to return new or updated PALB2 genetic results in the clinical laboratory setting.

The purpose of this study was to recontact individuals with clinically actionable test results identified through a retrospective research study and to provide a framework for laboratories to recontact patients. Genetic testing was conducted on 2977 individuals originally referred for BRCA1 and BRCA2 hereditary breast and ovarian cancer testing that had a negative genetic test result. A gene panel was used to identify pathogenic variants in known or newly discovered genes that could explain the underlying cause of disease; however, analysis was restricted to PALB2 for the purposes of this study. A patient recontact decision tree was developed to assist in the returning of updated genetic test results to clinics and patients. Novel clinically actionable pathogenic variants were identified in the PALB2 gene in 18 participants (0.6%), the majority of whom were recontacted with their new or updated genetic test results. Eight individuals were unable to be recontacted; five individuals had already learnt about their new or updated findings from genetic testing outside the context of this study; three individuals prompted cascade testing in family members; two individuals were deceased. Novel pathogenic variants in PALB2 were identified in 18 individuals through retrospective gene panel testing. Recontacting these individuals regarding these new or updated findings had a range of outcomes. The process of conveying genomic results within this framework can be effectively accomplished while upholding patient autonomy, potentially leading to advantageous outcomes for patients and their families.

Detecting Low-Variant Allele Frequency Mosaic Pathogenic Variants of NF1, TSC2, and AKT3 Genes from Blood in Patients with Neurodevelopmental Disorders

Growing evidence indicates that early and late postzygotic mosaicism can cause neurodevelopmental disorders (NDDs), but detection of low variant allele frequency (VAF) mosaic variants from blood remains a challenge. Data of 2162 patients with NDDs who underwent conventional genetic tests were reviewed and a deep sequencing was performed using a specifically designed mosaic next-generation sequencing (NGS) panel in the patients with negative genetic test results. Forty-four patents with neurocutaneous syndrome, malformation of cortical development, or nonlesional epileptic encephalopathies were included. In total, mosaic variants were detected from blood in 1.2% (25/2162) of the patients. Using conventional NGS panels, 22 mosaic variants (VAF, 8.8% to 29.8%) were identified in 18 different genes. Using a specifically designed mosaicism NGS panel, three mosaic variants of the NF1, TSC2, and AKT3 genes were identified (VAF, 2.0% to 11.2%). Mosaic variants were found frequently in the patients who had neurocutaneous syndrome (2/7, 28.6%), whereas only one or no mosaic variant was detected for patients who had malformations of cortical development (1/20, 5%) or nonlesional epileptic encephalopathies (0%, 0/17). In summary, mosaic variants that contribute to the spectrum of NDDs can be detected from blood via conventional NGS and specifically designed mosaicism NGS panels, and detection of mosaic variants using blood will increase diagnostic yield.

Abstract 5238: The functional role of promoter germline variants in breast cancer susceptibility genes

Abstract It is estimated that inherited deleterious or pathogenic germline variants in high- to moderate- penetrance breast cancer (BC) susceptibility genes such as BRCA1, BRCA2, STK11, CDH1, ATM, PALB2, and CHEK2 may explain up to 27% of the BC cases. For the remaining cases, BC develops as a result of the complex interaction between environmental and lifestyle risk factors as well as inherited familial predisposition. While low penetrance genetic variants have limited impact on BC risk when taken individually, their combined effect on polygenic risk scores may provide a risk elevated enough to justify clinical actions. Most of the previous work in hereditary breast cancer research has focused on variants located in the coding region of the genes and as a result, there is an abundance of information on the functional interpretation of such variants, while information on regulatory variants remains limited. The goal of this study was to assess the functional impact of germline variants in the promoter region of BC susceptibility genes on gene expression level. Genes evaluated include CDH1, STK11, and bidirectional promoter genes ATM/NPAT and PALB2/DCTN5. A bioinformatics approach was developed to identify and prioritize variants based on conservation level and predicted binding of transcription regulatory proteins. Selected variants will be introduced into pGL3 constructs harboring the promoter of interest using site-directed mutagenesis followed by transfection into HEK293T cells. Dual-glo luciferase expression assays are used to measure levels of promoter activities. Expression levels from promoters containing genetic variants are compared with those from constructs containing the reference sequence. The reference constructs for STK11 and CDH1 containing the genes complete promoters demonstrated functional activity. For bidirectional promoters, forwards and reverse construct were tested. Forward ATM/NPAT and PALB2/DCTN5 constructs showed luciferase expression under the influence of ATM and DCTN5 respectively. Work is on the way to assess promoter activity of the reverse complement sequence of those promoters and determine the impact of 13 candidate variants on the strength of these promoters. At the clinical level, identifying germline variants that contribute to BC risk could help better define BC risk in women with negative hereditary cancer genetic test results. Citation Format: Nelly Arlene Arroyo, Lenin J. Godoy, Julie Dutil. The functional role of promoter germline variants in breast cancer susceptibility genes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5238.

