Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement From the American Heart Association

Musunuru, Kiran; Hershberger, Ray E.; Day, Sharlene M.; Klinedinst, N. Jennifer; Landstrom, Andrew P.; Parikh, Victoria N.; Prakash, Siddharth K.; Semsarian, Christopher; Sturm, Amy C.; Biology, Vascular

doi:10.1161/hcg.0000000000000067

Cited by 228 publications

(225 citation statements)

References 49 publications

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“…The findings of this curation effort are also relevant for family-based clinical genetics care of patients with DCM. 39 Establishing genetic risk of DCM in family members as a component of a genetic evaluation presents considerable opportunity for disease mitigation and prevention. Genetic testing is a central component of a DCM genetic evaluation, and most commercially available DCM gene panels test several dozen genes, well exceeding the 19 genes curated here as definitive, strong, or moderate.…”

Section: Discussionmentioning

confidence: 99%

“…Current variant adjudication guidance 38, 40, 41 is intended for the clinical interpretation for the monogenic cause of disease in order to translate genetic test results into information to be applied to clinical, family-based care. 39 While many genes have been suggested to have a relationship with DCM as shown in the initial expansive list, only a minority were identified to have a possible monogenic role in idiopathic DCM. The rationale for commercial sequencing panels to include genes for DCM even beyond the 44 limited, moderate, strong, and definitive evidence genes curated here is unclear, although some represent syndromic conditions where the DCM phenotype may be observed as a feature of the syndrome.…”

Section: Discussionmentioning

confidence: 99%

“…This also creates the potential for misapplication of genetic information in the care for DCM patients and their at-risk family members. 39…”

Section: Discussionmentioning

confidence: 99%

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An Evidence-based Assessment of Genes in Dilated Cardiomyopathy

Jordan

Peterson

et al. 2020

Preprint

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Background: The cardiomyopathies are classically categorized as hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular (ARVC), and each have a signature genetic theme. HCM and ARVC are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning more than 10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. Methods: An international Panel with clinical and scientific expertise in DCM genetics was assembled to evaluate evidence supporting monogenic relationships of genes with idiopathic DCM. The Panel utilized the ClinGen semi-quantitative gene-disease clinical validity classification framework. Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from eight gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence. Seven genes (14%) (ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including two additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of the 19 genes classified as definitive, strong or moderate, six were similarly classified for HCM and three for ARVC. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of 16 commercially available genetic testing panels evaluated, most definitive genes were included, but panels also included numerous genes with minimal human evidence. Conclusions: In a systematic curation of published evidence for genes considered relevant for monogenic DCM, 12 were classified as definitive or strong and seven as moderate evidence spanning 10 gene ontologies. Notably, these 19 genes only explain a minority of DCM cases, leaving the remainder of DCM genetic architecture incompletely addressed. While clinical genetic testing panels include most high evidence genes, genes lacking robust evidence are also commonly included. Until the genetic architecture of DCM is more fully defined, care should be taken in the interpretation of variable evidence DCM genes in clinical practice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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An Evidence-based Assessment of Genes in Dilated Cardiomyopathy

Jordan

Peterson

et al. 2020

Preprint

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“…Workup includes attention to features of genetic arteriopathies, such as musculoskeletal abnormalities (scoliosis, pectus abnormalities), other concurrent aneurysms/dissections, arterial tortuosity, and family history of aneurysms, dissections, and sudden death. [9][10][11] Although genetic testing was delayed owing to insurance preauthorization, the heighted index of suspicion for MFS or Loeys Dietz syndrome as the etiology and ruling out thoracic outlet compression as part of the etiology allowed us to plan our approach and repair accordingly.…”

Section: Discussionmentioning

confidence: 99%

Extrathoracic subclavian artery aneurysm in a patient with suspected genetic arteriopathy

Banning

Malleis

et al. 2021

Journal of Vascular Surgery Cases, Innovations and Techniques

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This is a case of a 4-cm left extrathoracic subclavian artery aneurysm (SCAA) in a 58-year-old man with an aortic root and abdominal aortic aneurysm. The patient had features suggestive of genetic arteriopathy, including vertebral artery tortuosity, pectus excavatum, tall stature, and scoliosis. The SCAA was successfully repaired with an inline prosthetic graft and anastomotic pledgets via a supraclavicular approach. Genetic testing revealed an FBN1 pathogenic variant consistent with Marfan syndrome. Repair is satisfactory 2 years later. Patients with SCAA should include consideration of genetic arteriopathy. Open repair of the extrathoracic SCAA in Marfan syndrome is recommended.

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“…The American Society of Breast Surgeons consensus guidelines recently recommended germline genetic testing for all patients with a personal history of breast cancer (Manahan et al, 2019). Similarly, the American Heart Association, Heart Failure Society of America, American College of Medical Genetics and Genomics (ACMG), and Heart Rhythm Society/European Heart Rhythm Association have issued statements or guidelines regarding genetic testing for cardiovascular conditions including cardiomyopathies, arrhythmias, and familial hypercholesterolemia (Musunuru et al, 2020). In the area of reproductive genetics, the American College of Obstetricians and Gynecologists recently updated its guidelines for noninvasive prenatal screening in pregnant women to recommend discussing and offering testing with all pregnant women, not just those considered to be at high risk based on age or other factors.…”

Section: Genetics In Healthcare: Yesterday and Todaymentioning

confidence: 99%

Democratizing genomics: Leveraging software to make genetics an integral part of routine care

Snir

Nazareth

Simmons

et al. 2020

American J of Med Genetics Pt C

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Genetic testing can provide definitive molecular diagnoses and guide clinical management decisions from preconception through adulthood. Innovative solutions for scaling clinical genomics services are necessary if they are to transition from a niche specialty to a routine part of patient care. The expertise of specialists, like genetic counselors and medical geneticists, has traditionally been relied upon to facilitate testing and follow‐up, and while ideal, this approach is limited in its ability to integrate genetics into primary care. As individuals, payors, and providers increasingly realize the value of genetics in mainstream medicine, several implementation challenges need to be overcome. These include electronic health record integration, patient and provider education, tools to stay abreast of guidelines, and simplification of the test ordering process. Currently, no single platform offers a holistic view of genetic testing that streamlines the entire process across specialties that begins with identifying at‐risk patients in mainstream care settings, providing pretest education, facilitating consent and test ordering, and following up as a “genetic companion” for ongoing management. We describe our vision for using software that includes clinical‐grade chatbots and decision support tools, with direct access to genetic counselors and pharmacists within a modular, integrated, end‐to‐end testing journey.

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Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement From the American Heart Association

Cited by 228 publications

References 49 publications

An Evidence-based Assessment of Genes in Dilated Cardiomyopathy

An Evidence-based Assessment of Genes in Dilated Cardiomyopathy

Extrathoracic subclavian artery aneurysm in a patient with suspected genetic arteriopathy

Democratizing genomics: Leveraging software to make genetics an integral part of routine care

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