Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Hershberger, Ray E.; Givertz, Michael M.; Ho, Carolyn Y.; Judge, Daniel P.; Kantor, Paul F.; McBride, Kim L.; Morales, Ana; Taylor, Matthew R.G.; Vatta, Matteo; Ware, Stephanie M.; Practice, Acmg Professional

doi:10.1038/s41436-018-0039-z

Cited by 186 publications

(174 citation statements)

References 95 publications

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“…An array of cardiomyopathy genes, and other cardiac genes, harbored VUSs in these subjects, and MYBPC3 was noted as having the highest number of VUSs. MYBPC3 truncations are a common cause of hypertrophic cardiomyopathy (1,33), and the MYBPC3 VUSs were all missense, perhaps suggesting a distinct mode of action. In context of genetic testing for cardiomyopathies, variants of uncertain significance are typically returned and can sometimes be interpreted with further familial testing and segregation analysis (34,35).…”

Section: Variants Of Uncertain Significance and Echocardiographic Finmentioning

confidence: 99%

“…We observed the correlation of VUS with LV dimensions, when viewing the entire cohort, but this finding was evident when considering only those with a cardiomyopathy diagnosis. The identification of genetic variants contributing to cardiomyopathy affects management, especially for the accompanying arrhythmia risk (1). The inability to fully interpret these variants limits the use of this data for both the patients and their family members.…”

Section: Variants Of Uncertain Significance and Echocardiographic Finmentioning

confidence: 99%

“…Genetic information is increasingly being used in medical decision making, especially for familial cancers and cardiovascular diseases where the identification of rare genetic variants can inform care for patients and family members at risk (1)(2)(3). Genetic variants segregating with disease are interpreted as pathogenic or likely pathogenic, and this type of genetic information is diagnostic and useful for clinical management (4).…”

Section: Introductionmentioning

confidence: 99%

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Pathogenic and uncertain genetic variants have clinical cardiac correlates in diverse biobank participants

Pottinger¹,

Puckelwartz²,

Pesce

et al. 2019

Preprint

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Background: Genome sequencing coupled with electronic heath record data can uncover medically important genetic variation. Interpretation of rare genetic variation and its role in mediating cardiovascular phenotypes is confounded by variants of uncertain significance. Methods and Results:We analyzed the whole genome sequence of 900 racially and ethnically diverse biobank participants selected from a single US center. Participants were equally divided among European, African, Hispanic, and mixed race/ethnicities. We evaluated the American College of Medical Genetics and Genomics medically actionable list of 59 genes focusing on the cardiac genes. Variation was interpreted using the most recent reports in ClinVar, a database of medically relevant human variation. We identified 19 individuals with pathogenic/likely pathogenic variants in cardiac actionable genes (2%) and found evidence for clinical correlates in the electronic health record. African ancestry participants had more variants of uncertain significance in the medically actionable genes including the 30 cardiac actionable genes, even when normalized to total variant count per person. Longitudinal measures of left ventricle size, corrected for body surface area, from approximately 400 biobank participants (1,723 patient years) correlated with genetic findings. The presence of one or more uncertain variants in the actionable cardiac genes and a cardiomyopathy diagnosis correlated with increased left ventricular internal diameter in diastole and in systole. In particular, MYBPC3 was identified as a gene with excess variants of uncertain significance. Conclusions:These data indicate a subset of uncertain variants may confer risk and should not be considered benign.

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Section: Variants Of Uncertain Significance and Echocardiographic Finmentioning

confidence: 99%

Section: Variants Of Uncertain Significance and Echocardiographic Finmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pathogenic and uncertain genetic variants have clinical cardiac correlates in diverse biobank participants

Pottinger¹,

Puckelwartz²,

Pesce

et al. 2019

Preprint

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“…Identification of novel variants in these genes and other HCM-associated genes has increased dramatically due to the advancement of high throughput genome and exome sequencing technologies [19][20][21][22][23]. However, the advancement of variant identification has also increased the number of potential sequence variants that could contribute to the disease in each individual, confounding the ability to assign pathogenicity to an individual variant [24][25][26]. While computational methods can predict the damaging effect of a variant and assist in prioritizing variants [27][28][29][30][31][32], the current consensus on the determination of pathogenicity is dependent on the identification of multiple patients showing similar symptoms and genetic variants with strong evidence of functional impact.…”

