Double missense mutations in cardiac myosin‐binding protein C and myopalladin genes: A case report with diffuse coronary disease, complete atrioventricular block, and progression to dilated cardiomyopathy

Mastroianno, Sandra; Palumbo, Pietro; Castellana, Stefano; Leone, Maria Pia; Massaro, Rosalba; Potenza, Domenico; Mazza, Tommaso; Russo, Angelo; Castori, Marco; Carella, Massimo; Stolfo, Giuseppe Di

doi:10.1111/anec.12687

Cited by 7 publications

(8 citation statements)

References 26 publications

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“…A number of missense variants in MYPN have been reported in HCM, DCM and RCM patients in several studies [ 106 , 108 , 109 , 110 , 111 ] ( Table 3 ). However, only two of them would pass today’s scrutiny based on frequency in normal cohorts (MAF < 10 −4 ).…”

Section: Z-disc Proteins In Myopathy and Cardiomyopathymentioning

confidence: 99%

The Role of Z-disc Proteins in Myopathy and Cardiomyopathy

Wadmore

Azad

Gehmlich

2021

IJMS

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The Z-disc acts as a protein-rich structure to tether thin filament in the contractile units, the sarcomeres, of striated muscle cells. Proteins found in the Z-disc are integral for maintaining the architecture of the sarcomere. They also enable it to function as a (bio-mechanical) signalling hub. Numerous proteins interact in the Z-disc to facilitate force transduction and intracellular signalling in both cardiac and skeletal muscle. This review will focus on six key Z-disc proteins: α-actinin 2, filamin C, myopalladin, myotilin, telethonin and Z-disc alternatively spliced PDZ-motif (ZASP), which have all been linked to myopathies and cardiomyopathies. We will summarise pathogenic variants identified in the six genes coding for these proteins and look at their involvement in myopathy and cardiomyopathy. Listing the Minor Allele Frequency (MAF) of these variants in the Genome Aggregation Database (GnomAD) version 3.1 will help to critically re-evaluate pathogenicity based on variant frequency in normal population cohorts.

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Section: Z-disc Proteins In Myopathy and Cardiomyopathymentioning

confidence: 99%

The Role of Z-disc Proteins in Myopathy and Cardiomyopathy

Wadmore

Azad

Gehmlich

2021

IJMS

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“…The MYBPC3 gene is responsible for 40% to 50% of all cases of HCM, and complete AVB has been described in patients with MYBPC3 variants both with and without HCM. 27 , 28 In addition, ACTN2 variants are associated with HCM, and in a study of a family with HCM, complete AVB was frequent in patients with ACTN2 variants. 29 Variants in the gene encoding titin, TTN, have been found in up to 25% of patients with DCM.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Yield of Genetic Testing in Young Patients With Atrioventricular Block of Unknown Cause

Dyssekilde

Frederiksen

Christiansen

et al. 2022

JAHA

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Background The cause of atrioventricular block (AVB) remains unknown in approximately half of young patients with the diagnosis. Although variants in several genes associated with cardiac conduction diseases have been identified, the contribution of genetic variants in younger patients with AVB is unknown. Methods and Results Using the Danish Pacemaker and Implantable Cardioverter Defibrillator (ICD) Registry, we identified all patients younger than 50 years receiving a pacemaker because of AVB in Denmark in the period from January 1, 1996 to December 31, 2015. From medical records, we identified patients with unknown cause of AVB at time of pacemaker implantation. These patients were invited to a genetic screening using a panel of 102 genes associated with inherited cardiac diseases. We identified 471 living patients with AVB of unknown cause, of whom 226 (48%) accepted participation. Median age at the time of pacemaker implantation was 39 years (interquartile range, 32–45 years), and 123 (54%) were men. We found pathogenic or likely pathogenic variants in genes associated with or possibly associated with AVB in 12 patients (5%). Most variants were found in the LMNA gene (n=5). LMNA variant carriers all had a family history of either AVB and/or sudden cardiac death. Conclusions In young patients with AVB of unknown cause, we found a possible genetic cause in 1 out of 20 participating patients. Variants in the LMNA gene were most common and associated with a family history of AVB and/or sudden cardiac death, suggesting that genetic testing should be a part of the diagnostic workup in these patients to stratify risk and screen family members.

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“…[2][3][4][5][6] In most of these cases, AVB is only one component of several characteristics of the overall cardiac phenotype, whereas in other cases isolated genetically determined AVB is seen. [7][8][9] However, in the majority of patients with AVB no aetiology of AVB is identified. One recent study examined the heredity of cardiac conduction defects including both sinus node dysfunction and AVB, and found an increased risk among firstdegree family members.…”

Section: Introductionmentioning

confidence: 99%

“…In rare cases, AVB is found to be hereditary and may even be caused by a single genetic variant, for example, in genes coding for lamin A/C, titin, SCN5A or transthyretin amyloidosis 2–6. In most of these cases, AVB is only one component of several characteristics of the overall cardiac phenotype, whereas in other cases isolated genetically determined AVB is seen 7–9. However, in the majority of patients with AVB no aetiology of AVB is identified.…”

Section: Introductionmentioning

confidence: 99%

Familial risk of atrioventricular block in first-degree relatives

Dyssekilde

Christiansen

Johansen

et al. 2022

Heart

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ObjectiveRare cases of genetically inherited atrioventricular block (AVB) have been reported; however, the heredity of AVB remains unknown. We aimed to assess the heredity of AVB.Design, setting and participantsUsing data from the Danish Civil Registration Registry, we established a nationwide cohort of individuals with parental links. Data were merged with information from the Danish Pacemaker and Implantable Cardioverter Defibrillator Registry, containing information on all pacemaker implantations performed in Denmark during the study period, to identify patients who received a first-time pacemaker because of AVB.ResultsA total of 4 648 204 individuals had parental links and a total of 26 880 consecutive patients received a first-time pacemaker due to AVB. Overall, the adjusted rate ratio (RR) of pacemaker implantation due to AVB was 2.1 (95% CI 1.8 to 2.5) if a father, mother or sibling had AVB compared with the risk in the general population. The adjusted RR was 2.2 (1.7–2.9) for offspring of mothers with AVB, 1.9 (1.5–2.4) for offspring of fathers with AVB and 3.5 (2.3–5.4) for siblings to a patient with AVB. The risk increased inversely proportionally with the age of the index case at the time of pacemaker implantation. The corresponding adjusted RRs were 15.8 (4.8–52.3) and 10.0 (3.3–30.4) if a mother or father, respectively, had a pacemaker implantation before 50 years.Conclusion and relevanceFirst-degree relatives to a patient with AVB carry an increased risk of AVB with the risk being strongly inversely associated with the age of the index case at pacemaker implantation. These findings indicate a genetic component in the development of AVB in families with an early-onset disease.

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Double missense mutations in cardiac myosin‐binding protein C and myopalladin genes: A case report with diffuse coronary disease, complete atrioventricular block, and progression to dilated cardiomyopathy

Cited by 7 publications

References 26 publications

The Role of Z-disc Proteins in Myopathy and Cardiomyopathy

The Role of Z-disc Proteins in Myopathy and Cardiomyopathy

Diagnostic Yield of Genetic Testing in Young Patients With Atrioventricular Block of Unknown Cause

Familial risk of atrioventricular block in first-degree relatives

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