A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy

Horvat, Claire; Johnson, Renée; Lam, Lien; Munro, Jacob E.; Mazzarotto, Francesco; Roberts, Angharad; Herman, Daniel S.; Parfenov, Michael; Haghighi, Alireza; McDonough, Barbara; DePalma, Steven R.; Keogh, Anne; Macdonald, P.; Hayward, Christopher; Roberts, Amy; Barton, Paul J.R.; Felkin, Leanne E.; Giannoulatou, Eleni; Cook, Stuart A.; Seidman, Jonathan G.; Seidman, Christine E.; Fatkin, Diane

doi:10.1038/s41436-018-0036-2

Cited by 26 publications

(22 citation statements)

References 41 publications

(3 reference statements)

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“…Recently, we found that in patients with severe forms of DCM, more than 50% of the HTx candidates might be affected by a genetic etiology (Klauke et al, 2017). Until now, rare variants in at least 40 different genes have been shown to be associated with DCM (Brodehl et al, 2019; Horvat et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Cardiomyopathy‐associated mutations in the RS domain affect nuclear localization of RBM20

et al. 2020

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Mutations in RBM20 encoding the RNA-binding motif protein 20 (RBM20) are associated with an early onset and clinically severe forms of cardiomyopathies. Transcriptome analyses revealed RBM20 as an important regulator of cardiac alternative splicing. RBM20 mutations are especially localized in exons 9 and 11 including the highly conserved arginine and serine-rich domain (RS domain). Here, we investigated in several cardiomyopathy patients, the previously described RBM20-mutation p.Pro638Leu localized within the RS domain. In addition, we identified in a patient the novel mutation p.Val914Ala localized in the (glutamaterich) Glu-rich domain of RBM20 encoded by exon 11. Its impact on the disease was investigated with a novel TTN-and RYR2-splicing assay based on the patients' cardiac messenger RNA. Furthermore, we showed in cell culture and in human cardiac tissue that mutant RBM20-p.Pro638Leu is not localized in the nuclei but causes an abnormal cytoplasmic localization of the protein. In contrast the splicing deficient RBM20-p.Val914Ala has no influence on the intracellular localization. These results indicate that disease-associated variants in RBM20 lead to aberrant splicing through different pathomechanisms dependent on the localization of the mutation. This might have an impact on the future development of therapeutic strategies for the treatment of RBM20-induced cardiomyopathies.

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Section: Introductionmentioning

confidence: 99%

Cardiomyopathy‐associated mutations in the RS domain affect nuclear localization of RBM20

et al. 2020

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“…In contrast, ttnb is primarily expressed in skeletal muscle, and is not required for heart function, as loss of ttnb does not lead to cardiac defects [ 59 , 60 ]. Furthermore, ttnb is unable to compensate for the loss of ttna in the embryonic heart [ 43 , 59 , 61 , 62 , 63 ]. Importantly, Seeley et al (2007) provided a detailed annotation of ttna and ttnb exons in comparison to human TTN and confirmed that the cardinal splicing events that give rise to the main TTN isoforms are also conserved in zebrafish.…”

Section: Titin In the Heart: Insights From Zebrafishmentioning

confidence: 99%

Mechanisms of TTNtv-Related Dilated Cardiomyopathy: Insights from Zebrafish Models

Santiago

Huttner

Fatkin

2021

JCDD

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Dilated cardiomyopathy (DCM) is a common heart muscle disorder characterized by ventricular dilation and contractile dysfunction that is associated with significant morbidity and mortality. New insights into disease mechanisms and strategies for treatment and prevention are urgently needed. Truncating variants in the TTN gene, which encodes the giant sarcomeric protein titin (TTNtv), are the most common genetic cause of DCM, but exactly how TTNtv promote cardiomyocyte dysfunction is not known. Although rodent models have been widely used to investigate titin biology, they have had limited utility for TTNtv-related DCM. In recent years, zebrafish (Danio rerio) have emerged as a powerful alternative model system for studying titin function in the healthy and diseased heart. Optically transparent embryonic zebrafish models have demonstrated key roles of titin in sarcomere assembly and cardiac development. The increasing availability of sophisticated imaging tools for assessment of heart function in adult zebrafish has revolutionized the field and opened new opportunities for modelling human genetic disorders. Genetically modified zebrafish that carry a human A-band TTNtv have now been generated and shown to spontaneously develop DCM with age. This zebrafish model will be a valuable resource for elucidating the phenotype modifying effects of genetic and environmental factors, and for exploring new drug therapies.

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“…As the lists of genes in commercial DCM panels grow, expert curation adds context for interpretation. Independent groups have identified genes that consistently accounted for pathogenic and likely pathogenic variants for DCM: TTN, MYH7, DSP, SCN5A, LMNA, TPM1, TNNC1, TNNT2, BAG3, PLN, RBM20, LDB3, DMD, DES, ACTC1, NEXN, and VCL [5,[38][39][40][41]. FLNC was subsequently identified as an important gene for DCM and should be included in this group [5].…”

Section: Genes Implicated In Monogenic Dominant Dcmmentioning

confidence: 99%

“…Titin TTN encodes the largest protein (~35,000 amino acids) expressed in the body. TTN protein spans one-half of the [5,[38][39][40][41]. Daggers indicates a MalaCards score greater than 100 [26] sarcomere from the Z disc to the M line and comprises four domains: the Z disc binding region, I band domain that overlaps sarcomeric actin filaments, A band domain that overlaps myosin filaments, and the M line binding region.…”

Section: Genes Implicated In Dcm: Recent Updatesmentioning

confidence: 99%

“…Ranking genes for evidence of pathogenicity significantly increased the odds ratio of a variant appearing in an individual with DCM; the highest ranked group of genes required evidence of segregation in 5 or more family members, in vitro functional studies, and heterozygous or humanized variant animal models [ 40 ]. Each of these criteria are components of the ACMG/AMP variant classification scheme, but they are not strictly required together for a variant to meet likely pathogenic or pathogenic classification [ 29 ••].…”

Section: Genes Implicated In Monogenic Dominant Dcmmentioning

confidence: 99%

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Clinical Implications of the Genetic Architecture of Dilated Cardiomyopathy

Wilsbacher

2020

Curr Cardiol Rep

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Purpose of Review Dilated cardiomyopathy (DCM) frequently involves an underlying genetic etiology, but the clinical approach for genetic diagnosis and application of results in clinical practice can be complex. Recent Findings International sequence databases described the landscape of genetic variability across populations, which informed guidelines for the interpretation of DCM gene variants. New evidence indicates that loss-of-function mutations in filamin C (FLNC) contribute to DCM and portend high risk of ventricular arrhythmia. Summary A clinical framework aids in referring patients for DCM genetic testing and applying results to patient care. Results of genetic testing can change medical management, particularly in a subset of genes that increase risk for life-threatening ventricular arrhythmias, and can influence decisions for defibrillator therapy. Clinical screening and cascade genetic testing of family members should be diligently pursued to identify those at risk of developing DCM.

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A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy

Cited by 26 publications

References 41 publications

Cardiomyopathy‐associated mutations in the RS domain affect nuclear localization of RBM20

Cardiomyopathy‐associated mutations in the RS domain affect nuclear localization of RBM20

Mechanisms of TTNtv-Related Dilated Cardiomyopathy: Insights from Zebrafish Models

Clinical Implications of the Genetic Architecture of Dilated Cardiomyopathy

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