scholarly journals Genetic diagnosis in hypertrophic cardiomyopathy: two steps forward, one step back

2021 ◽  
Vol 51 (2) ◽  
pp. 109-117
Author(s):  
Lidia Hategan ◽  
Beáta Csányi ◽  
János Borbás ◽  
Eszter Dalma Pálinkás ◽  
Hedvig Takács ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Expert Panel ◽  
Clinical Care ◽  
Genetic Diagnosis ◽  
Cardiovascular Disorder ◽  
Chain Gene ◽  
Web Based ◽  
Inherited Cardiomyopathy ◽  
Next Generation Sequencing Ngs

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disorder worldwide which exhibits considerable genetic heterogeneity. Widespread utilization of next-generation sequencing (NGS) in HCM has uncovered substantial genetic variation and highlighted the importance of a standardized approach to variant interpretation. According to this, accurate and consistent interpretation of sequence variants is essential for effective clinical care for individuals and their families with HCM. With this regard, the 2015 guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) were widely applicable, but several elements lacked specificity for given genes or diseases. The latter guideline was adapted for the most frequent causative HCM gene, the beta myosin heavy chain gene (MYH7) by the ClinGen (Clinical Genome Resource) expert panel, the Inherited Cardiomyopathy Expert Panel. Due to the adaptation, the guideline became gene-specific, with general considerations which are widely adaptable for most of the causative genes in HCM. Based on the modified guideline, web-based interpretation algorithms have been developed which integrate data from population databases and define pathogenicity of different variants independent of the observer, therefore aiding standardized clinical interpretation of genetic testing. The latter approach serves as a basis for recommendation for genetic testing in the recent ACC/AHA HCM guideline published in 2020. The current review is meant to compile the latest advances in HCM genetic testing in clinical practice, while bringing into focus some of the ongoing challenges clinical geneticists are still facing. Although nowadays the interpretation of genetic findings is two steps closer to a more accurate approach due to gene adaptation and automatization, the multitude of putative causative genes have been once again reduced to the 8 sarcomere genes, a backward step.

scholarly journals Új lehetőség a szisztolés szívelégtelenség (HFrEF) kezelésében: omecamtiv-mecarbil

2021 ◽  
Vol 51 (2) ◽  
pp. 118-124
Author(s):  
Arnold Péter Ráduly ◽  
Attila Tóth ◽  
Zoltán Papp ◽  
Attila Borbély
Keyword(s):  
Genetic Testing ◽  
Expert Panel ◽  
Clinical Care ◽  
Cardiovascular Disorder ◽  
Chain Gene ◽  
Web Based ◽  
Inherited Cardiomyopathy ◽  
Omecamtiv Mecarbil ◽  
Next Generation Sequencing Ngs ◽  
Population Databases

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disorder worldwide which exhibits considerable genetic heterogeneity. Widespread utilization of next-generation sequencing (NGS) in HCM has uncovered substantial genetic variation and highlighted the importance of a standardized approach to variant interpretation. According to this, accurate and consistent interpretation of sequence variants is essential for effective clinical care for individuals and their families with HCM. With this regard, the 2015 guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) were widely applicable, but several elements lacked specificity for given genes or diseases. The latter guideline was adapted for the most frequent causative HCM gene, the beta myosin heavy chain gene (MYH7) by the ClinGen (Clinical Genome Resource) expert panel, the Inherited Cardiomyopathy Expert Panel. Due to the adaptation, the guideline became gene-specific, with general considerations which are widely adaptable for most of the causative genes in HCM. Based on the modified guideline, web-based interpretation algorithms have been developed which integrate data from population databases and define pathogenicity of different variants independent of the observer, therefore aiding standardized clinical interpretation of genetic testing. The latter approach serves as a basis for recommendation for genetic testing in the recent ACC/AHA HCM guideline published in 2020. The current review is meant to compile the latest advances in HCM genetic testing in clinical practice, while bringing into focus some of the ongoing challenges clinical geneticists are still facing. Although nowadays the interpretation of genetic findings is two steps closer to a more accurate approach due to gene adaptation and automatization, the multitude of putative causative genes have been once again reduced to the 8 sarcomere genes, a backward step.

scholarly journals Choosing Impairment: conflicting interests

2019 ◽  
Vol 18 (2) ◽  
pp. 229
Author(s):  
Selina Carolyne Metternick-Jones
Keyword(s):  
Genetic Testing ◽  
Case Studies ◽  
Moral Obligation ◽  
Clinical Care ◽  
Genetic Diagnosis ◽  
Future Generations ◽  
Parental Responsibility ◽  
Number Of Children ◽  
Conflicting Interests ◽  
The Relationship

