Next-generation Genetic Sequencing Research Articles

Primary lateral sclerosis associated with PSEN1 Pro284Leu variant in a Colombian family: Clinical and neuropathological features.

This study investigates primary lateral sclerosis (PLS) as a rare manifestation of the presenilin 1 (PSEN1) NM_000021 c.851C>T p.Pro284Leu variant in three siblings of a Colombian family, outlining its clinical and neuropathological features and their relationship to Alzheimer's disease (AD). Data were gathered using clinical evaluations, next-generation genetic sequencing, magnetic resonance imaging, biomarker analysis, and neuropathological examination. Carriers of the PSEN1 Pro284Leu variant exhibited classic PLS symptoms, including unilateral onset and bulbar syndromes, along with cognitive decline. Neuropathology showed corticospinal tract degeneration without amyloid beta deposition in spinal white matter. Our findings suggest an overlap between PLS and AD pathology in PSEN1 variant carriers. Results support considering PLS when diagnosing AD-related motor syndromes and including PSEN1 evaluation when performing genetic testing for PLS. The study highlights the need for further research to clarify the PLS-AD relationship, informing future treatments and clinical trials. Pathogenic variants in presenilin 1 (PSEN1) can manifest as hereditary primary lateral sclerosis PSEN1 Pro284Leu carriers present motor, cognitive, and behavioral alterations Cases had corticospinal tract microgliosis and severe Aβ pathology in motor cortex There was no evidence of amyloid deposition in the spinal cord white matter All the neuropathology images are available for online visualization Myelin pallor in the spinal cord is confined to the lateral corticospinal tracts.

Next-Generation Sequencing of Microbial Cell-Free DNA to Rapidly Detect Fluoribacter Bozemanae Pneumonia in an Immunocompromised Host

Background: Fluoribacter bozemanae is an uncommon pathogen that accounts for just 3-5% of cases of pneumonia caused by the different Legionella species. The mortality rate has been reported to be up to 40%. This organism is difficult to identify, making diagnosis extremely challenging with current diagnostic modalities. Case Report: We present a case of a 75-year-old female with a history of multiple myeloma undergoing active treatment with immunosuppressive agents who presented with confusion, hypoxemic respiratory failure and sepsis. Her initial presentation was consistent with Legionella infection, however, all routine testing including a Legionella urine antigen test came back negative. A CT scan of the chest was completed which showed near complete left lower lobe consolidation concerning for pneumonia. An infectious workup was initiated. Atypical and viral pneumonia polymerase chain reaction panel was negative. Microbial cell-free DNA sequencing returned positive for Fluoribacter bozemanae, a subspecies of the Legionellaceae family that is known to cause severe pneumonia in immunocompromised hosts. This information allowed a therapy adjustment resulting in rapid improvement of our patient’s symptoms. Conclusion: In cases such as this one, the diagnosis of Legionella species is often missed due to the many challenges associated with the different testing modalities. In these circumstances, next-generation genetic sequencing can be extremely useful. Now with the increasing availability of next-generation sequencing as a microbiological diagnostic tool, we can diagnose many more infections that once would have gone undiagnosed and either untreated or delayed in treatment.

Functional identification of hot-spot mutations in cardiac calcium channel genes associated with the J wave syndromes.

J wave syndrome (JWS) is an inherited cardiac channelopathy associated with malignant ventricular arrhythmias and sudden cardiac death (SCD), which comprises early repolarization syndrome and Brugada syndrome. Here, we explore the association between variants in the L-type calcium channel gene subunits, α1C (CACNA1C) and β2b (CACNB2b), and the JWS phenotype. Using next-generation genetic sequencing of 402 JWS probands and their family members, we identified a CACNA1C-G37R (p.Gly37Arg) mutation in five individuals in four families, two of which had a family history of SCD as well as a CACNB2b-S143F (p.Ser143Phe) mutation in seven individuals in three families, two of which had a family history of SCD. The variants were located in exon 2 in CACNA1C and exon 5 in CACNB2b; both were in highly conserved amino acid residues. Whole-cell patch-clamp results showed that compared with the wild-type group, calcium current density of CACNB2b-S143F and CACNA1C-G37R were significantly lower displaying a dominant-negative effect. Our findings provide further support for the hypothesis that variants in CACNA1C and CACNB2b are associated with JWS. The results suggest that mutations in these two genes lead to loss-of-function of the cardiac calcium channel current warranting their inclusion in genetic screening protocols. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Update of pediatric bone tumors-other mesenchymal tumors of bone, hematopoietic neoplasms of bone, and WHO classification of undifferentiated small round cell sarcomas of bone.