Abstract P5-12-02: Germline variants detected by next-generation sequencing-based multigene panel testing in patients with suspected hereditary breast cancer at a University Hospital in Japan

Abstract Background: The usefulness of prophylactic surgery and surveillance for hereditary breast cancer has been demonstrated, and germline testing for BRCA1 and BRCA2 had been covered by insurance since 2020 in Japan. In addition to BRCA1 and BRCA2, several other genes are also associated with an increased risk of developing breast cancer, such as PALB2, ATM, BARD1, CHEK2, PTEN, and TP53. Next-generation sequencing-enabled multigene panel tensing provides information about these gene variants at the same time, and at a low cost. Although germline testing of BRCA1 and BRCA2 has become widespread in Japan, multi-panel gene testing for germline variants has been conducted only in a limited number of facilities, partly due to the difficulty associated with dealing with the gene variant information obtained from the test. The aim of this study was to clarify the current status of multigene panel testing in our institute, and reveal the characteristics of the variants detected in patients with, or predisposed to, hereditary breast cancer. Methods: This retrospective study included 37 individuals who underwent next-generation sequencing-based multigene panel testing in order to investigate any inherited genetic variants due to a suspicion of hereditary breast cancer. Eighteen patients had a diagnosis of breast cancer with a family history of breast and/or ovarian cancer, nine patients had a diagnosis of breast cancer without family history of breast or ovarian cancer, and 10 patients had a family history of breast cancer but had not developed breast cancer themselves. Results: Utilizing mutigene panel testing, at least one alteration was found in 24 genes, and a total of 39 variants were found in the 37 patients. Of these 37 patients, nine (24.3%) had a pathogenic/likely pathogenic variant with or without other variants of uncertain significance (VUS), 15 (40.5%) had VUS, and 13 (35.1%) had negative genetic test results. Among the nine patients with pathogenic/likely pathogenic variants, seven had variants in either BRCA1 or BRCA2 (one BRCA1 pathogenic variant, five BRCA2 pathogenic variants, and one BRCA2 likely pathogenic variant), while the remaining positive results were attributed to other genes (one MLH1 pathogenic variant, and one SDHB pathogenic variant). VUS included BRCA1 and BRCA2, as well as other breast cancer-associated genes, such as ATM (n=2), CDH1 (n=2), NF1 (n=2), PALB2 (n=1), CHEK2 (n=1), NBN (n=1), and RAD51D (n=1). VUS also included other cancer syndrome-related genes, such as MLH1 (n=2), MUTYH (n=2), APC (n=1), and RET (n=1). Conclusion: Multigene panel tests in our institute revealed pathogenic/likely pathogenic variants in 24.3% of individuals who suspected hereditary breast cancer. As expected, multigene panel tests also revealed more VUS than pathogenic variants and 40.5% individuals were detected with VUS, which included many genes associated with hereditary breast cancer and other cancer syndromes, in addition to BRCA1 and BRCA2. Individuals with VUS will need to cope with new information if the interpretation of the variant changes in the future. We need to be aware of the characteristics and limitations of this type of panel testing, and to properly utilize the test results and information obtained for good quality patient care. Citation Format: Yusa Atake, Masayuki Nagahashi, Haruka Kanaoka, Akira Hattori, Ayako Bun, Reiko Fukui, Hiromi Ozawa, Yukie Fujimoto, Tomoko Higuchi, Michiko Imamura, Keiko Murase, Yuichi Takatsuka, Mina Kashima, Chiho Okada, Chinatsu Kinjo, Mikako Miyata, Ayako Miyazaki, Mako Ueda, Hiroshi Tsubamoto, Hideaki Sawai, Yasuo Miyoshi. Germline variants detected by next-generation sequencing-based multigene panel testing in patients with suspected hereditary breast cancer at a University Hospital in Japan [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-12-02.