The integration of reproductive genetic testing into clinical care presents both opportunities and challenges to parents in regards to shaping the lives of their future children. The relationship between parents and their future children has become more complex and new questions are being raised in relation to the extent of parental responsibility to future generations. This paper explores the ethical permissibility of using pre-implantation genetic diagnosis (PGD) to select for impairment, through the use of two case studies involving identify affecting decisions. Through analysing harm through both a personal and impersonal approach it is concluded that if a couple, or single reproducer, have a choice between an impaired and healthy embryo, and that the same number of children would result from selection, there is a moral obligation for parents to select the ones which will have an acceptable level of interest fulfilment and a normal opportunity for health.

scholarly journals Choosing Impairment: Conflicting Interests

2019 ◽  
Vol 18 (2) ◽  
pp. 229
Author(s):  
Selina Metternick-Jones
Keyword(s):  
Genetic Testing ◽  
Case Studies ◽  
Moral Obligation ◽  
Clinical Care ◽  
Genetic Diagnosis ◽  
Future Generations ◽  
Parental Responsibility ◽  
Number Of Children ◽  
Conflicting Interests ◽  
The Relationship

The integration of reproductive genetic testing into clinical care presents both opportunities and challenges for parents in regards to shaping the lives of their future children. The relationship between parents and their future children has become more complex and new questions are being raised in relation to the extent of parental responsibility to future generations. This paper explores the ethical permissibility of using pre-implantation genetic diagnosis (PGD) to select for impairment, through the use of two case studies involving identity-affecting decisions. Through analysing harm using both a personal and impersonal approach, it is concluded that if a couple, or single reproducer, have a choice between an impaired and healthy embryo, and that the same number of children would result from selection, there is a moral obligation for parents to select the ones which will have an acceptable level of interest fulfilment and a normal opportunity for health.

scholarly journals Transcriptome Sequencing of Patients with Hypertrophic Cardiomyopathy Reveals Novel Splice-altering Variants in MYBPC3

2021 ◽  
Author(s):  
Mira Holliday ◽  
Emma S. Singer ◽  
Samantha B. Ross ◽  
Seakcheng Lim ◽  
Sean Lal ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Transcriptome Sequencing ◽  
Cardiac Tissue ◽  
Therapeutic Option ◽  
Genetic Diagnosis ◽  
Induced Pluripotent Stem Cell ◽  
Patient Specific ◽  
Cryptic Exon ◽  
Exon Splicing

Background - Transcriptome sequencing can improve genetic diagnosis of Mendelian diseases but requires access to tissue expressing disease-relevant transcripts. We explored genetic testing of hypertrophic cardiomyopathy (HCM) using transcriptome sequencing of patient-specific human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). We also explored whether antisense oligonucleotides (AOs) could inhibit aberrant mRNA splicing in hiPSC-CMs. Methods - We derived hiPSC-CMs from patients with HCM due to MYBPC3 splice-gain variants, or an unresolved genetic cause. We used transcriptome sequencing of hiPSC-CM RNA to identify pathogenic splicing and used AOs to inhibit this splicing. Results - Transcriptome sequencing of hiPSC-CMs confirmed aberrant splicing in two people with previously identified MYBPC3 splice-gain variants (NM_000256.3:c.1090+453C>T and NM_000256.3:c.1224-52G>A). In a patient with an unresolved genetic cause of HCM following genome sequencing, transcriptome sequencing of hiPSC-CMs revealed diverse cryptic exon splicing due to an MYBPC3 NM_000256.3:c.1928-569G>T variant, and this was confirmed in cardiac tissue from an affected sibling. AO treatment demonstrated almost complete inhibition of cryptic exon splicing in one patient-specific hiPSC-CM line. Conclusions - Transcriptome sequencing of patient specific hiPSC-CMs solved a previously undiagnosed genetic cause of HCM and may be a useful adjunct approach to genetic testing. AO inhibition of cryptic exon splicing is a potential future personalised therapeutic option.

scholarly journals Framing Effects on Decision-Making for Diagnostic Genetic Testing: Results from a Randomized Trial

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 941
Author(s):  
Andrew A. Dwyer ◽  
Hongjie Shen ◽  
Ziwei Zeng ◽  
Matt Gregas ◽  
Min Zhao
Keyword(s):  
Genetic Testing ◽  
Behavioral Control ◽  
Clinical Care ◽  
Framing Effects ◽  
Web Based ◽  
Common Life ◽  
Decision Frames ◽  
Opt Out ◽  
Life Threatening ◽  
Individual Self

