Identification of actionable genetic variants in 4,198 Scottish volunteers from the Viking Genes research cohort and implementation of return of results DOI Creative Commons
Shona M. Kerr, Lucija Klarić, Marisa D. Muckian

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 5, 2024

Abstract The benefits of returning clinically actionable genetic results to participants in research cohorts are accruing, yet such a genome-first approach is challenging. Here, we describe the return two founder populations from Scotland. Between 2005 and 2015, recruited >4,000 adults with grandparents Orkney Shetland into Viking Genes cohort. Return data was not offered at baseline, but 2023 sent invitations for consent findings participants. We generated exome sequence 4,198 participants, used ACMG v3.2 list 81 genes, ClinVar review pathogenicity status, plus manual curation, develop pipeline identify potentially variants. identified 104 individuals (2.5%) carrying 108 genotypes 39 variants 23 validated these. Working NHS clinical genetics service, which provided counselling verification results, after expert review, notified 64 consenting (or their next kin) genotypes. Ten across seven genes ( BRCA1, BRCA2, ATP7B, TTN, KCNH2, MUTYH, GAA ) have risen 50 >3,000-fold frequency through drift ancestral island localities. one first UK findings, providing an ethical logistical exemplar results. structure Northern Isles Scotland, multiple effects, provides unique opportunity tailored primary secondary prevention screening.

Язык: Английский

Evaluation of Women with Peripartum or Dilated Cardiomyopathy and Their First-Degree Relatives: The DCM Precision Medicine Study DOI Creative Commons
E. Kransdorf, Rashmi Jain,

Jonathan O. Mead

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 21, 2025

Abstract Background Peripartum cardiomyopathy (PPCM) presents substantial risk of maternal mortality, but underlying cause remains unsettled. Methods We compared the prevalence dilated (DCM)-relevant genetic variants in 452 female patients (probands) African and European ancestry (AA, EA) with PPCM or DCM who had been pregnant at least once. Pathogenic likely pathogenic (P/LP) were identified DCM-associated genes. Risk partial DCM, defined as left ventricular enlargement a ejection fraction <50%, 665 FDRs probands. Results The estimated prevalences P/LP findings among 67 probands to 385 comparable within (for AA, 7.8% [95% CI: 0.0%- 15.7%] vs. 1.1%-14.4%]; for EA, 29.5% [12.5%-46.5%] 29.8% [15.5%-44.2%]). DCM/partial was not lower relative (HR, 0.77; 95% CI, 0.47 – 1.28). For an FDR non-Hispanic EA proband PPCM, lowest by age 80 26.8% (95% 15.0%-45.0%) 33.2% 21.2%-49.5%) DCM. Further validating using set genes common between studies, (26.6%; 12.6%- 40.6%) higher than general population estimate from UK Biobank study (0.6%), Also, lowest-risk (7.0% 0%-14.1%] females, 9.0% 1.6%-16.3%] males) estimates another (0.30% 0.63% males). Conclusions Comparing women those similar DCM-relevant their first-degree relatives observed. These findings, along comparisons showing FDRs, strengthen evidence basis underscore need clinical evaluations patients. Clinical Trial clinicaltrials.gov, NCT03037632 Perspective What is new? This first use familial risk, shown phenotypes (FDRs) gain insight into genetics PPCM. rare diagnosed groups. In ancestry, estimate. phenotype population-based are implications? this strengthens that DCM-related key factor A evaluation indicated following established guidelines case men

Язык: Английский

Процитировано

0
2024 ASHG presidential address: Incomplete penetrance and variable expressivity: Old concepts, new urgency DOI Creative Commons
Bruce D. Gelb

The American Journal of Human Genetics, Год журнала: 2025, Номер 112(3), С. 461 - 466

Опубликована: Март 1, 2025

Язык: Английский

Процитировано

0
Actionable genetic variants in 4,198 Scottish participants from the Orkney and Shetland founder populations and implementation of return of results DOI Creative Commons
Shona M. Kerr, Lucija Klarić, Marisa D. Muckian

и другие.

The American Journal of Human Genetics, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

Процитировано

0
On Penetrance Estimation in Family, Clinical, and Population Cohorts DOI
Marija Zaicenoka, Vasily Ramensky, А. В. Киселева

и другие.

Circulation Genomic and Precision Medicine, Год журнала: 2025, Номер unknown

Опубликована: Март 28, 2025

In recent years, there has been a considerable influx of publications assessing the penetrance pathogenic variants associated with monogenic diseases dominant inheritance. As large and diverse groups have sequenced, it become clear that incomplete is common to most hereditary diseases, as numerous molecular, genetic, or environmental factors can cause clinical diversity among carriers same variant. this review, we discuss some these focus on existing approaches estimating penetrance, depending data available their application different sets. We also list currently large-scale sets estimates.

Язык: Английский

Процитировано

0
Precision Medicine Applications in Dilated Cardiomyopathy: Advancing Personalized Care DOI
Elina Khattab,

Michael Myrianthefs,

Stefanos Sakellaropoulos

и другие.