There are numerous bone tumors in the pediatric population, with imaging playing an essential role in diagnosis and management. Our understanding of certain bone tumors has rapidly evolved over the past decade with advancements in next-generation genetic sequencing techniques. This increased level of understanding has altered the nomenclature, management approach, and prognosis of certain lesions. We provide a detailed update of bone tumors that occur in the pediatric population with emphasis on the recently released nomenclature provided in the 5th edition of the World Health Organization Classification of Soft Tissue and Bone Tumours. We discuss other mesenchymal tumors of bone, hematopoietic neoplasms of bone, and WHO classification of undifferentiated small round cell sarcomas of bone. We have detailed osteogenic tumors and osteoclastic giant cell-rich tumors, as well as notochordal tumors, chondrogenic tumors, and vascular tumors of the bone in separate manuscripts.

Clinical characteristics and electrophysiologic properties of SCN5A variants in fever-induced Brugada syndrome.

Brugada syndrome (BrS) is a severe inherited arrhythmia syndrome that can be unmasked by fever. A multicentre clinical analysis was performed in 261 patients diagnosed with fever-induced BrS, including 198 (75.9%) and 27 (10.3%) patients who received next-generation genetic sequencing and epicardial arrhythmogenic substrate (AS) mapping, respectively. In fever-induced BrS patients, pathogenic or likely pathogenic (P/LP) SCN5A variant carriers developed fever-induced BrS at a younger age, and more often in females and those of Caucasian descent. They exhibited significant electrophysical abnormalities, including a larger epicardial AS area, and more prolonged abnormal epicardial electrograms. During a median follow-up of 50.5 months (quartiles 32.5-81.5 months) after the diagnosis, major cardiac events (MCE) occurred in 27 (14.4%) patients. Patients with P/LP SCN5A variants had a higher ratio of MCE compared with the rest. Additionally, history of syncope, QRS duration, and Tpe interval could also predict an increased risk for future MCE according to univariate analysis. Multivariate analysis indicated that only P/LP SCN5A variants were independent significant predictors of MCE. Computational structural modelling showed that most variants are destabilizing, suggesting that Nav1.5 structure destabilization caused by SCN5A missense variants may contribute to fever-induced BrS. In our cohort, P/LP SCN5A variant carriers with fever-induced BrS are more prevalent among patients of Caucasian descent, females, and younger patients. These patients exhibit aggressive electrophysiological abnormalities and worse outcome, which warrants closer monitoring and more urgent management of fever. The current work was supported by the National Natural Science Foundation Project of China (Nos.82270332 & 81670304), The Fundamental Research Funds for the Central Universities of China - Independent Research Project of Wuhan University (No. 2042022kf1217) from China; the National Institutes of Health of USA [NIH R56 (HL47678), NIH R01 (HL138103), and NIH R01 (HL152201)], the W. W. Smith Charitable Trust and the Wistar and Martha Morris Fund, Sharpe-Strumia Research Foundation, the American Heart Association Postdoctoral Fellowship (20POST35220002) from United States; the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences (PREDICT2) from the Netherlands.

Update of pediatric bone tumors-notochordal tumors, chondrogenic tumors, and vascular tumors of the bone.

There are numerous bone tumors in the pediatric population, with imaging playing an essential role in diagnosis and management. Our understanding of certain bone tumors has rapidly evolved over the past decade with advancements in next-generation genetic sequencing techniques. This increased level of understanding has altered the nomenclature, management approach, and prognosis of certain lesions. We provide a detailed update of bone tumors that occur in the pediatric population with emphasis on the recently released nomenclature provided in the 5th edition of the World Health Organization Classification of Soft Tissue and Bone Tumours. In the current manuscript, we address notochordal tumors, chondrogenic tumors, and vascular tumors of the bone.

Update of pediatric bone tumors: osteogenic tumors and osteoclastic giant cell-rich tumors.

There are numerous bone tumors in the pediatric population, with imaging playing an essential role in diagnosis and management. Our understanding of certain bone tumors has rapidly evolved over the past decade with advancements in next-generation genetic sequencing techniques. This increased level of understanding has altered the nomenclature, management approach, and prognosis of certain lesions. We provide a detailed update of bone tumors that occur in the pediatric population with emphasis on the recently released nomenclature provided in the 5th edition of the World Health Organization Classification of Soft Tissue and Bone Tumours.