Section: Introductionmentioning

confidence: 99%

“…While computational methods can predict the damaging effect of a variant and assist in prioritizing variants [27][28][29][30][31][32], the current consensus on the determination of pathogenicity is dependent on the identification of multiple patients showing similar symptoms and genetic variants with strong evidence of functional impact. Functional testing is therefore critical for disorders that are associated with rare variants in genes affecting a small subset of the patients [25,33,34] Variants in the gene MYL2 are associated with <5% of cases of HCM [5,35]. MYL2 encodes the Myosin regulatory light chain expressed in the ventricular heart and slow-twitch skeletal muscles [36].…”

Section: Introductionmentioning

confidence: 99%

Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy

Manivannan

Darouich

Masmoudi

et al. 2019

Preprint

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Hypertrophic cardiomyopathy (HCM) is characterized by enlargement of the ventricular muscle without dilation and is often associated with dominant pathogenic variants in cardiac sarcomeric protein genes. Here, we report a family with two infants diagnosed with infantile-onset HCM and mitral valve dysplasia that led to death before one year of age. Using exome sequencing, we discovered that one of the affected children had a homozygous frameshift variant in Myosin light chain 2 (MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57;MYL2-fs), which alters the last 20 amino acids of the protein and is predicted to impact the C-terminal EF-hand (CEF) domain. The parents are unaffected heterozygous carriers of the variant and the variant is absent in control cohorts from gnomAD. The absence of the phenotype in carriers and infantile presentation of severe HCM is in contrast to HCM associated with dominant MYL2 variants. Immunohistochemical analysis of the ventricular muscle of the deceased patient with the MYL2fs variant showed marked reduction of MYL2 expression compared to an unaffected control. In vitro overexpression studies further indicate that the MYL2-fs variant is actively degraded. In contrast, an HCM-associated missense variant (MYL2:p.Gly162Arg) and three other MYL2 stopgain variants that lead to loss of the CEF domain are stably expressed. However, stopgain variants show impaired localization suggesting a functional role for the CEF domain. The degradation of the MYL2-fs can be rescued by inhibiting the cell's proteasome function supporting a post-translational effect of the variant. In vivo rescue experiments with a Drosophila MYL2homolog (Mlc2) knockdown model indicate that neither MYL2-fs nor MYL2:p.Gly162Argsupports regular cardiac function. The tools that we have generated provide a rapid screening platform for functional assessment of variants of unknown significance in MYL2. Our study 3 supports an autosomal recessive model of inheritance for MYL2 loss-of-function variants and highlights the variant-specific molecular differences found in MYL2-associated cardiomyopathies. Author SummaryWe report a novel frameshift variant in MYL2 that is associated with a severe form of infantile-onset hypertrophic cardiomyopathy. The impact of the variant is only observed in the recessive form of the disease in the proband and not in the parents who are carriers of the variant. This is in contrast to other dominant variants in MYL2 that are associated with cardiomyopathies.We compared the stability of this variant to that of other cardiomyopathy associated MYL2 variants and found molecular differences in the disease pathology. We also show different protein domain requirement for stability and localization of MYL2 in cardiomyocytes. Further, we used a fly model to demonstrate functional deficits due to the variant in the developing heart. Overall, our study shows a molecular mechanism by which loss-of-function variants in MYL2 are recessive while missense variants are dominant. We highlight the use of exome sequencing...

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Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry

Jordan

Kinnamon

Haas

et al. 2023

JAMA

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ImportanceBlack patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients.ObjectiveTo compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM.DesignCross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance.ExposurePresence of DCM.Main Outcomes and MeasuresVariants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic).ResultsA total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, −0.09 [95% CI, −0.14 to −0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, −0.06 [95% CI, −0.11 to −0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, −0.07 [95% CI, −0.22 to 0.09]) due to a larger number of non-TTN non–predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P &lt; .001).Conclusion and RelevancePatients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.

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Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Abstract: Genetic testing is indicated for cardiomyopathy to assist in patient care and management of at-risk family members.

Cited by 186 publications

References 95 publications

Pathogenic and uncertain genetic variants have clinical cardiac correlates in diverse biobank participants

Pathogenic and uncertain genetic variants have clinical cardiac correlates in diverse biobank participants

Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy

Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry

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