Predictors of Women’s Intentions to Communicate Updated Genetic Test Results to Immediate and Extended Family Members

Introduction: Many individuals who previously received negative genetic test results are eligible for updated testing. This study examined intention to communicate updated genetic test results to relatives in participants who previously received negative genetic test results. Methods: Women with a personal or family history of breast or ovarian cancer who tested negative for BRCA1/2 before 2013 were enrolled between April 2018 and October 2019. Proportions were calculated to assess intention to communicate updated genetic test results to living immediate family, extended family, and all family. Potential predictors of intentions from the theory of planned behavior (attitudes, subjective norms, perceived behavioral control) were assessed. The three outcomes were analyzed using generalized linear models with a quasi-binomial probability distribution. Results: 110 women completed the baseline assessment prior to updated testing. Participants intended to communicate genetic test results to 90% of immediate family, 51% of extended family, and 66% of all living relatives. Participants with higher subjective norms (aOR = 1.93, 95% CI: 1.08–3.57) had higher intentions to communicate genetic test results to extended family, while participants with more positive attitudes (aOR = 1.27, 95% CI: 1.01–1.60) had higher intentions to communicate to all family. Placing higher importance on genetic information was associated with higher intentions to communicate to immediate family (aOR = 1.40, 95% CI: 1.06–1.83). Lower subjective numeracy was associated with higher intentions to communicate to extended family (aOR = 0.50, 95% CI: 0.32–0.76). Conclusion: Attitudes and subjective norms were predictors of intention to communicate updated genetic information to at-risk biological relatives, and predictors may vary by degree of relationship.

O050 A ten-year review of methodological trends and outcomes in riskreducing mastectomy and associated reconstruction at a tertiary referral centre

Abstract Introduction Risk-reducing mastectomy (RRM) is the removal of breast tissue to substantially decrease the risk of developing breast cancer in individuals with higher breast cancer susceptibility due to strong family history or genetic mutations. This retrospective study evaluates cases of RRM, and subsequent reconstruction performed at a tertiary referral centre over the last decade, with emphasis on mastectomy and reconstructive trends. Methods A retrospective review of all cases of RRM performed between January 2010 and January 2020, divided into two groups corresponding to the first half (group 1) and second half (group 2) of the decade was conducted. Data collected included demographics, genetic test results, family and personal history of breast cancer, co-morbidities, mastectomy type, reconstruction type, surgical histopathology findings and complications. Results A total of 167 patients (group 1=76, group 2=91) underwent RRM, with a significant increase in cases of RRM despite negative genetic test results (p=0.047). The proportion of nipple sparing techniques for RRM compared to more traditional skin-sparing techniques. Concomitantly, post-RRM reconstruction has progressively become solely implant-based, to coincide with a rise in ADM usage. This is consistent with national trends towards fewer complex autologous procedures. Take-home message Emergent trends in risk-reducing mastectomy and reconstructive techniques are occurring against a background of broadened indications for RRM and more frequent patient requests for RRM in the absence of any documented pathogenic gene mutation. As breast surgery continues to evolve, it is important to evaluate specific trends such as more conservative forms of mastectomy and novel techniques/devices for breast reconstruction to ensure optimal patient care and levels of satisfaction.

The uptake and utility of genetic testing and genetic counseling for hypertrophic cardiomyopathy-A systematic review and meta-analysis.