Impacts of genotypic variants on survival following reoperation for recurrent glioblastoma.

Recurrent glioblastoma (rGBM) prognosis is dismal. In the absence of effective adjuvant treatments for rGBM, re-resections remain prominent in our arsenal. This study evaluates the impact of reoperation on post-progression survival (PPS) considering rGBM genetic makeup. To assess the genetic heterogeneity and treatment-related changes (TRC) roles in re-operated or medically managed rGBMs, we compiled demographic, clinical, histopathological, and next-generation genetic sequencing (NGS) characteristics of these tumors from 01/2005 to 10/2019. Survival data and reoperation were analyzed using conventional and random survival forest analysis (RSF). Patients harboring CDKN2A/B loss (p = 0.017) and KDR mutations (p = 0.031) had notably shorter survival. Reoperation or bevacizumab were associated with longer PPS (11.2 vs. 7.4-months, p = 0.006; 13.1 vs 6.2, p < 0.001). Reoperated patients were younger, had better performance status and greater initial resection. In 136/273 (49%) rGBMs undergoing re-operation, CDKN2A/B loss (p = 0.03) and KDR mutations (p = 0.02) were associated with shorter survival. In IDH-WT rGBMs with NGS data (n = 166), reoperation resulted in 7.0-month longer survival (p = 0.004) than those managed medically. This reoperation benefit was independently identified by RSF analysis. Stratification analysis revealed that EGFR-mutant, CDKN2A/B-mutant, NF1-WT, and TP53-WT rGBM IDH-WT subgroups benefit most from reoperation (p = 0.03). Lastly, whether or not TRC was prominent at re-operation does not have any significant impact on PPS (10.5 vs. 11.5-months, p = 0.77). Maximal safe re-resection significantly lengthens PPS regardless of genetic makeup, but reoperations are especially beneficial for IDH-WT rGBMs with EGFR and CDKN2A/B mutations with TP53-WT, and NF1-WT. Histopathology at recurrence may be an imperfect gauge of disease severity at progression and the imaging progression may be more reflective of the prognosis.

Molecular insights into malignant progression of atypical choroid plexus papilloma.

Choroid plexus tumors are rare pediatric neoplasms ranging from low-grade papillomas to overtly malignant carcinomas. They are commonly associated with Li–Fraumeni syndrome and germline TP53 mutations. Choroid plexus carcinomas associated with Li–Fraumeni syndrome are less responsive to chemotherapy, and there is a need to avoid radiation therapy leading to poorer outcomes and survival. Malignant progression from choroid plexus papillomas to carcinomas is exceedingly rare with only a handful of cases reported, and the molecular mechanisms of this progression remain elusive. We report a case of malignant transformation of choroid plexus papilloma to carcinoma in a 7-yr-old male with a germline TP53 mutation in which we present an analysis of molecular changes that might have led to the progression based on the next-generation genetic sequencing of both the original choroid plexus papilloma and the subsequent choroid plexus carcinoma. Chromosomal aneuploidy was significant in both lesions with mostly gains present in the papilloma and additional significant losses in the carcinoma. The chromosomal loss that occurred, in particular loss of Chromosome 13, resulted in the losses of two critical tumor suppressor genes, RB1 and BRCA2, which might play a possible role in the observed malignant transformation.

Clinical Characteristics and Electrophysiologic Properties of&amp;nbsp; &lt;i&gt;SCN5A&lt;/i&gt; Variants in Fever-Induced Brugada Syndrome

