@article {933, title = { truncations cause arrhythmogenic right ventricular cardiomyopathy.}, journal = {J Med Genet}, volume = {57}, year = {2020}, month = {2020 04}, pages = {254-257}, abstract = {

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease that affects predominantly the right ventricle and is part of the spectrum of arrythmogenic cardiomyopathies (ACMs). ARVC is a genetic condition; however, a pathogenic gene variant is found in only half of patients.

OBJECTIVE: Filamin C gene truncations () have recently been identified in dilated cardiomyopathy with ventricular arrhythmia and sudden cardiac death, a phenotype partially overlapping with ARVC and part of the ACM spectrum. We hypothesised that could be a novel gene associated with ARVC.

METHODS: One hundred fifty-six patients meeting 2010 ARVC Task Force Criteria and lacking variants in known ARVC genes were evaluated for variants. Available family members were tested for cosegregation.

RESULTS: We identified two unique variants in two families (c.6565 G>T, p.Glu2189Ter and c.8107delG, p.Asp2703ThrfsTer69), with phenotypes of dominant RV disease fulfilling {\textquoteright}definite{\textquoteright} diagnosis of ARVC according to the 2010 Task Force Criteria. Variants in other cardiomyopathy genes were excluded in both kindreds, and segregation analysis revealed that p.Asp2703ThrfsTer69 was a de novo variant. In both families, the disease phenotype was characterised by prominent ventricular arrhythmias and sudden cardiac arrest.

CONCLUSION: The identification of as a novel cause of ARVC in two unrelated families expands the spectrum of ARVC disease genes for this disorder. Our findings should prompt inclusion of genetic testing in ARVC to improve diagnostic yield and testing of at-risk relatives in ARVC.

}, keywords = {Adult, Aged, Arrhythmogenic Right Ventricular Dysplasia, Female, Filamins, Genetic Predisposition to Disease, Genetic Testing, Heart Ventricles, Humans, Male, Middle Aged, Mutation, Phenotype}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2019-106394}, author = {Brun, Francesca and Gigli, Marta and Graw, Sharon L and Judge, Daniel P and Merlo, Marco and Murray, Brittney and Calkins, Hugh and Sinagra, Gianfranco and Taylor, Matthew Rg and Mestroni, Luisa and James, Cynthia A} } @article {631, title = {Enrolling Genomics Research Participants through a Clinical Setting: the Impact of Existing Clinical Relationships on Informed Consent and Expectations for Return of Research Results.}, journal = {J Genet Couns}, volume = {27}, year = {2018}, month = {2018 02}, pages = {263-273}, abstract = {

Genetic counselors working in a clinical setting may find themselves recruiting, enrolling, and returning results for genomic research, and existing clinical relationships with study participants may impact these research interactions. We present a qualitative study using semi-structured interviews of participants enrolled in a genome sequencing/exome sequencing (GS/ES) study at the same institution where they receive clinical care. Interviews were coded for motivations to participate and expectations of this research. The interviews revealed common motivations for participation, including altruism and hope for benefit for themselves, family members, and/or others with their condition. Additionally, themes emerged related to unintentional influence based on trust of the clinical provider that recruited them to the study. Participant trust in the enrolling provider at times appeared to extend to the study team to decide which research results to return and to do so in an appropriate format. Participants also based expectations for research results return on previous clinical genetic testing experiences, which may or may not be realistic depending on study design. It is imperative that genetic counselors enrolling patients into research studies be aware of the potential influence of their clinical relationship on potential subjects, be transparent about their role on the study team, and help set expectations about the study process, including results return.

}, keywords = {Base Sequence, Decision Making, Family, Female, Genetic Testing, Humans, Informed Consent, Male, Motivation, Qualitative Research, Research Design, Trust}, issn = {1573-3599}, doi = {10.1007/s10897-017-0143-2}, author = {Berrios, Courtney and James, Cynthia A and Raraigh, Karen and Bollinger, Juli and Murray, Brittney and Tichnell, Crystal and Applegate, Carolyn D and Bergner, Amanda L} } @article {336, title = {Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis.}, journal = {Cardiovasc Res}, volume = {113}, year = {2017}, month = {2017 01}, pages = {102-111}, abstract = {

AIMS: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is often associated with desmosomal mutations. Recent studies suggest an interaction between the desmosome and sodium channel protein Na1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding Na1.5) in ARVD/C.