Current Problems in Cardiology, Год журнала: 2025, Номер unknown, С. 103076 - 103076

Опубликована: Май 1, 2025

Язык: Английский

Процитировано

0
Basic Principles of Genetics and Genetic Counselling DOI Creative Commons
Nina J. Beelen, Jitendra K. Vohra, Job A.J. Verdonschot

и другие.

Indian Pacing and Electrophysiology Journal, Год журнала: 2025, Номер unknown

Опубликована: Май 1, 2025

Язык: Английский

Процитировано

0
Promise and Peril of a Genotype‐First Approach to Mendelian Cardiovascular Disease DOI Creative Commons
Babken Asatryan, Brittney Murray, Rafik Tadros

и другие.

Journal of the American Heart Association, Год журнала: 2024, Номер unknown

Опубликована: Окт. 18, 2024

Precision medicine, which among other aspects includes an individual's genomic data in diagnosis and management, has become the standard‐of‐care for Mendelian cardiovascular disease (CVD). However, early identification management of asymptomatic patients with potentially lethal manageable CVD through screening, is promise precision health, remains unsolved challenge. The reduced costs sequencing have enabled creation biobanks containing in‐depth genetic health information, facilitated understanding variation, penetrance, expressivity, moving us closer to genotype‐first screening individuals CVD. This approach could transform care by diagnostic refinement facilitating prevention or therapeutic interventions. Yet, potential benefits must be weighed against risks, include evolving variant pathogenicity assertion variants low penetrance; costly, stressful, inappropriate evaluations; negative psychological impact; disqualification employment competitive sports; denial insurance. Furthermore, natural history often unpredictable, making those who will benefit from preventive measures a priority. Currently, there insufficient evidence that population‐based can reduce adverse outcomes at reasonable cost extent outweighs harms true‐positive false‐positive results. Besides technical, clinical, financial burdens, ethical legal pose unprecedented challenges. review highlights key developments field approaches summarizes challenges solutions pave way implementing this clinical care.

Язык: Английский

Процитировано

2
The Genetic Factors Influencing Cardiomyopathies and Heart Failure across the Allele Frequency Spectrum DOI Creative Commons
Srinjay Mukhopadhyay,

Prithvi Dixit,

Najiyah Khanom

и другие.

Journal of Cardiovascular Translational Research, Год журнала: 2024, Номер 17(5), С. 1119 - 1139

Опубликована: Май 21, 2024

Abstract Heart failure (HF) remains a major cause of mortality and morbidity worldwide. Understanding the genetic basis HF allows for development disease-modifying therapies, more appropriate risk stratification, personalised management patients. The advent next-generation sequencing has enabled genome-wide association studies; moving beyond rare variants identified in Mendelian fashion detecting common DNA associated with disease. We summarise latest GWAS variant data on mixed refined aetiologies, cardiomyopathies. describe recent understanding functional impact titin highlight FHOD3 as novel cardiomyopathy-associated gene. future directions research this field how can be leveraged to improve care patients HF. Graphical

Язык: Английский

Процитировано

1
Clinical Outcome of Hypertrophic Cardiomyopathy in Probands with the Founder Variant c.913_914del in MYBPC3: A Slovenian Cohort Study DOI Creative Commons
Nina Vodnjov, Aleš Maver,

Nataša Teran

и другие.

Journal of Cardiovascular Translational Research, Год журнала: 2024, Номер 18(1), С. 110 - 120

Опубликована: Авг. 19, 2024

Hypertrophic cardiomyopathy is often caused by pathogenic MYBPC3 variants. The study of Italian patients with HCM and MYBPC3(NM_000256.3):c.913_914del showed a higher disease penetrance in males frequency arrhythmias compared to other likely (LP/P) We investigated the clinical outcomes Slovenian probands LP/P variants, estimated variant results an study. identified 31 haplotype-matched individuals MYBPC3:c.913_914del 34 observed some significant differences echocardiographic characteristics adverse cardiac events between MYBPC3:c913_914del. were unable replicate previous findings for MYBPC3:c.913_914del, highlighting complexity genotype-phenotype associations.

Язык: Английский

Процитировано

1
Dilated Cardiomyopathy: A Genetic Journey from Past to Future DOI Open Access
Noah Newman, Michael A. Burke

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(21), С. 11460 - 11460

Опубликована: Окт. 25, 2024

Dilated cardiomyopathy (DCM) is characterized by reduced systolic function and cardiac dilation. Cases without an identified secondary cause are classified as idiopathic dilated (IDC). Over the last 35 years, many cases of IDC have increasingly been recognized to be genetic in etiology with a core set definitively causal genes up 40% cases. While over 200 associated DCM, evidence supporting pathogenicity for most remains limited. Further, rapid advances sequencing bioinformatics recently revealed complex spectrum ranging from monogenic polygenic DCM. These also led discovery modifier variants forms DCM (e.g., alcohol-induced cardiomyopathy). Current guidelines recommend counseling screening, well endorsing handful genotype-specific therapies device placement

Язык: Английский

Процитировано

1