Background: Brugada syndrome (BrS) is a severe inherited arrhythmia syndrome which can be unmasked by fever. Methods: A clinical analysis was performed in 134 probands diagnosed with fever-induced BrS, including 59 patients who received next-generation genetic sequencing. We employed a biophysics-based computational protocol to investigate whether protein structure destabilization contributes to Nav1.5 variant-mediated fever-induced BrS. Findings: Among all cases enrolled, the symptoms at diagnosis were syncope in 26 (19.40%) and major arrhythmic events (MAE) in 16 (11.94%). SCN5A variant carriers were significantly younger than probands free of SCN5A variants. Compared with a historical cohort of non-fever BrS probands carrying SCN5A variants, carriers with fever-induced BrS were prone to MAE at younger age, and had a higher proportion of variants localizing at the interdomain linkers. Modeling result showed that most variants are destabilizing when temperature increases, suggesting that Nav1.5 structure destabilization is the cause of fever-induced BrS associated with SCN5A variants. Interpretation: In our cohort, SCN5A variant carriers with fever-induced BrS present at a younger age and harbor SCN5A variants predominantly localized to interdomain linker regions of Nav1.5. These SCN5A variants typically induce destabilization of Nav1.5 structure at higher body temperatures. Patients with SCN5A mutations present within interdomain linker regions may warrant more aggressive monitoring and management of fever. Funding Statement: The current work was supported by the National Natural Science Foundation Project of China (Grant No. 81670304); the National Institutes of Health of USA (NIH R56 - HL47678], NIH R01 [HL138103]), NIH R01 [HL152201], the W.W. Smith Charitable Trust and the Wistar and Martha Morris Fund. Declaration of Interests: The authors report no relationships that could be construed as a conflict of interest. Ethics Approval Statement: This study was approved by the Institutional Review Board of each hospital and performed in accordance with the declaration of Helsinki. All participants gave written informed consent.

Development of an Algorithm for Determining of Genetic Risk at the Primary Healthcare Level - A New Tool for Primary Prevention: A Study Protocol.

IntroductionFamily history (FH) is an important part of the patients’ medical history during preventive management at model family medicine practices (MFMP). It currently includes a one (or two) generational inquiry, predominately in terms of cardiovascular diseases, arterial hypertension, and diabetes, but not of other diseases with a probable genetic aetiology. Beside family history, no application-based algorithm is available to determine the risk level for specific chronic diseases in Slovenia.MethodsA web application-based algorithm aimed at determining the risk level for selected monogenic and polygenic diseases will be developed. The data will be collected in MFMP; approximately 40 overall with a sample including healthy preventive examination attendees (approximately 1,000). Demographic data, a three-generational FH, a medical history of acquired and congenital risk factors for the selected diseases, and other important clinical factors will be documented.ResultsThe results will be validated by a clinical genetic approach based on family pedigrees and the next-generation genetic sequencing method. After the risk of genetic diseases in the Slovenian population has been determined, clinical pathways for acting according to the assessed risk level will be prepared.ConclusionBy means of a public health tool providing an assessment of family predisposition, a contribution to the effective identification of people at increased risk of the selected monogenic and polygenic diseases is expected, lessening a significant public health burden.

Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series

Next-generation genetic sequencing (NGS) technologies facilitate the screening of multiple genes linked to neurodegenerative dementia, but there are few reports about their use in clinical practice. Which patients would most profit from testing, and information on the likelihood of discovery of a causal variant in a clinical syndrome, are conspicuously absent from the literature, mostly for a lack of large-scale studies. We applied a validated NGS dementia panel to 3241 patients with dementia and healthy aged controls; 13,152 variants were classified by likelihood of pathogenicity. We identified 354 deleterious variants (DV, 12.6% of patients); 39 were novel DVs. Age at clinical onset, clinical syndrome and family history each strongly predict the likelihood of finding a DV, but healthcare setting and gender did not. DVs were frequently found in genes not usually associated with the clinical syndrome. Patients recruited from primary referral centres were compared with those seen at higher-level research centres and a national clinical neurogenetic laboratory; rates of discovery were comparable, making selection bias unlikely and the results generalisable to clinical practice. We estimated penetrance of DVs using large-scale online genomic population databases and found 71 with evidence of reduced penetrance. Two DVs in the same patient were found more frequently than expected. These data should provide a basis for more informed counselling and clinical decision making.

Needles, Haystacks, and Next-Generation Genetic Sequencing

Genetic testing is becoming more frequent and the results more complex. Not infrequently, genetic testing that is conducted for one purpose reveals information about other features of the genome that may be of clinical significance. These unintended findings have been referred to as “incidental” or “secondary.” In 2013, the American College of Medical Genetics (ACMG) recommended that clinical laboratories inform people if their genetic analyses indicate that they have certain secondary mutations. These mutations were selected because they probably cause a serious disease, which is treatable, and may go undetected. The ACMG’s recommendations galvanized critical responses by the genetics and ethics community. One of the most important open questions concerns the scope of negligence liability for clinical laboratories if they failed to provide any of these SFs to patients who never requested them. To answer this question, this article argues that while there might be an ethical or professional obligation to share knowledge about these specific genetic mutations, laboratories should not be subject to tort liability for failure to share secondary findings directly with patients. The paper analyzes traditional common law doctrines surrounding the duty to warn to explain why the harm is not foreseeable enough and the burden is too great.

