Testing Approach Research Articles

Germline BRCA testing in Denmark following invasive breast cancer: Progress since 2000.

Despite advancements in genetic testing and expanded eligibility criteria, underutilisation of germline testing for pathogenic variants in BRCA1 and BRCA2 (BRCA) remains evident among breast cancer (BC) patients. This observational cohort study presents real-world data on BRCA testing within the context of clinical practice challenges, including incomplete family history and under-referral. From the Danish Breast Cancer Group (DBCG) clinical database, we included 65,117 females with unilateral stage I-III BC diagnosed in 2000-2017, of whom 9,125 (14%) were BRCA tested. Test results spanned from 1999 to 2021. We evaluated test rates overall and in three diagnosis periods. In logistic regression models, we examined the correlation between a BRCA test and patients' age, residency region, receptor status, and diagnosis period. Test rates rose most significantly among patients aged under 40 years, increasing from 47% (2000-2005) to 88% (2012-2017), albeit with regional discrepancies. Test timing shifted in recent years, with most results within 6 months of BC diagnosis, primarily among the youngest patients. BRCA test rates were higher for oestrogen receptor-negative/human epidermal growth factor receptor 2-negative BC (25% in 2000-2005 vs. 38% in 2012-2017), and these findings were confirmed in multivariate regression models. Our results indicate a critical need for an intensified focus on BRCA testing among BC patients older than 40, where a mainstreamed testing approach might overcome delayed or missed testing. Current DBCG guidelines recommend BRCA testing of all BC patients younger than 50 years, while a general recommendation for older patients is still missing.

Sistem Informasi Transaksi Berbasis Web pada Koperasi Tri Dasi Caka Tunggal di Desa Pegadungan

This research aims to design and implement a transaction information system at the Tri Dasi Caka Tunggal Cooperative in Pegadungan Village. This system development used the Waterfall development method. The methods used for data collection in this research were observation, interviews and literature study. In this research, the testing method uses a set of validation activities, with a black box testing approach. The results of the research show that the implementation of the Web-Based Transaction Information System at the Tri Dasi Caka Tunggal Cooperative in Pegadungan Village uses visual programming. System testing using the black box method from the test results was all successful.

A Droplet Microfluidic Sensor for Point-of-Care Measurement of Plasma/Serum Total Free Thiol Concentrations.

Total free thiols are an important marker of the whole-body redox state, which has been shown to be associated with clinical outcome in health and disease. Recent investigations have suggested that increased insight may be gained by monitoring alterations of redox state in response to exercise and hypoxia and to monitor redox trajectories in disease settings. However, conducting such studies is challenging due to the requirement for repeated venous blood sampling and intensive lab work. Droplet microfluidic sensors offer an alternative platform for developing a point-of-care testing approach using small sample volumes and automated systems to complement or ultimately replace laboratory testing. Here we developed a small, portable droplet microfluidic sensor that can measure total free thiol concentrations in 20 μL human plasma (or serum) samples, providing a reading in less than 10 min. This system features a novel method to enhance the mixing of reagent and analyte in droplets containing viscous biological fluids. The results in a range of real-world human plasma samples showed equivalence with current standard laboratory assays while reducing sample volume requirements 9-fold and fully automating the process. Micro hematocrit capillaries allowed testing of capillary blood samples collected by fingerprick lancing. The system was used to monitor total free thiols using fingerprick samples in healthy volunteers and revealed significant changes in total free thiols in response to food intake and exercise. This device has the potential to improve our ability to conduct physiological studies of total free thiol level changes and improve our understanding of redox physiology, which may ultimately be applied in redox medicine to improve patient care.

AI-driven Test Automation for Salesforce and System Integration

Integrating artificial intelligence into test automation frameworks has transformed quality assurance practices in Salesforce environments and system integrations. AI-driven solutions have revolutionized testing approaches through smart test selection, risk-based analysis, and dynamic element identification capabilities. These advancements enable organizations to detect defects earlier, reduce false positives, and significantly decrease test maintenance efforts. Self-healing locators and context-aware selection mechanisms have enhanced test stability across dynamic web applications, while pattern recognition and anomaly detection capabilities proactively identify potential issues. Real-world implementations demonstrate substantial improvements in testing efficiency, reliability, and cost-effectiveness. Despite the challenges of data requirements and implementation complexity, AI-powered testing solutions have proven particularly effective in handling complex Salesforce configurations and multi-system integrations. The continuous evolution of these technologies promises enhanced predictive capabilities, improved integration support, and more sophisticated automated testing approaches, marking a significant shift in how organizations approach quality assurance in modern software development.