Genetic testing and genetic counseling are routinely indicated for patients with hypertrophic cardiomyopathy (HCM); however, the uptake and utility of these services is not entirely understood. This systematic review and meta-analysis summarizes the uptake and utility of genetic counseling and genetic testing for patients with HCM and their at-risk family members, as well as the impact of genetic counseling/testing on patient-reported outcomes (PROs). A systematic search was performed through March 12, 2021. Meta-analyses were performed whenever possible; other findings were qualitatively summarized. Forty-eight studies met inclusion criteria (47 observational, 1 randomized). Uptake of genetic testing in probands was 57% (95% confidence interval [CI]: 40, 73). Uptake of cascade screening for at-risk relatives were as follows: 61% for cascade genetic testing (95% CI: 45, 75), 58% for cardiac screening (e.g. echocardiography) (95% CI: 40, 73), and 69% for either/both approaches (95% CI: 43, 87). In addition, relatives of probands with a positive genetic test result were significantly more likely to undergo cascade screening compared to relatives of probands with a negative result (odds ratio=3.17, 95% CI: 2.12, 4.76). Overall, uptake of genetic counseling in both probands and relatives ranged from 37% to 84%. Multiple studies found little difference in PROs between individuals receiving positive versus negative genetic test results; however, other studies found that individuals with positive genetic test results experienced worse psychological outcomes. Genetic testing may also inform life choices, particularly decisions related to reproduction and insurance. Genetic counseling was associated with high satisfaction, increased perceived personal control and empowerment, and decreased anxiety. Approximately half to three-quarters of patients with HCM and their relatives undergo genetic testing or cascade screening. PROs after genetic testing varied and genetic counseling was associated with high satisfaction and improved PROs.

Cascade testing for inherited cardiac conditions: Risk perception and screening after a negative genetic test result.

First-degree relatives of a proband with an inherited cardiac condition (ICC) are offered predictive genetic testing for the pathogenic or likely pathogenic (P/LP) cardiac gene variant (CGV) to clarify their risk for the familial condition. Relatives who test negative for a familial P/LP CGV typically do not require longitudinal cardiac surveillance. To our knowledge, no previous study has investigated adjustment to risk reduction and subsequent screening practices in genotype-negative relatives from an ICC population. We thus investigated risk perception and ongoing screening practices in genotype-negative adults who received cardiac genetic counseling. Correlations between clinical and demographic variables and risk perception and screening practices were also investigated. On average, participants (n= 71) reported a perceived 19.5% lifetime risk of developing the ICC in their family, despite their negative genetic test result. The majority (54%) of participants reported having undergone cardiac screening after disclosure of their negative result. There were no significant correlations between clinical and demographic variables and risk perception or screening practices. Furthermore, risk perception was not found to impact the likelihood of cardiac screening. These findings suggest that even with comprehensive cardiac genetic counseling, a proportion of this population did not accurately comprehend or recall their cardiac disease risk. Additional interventions beyond traditional result disclosure should be explored to help genotype-negative individuals adjust to their reduction in risk for a familial ICC.

Ovarian tumors and genetic predisposition.

Summary of knowledge in the field of ovarian cancer and genetic predisposition. Ovarian tumors are usually diagnosed at advanced stages of the disease and the prognosis for these patients is generally poor. The 5-year overall survival rate, regardless of the histopathological type of tumor, is around 44%. Germline mutations causing hereditary tumor syndromes are predominantly involved in the development of epithelial ovarian tumors. The most common is hereditary breast and ovarian cancer syndrome, which is caused by germline mutations in the tumor suppressor genes BRCA1 and BRCA2. Several other tumor suppressor genes and oncogenes are known to be associated with ovarian tumors and cause other types of tumor syndromes. Inherited tumor syndromes include Lynch syndrome, Peutz-Jegers syndrome, Gorlin syndrome, Li-Fraumeni syndrome and others. The indication for genetic examination of germline mutations is given by a clinical geneticist on the basis of the recommendation of the attending physician. At present, every ovarian tumor, primary peritoneal tumor and tube tumor diagnosed at any age is indicated for genetic testing. Early identification of genes for hereditary cancer syndromes, thanks to rapidly developing molecular genetic methods, is an important step towards personalized treatment of ovarian cancer and preventive measures in families at risk. It is also important to note that a negative molecular genetic test result does not exclude genetic risk.

