Assigning a Causal Role to Genetic Variants in Hypertrophic Cardiomyopathy

Watkins, Hugh

doi:10.1161/circgenetics.111.000032

Cited by 9 publications

(9 citation statements)

References 15 publications

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“…Combined with an increased number of genes per genetic test, this has led to more variants passing through the hands of clinicians. At the same time that the volume of genetic test results has been rising, uncertainty about those results has become increasingly evident (Caleshu and Ashley 2016;Manrai et al 2016;Rehm 2017;Walsh et al 2016;Watkins 2013). Large sequencing databases like gnomAD and ExAC have led to the realization that many of the variants previously thought to be diseasecausing are in fact benign, revealing problems with how we have historically classified variants (Andreasen et al 2013;Lek et al 2016;Manrai et al 2016;Shah et al 2016;Walsh et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Clinical Cardiovascular Genetic Counselors Take a Leading Role in Team‐based Variant Classification

Reuter

Grove

Orland

et al. 2017

Journal of Genetic Counseling

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We sought to delineate the genetic test review and interpretation practices of clinical cardiovascular genetic counselors. A one-time anonymous online survey was taken by 46 clinical cardiovascular genetic counselors recruited through the National Society of Genetic Counselors Cardiovascular Special Interest Group. Nearly all (95.7%) gather additional information on variants reported on clinical genetic test reports and most (81.4%) assess the classification of such variants. Clinical cardiovascular genetic counselors typically (81.0%) classify variants in collaboration with cardiologist and/or geneticist colleagues, with the genetic counselor as the team member who is primarily responsible. Variant classification is a relatively recent (mean 3.2 years) addition to practice. Most genetic counselors learned classification skills on the job from clinical and laboratory colleagues. Recent graduates were more likely to have learned this in graduate school (p < 0.001). Genetic counselors are motivated to take responsibility for the classification of variants because of prior experiences with variant reclassification, inconsistencies between laboratories, and incomplete laboratory reports. They are also driven by a sense of professional duty and their proximity to the clinical context. This practice represents a broadening of the skill set of clinical cardiovascular genetic counselors and a unique expertise that they contribute to the interdisciplinary teams in which they work.

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Section: Introductionmentioning

confidence: 99%

Clinical Cardiovascular Genetic Counselors Take a Leading Role in Team‐based Variant Classification

Reuter

Grove

Orland

et al. 2017

Journal of Genetic Counseling

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“…This may imply that further genes remain to be defined, but more likely, this is consistent with nonmendelian inheritance or nongenetic factors. 5 The model of HCM as a monogenic disease following mendelian patterns of inheritance is increasingly recognized as an oversimplification. Both compound heterozygosity and oligogenic disease have been identified in HCM, although in a small minority, with >1 sarcomeric mutation identified in approximately 2.5% to 5%.…”

Section: Hypertrophic Cardiomyopathymentioning

confidence: 99%

“…Differentiating rare but benign sequence variants from disease-causing mutations is difficult and is now magnified by the increased detection of low-frequency or rare polymorphisms with NGS. 5 It is clear that variants in the individual genome are far more numerous than anticipated. Moreover, existing predictive tools purporting to distinguish benign variants from causative mutations on the basis of sequence conservation or putative effects on protein structure are of limited utility.…”

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confidence: 99%

Genetic Cardiomyopathies Causing Heart Failure

Cahill

Ashrafian

Watkins

2013

Circulation Research

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135

117

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Despite the striking advances in medical and surgical therapy, the morbidity, mortality, and economic burden of heart failure (HF) remain unacceptably high. There is increasing evidence that the risk and course of HF depend on genetic predisposition; however, the genetic contribution to HF is heterogeneous and complex. At one end of the spectrum are the familial monogenic HF syndromes in which causative mutations are rare but highly penetrant. At the other, HF susceptibility and course may be influenced by more common, less penetrant genetic variants. As detailed in this review, efforts to unravel the basis of the familial cardiomyopathies at the mendelian end of the spectrum already have begun to deliver on the promise of informative mechanisms, novel gene-based diagnostics, and therapies for distinct subtypes of HF. However, continued progress requires the differentiation of pathogenic mutations, disease modifiers, and rare, benign variants in the deluge of data emerging from increasingly accessible novel sequencing technologies. This represents a significant challenge and demands a sustained effort in analysis of extended family pedigrees, diligent clinical phenotyping, and systematic annotation of human genetic variation. (Circ Res. 2013;113:660-675.)

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“… 84 , 90 , 91 Although providing increased scientific insight, NGS substantially increases the recognition of VUS, creating further ambiguity in test reports. 24 , 92 , 93 Targeted resequencing allows a reduction in the number of VUS identified while increasing the depth of coverage when compared with exome sequencing and genome sequencing. 76 Lopes et al, using their targeted NGS strategy, identified a large number of rare non-synonymous sequence variants in non-sarcomeric genes (such as RYR2 , ANK2 , CAV3 , and SCN5A ) that may be potential phenotype modifiers in HCM and could explain the genetic heterogeneity of the disease.…”

Section: Next-generation Sequencingmentioning

confidence: 99%

Genetics of hypertrophic cardiomyopathy: advances and pitfalls in molecular diagnosis and therapy

Roma‐Rodrigues¹,

Fernandes²

2014

TACG

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Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle that occurs mainly due to mutations (>1,400 variants) in genes encoding for the cardiac sarcomere. HCM, the most common familial form of cardiomyopathy, affecting one in every 500 people in the general population, is typically inherited in an autosomal dominant pattern, and presents variable expressivity and age-related penetrance. Due to the morphological and pathological heterogeneity of the disease, the appearance and progression of symptoms is not straightforward. Most HCM patients are asymptomatic, but up to 25% develop significant symptoms, including chest pain and sudden cardiac death. Sudden cardiac death is a dramatic event, since it occurs without warning and mainly in younger people, including trained athletes. Molecular diagnosis of HCM is of the outmost importance, since it may allow detection of subjects carrying mutations on HCM-associated genes before development of clinical symptoms of HCM. However, due to the genetic heterogeneity of HCM, molecular diagnosis is difficult. Currently, there are mainly four techniques used for molecular diagnosis of HCM, including Sanger sequencing, high resolution melting, mutation detection using DNA arrays, and next-generation sequencing techniques. Application of these methods has proven successful for identification of mutations on HCM-related genes. This review summarizes the features of these technologies, highlighting their strengths and weaknesses. Furthermore, current therapeutics for HCM patients are correlated with clinically observed phenotypes and are based on the alleviation of symptoms. This is mainly due to insufficient knowledge on the mechanisms involved in the onset of HCM. Tissue engineering alongside regenerative medicine coupled with nanotherapeutics may allow fulfillment of those gaps, together with screening of novel therapeutic drugs and target delivery systems.

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Assigning a Causal Role to Genetic Variants in Hypertrophic Cardiomyopathy

Cited by 9 publications

References 15 publications

Clinical Cardiovascular Genetic Counselors Take a Leading Role in Team‐based Variant Classification

Clinical Cardiovascular Genetic Counselors Take a Leading Role in Team‐based Variant Classification

Genetic Cardiomyopathies Causing Heart Failure

Genetics of hypertrophic cardiomyopathy: advances and pitfalls in molecular diagnosis and therapy

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