Genetic testing is increasingly part of routine clinical care. However, testing decisions may be characterized by regret as findings also implicate blood relatives. It is not known if genetic testing decisions are affected by the way information is presented (i.e., framing effects). We employed a randomized factorial design to examine framing effects on hypothetical genetic testing scenarios (common, life-threatening disease and rare, life-altering disease). Participants (n = 1012) received one of six decision frames: choice, default (n = 2; opt-in, opt-out), or enhanced choice (n = 3, based on the Theory of Planned Behavior). We compared testing decision, satisfaction, regret, and decision cognitions across decision frames and between scenarios. Participants randomized to ‘choice’ were least likely to opt for genetic testing compared with default and enhanced choice frames (78% vs. 83–91%, p < 0.05). Neither satisfaction nor regret differed across frames. Perceived autonomy (behavioral control) predicted satisfaction (B = 0.085, p < 0.001) while lack of control predicted regret (B = 0.346, p < 0.001). Opting for genetic testing did not differ between disease scenarios (p = 0.23). Results suggest framing can nudge individuals towards opting for genetic testing. These findings have important implications for individual self-determination in the genomic era. Similarities between scenarios with disparate disease trajectories point to possible modular approaches for web-based decisional support.

scholarly journals Current management of Inherited Retinal Degenerations (IRD) patients in Europe. Results of a multinational survey by the European Vision Institute Clinical Research Network EVICR.net

2021 ◽  
Author(s):  
Birgit Lorenz ◽  
Joana Tavares ◽  
L. Ingeborgh van den Born ◽  
João Pedro Marques ◽  
Hendrik P.N. Scholl
Keyword(s):  
Health Insurance ◽  
Genetic Testing ◽  
Age Of Onset ◽  
Genetic Diagnosis ◽  
Research Network ◽  
Fundus Photography ◽  
Significant Heterogeneity ◽  
Autofluorescence Imaging ◽  
Web Based ◽  
Retinal Degenerations

Purpose: An increasing number of gene therapies are developed for Inherited Retinal Degenerations (IRD). To date, one treatment has been approved for clinical use (FDA USA 2017, EMA Europe 2018, MoHAP UAE 2019, SFDA Saudi Arabia 2019, Swiss Medic Switzerland 2020, TGA Australia 2020, BFR Brazil 2020). Whilst such therapies do not provide complete cure, they may halt degeneration or partially restore function. Identification of well-characterized patients is an emerging need. We conducted the first multinational survey to understand the management of IRDs in Europe. Methods: An electronic survey questionnaire containing 112 questions was developed and sent to the 101 EVICR.net Clinical Centers (14 European Countries and Israel). Results: The overall response rate was 49%. Only 14% of responding centers do not see IRD patients; 52% that manage IRD patients follow ≥200 patients, 16% >1000. Databases exist in 86% of the centers; of these 75% are local files, 28% local web-based database and 19% national web-based. IRD patients are referred to EVICR.net centers mainly by general ophthalmologists, patient self-referrals and medical retina specialists. Most IRD patients are first seen in adulthood. Most prominent signs and symptoms depend on age of onset, e.g. nystagmus in infancy, or night blindness and reduced visual acuity at older age. The time from inquiring for first appointment and clinical diagnosis varies among countries: in 29% of centers, the mean time is < 4 weeks, although can be up to 35 months in others. The time to genetic diagnosis is ≥4 weeks, the maximum 10 years, likely depending on access to genetic testing, and the improvement of the tests available. Comprehensive eye examination always includes autofluorescence imaging and perimetry (86% static; 76% kinetic; 21% microperimetry), and frequently optical coherence tomography (95%), electroretinography (93%) and fundus photography (93%). Identified genotypes were reported in 40 to 80% patients by 69% of centers, and in 80 to 100% by 5%. Genetic testing is provided by public health insurance in 77% of centers, private health insurance in 38%, center budget in 13%, research funds in 18%; 15% of centers do not have access to genetic testing. Conclusion: At the start of this era of ocular gene therapy for IRD patients, this first international survey on management of IRDs in Europe highlights significant heterogeneity between centers and across countries and provides important baseline data for researchers, clinicians, pharmaceutical companies and investors.

scholarly journals A framework for the evaluation of patients with congenital facial weakness

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Bryn D. Webb ◽  
Irini Manoli ◽  
Elizabeth C. Engle ◽  
Ethylin W. Jabs
Keyword(s):  
Genetic Counseling ◽  
Genetic Testing ◽  
Patient Population ◽  
Clinical Care ◽  
Diagnostic Algorithm ◽  
Accurate Diagnosis ◽  
Facial Weakness ◽  
The Core ◽  
Follow Up Studies

