ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG)

Miller, David T.; Lee, Kristy; Abul‐Husn, Noura S.; Amendola, Laura M.; Brothers, Kyle B.; Chung, Wendy K.; Gollob, Michael H.; Gordon, Adam S.; Harrison, Steven M.; Hershberger, Ray E.; Klein, Teri E.; Richards, C. Sue; Stewart, Douglas R.; Martin, Christa Lese

doi:10.1016/j.gim.2022.04.006

Cited by 197 publications

(166 citation statements)

References 20 publications

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“…Since rare genetic variants are the major cause of inherited cardiomyopathies, a large dataset is needed to accurately identify the population prevalence of these variants. Prevalence of pathogenic variants in populations has been the focus of several previous studies 4,13-15 , however they were mostly limited by the number of included individuals. At time of analysis, we had access to an unprecedented number of 200,643 individuals.…”

Section: Discussionmentioning

confidence: 99%

“…Technical advances and commercial availability of NGS, have led to more affordable and accessible genetic testing. The American College of Medical Genetics and Genomics (ACMG) has developed recommendations for the reporting of incidental or secondary findings unrelated to the test indication 4 . In this framework, variants in genes associated with ARVC, DCM and HCM are recommended to be reported as secondary findings from clinical exome and other genome sequencing tests 4 .…”

Section: Introductionmentioning

confidence: 99%

“…The American College of Medical Genetics and Genomics (ACMG) has developed recommendations for the reporting of incidental or secondary findings unrelated to the test indication 4 . In this framework, variants in genes associated with ARVC, DCM and HCM are recommended to be reported as secondary findings from clinical exome and other genome sequencing tests 4 . Although this offers the potential to prevent morbidity and mortality of heart failure and sudden cardiac death by early treatment, it also fuels uncertainty in carriers of likely pathogenic or pathogenic variants (G+) and their family members, since factors that influence disease penetrance in the general population are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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Prevalence and disease expression of pathogenic and likely pathogenic variants associated with inherited cardiomyopathies in the general population

Bourfiss

Vugt

Alasiri

et al. 2022

Preprint

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Background. (Likely) pathogenic variants associated with arrhythmogenic cardiomyopathy (ACM), dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are recommended to be reported as secondary findings in genome sequencing studies. This provides opportunities for early diagnosis, but also fuels uncertainty in variant carriers (G+), since disease penetrance is incomplete. We assessed the prevalence and disease expression of G+ in the general population. Methods. We identified (likely) pathogenic variants associated with ACM, DCM and/or HCM in 200,643 UK Biobank individuals, who underwent whole exome sequencing. We calculated the prevalence of G+ and analysed the frequency of cardiomyopathy/heart failure diagnosis. In undiagnosed individuals, we analysed early signs of disease expression. Results. We found a prevalence of 1:578, 1:251 and 1:149 for (likely) pathogenic variants associated with ACM, DCM and HCM respectively. Compared to controls, cardiovascular mortality was higher in DCM G+ (OR 1.67 [95% CI 1.04;2.59], p=0.030), but similar in ACM and HCM G+ (p≥0.100). More specifically, cardiomyopathy or heart failure diagnosis were more frequent in DCM G+ (OR 3.66 [95% CI 2.24;5.81], p=4.9×10-7) and HCM G+ (OR 3.03 [95% CI 1.98;4.56], p=5.8×10-7), but comparable in ACM G+ (p=0.172). In contrast, ACM G+ had more ventricular arrhythmias (p=3.3×10-4). In undiagnosed individuals, left ventricular ejection fraction was reduced in DCM G+ (p=0.009). Conclusions. In the general population, (likely) pathogenic variants associated with ACM, DCM or HCM are not uncommon. Although G+ have increased mortality and morbidity, disease expression in these carriers from the general population remains low. Decisions on application of cascade screening and frequency of cardiological examination should be based on multiple factors, such as the variant and disease expression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prevalence and disease expression of pathogenic and likely pathogenic variants associated with inherited cardiomyopathies in the general population

Bourfiss

Vugt

Alasiri

et al. 2022

Preprint

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“…In the UKBB cohort, PuPV in these genes were associated with higher all-cause mortality, supporting the ACMG recommendations for actionability. (15) It should be noted the ACMG recommendations for actionability are based on incidental findings in these genes and not specifically to population-based screening, because of a lack of sufficient evidence.…”

Section: Discussionmentioning

confidence: 99%

“…(14) Another subgroup of CMP genes, listed among the 78 actionable genes recommended by the American Council of Medical genetics and Genomics (ACMG) for reporting of secondary findings in clinical exome/genome sequencing, were also analyzed. (15) Details regarding gene selection, gene-disease associations and disease-causality evidence levels according to the ClinGen GCEPs are provided in the Supplemental Methods .…”

Section: Methodsmentioning

confidence: 99%

Screening for Pathogenic Variants in Cardiomyopathy Genes Predicts Mortality and Composite Outcomes in UK Biobank