Spectrum of germline pathogenic variants using a targeted next generation sequencing panel and genotype-phenotype correlations in patients with suspected hereditary breast cancer at an academic medical centre in Pakistan

BackgroundBreast cancer is the most common malignancy in women, affecting over 1.5 million women every year, which accounts for the highest number of cancer-related deaths in women globally.Hereditary breast cancer (HBC), an important subset of breast cancer, accounts for 5–10% of total cases. However, in Low Middle-Income Countries (LMICs), the population-specific risk of HBC in different ethnicities and the correlation with certain clinical characteristics remain unexplored.MethodsRetrospective chart review of patients who visited the HBC clinic and proceeded with multi-gene panel testing from May 2017 to April 2020.Descriptive and inferential statistics were used to analyze clinical characteristics of patients. Fisher’s exact, Pearson’s chi-squared tests and Logistic regression analysis were used for categorical variables and Wilcoxon rank-sum test were used for quantitative variables. For comparison between two independent groups, Mann-Whitney test was performed. Results were considered significant at a p value of < 0.05.ResultsOut of 273 patients, 22% tested positive, 37% had a VUS and 41% had a negative genetic test result. Fifty-five percent of the positive patients had pathogenic variants in either BRCA1 or BRCA2, while the remaining positive results were attributed to other genes. Patients with a positive result had a younger age at diagnosis compared to those having a VUS and a negative result; median age 37.5 years, IQR (Interquartile range) (31.5–48). Additionally, patients with triple negative breast cancer (TNBC) were almost 3 times more likely to have a positive result (OR = 2.79, CI = 1.42–5.48 p = 0.003). Of all patients with positive results, 25% of patients had a negative family history of breast and/or related cancers.ConclusionsIn our HBC clinic, we observed that our rate of positive results is comparable, yet at the higher end of the range which is reported in other populations. The importance of expanded, multi-gene panel testing is highlighted by the fact that almost half of the patients had pathogenic or likely pathogenic variants in genes other than BRCA1/2, and that our test positivity rate would have only been 12.8% if only BRCA1/2 testing was done. As the database expands and protocol-driven referrals are made across the country, our insight about the genetic architecture of HBC in our population will continue to increase.

The symptom discounting effect: what to do when negative genetic test results become risk factors for alcohol use disorder

Most consumers of genetic testing for health conditions test negative, yet the psychological perils of this are hardly known. In three experiments (N = 2103) participants discounted repercussions of alcohol use disorder (AUD), after learning or imagining that they were not genetically predisposed to AUD. Such discounting can lead people to avoid treatment and to feel safe to continue or even increase their drinking, ironically turning the negative genetic feedback into a risk factor for AUD. Concerningly, the debriefing currently used by a direct-to-consumer genetic testing company failed to counteract this discounting among those already engaging in problematic drinking in all three studies. It was hypothesized that this discounting derives from not understanding the Causal Markov condition; once AUD symptoms are present, their ramifications remain the same regardless of whether genes or environmental factors caused the symptoms. Educating participants about this principle successfully mitigated the irrational discounting of threats of AUD.

Investigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort.

ObjectivesPhaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours with malignant potential and a hereditary basis in almost 40% of patients. Germline genetic testing has transformed the management of PPGL enabling stratification of surveillance approaches, earlier diagnosis and predictive testing of at‐risk family members. Recent studies have identified somatic mutations in a further subset of patients, indicating that molecular drivers at either a germline or tumour level can be identified in up to 80% of PPGL cases. The aim of this study was to investigate the clinical utility of somatic sequencing in a large cohort of patients with PPGL in the United Kingdom.Design and PatientsProspectively collected matched germline and tumour samples (development cohort) and retrospectively collected tumour samples (validation cohort) of patients with PPGL were investigated.MeasurementsClinical characteristics of patients were assessed and tumour and germline DNA was analysed using a next‐generation sequencing strategy. A screen for variants within ‘mutation hotspots’ in 68 human cancer genes was performed.ResultsOf 141 included patients, 45 (32%) had a germline mutation. In 37 (26%) patients one or more driver somatic variants were identified including 26 likely pathogenic or pathogenic variants and 19 variants of uncertain significance. Pathogenic somatic variants, observed in 25 (18%) patients, were most commonly identified in the VHL, NF1, HRAS and RET genes. Pathogenic somatic variants were almost exclusively identified in patients without a germline mutation (all but one), suggesting that somatic sequencing is likely to be most informative for those patients with negative germline genetic test results.ConclusionsSomatic sequencing may further stratify surveillance approaches for patients without a germline genetic driver and may also inform targeted therapeutic strategies for patients with metastatic disease.

Genetic Counseling and Testing for Pulmonary Arterial Hypertension in the United States

Genetic Counseling and Testing for Pulmonary Arterial Hypertension in the United States

Clustering of Hypoglycemia Events in Patients With Hyperinsulinism: Extension of the Digital Phenotype Through Retrospective Data Analysis.

BackgroundHyperinsulinism (HI) due to excess and dysregulated insulin secretion is the most common cause of severe and recurrent hypoglycemia in childhood. High cerebral glucose use in the early hours results in a high risk of hypoglycemia in people with diabetes and carries a significant risk of brain injury. Prevention of hypoglycemia is the cornerstone of the management of HI, but the risk of hypoglycemia at night or the timing of hypoglycemia in children with HI has not been studied; thus, the digital phenotype remains incomplete and management suboptimal.ObjectiveThis study aims to quantify the timing of hypoglycemia in patients with HI to describe glycemic variability and to extend the digital phenotype. This will facilitate future work using computational modeling to enable behavior change and reduce exposure of patients with HI to injurious hypoglycemic events.MethodsPatients underwent continuous glucose monitoring (CGM) with a Dexcom G4 or G6 CGM device as part of their clinical assessment for either HI (N=23) or idiopathic ketotic hypoglycemia (IKH; N=24). The CGM data were analyzed for temporal trends. Hypoglycemia was defined as glucose levels <3.5 mmol/L.ResultsA total of 449 hypoglycemic events totaling 15,610 minutes were captured over 237 days from 47 patients (29 males; mean age 70 months, SD 53). The mean length of hypoglycemic events was 35 minutes. There was a clear tendency for hypoglycemia in the early hours (3-7 AM), particularly for patients with HI older than 10 months who experienced hypoglycemia 7.6% (1480/19,370 minutes) of time in this period compared with 2.6% (2405/92,840 minutes) of time outside this period (P<.001). This tendency was less pronounced in patients with HI who were younger than 10 months, patients with a negative genetic test result, and patients with IKH. Despite real-time CGM, there were 42 hypoglycemic events from 13 separate patients with HI lasting >30 minutes.ConclusionsThis is the first study to have taken the first step in extending the digital phenotype of HI by describing the glycemic trends and identifying the timing of hypoglycemia measured by CGM. We have identified the early hours as a time of high hypoglycemia risk for patients with HI and demonstrated that simple provision of CGM data to patients is not sufficient to eliminate hypoglycemia. Future work in HI should concentrate on the early hours as a period of high risk for hypoglycemia and must target personalized hypoglycemia predictions. Focus must move to the human-computer interaction as an aspect of the digital phenotype that is susceptible to change rather than simple mathematical modeling to produce small improvements in hypoglycemia prediction accuracy.

Understanding and interpretation of a variant of uncertain significance (VUS) genetic test result by pediatric providers who do not specialize in genetics.