AbstractThere is a broad differential for patients presenting with congenital facial weakness, and initial misdiagnosis unfortunately is common for this phenotypic presentation. Here we present a framework to guide evaluation of patients with congenital facial weakness disorders to enable accurate diagnosis. The core categories of causes of congenital facial weakness include: neurogenic, neuromuscular junction, myopathic, and other. This diagnostic algorithm is presented, and physical exam considerations, additional follow-up studies and/or consultations, and appropriate genetic testing are discussed in detail. This framework should enable clinical geneticists, neurologists, and other rare disease specialists to feel prepared when encountering this patient population and guide diagnosis, genetic counseling, and clinical care.

scholarly journals Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases

2021 ◽  
Vol 22 (4) ◽  
pp. 1508
Author(s):  
Jordi Maggi ◽  
Samuel Koller ◽  
Luzy Bähr ◽  
Silke Feil ◽  
Fatma Kivrak Pfiffner ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Long Range ◽  
Copy Number Variants ◽  
Retinal Disease ◽  
Promoter Regions ◽  
Long Range Pcr ◽  
Cost Efficient ◽  
Nucleotide Resolution ◽  
Genomic Regions ◽  
Next Generation Sequencing Ngs

The purpose of this study was to develop a flexible, cost-efficient, next-generation sequencing (NGS) protocol for genetic testing. Long-range polymerase chain reaction (PCR) amplicons of up to 20 kb in size were designed to amplify entire genomic regions for a panel (n = 35) of inherited retinal disease (IRD)-associated loci. Amplicons were pooled and sequenced by NGS. The analysis was applied to 227 probands diagnosed with IRD: (A) 108 previously molecularly diagnosed, (B) 94 without previous genetic testing, and (C) 25 undiagnosed after whole-exome sequencing (WES). The method was validated with 100% sensitivity on cohort A. Long-range PCR-based sequencing revealed likely causative variant(s) in 51% and 24% of proband from cohorts B and C, respectively. Breakpoints of 3 copy number variants (CNVs) could be characterized. Long-range PCR libraries spike-in extended coverage of WES. Read phasing confirmed compound heterozygosity in 5 probands. The proposed sequencing protocol provided deep coverage of the entire gene, including intronic and promoter regions. Our method can be used (i) as a first-tier assay to reduce genetic testing costs, (ii) to elucidate missing heritability cases, (iii) to characterize breakpoints of CNVs at nucleotide resolution, (iv) to extend WES data to non-coding regions by spiking-in long-range PCR libraries, and (v) to help with phasing of candidate variants.

scholarly journals Local Laboratory Testing of Germline BRCA Mutations vs. Myriad: A Single-Institution Experience in Korea

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 370
Author(s):  
Joohyun Hong ◽  
Jiyun Lee ◽  
Minsuk Kwon ◽  
Ji-Yeon Kim ◽  
Jong-Won Kim ◽  
...  
Keyword(s):  
Genetic Testing ◽  
High Risk ◽  
Salt Lake ◽  
Medical Center ◽  
Brca Mutation ◽  
Genetic Diagnosis ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Brca 1 ◽  
Local Laboratory

Genetic diagnosis for human epidermal growth factor receptor 2-negative metastatic breast cancer patients with the germline BRCA (gBRCA) mutation has been emphasized since the development of polyadenosine diphosphate-ribose polymerase inhibitors. Myriad Genetics, Inc.’s (Salt Lake City, UT, USA) companion diagnostics service is almost exclusively used for genetic testing. The aim of this study was to compare the results of germline BRCA mutation tests returned by a local laboratory and those performed by Myriad. Between April 2014 and February 2018, 31 patients with gBRCA 1/2 mutation test results from both Samsung Medical Center (Seoul, Korea) and Myriad were enrolled. “Discordant: Opposite classification” was observed for only one among 27 (3.7%). This discrepancy was due to the detection of a deleterious large genomic rearrangement of BRCA 1 by Myriad. Samsung Medical Center performed multiple ligation-dependent probe amplifications (MLPA) to detect large genomic rearrangements only in high-risk patients. This one case was not suspected as high risk and MLPA was not performed. The concordant rate was 74.1% for all 27 patients. “Discordant: Laboratory’s uncertain classification” was found in 22.2% of the sample (six patients). All discrepancies were generated during interpretation of BRCA 2 gene sequencing. Further studies and standardization of genetic testing for BRCA 1/2 genes are required.

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