Asatryan

Shah

Dabbagh

et al. 2022

Preprint

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Background: Inherited cardiomyopathies can present with broad variation of phenotype. Data are limited regarding genetic screening strategies and outcomes associated with putative pathogenic variants (PuPV) in cardiomyopathy-associated genes in the general population. Objective: We aimed to determine the risk of mortality and cardiomyopathy-related outcomes associated with PuPV in cardiomyopathy-associated genes in UK Biobank. Methods: Using whole exome sequencing data, variants in dilated, hypertrophic and arrhythmogenic cardiomyopathy-associated genes with at least limited evidence of disease causality according to ClinGen Expert Panel curations, were annotated using REVEL (≥0.65) and ANNOVAR (predicted loss of function) to identify PuPVs. Individuals with PuPV comprised the genotype-positive (G+) and those without PuPV the genotype-negative (G-) cohorts. Group comparisons were made using time-to-event analyses for the primary (all-cause mortality) and secondary outcomes (diagnosis of cardiomyopathy; composite outcome of diagnosis of cardiomyopathy, heart failure, arrhythmia, stroke, and death). Results: Among 200,619 participants, 22,401 (11.2%) were found to host ≥1 PuPV in cardiomyopathy-associated genes (G+). After adjusting for age and sex, G+ individuals had increased all-cause mortality [HR 1.07 (95%CI 1.02-1.13; p=0.011)] and increased rates of diagnosis of cardiomyopathy later in life [HR 2.37 (95%CI 1.98-2.85; p<0.0001)], which further increased in those with PuPV in definitive/strong evidence ClinGen genes [3.25 (95%CI 2.63-4.00; p<0.0001)]. G+ individuals had a higher risk of developing the composite outcome [HR 1.11 (95%CI 1.06-1.15; p<0.0001)]. Conclusions: Adults with PuPV in cardiomyopathy-associated genes have higher all-cause mortality and increased risk of developing cardiomyopathy-associated features and complications, compared to genotype-negative controls.

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Cardiac Amyloidosis Due to Transthyretin Protein

Ruberg,

Maurer

2024

JAMA

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ImportanceSystemic amyloidosis from transthyretin (ATTR) protein is the most common type of amyloidosis that causes cardiomyopathy.ObservationsTransthyretin (TTR) protein transports thyroxine (thyroid hormone) and retinol (vitamin A) and is synthesized predominantly by the liver. When the TTR protein misfolds, it can form amyloid fibrils that deposit in the heart causing heart failure, heart conduction block, or arrhythmia such as atrial fibrillation. The biological processes by which amyloid fibrils form are incompletely understood but are associated with aging and, in some patients, affected by inherited variants in the TTR genetic sequence. ATTR amyloidosis results from misfolded TTR protein deposition. ATTR can occur in association with normal TTR genetic sequence (wild-type ATTR) or with abnormal TTR genetic sequence (variant ATTR). Wild-type ATTR primarily manifests as cardiomyopathy while ATTR due to a genetic variant manifests as cardiomyopathy and/or polyneuropathy. Approximately 50 000 to 150 000 people in the US have heart failure due to ATTR amyloidosis. Without treatment, heart failure due to ATTR amyloidosis is associated with a median survival of approximately 5 years. More than 130 different inherited genetic variants in TTR exist. The most common genetic variant is Val122Ile (pV142I), an allele with an origin in West African countries, that is present in 3.4% of African American individuals in the US or approximately 1.5 million persons. The diagnosis can be made using serum free light chain assay and immunofixation electrophoresis to exclude light chain amyloidosis combined with cardiac nuclear scintigraphy to detect radiotracer uptake in a pattern consistent with amyloidosis. Loop diuretics, such as furosemide, torsemide, and bumetanide, are the primary treatment for fluid overload and symptomatic relief of patients with ATTR heart failure. An ATTR-directed therapy that inhibited misfolding of the TTR protein (tafamidis, a protein stabilizer), compared with placebo, reduced mortality from 42.9% to 29.5%, reduced hospitalizations from 0.7/year to 0.48/year, and was most effective when administered early in disease course.Conclusions and RelevanceATTR amyloidosis causes cardiomyopathy in up to approximately 150 000 people in the US and tafamidis is the only currently approved therapy. Tafamidis slowed progression of ATTR amyloidosis and improved survival and prevented hospitalization, compared with placebo, in people with ATTR-associated cardiomyopathy.

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ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG)

Cited by 197 publications

References 20 publications

Prevalence and disease expression of pathogenic and likely pathogenic variants associated with inherited cardiomyopathies in the general population

Prevalence and disease expression of pathogenic and likely pathogenic variants associated with inherited cardiomyopathies in the general population

Screening for Pathogenic Variants in Cardiomyopathy Genes Predicts Mortality and Composite Outcomes in UK Biobank

Cardiac Amyloidosis Due to Transthyretin Protein

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