The Affect Of Agricultural Export And Employment On Economic Growth In Turkiye: Evidence From ARDL Approach

The agricultural sector has historically been significant. However, today, eventhough the share of the agricultural sector in the total output is lower compared to other sectors in both developed and developing countries, it remains a sector of great importance in terms of both food production and economic indicators. To reveal the economic impacts of the agricultural sector, this study examines the relationship between agricultural exports, agricultural employment, and economic growth in Turkey for the period 1990-2022. In the study, per capita income is used as an indicator of economic growth, the share of agricultural exports in total exports as an indicator of agricultural exports, and the share of agricultural employment in total employment as an indicator of agricultural employment. The ADF and Phillips-Perron (PP) unit root tests and the ARDL bounds testing approach were used as methods in the study. According to the obtained results, there is a cointegration relationship for the model. Based on the long-term coefficients, agricultural exports increase economic growth, while agricultural employment decreases it. According to the short-term results, there is no deviation in agricultural employment, while agricultural exports also statistically significantly and positively affect economic growth in the short term. Turkey should increase agricultural mechanization and shift agricultural employment to other sectors. Furthermore, instead of exporting agricultural products as raw materials, processing them and exporting them as higher value-added products would contribute more to economic growth.

Faster and Better Quantum Software Testing through Specification Reduction and Projective Measurements

Quantum computing (QC) promises polynomial and exponential speedups in many domains, such as unstructured search and prime number factoring. However, quantum programs yield probabilistic outputs from exponentially growing distributions and are vulnerable to quantum-specific faults. Existing quantum software testing (QST) approaches treat quantum superpositions as classical distributions. This leads to two major limitations when applied to quantum programs: (1) an exponentially growing sample space distribution and (2) failing to detect quantum-specific faults such as phase flips. To overcome these limitations, we introduce a QST approach, which applies a reduction algorithm to a quantum program specification. The reduced specification alleviates the limitations (1) by enabling faster sampling through quantum parallelism and (2) by performing projective measurements in the mixed Hadamard basis. Our evaluation of 143 quantum programs across four categories demonstrates significant improvements in test runtimes and fault detection with our reduction approach. Average test runtimes improved from 169.9s to 11.8s, with notable enhancements in programs with large circuit depths (383.1s to 33.4s) and large program specifications (464.8s to 7.7s). Furthermore, our approach increases mutation scores from \(54.5\%\) to \(74.7\%\) , effectively detecting phase flip faults that non-reduced specifications miss. These results underline our approach’s importance to improve QST efficiency and effectiveness

Signal Feature Coverage and Testing for CPS Dataflow Models

Design of cyber-physical systems (CPS) typically involves dataflow modelling. The structure of dataflow models differs from the traditional software, making standard coverage metrics not appropriate for measuring the thoroughness of testing. To address this limitation, this paper proposes signal feature coverage as a new coverage metric for systematically testing CPS dataflow models. We derive signal feature coverage by leveraging signal features. We developed a testing framework in Simulink ® , a popular dataflow modelling and simulation environment, that automates the generation and execution of test cases based on the defined coverage metric. We evaluated the effectiveness of our approach by carrying out experiments on five Simulink ® models tested against ten Signal Temporal Logic specifications. We compared our coverage-based testing approach to adaptive random testing, falsification testing, output diversity-based approaches, and testing using MathWorks’ Simulink ® Design Verifier™. The results demonstrate that our coverage-based testing approach outperforms the conventional techniques regarding fault detection capability.

Clinical Validation of MyProstateScore 2.0 Testing Using First-Catch, Non-DRE Urine.