The advancement of genetic testing technologies has allowed for better diagnosis and management of patients, but also results in more variants of uncertain significance (VUSs) due to the increased number of genes being analyzed. There are more genetic tests available and more providers who do not specialize in genetics ordering genetic testing, but few studies examining how providers who do not specialize in genetics interpret VUSs. This study surveyed pediatric providers at a midwestern pediatric care center who do not specialize in genetics about their understanding of a mock genetic test report with a VUS result and whether their understanding of the result was associated with experience ordering genetic tests. Participants' preferences about content of the report and steps taken to understand the result were also examined. Of the 51 participants, 33% correctly answered both knowledge questions about the VUS result: one asking them to interpret the result and one asking them how they would explain the result to the patient. There was no association between answering both knowledge questions correctly and types of previous genetic tests ordered (p>.1 for 8 types of genetic tests), having received a genetic test report with a VUS result (p=.58), having referred patients to a genetics professional (p=.74), or feeling comfortable discussing a positive, negative, or VUS genetic test result (p>.4). This suggests that having previous experience ordering genetic tests does not contribute to the participants' knowledge about a variant of uncertain significance. Most participants reported that the amount of information in each section of the mock report was adequate. Participants were likely to reference multiple resources to better understand a VUS result, including published literature (82%), gene-specific databases (67%), and colleagues (63%). While these results cannot be generalized to all institutions, institutions can use the two knowledge questions to determine participants' understanding of genetic test results. This will help healthcare institutions determine methods that will best aide their providers who order genetic testing but do not specialize in genetics in learning more about the genetic testing process and better utilize results to improve patient care.

Frequency of Contralateral Prophylactic Mastectomy in Breast Cancer Patients with a Negative BRCA1 and BRCA2 Rapid Genetic Test Result.

There is an increasing desire for contralateral prophylactic mastectomy (CPM) among patients with unilateral breast cancer. It is unknown if risk assessment and genetic testing at the time of diagnosis will aid women in their surgical choice. We report on the uptake and predictors of CPM in women receiving a negative genetic test result for BRCA1 and BRCA2 mutations before surgery. Women diagnosed with breast cancer between June 2013 and May 2018 were recruited from four academic health sciences centers in Toronto, Canada. Genetic counseling (risk assessment) and genetic testing was performed prior to surgery. Women were asked about their surgical preference before surgery. At 1year post-surgery we asked what surgery was completed. This study reports on women who received a negative BRCA1/BRCA2 result. A total of 766 women with a mean age of 46 years (range 21-82) were included in the analysis. Before genetic counseling and testing, 37% of the women were undecided or leaning towards CPM; however, after receiving a negative BRCA test, 15% of the women opted for CPM. Thirty percent of women whose mother died of breast cancer elected for CPM, compared with 15% of women whose mother did not die of breast cancer (p=0.03). Women receiving a risk assessment and negative BRCA1/BRCA2 genetic test result before surgery use this information to guide their surgical decision. Uptake of CPM for women who were planning on CPM before genetic testing decreases after receiving a negative BRCA1/BRCA2 genetic test result.

Genetic counselling for infertile men of known and unknown etiology.

Of the couples trying to conceive (had frequent, unprotected sexual intercourse for a year or longer) 15% will experience infertility with the annual incidence of infertility estimated at 1.2 couples per 1,000 total in the general population. Male factors contribute to over 50% of the cases with 7% of the male population experiencing infertility. Not being able to conceive a child is emotionally traumatic and frustrating and can affect the person’s self esteem and the couple’s relationship. Major progress has been achieved in identifying the etiology of male infertility and especially the genetic causes. However, in about 40% of the male infertility cases, the etiology remains unknown and both the diagnosis and/or treatment are a challenge. Genetic testing to determine the underlying genetic cause of infertility is not 100% and genes involved are still being discovered. Consequently, negative genetic test results do not rule out a genetic cause. Thus, genetic counselling should include information regarding the genetic etiology, if known, and the treatment options available. Furthermore, when the infertile couple/male is seeking assisted reproductive technology (ART) using intracytoplasmic sperm injection (ICSI), genetic counselling should include information regarding the risk of transmitting the genetic disorder, causing the male infertility, to the offspring. Therefore, the provision of genetic counselling is an integral component in the investigation and treatment of male infertility. This article will discuss the genetic counselling approach in cases with male infertility.