METHODS AND RESULTS: We performed whole-exome sequencing in six ARVD/C patients (33\% male, 38.2 {\textpm} 12.1 years) without a desmosomal mutation. We found a rare missense variant (p.Arg1898His; R1898H) in SCN5A in one patient. We generated induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CMs) from the patient{\textquoteright}s peripheral blood mononuclear cells. The variant was then corrected (R1898R) using Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 technology, allowing us to study the impact of the R1898H substitution in the same cellular background. Whole-cell patch clamping revealed a 36\% reduction in peak sodium current (P = 0.002); super-resolution fluorescence microscopy showed reduced abundance of Na1.5 (P = 0.005) and N-Cadherin (P = 0.026) clusters at the intercalated disc. Subsequently, we sequenced SCN5A in an additional 281 ARVD/C patients (60\% male, 34.8 {\textpm} 13.7 years, 52\% desmosomal mutation-carriers). Five (1.8\%) subjects harboured a putatively pathogenic SCN5A variant (p.Tyr416Cys, p.Leu729del, p.Arg1623Ter, p.Ser1787Asn, and p.Val2016Met). SCN5A variants were associated with prolonged QRS duration (119 {\textpm} 15 vs. 94 {\textpm} 14 ms, P < 0.01) and all SCN5A variant carriers had major structural abnormalities on cardiac imaging.

CONCLUSIONS: Almost 2\% of ARVD/C patients harbour rare SCN5A variants. For one of these variants, we demonstrated reduced sodium current, Na1.5 and N-Cadherin clusters at junctional sites. This suggests that Na1.5 is in a functional complex with adhesion molecules, and reveals potential non-canonical mechanisms by which Na1.5 dysfunction causes cardiomyopathy.

}, keywords = {Adult, Antigens, CD, Arrhythmogenic Right Ventricular Dysplasia, Cadherins, Cell Differentiation, CRISPR-Cas Systems, DNA Mutational Analysis, Electrocardiography, Exome, Female, Gene Editing, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, HEK293 Cells, Humans, Induced Pluripotent Stem Cells, Magnetic Resonance Imaging, Male, Membrane Potentials, Middle Aged, Multilevel Analysis, Mutation, Missense, Myocytes, Cardiac, NAV1.5 Voltage-Gated Sodium Channel, Netherlands, Phenotype, Sodium, Transfection, United States, Young Adult}, issn = {1755-3245}, doi = {10.1093/cvr/cvw234}, author = {Te Riele, Anneline S J M and Agullo-Pascual, Esperanza and James, Cynthia A and Leo-Macias, Alejandra and Cerrone, Marina and Zhang, Mingliang and Lin, Xianming and Lin, Bin and Sobreira, Nara L and Amat-Alarcon, Nuria and Marsman, Roos F and Murray, Brittney and Tichnell, Crystal and van der Heijden, Jeroen F and Dooijes, Dennis and van Veen, Toon A B and Tandri, Harikrishna and Fowler, Steven J and Hauer, Richard N W and Tomaselli, Gordon and van den Berg, Maarten P and Taylor, Matthew R G and Brun, Francesca and Sinagra, Gianfranco and Wilde, Arthur A M and Mestroni, Luisa and Bezzina, Connie R and Calkins, Hugh and Peter van Tintelen, J and Bu, Lei and Delmar, Mario and Judge, Daniel P} } @article {221, title = {Informed consent for exome sequencing research in families with genetic disease: the emerging issue of incidental findings.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Nov}, pages = {2745-52}, abstract = {

Genomic sequencing technology is increasingly used in genetic research. Studies of informed consent for exome and genome sequencing (ES/GS) research have largely involved hypothetical scenarios or healthy individuals enrolling in population-based studies. Studies have yet to explore the consent experiences of adults with inherited disease. We conducted a qualitative interview study of 15 adults recently enrolled in a large-scale ES/GS study (11 affected adults, four parents of affected children). Our study had two goals: (1) to explore three theoretical barriers to consent for ES/GS research (interpretive/technical complexity, possibility of incidental findings, and risks of loss of privacy); and (2) to explore how interviewees experienced the consent process. Interviewees could articulate study goals and processes, describe incidental findings, discuss risks of privacy loss, and reflect on their consent experience. Few expected the study would identify the genetic cause of their condition. All elected to receive incidental findings. Interviewees acknowledged paying little attention to potential implications of incidental findings in light of more pressing goals of supporting research regarding their own medical conditions. Interviewees suggested that experience living with a genetic condition prepared them to adjust to incidental findings. Interviewees also expressed little concern about loss of confidentiality of study data. Some experienced the consent process as very long. None desired reconsent prior to return of study results. Families with inherited disease likely would benefit from a consent process in which study risks and benefits were discussed in the context of prior experiences with genetic research and genetic disease.

}, keywords = {Adolescent, Adult, Aged, Confidentiality, Ethics, Medical, Exome, Family, Female, Genetic Diseases, Inborn, Genetic Research, High-Throughput Nucleotide Sequencing, Humans, Incidental Findings, Informed Consent, Male, Middle Aged, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36706}, author = {Bergner, Amanda L and Bollinger, Juli and Raraigh, Karen S and Tichnell, Crystal and Murray, Brittney and Blout, Carrie Lynn and Telegrafi, Aida Bytyci and James, Cynthia A} }