The 18-gene MyProstateScore 2.0 (MPS2) test was previously validated for detection of Grade Group≥2 (GG≥2) prostate cancer using post-digital rectal examination (DRE) urine. To improve ease of testing, we validated MPS2 using first-catch, non-DRE urine. Patients provided first-catch urine prior to biopsy. MPS2 values were calculated using previously-validated models differing only by extent of clinical data included: biomarkers alone (BA; no clinical data), biomarkers and clinical factors (BA+CF), and biomarkers, clinical factors, and prostate volume (BA+CF+PV). The primary outcome was GG≥2 cancer on biopsy. MPS2 performance and clinical consequences of testing were compared to PSA and the Prostate Cancer Prevention Trial risk calculator (PCPTrc). The cohort included 266 men with median PSA 6.6 ng/mL (IQR 4.9-9.1), of which 103 (39%) had GG≥2 cancer on biopsy. The area under the curve for GG≥2 cancer was 57% for PSA, 62% for PCPTrc, and 71%, 74%, and 77% for MPS2 models. Under a testing approach detecting >90% of GG≥2 cancers, MPS2 testing would have avoided 36-42% of unnecessary biopsies, as compared to 13% using the PCPTrc. In patients with a prior negative biopsy, MPS2 testing would have avoided 44-53% of repeat biopsies, as compared to only 2.6% using PCPTrc. Using first-catch urine, MPS2 meaningfully improved the proportion of biopsies avoided relative to PCPTrc while maintaining highly-sensitive detection of GG≥2 cancer. Non-DRE testing provides a convenient, objective, and highly-accurate testing option to reduce the need for imaging and biopsy in men with elevated PSA.

Immunochromatographic food control tools: New developments and practical prospects

In the modern food production technologies, the tools and means of simple and rapid testing raw materials, intermediate products and the final ready-to-consume food products are in high demand. This monitoring allows determining the content of toxic and pathogenic contaminants and confirms the compliance of the objects being tested with the established regulatory requirements. Mobile tests tools and means (so called test systems) provide the opportunity of wide range monitoring without involving the specialized laboratories and highly qualified specialists. Thus, test systems for detection of toxic and pathogenic contaminants serve as the useful addition to confirming instrumental analytical methods. An actively developing approach for this field testing is the using of immunochromatographic test strips, in which strips all the necessary reagents are applied to the membrane components of the analytical system. Contact of the test strip with the sample being tested, initiates all further interactions and generates the recordable or visually assessable optical signal. The market of test systems based on immunochromatographic analysis is constantly growing, thus offering the permanently widening choice of solutions. However, in recent years there has been a real boom of new developments in immunochromatography field, thus offering various options for highly sensitive and information capacitive analytical systems. This study systematizes these developments and provides their comparative assessment in terms of prospects for their technological implementation and practical application in the coming years. The opportunities of designing the antibodies and alternative receptor molecules for controlling the affinity and the selectivity of recognition of the compounds being monitored are considered. The advantages and limitations of the new nanodispersed markers and non-optical methods for their registration in immunochromatography are discussed. The methods for quantitative assessment of the contaminants content via immunochromatography are characterized. The developed design options of the test systems for multiplex control — simultaneous detection of several compounds — are presented. Examples of integration of immunochromatographic tests with the systems of automatic registration, processing, transfer, storage and analysis of results of numerous tests are represented.

Navigating ethics in HIV data and biomaterial management within Black, African, and Caribbean communities in Canada

BackgroundThis study explored the ethical issues associated with community-based HIV testing among African, Caribbean, and Black (ACB) populations in Canada, focusing on their perceptions of consent, privacy, and the management of HIV-related data and bio-samples.MethodsA qualitative community-based participatory research (CBPR) approach was employed to actively engage ACB community members in shaping the research process. The design included in-depth qualitative interviews with 33 ACB community members in Manitoba, Canada. The study was guided by a Community Guiding Circle, which contributed to study design, data analysis, and interpretation. A diverse sample was recruited through community agencies, social media, and flyers, with considerations for variations in age, gender, sexual orientation, and geographical location. The study employed iterative inductive thematic data analysis.FindingsParticipants expressed significant concerns about the collection, sharing, and use of HIV data from healthcare encounters, revealing mistrust towards institutions like police, child welfare, and immigration accessing their health information. Their worries centered on the handling of biological samples, data misuse, potential human rights violations, HIV criminalization, deportations, challenging consent, privacy, and bodily autonomy principles. While open to contributing to medical research, they unanimously demanded greater transparency, informed consent, and control over the secondary use of their health data.ConclusionsThe study underscores the need for culturally safe approaches in HIV testing and ethical governance in healthcare for ACB communities. It highlights the importance of prioritizing participant empowerment, ensuring transparency, practicing informed consent, and implementing robust data security measures to balance effective HIV information management with the protection of individual rights.