3:27 PM Abstract No. 264 PI3K pathway mutations predict response on PET/CT after radioembolization as salvage therapy for heavily pretreated patients with breast cancer liver metastases

Transarterial radioembolization (RE) is an emerging treatment for patients with hepatic metastasis due to breast cancer. This single-center retrospective review was conducted to identify factors predicting favorable outcomes and survival after RE. Thirty-one heavily pretreated female patients underwent RE between January 2011 and September 2017 (9 with glass and 22 with resin microspheres). Of these, 24 also underwent next-generation genetic sequencing with MSK-IMPACT or Sequenom, and 26 had PET/CTs available to document imaging response performed on average 38 ± 35 before and 80 ± 33 days after RE. Response was categorized as complete response when the SUVmax in the targeted liver segments decreased by >80%, partial response when SUVmax decreased by 30-80%, stable disease when a change in by normalized SUVmax between -30% and 30%, and progressive disease when normalized SUVmax increased by more than 30%. Kaplan-Meier survival analysis demonstrated a median survival after RE of 10.8 months. Complete or partial response was achieved in 18/26 (69%). PI3K pathway mutations were associated with imaging response (p = 0.006) but not survival (p = 0.58). Imaging response predicted longer survival (p = 0.005). Trends for lower bilirubin levels (p = 0.15), lower preprocedure neutrophil-to-lymphocyte ratio (p = 0.06), younger age (p = 0.15), and lower total bilirubin level (p = 0.06) to predict improved survival were not significant. Mutations in TP53, the MAPK-ERK pathway, hormonal status, and preradioembolization imaging variables (lung shunt fraction, arterial enhancement fraction, or tumor burden) did not correlate with imaging response (p>0.05). Three (9.6%) patients had major adverse events after resin microsphere-radioembolization, including two with gastric ulcers managed conservatively and one with liver failure and death 26 days after the first lobar treatment. These preliminary observations confirm the prognostic relevance of early interval follow-up imaging after RE to survival. Furthermore, these data suggest that genomic profiling may help predict which metastatic breast cancer patients could benefit most from RE.

Needles, Haystacks, and Next-Generation Genetic Sequencing

Genetic testing is becoming more frequent and the results more complex. Not infrequently, genetic testing that is conducted for one purpose reveals information about other features of the genome that may be of clinical significance. These unintended findings have been referred to as “incidental” or “secondary.” In 2013, the American College of Medical Genetics (ACMG) recommended that clinical laboratories inform people if their genetic analyses indicate that they have certain secondary mutations. These mutations were selected because they probably cause a serious disease, which is treatable, and may go undetected. The ACMG’s recommendations galvanized critical responses by the genetics and ethics community. One of the most important open questions concerns the scope of negligence liability for clinical laboratories if they failed to provide any of these SFs to patients who never requested them. To answer this question, this article argues that while there might be an ethical or professional obligation to share knowledge about these specific genetic mutations, laboratories should not be subject to tort liability for failure to share secondary findings directly with patients. The paper analyzes traditional common law doctrines surrounding the duty to warn to explain why the harm is not foreseeable enough and the burden is too great.

CLINICAL PROGRESS IN INHERITED RETINAL DEGENERATIONS: GENE THERAPY CLINICAL TRIALS AND ADVANCES IN GENETIC SEQUENCING.

Inherited retinal dystrophies are a significant cause of vision loss and are characterized by the loss of photoreceptors and the retinal pigment epithelium (RPE). Mutations in approximately 250 genes cause inherited retinal degenerations with a high degree of genetic heterogeneity. New techniques in next-generation sequencing are allowing the comprehensive analysis of all retinal disease genes thus changing the approach to the molecular diagnosis of inherited retinal dystrophies. This review serves to analyze clinical progress in genetic diagnostic testing and implications for retinal gene therapy. A literature search of PubMed and OMIM was conducted to relevant articles in inherited retinal dystrophies. Next-generation genetic sequencing allows the simultaneous analysis of all the approximately 250 genes that cause inherited retinal dystrophies. Reported diagnostic rates range are high and range from 51% to 57%. These new sequencing tools are highly accurate with sensitivities of 97.9% and specificities of 100%. Retinal gene therapy clinical trials are underway for multiple genes including RPE65, ABCA4, CHM, RS1, MYO7A, CNGA3, CNGB3, ND4, and MERTK for which a molecular diagnosis may be beneficial for patients. Comprehensive next-generation genetic sequencing of all retinal dystrophy genes is changing the paradigm for how retinal specialists perform genetic testing for inherited retinal degenerations. Not only are high diagnostic yields obtained, but mutations in genes with novel clinical phenotypes are also identified. In the era of retinal gene therapy clinical trials, identifying specific genetic defects will increasingly be of use to identify patients who may enroll in clinical studies and benefit from novel therapies.

