Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center

Mazzarotto, Francesco; Girolami, Francesca; Boschi, Beatrice; Barlocco, Fausto; Tomberli, Alessia; Baldini, Katia; Coppini, Raffaele; Tanini, Ilaria; Bardi, Sara; Contini, Elisa; Cecchi, Francesca; Pelo, Elisabetta; Cook, Stuart A.; Cerbai, Elisabetta; Poggesi, Corrado; Torricelli, Francesca; Walsh, Roddy; Olivotto, Iacopo

doi:10.1038/s41436-018-0046-0

Cited by 61 publications

(48 citation statements)

References 33 publications

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“…( A ) Mendelian variants are identified in less than half of HCM/DCM patients. 7 ( B ) Additional genetic risk variants may include intermediate effect variants like TNNT2:p.R278C, enriched in European HCM cases 31 , 32 and often occurring as a secondary sarcomeric variant (https://www.ncbi.nlm.nih.gov/clinvar/variation/12411/). ( C ) Common susceptibility variants may be identified using direct case–control GWAS.…”

Section: Identification Of Genetic Risk Variants In Rare Cardiac Disementioning

confidence: 99%

When genetic burden reaches threshold

Walsh

Tadros

Bezzina

2020

European Heart Journal

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Rare cardiac genetic diseases have generally been considered to be broadly Mendelian in nature, with clinical genetic testing for these conditions predicated on the detection of a primary causative rare pathogenic variant that will enable cascade genetic screening in families. However, substantial variability in penetrance and disease severity among carriers of pathogenic variants, as well as the inability to detect rare Mendelian variants in considerable proportions of patients, indicates that more complex aetiologies are likely to underlie these diseases. Recent findings have suggested genetic variants across a range of population frequencies and effect sizes may combine, along with non-genetic factors, to determine whether the threshold for expression of disease is reached and the severity of the phenotype. The availability of increasingly large genetically characterized cohorts of patients with rare cardiac diseases is enabling the discovery of common genetic variation that may underlie both variable penetrance in Mendelian diseases and the genetic aetiology of apparently non-Mendelian rare cardiac conditions. It is likely that the genetic architecture of rare cardiac diseases will vary considerably between different conditions as well as between patients with similar phenotypes, ranging from near-Mendelian disease to models more akin to common, complex disease. Uncovering the broad range of genetic factors that predispose patients to rare cardiac diseases offers the promise of improved risk prediction and more focused clinical management in patients and their families.

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Section: Identification Of Genetic Risk Variants In Rare Cardiac Disementioning

confidence: 99%

When genetic burden reaches threshold

Walsh

Tadros

Bezzina

2020

European Heart Journal

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“…Where 74–85.1% of all mutations are in the genes of MYBPC3 (36.2–54.8%) and MYH7 (25–48.9%) [42,43,44,45,46,47]. …”

Section: Introductionmentioning

confidence: 99%

Cardiomyopathies and Related Changes in Contractility of Human Heart Muscle

Vikhorev

Vikhoreva

2018

IJMS

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About half of hypertrophic and dilated cardiomyopathies cases have been recognized as genetic diseases with mutations in sarcomeric proteins. The sarcomeric proteins are involved in cardiomyocyte contractility and its regulation, and play a structural role. Mutations in non-sarcomeric proteins may induce changes in cell signaling pathways that modify contractile response of heart muscle. These facts strongly suggest that contractile dysfunction plays a central role in initiation and progression of cardiomyopathies. In fact, abnormalities in contractile mechanics of myofibrils have been discovered. However, it has not been revealed how these mutations increase risk for cardiomyopathy and cause the disease. Much research has been done and still much is being done to understand how the mechanism works. Here, we review the facts of cardiac myofilament contractility in patients with cardiomyopathy and heart failure.

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“…Screening of LAMP2 gene mutations by next‐generation sequencing (NGS) in selected series of patients has permitted the identification of an increasing number of DD patients (i.e. DD is more frequent than previously thought), for example, the disease frequency is estimated to be 4–6% among children with hypertrophic cardiomyopathy (HCM) , 0.7–4% among adults with HCM , 6–8% among adults with concentric HCM , 17–30% among patients with both thickened left ventricular (LV) walls and pre‐excitation on ECG , and 33% among patients with vacuolar myopathy and HCM . No DD patient was identified by NGS screening among 72 children with idiopathic dilated cardiomyopathy (DCM) .…”

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confidence: 99%

Review: Danon disease: Review of natural history and recent advances

Cenacchi

Papa

Pegoraro

et al. 2019

Neuropathology Appl Neurobio

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Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients, and by a milder phenotype (predominantly involving cardiac muscle) in female patients. The disease is inherited as an X‐linked dominant trait. The primary deficiency of lysosome‐associated membrane protein‐2 (LAMP‐2) causes disruption of autophagy, leading to an impaired fusion of lysosomes to autophagosomes and biogenesis of lysosomes. We surveyed over 500 Danon disease patients reported in the literature from the first description to the present, in order to summarize the clinical, pathological and molecular data and treatment perspectives. An early molecular diagnosis is of crucial importance for genetic counselling and for therapeutic interventions: in male patients, the prognosis is poor due to rapid progression towards heart failure, and only heart transplantation modifies the disease course.

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Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center

Cited by 61 publications

References 33 publications

When genetic burden reaches threshold

When genetic burden reaches threshold

Cardiomyopathies and Related Changes in Contractility of Human Heart Muscle

Review: Danon disease: Review of natural history and recent advances

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