Brief exposure to (-) THC affects zebrafish embryonic locomotion with effects that persist into the next generation

Cannabis is one of the most widely used drugs, and yet an understanding of its impact on the human brain and body is inconclusive. Medicinal and recreational use of cannabis has increased in the last decade with a concomitant increase in use by pregnant women. The major psychoactive compound in cannabis, Δ9-tetrahydrocannabinol (THC), exists in different isomers, with the (-) trans isomer most common. Prenatal exposure to THC can alter neural and behavioral development, but it is unknown how exposure to (-) trans-THC ((-)THC) during very early stages of development impacts fetal growth and movement, and whether effects persist to adulthood, or into the next generation. Here we exposed zebrafish (Danio rerio) to a single exposure of (-)THC (0.001 mg/L (3.2 nM) to 20 mg/L (63.6 µM), for 5 h) during gastrulation (5.25 hpf to 10.75 hpf) when key neurons involved in locomotion such as the primary motor neurons and Mauthner cell first appear. We then examined the impact on embryo morphology and locomotion, adult behavior, and locomotion in the next (F1) generation. Embryos treated with (-)THC experienced changes in morphology, were shorter in length and experienced altered hatching and survival. Spontaneous coiling of 1 dpf embryos was reduced, swimming after touch-evoked responses was reduced and basal swimming in 5 dpf larvae was also reduced. Adult zebrafish tested in the open field test and novel object approach test demonstrated no differences in locomotion, anxiety-like behavior, nor boldness, compared to controls. The (-)THC F1 generation embryos at 1 dpf showed reduced coiling activity, while swimming after touch-evoked responses was reduced in 2 dpf animals but basal swimming at 5 dpf remained similar to controls. Taken together, exposure to (-)THC only once for 5 h during gastrulation has a significant impact on locomotion in embryos and larvae, a minimal impact on adult behavior, and effects that persist into the next generation.

Novel approach for quality control testing of medical displays using deep learning technology

Objectives:In digital image diagnosis using medical displays, it is crucial to rigorously manage display devices to ensure appropriate image quality and diagnostic safety. The aim of this study was to develop a model for the efficient quality control (QC) of medical displays, specifically addressing the measurement items of contrast response and maximum luminance as part of constancy testing, and to evaluate its performance. In addition, the study focused on whether these tasks could be addressed using a multitasking strategy.Methods:The model used in this study was constructed by fine-tuning a pretrained model and expanding it to a multioutput configuration that could perform both contrast response classification and maximum luminance regression. QC images displayed on a medical display were captured using a smartphone, and these images served as the input for the model. The performance was evaluated using the area under the receiver operating characteristic curve (AUC) for the classification task. For the regression task, correlation coefficients and Bland-Altman analysis were applied. We investigated the impact of different architectures and verified the performance of multi-task models against single-task models as a baseline.Results:Overall, the classification task achieved a high AUC of approximately 0.9. The correlation coefficients for the regression tasks ranged between 0.6 and 0.7 on average. Although the model tended to underestimate the maximum luminance values, the error margin was consistently within 5% for all conditions.Conclusion:These results demonstrate the feasibility of implementing an efficient QC system for medical displays and the usefulness of a multitask-based method. Thus, this study provides valuable insights into the potential to reduce the workload associated with medical-device management the development of QC systems for medical devices, highlighting the importance of future efforts to improve their accuracy and applicability.