Combined Genetic Biomarkers Confer Susceptibility to Risk of Urothelial Bladder Carcinoma in a Saudi Population.

We evaluated the associations between seven single nucleotide polymorphisms and susceptibility to urothelial bladder carcinoma (UBC) in a Saudi population. Genomic DNA was taken from buccal cells of 52 patients with UBC and 104 controls for genotyping of GSTT1, GSTM1, rs4646903, rs1048943, TP53 rs1042522, rs1801133, and rs1801394 using PCR and TaqMan® assays. The rs1801133 and rs1801394 variants showed strong associations with UBC (OR = 2.3, P = 0.0002; OR = 2.6, P = 0.0001, resp.). Homozygosity of Pro72 conferred a significant double risk in cases compared with controls (30.8% versus 15.4%), but the homozygote Arg/Arg had no effect on risk. Genotypic combinations of GSTM1/GSTT1, rs4646903/rs1048943, and rs1801133/rs1801394 exhibited significant linkage with the disease (χ2 = 10.3, P = 0.006; χ2 = 13.9, P = 0.003; and χ2 = 20.4, P = 0.0004, resp.). The GSTM1 and rs1042522Arg and rs1801394G variant alleles were more frequent in current smokers with UBC (52.4%, 52.5%, and 64.3%, resp.) than were the corresponding wild-types. Despite some variants having only a slight effect on UBC risk, the interaction effect of combined genetic biomarkers—or even the presence of one copy of a variant allele—is potentially much greater. Perhaps more studies regarding next-generation genetic sequencing and its utility can add to the risk of UBC.

Diagnostic Approach to Unexplained Cardiac Arrest (from the FIVI-Gen Study)

Unexplained cardiac arrest (UCA) can be caused by low-penetrance genetic disorders. The aim of this cross-sectional study is to assess the usefulness of a new diagnostic protocol: Thirty-five patients were recruited from 9 Spanish centers. Electrocardiogram, echocardiogram, and coronary catheterization were used to rule out electrical or structural heart disease in all subjects. Patients underwent pharmacologic tests with epinephrine and flecainide, followed by assessment of family members using electrocardiogram and echocardiogram, and next-generation genetic sequencing to analyze 126 genes if all the other test results were negative. A firm diagnosis of channelopathy required phenotypic proof of the condition in unmasking tests, the presence of a pathogenic variant consistent with the phenotype observed, and/or co-segregation of the mutation found in a family member's phenotype. A firm diagnosis was made in 18 cases. The diagnoses were 7 Brugada syndrome, 5 catecholaminergic polymorphic ventricular tachycardia, 3 long QT syndrome, 2 early repolarization syndrome, and 1 short QT syndrome. Pharmacologic testing was the most frequent method of diagnosis. In 5 cases, the diagnosis was made based on positive genetic testing without phenotypic alterations. In conclusion, this sequential diagnostic protocol allows diagnoses to be made in approximately half of the UCA cases. These diagnoses are low clinical penetrance channelopathies. If interpreted carefully, genetic tests can be a useful tool for diagnosing UCA without a phenotype.

Do Researchers Have an Obligation to Actively Look for Genetic Incidental Findings?

The rapid growth of next-generation genetic sequencing has prompted debate about the responsibilities of researchers toward genetic incidental findings. Assuming there is a duty to disclose significant incidental findings, might there be an obligation for researchers to actively look for these findings? We present an ethical framework for analyzing whether there is a positive duty to look for genetic incidental findings. Using the ancillary care framework as a guide, we identify three main criteria that must be present to give rise to an obligation to look: high benefit to participants, lack of alternative access for participants, and reasonable burden on researchers. Our analysis indicates that there is no obligation to look for incidental findings today, but during the ongoing translation of genomic analysis from research to clinical care, this obligation may arise.