A Cloud Detection System for UAV Sense and Avoid: Analysis of a Monocular Approach in Simulation and Flight Tests

In order to contribute to the operation of unmanned aerial vehicles (UAVs) according to visual flight rules (VFR), this article proposes a monocular approach for cloud detection using an electro-optical sensor. Cloud avoidance is motivated by several factors, including improving visibility for collision prevention and reducing the risks of icing and turbulence. The described workflow is based on parallelized detection, tracking and triangulation of features with prior segmentation of clouds in the image. As output, the system generates a cloud occupancy grid of the aircraft’s vicinity, which can be used for cloud avoidance calculations afterwards. The proposed methodology was tested in simulation and flight experiments. With the aim of developing cloud segmentation methods, datasets were created, one of which was made publicly available and features 5488 labeled, augmented cloud images from a real flight experiment. The trained segmentation models based on the YOLOv8 framework are able to separate clouds from the background even under challenging environmental conditions. For a performance analysis of the subsequent cloud position estimation stage, calculated and actual cloud positions are compared and feature evaluation metrics are applied. The investigations demonstrate the functionality of the approach, even if challenges become apparent under real flight conditions.

Adolescent Sports Participation and Health in Early Adulthood: An Observational Study

We study the impact of teenage sports participation on early-adulthood health using data from the National Study of Youth and Religion. We focus on two primary outcomes measured at ages 23 to 28 (self-rated health and PHQ9 Patient Depression Questionnaire score) and control for several demographic and socioeconomic confounders. To probe the possibility that certain types of sports participation may have larger effects on health than others, we conduct matched observational studies at each level within a hierarchy of exposures. Our hierarchy ranges from broadly defined exposures (e.g., participation in any organized after-school activity) to narrow (e.g., participation in collision sports). We maintained a fixed family-wise error rate using an ordered testing approach that exploits the hierarchical relationships between our exposure definitions. Compared to teenagers who did not participate in any after-school activities, those who participated in sports had statistically significantly better self-rated and mental health outcomes in early adulthood.

Improving UTI Diagnostics in Oncology: Reliability of Reflex Urine Culture in Immunosuppressed Neutropenic and Non-neutropenic Cancer Patients.

Urinary tract infections are prone to overdiagnosis, and reflex urine culture protocols offer a valuable opportunity for diagnostic stewardship in this arena. However, there is no recommended standard testing approach. Cancer patients are often excluded from reflex urine culture protocols, especially if severely immunosuppressed or neutropenic. The aim of this study was to evaluate the performance characteristics of urine screening studies, including dipstick urinalysis for nitrite and leukocyte esterase and urine microscopy for white blood cell count, to detect significant pathogen growth. A retrospective study of 58,098 urine cultures with a paired dipstick urinalysis with or without urine microscopy was performed at Memorial Sloan Kettering Cancer Center in New York City, evaluating data from January 1, 2018, to December 31, 2020. A dipstick urinalysis was considered negative only if leukocyte esterase and nitrite were undetected. A negative dipstick urinalysis had a negative predictive value (NPV) of 98% for clinically significant bacteriuria in voided urine, and 95% for catheterized urine. Notably, a negative urine dipstick test screen maintained a high NPV among patients with neutropenia and in those with antibiotic exposure before testing. Finally, the presence of pyuria ≥10 white blood cells per high power field on urine microscopy offered negligible incremental diagnostic benefit in samples with a negative dipstick urinalysis. Reflex urine culture protocols contingent upon a screening dipstick urinalysis are a safe and effective platform for diagnostic stewardship in patients with cancer including those with neutropenia.

Effectiveness and user experience of nose and throat swabbing techniques for SARS-CoV-2 detection: results from the UK COVID-19 National Testing Programme

BackgroundThe UK’s National Health Service Test and Trace (NHSTT) program aimed to provide the most effective and accessible SARS-CoV-2 testing approach possible. Early user feedback indicated that there were accessibility issues associated with throat swabbing. We report the results of service evaluations performed by NHSTT to assess the effectiveness and user acceptance of swabbing approaches, as well as qualitative findings of user experiences from research reports, surveys, and incident reports. Our intent is to present and summarize our findings about the application of alternative swabbing approaches during the COVID-19 pandemic in the UK.MethodsFrom May 2020 to December 2021, NHSTT conducted a series of service evaluations assessing self-swabbing and assisted swabbing of the nose and throat, and nose only (anterior nares/mid-turbinate) using polymerase chain reaction (PCR) and lateral flow devices (LFDs), for diagnostic suitability within the COVID-19 National Testing Programme. Outcomes included observational user feedback on swabbing approaches and quantitative testing performance (concordance, sensitivity, and specificity). A post-hoc indirect comparison of swabbing approaches was also performed. Additionally, an analysis of existing cross-service research was conducted in April 2021 to determine user feedback regarding swabbing approaches.ResultsObservational data from cross-service research indicated a user preference for nose swabbing over throat swabbing. Significantly more users reported that nose swabbing was easier to perform than throat swabbing (50% vs. 12%) and there were significantly fewer reported incidents. In the service evaluations, while there was reduced sensitivity for nose-only swabbing for PCR (88%) compared with nose and throat swabbing, similar sensitivities were observed for nose-only and nose and throat swabbing for LFDs. The sensitivity of nose-only swabbing for LFDs was higher for individuals with higher viral concentrations.ConclusionsUser experience analyses supported a preference for nose-only swabbing. Nose-only swabbing for LFDs provided sufficient diagnostic accuracy, supporting its use as a viable option in the COVID-19 National Testing Programme. Less invasive swabbing approaches are important to maximize testing accessibility and alongside other behavioral interventions, increase user uptake.

Intelligence is not deception: from the Turing test to community-based ascriptions

Abstract The Turing test has a peculiar status in the artificial intelligence (AI) research community. On the one hand, it is presented as an important topic in virtually every AI textbook, and the research direction focused on developing AI systems that behave in human-like fashion is standardly called the “Turing test approach”. On the other hand, reports of computer programs passing the Turing test have had relatively little effect. Does this mean that the Turing test is no longer relevant as a test, doomed to be a theoretical notion with little connection to AI practice? In this paper, I argue that there is one problem in particular with common traditional versions of the Turing test, namely their focus on deception. The criterion for passing the Turing test is standardly connected to an AI system’s ability to deceive the interrogator about its identity. But why should we connect intelligence to the ability deceive? Here I present a revised version of an intelligence test that is not based on deception. In what I call the Community-based intelligence test (CBIT), an AI is introduced to a community of human subjects. If after a sufficient number of interactions within that community the humans are not able to identify the AI system as a computer, it is considered to have passed CBIT. I discuss whether that should be enough to ascribe intelligence to the AI, and if not, what more would be needed?

Exploring Demographic Disparities in Private Well Water Testing in North Carolina.

The natural, built, and social environments shape drinking water quality supplied by private wells. However, the combined effects of these factors are not well understood. Using North Carolina as a case study, we (i) estimate the demographic characteristics of the private well population; (ii) evaluate representation in well testing records; and (iii) demonstrate how spatial scale influences knowledge of well-using household demographics and representation in testing. We leverage a statewide database of 117,960 well testing records collected over 20 years and a national model predicting well locations. An estimated 25% well-using households identify as Black, Indigenous, and Persons of Color (BIPOC) and 15% have incomes below the poverty threshold. While there is robust well sampling (an average of 4,269 wells tested annually), we observed that most testing records were from predominately White block groups (BGs). Well-using households that did not participate in state testing were 2.4 times more likely to be from predominately BIPOC BGs compared predominately White BGs. Due to the spatial heterogeneity of the well population, demographic differences in well populations were more evident using higher resolution data. Multifaceted testing approaches that couple government-driven efforts with localized studies that engage underrepresented communities are needed to facilitate evidence-based management.

Deleterious coding variation associated with autism is consistent across populations, as exemplified by admixed Latin American populations.

Branko Aleksic, Mykyta Artomov, Mafalda Barbosa, Elisa Benetti, Catalina Betancur, Monica Biscaldi-Schafer, Anders D. Børglum, Harrison Brand, Alfredo Brusco, Joseph D. Buxbaum, Gabriele Campos, Simona Cardaropoli, Diana Carli, Angel Carracedo, Marcus C. Y. Chan, Andreas G. Chiocchetti, Brian H. Y. Chung, Brett Collins, Ryan L. Collins, Edwin H. Cook, Hilary Coon, Claudia I. S. Costa, Michael L. Cuccaro, David J. Cutler, Mark J. Daly, Silvia De Rubeis, Bernie Devlin, Ryan N. Doan, Enrico Domenici, Shan Dong, Chiara Fallerini, Magdalena Fernandez, Montserrat Fernández-Prieto, Giovanni Battista Ferrero, Eugenio Ferro, Jennifer Foss Feig, Christine M. Freitag, Jack M. Fu, Liliana Galeano, J. Jay Gargus, Sherif Gerges, Elisa Giorgio, Ana Cristina Girardi, Stephen Guter, Emily Hansen-Kiss, Erina Hara, Danielle Halpern, Gail E. Herman, Luis C. Hernandez, Irva Hertz-Picciotto, David M. Hougaard, Christina M. Hultman, Suma Jacob, Miia Kaartinen, Lambertus Klei, Alexander Kolevzon, Itaru Kushima, Maria C. Lattig, So Lun Lee, Terho Lehtimäki, Lindsay Liang, Carla Lintas, Alicia Ljungdahl, Andrea del Pilar Lopez, Caterina Lo Rizzo, Yunin Ludena, Patricia Maciel, Behrang Mahjani, Nell Maltman, Marianna Manara, Dara S. Manoach, Dalia Marquez, Gal Meiri, Idan Menashe, Judith Miller, Nancy Minshew, Matthew Mosconi, Marina Natividad Avila, Rachel Nguyen, Norio Ozaki, Aarno Palotie, Mara Parellada, Maria Rita Passos-Bueno, Lisa Pavinato, Katherine P. Peña, Minshi Peng, Margaret Pericak-Vance, Antonio M. Persico, Isaac N. Pessah, Thariana Pichardo, Kaija Puura, Abraham Reichenberg, Alessandra Renieri, Kathryn Roeder, Catherine Sancimino, Stephan J. Sanders, Sven Sandin, F. Kyle Satterstrom, Stephen W. Scherer, Sabine Schlitt, Rebecca J. Schmidt, Lauren Schmitt, Katja Schneider-Momm, Paige M. Siper, Laura Sloofman, Moyra Smith, Renee Soufer, Christine R. Stevens, Pål Suren, James S. Sutcliffe, John A. Sweeney, Michael E. Talkowski, Flora Tassone, Karoline Teufel, Elisabetta Trabetti, Slavica Trajkova, Maria del Pilar Trelles, Brie Wamsley, Jaqueline Y. T. Wang, Lauren A. Weiss, Mullin H. C. Yu, Ryan Yuen, Jessica Zweifach.

Genetic landscape in undiagnosed patients with syndromic hearing loss revealed by whole exome sequencing and phenotype similarity search.

There are hundreds of rare syndromic diseases involving hearing loss, many of which are not targeted for clinical genetic testing. We systematically explored the genetic causes of undiagnosed syndromic hearing loss using a combination of whole exome sequencing (WES) and a phenotype similarity search system called PubCaseFinder. Fifty-five families with syndromic hearing loss of unknown cause were analyzed using WES after prescreening of several deafness genes depending on patient clinical features. Causative genes were identified in 22 families, including both established genes associated with syndromic hearing loss (PTPN11, CHD7, KARS1, OPA1, DLX5, MITF, SOX10, MYO7A, and USH2A) and those associated with nonsyndromic hearing loss (STRC, EYA4, and KCNQ4). Association of a DLX5 variant with incomplete partition type I (IP-I) anomaly of the inner ear was identified in a patient with cleft lip and palate and acetabular dysplasia. The study identified COL1A1, CFAP52, and NSD1 as causative genes through phenotype similarity search or by analogy. ZBTB10 was proposed as a novel candidate gene for syndromic hearing loss with IP-I. A mouse model with homozygous Zbtb10 frameshift variant resulted in embryonic lethality, suggesting the importance of this gene for early embryonic development. Our data highlight a wide spectrum of rare causative genes in patients with syndromic hearing loss, and demonstrate that WES analysis combined with phenotype similarity search is a valuable approach for clinical genetic testing of undiagnosed disease.